Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O-].[Na+].[Na].[O:9]=[C:10]([CH:22]=[CH2:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(OC(=O)C)C.CO>[O:9]=[C:10]([CH2:22][CH2:23][CH2:4][N+:1]([O-:3])=[O:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C=CC(=O)CCCCCCCC(=O)OC
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCCCCCCC(=O)CCC[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Nitromethane (10.6 g) is added dropwise to a solution at 0°-5° C. of sodium methoxide prepared from sodium (3.8 g; 0.2 mole) and methanol (165 ml). Ethylacetate (165 ml) is added. The solution is cooled to -20° C. and, in 1 hour, the methyl ester (III) (17.5 g) is added dropwise. The mixture is stirred at -20° C. for 15 minutes and then poured into water/ice. The phases are separated and extracted with ethyl acetate to obtain a thick oil (16.5 g; yield=73%) which is crystallized with pentane to yield the ester (IV).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:15])[NH:11]2)=[CH:6][C:5]=1[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CS(Cl)(=O)=O.CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1COCC1.C(N(CC)CC)C>[CH3:14][C:13]1[C:4]2[CH2:3][CH2:2][N:18]([C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[CH2:17][CH2:16][C:5]=2[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2
Reactant: Cc1c(CCO)c(CCNC(=O)OC(C)(C)C)cc2c1NC(=O)CC2
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c2c(cc3c1NC(=O)CC3)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a solution of 1.793 g of t-butyl {2-[7-(2-hydroxyethyl)-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]ethyl}carbamate in 30 ml of THF were added 0.48 ml of methanesulfonyl chloride and 1.5 ml of triethylamine under ice-cooling, followed by stirring for 30 minutes. To the reaction mixture was added portionwise 1.8 g of potassium t-butoxide under ice-cooling, followed by stirring for 1.5 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 1.06 g of t-butyl 11-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a white foamed substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: O=C(O)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoic acid (196 mg, 0.653 mmol) in CH2Cl2 (6.0 mL) was added oxalyl chloride (0.28 mL, 3.3 mmol) followed by DMF (2 drops). The mixture was stirred under nitrogen at rt for 15 hours. The reaction was concentrated to yield 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoyl chloride, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[C:3]#[CH:4]>C1(C)C=CC=CC=1>[CH3:5][C:2]1([CH3:1])[CH:3]=[CH:4][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1
Reactant: C#CC(C)(C)Nc1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)C=Cc2ccccc2N1

Procedure:
A mixture of N-[3,3-dimethylpropyn-3-yl]aniline and cuprous chloride (3.9 g) in toluene (140 mL) was refluxed under nitrogen for 4½ hrs. The reaction mixture was filtered and the filtrate washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane:hexane (1:1) to provide the desired compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26](/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.[Li+].[OH-]>C1COCC1>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 16 %

Procedure:
To a stirred solution of (E)-ethyl 3-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylate from the previous step in THF (2 mL) was added 1M aq LiOH (2 mL) and the mixture was stirred at rt for 48 h. The mixture was then acidified and concentrated under reduced pressure. The residue was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (E)-3-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylic acid as a solid (22 mg, 16%). 1H NMR (500 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.90-8.01 (m, 2H), 7.68 (d, J=15.8 Hz, 1H), 7.66 (d, J=1.0 Hz, 1H), 7.58 (s, 2H), 7.29 (d, J=10 Hz, 1H), 7.20 (dd, J=1.2, 8.1 Hz, 1H), 6.48 (d, J=15.8 Hz, 1H), 5.48 (s, 2H), 4.73 (br s, 1H), 3.47-3.57 (br m, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.55-1.67 (m, 2H), 1.12-1.32 (m, 4H). LCMS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:23]([O:25][CH3:26])=[O:24]>ClCCl.CN(C=O)C.C(N(CC)CC)C>[N:1]1[CH:2]=[C:3]([C:10]([NH:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])=[O:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 25 °C

Procedure:
To a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (4.09 g, 25.3 mmol) in dichloromethane (100 mL) and DMF (0.25 mL) at 0° C. was added oxalyl chloride (4.15 mL, 48.0 mmol) dropwise over 10 minutes. The reaction was slowly warmed to room temperature and stirred until complete conversion was detected by LCMS. The reaction was subsequently reduced to dryness and suspended in dichloromethane (100 mL) and was added a solution of methyl 3-amino-4-methylbenzoate (2) (4.6 g, 27.9 mmol) in dichloromethane (100 mL) and triethylamine (7.1 mL). Contents were stirred at room temperature for 4 hours and diluted with dichloromethane (100 mL). The reaction was washed with water, saturated NaHCO3, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude solid was triturated with diethyl ether to remove excess aniline and dried to afford methyl 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoate (3) as a white solid. MS m/z 310.1 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][C@@H:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([O:27]CC)=[O:26])[CH2:20]3)[CH2:14][O:15]2)=[CH:10][CH:9]=1.[OH-].[Na+].[ClH:44].Cl.O1CCOCC1>CCO.O1CCOCC1.C1COCC1>[ClH:44].[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][C@@H:34]([CH3:39])[C:35]([F:36])([F:37])[F:38])[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([OH:27])=[O:26])[CH2:20]3)[CH2:14][O:15]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CC2=Cc3ccc(OCc4ccc(O[C@@H](C)C(F)(F)F)c(C(F)(F)F)c4)cc3OC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1COCCO1
Product: C[C@H](Oc1ccc(COc2ccc3c(c2)OCC(CN2CCC[C@@H](C(=O)O)C2)=C3)cc1C(F)(F)F)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylate (271 mg) in EtOH (5.4 mL)-THF (2.7 mL) was added a 1 M aqueous NaOH solution (923 μL), followed by stirring at 50° C. for 2 hours. The reaction liquid was cooled to room temperature, then 1 M hydrochloric acid (923 μL) was added thereto, and the vehicle was evaporated. The residue was purified by reverse phase chromatography (H2O:MeCN=100:0 to 30:70) to obtain a yellow oily substance, which was dissolved in dioxane (3 mL), treated with 4 N HCl/dioxane (1 mL), and washed with IPE to obtain (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid hydrochloride (215 mg) as a white powder.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[OH:50][CH2:51][C@H]1[C@@H](O)CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@H:51]([OH:50])[C@@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OC[C@@H]1NCC[C@@H]1O
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,3S)-2-(hydroxymethyl)pyrrolidin-3-ol and isolated as light-yellow gum (10.3 mg, 52%). MS(m/e): 417.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[C@H:11]2[C@H:6]([C@H:7]3[CH2:12][C@@H:10]2[CH2:9][CH2:8]3)[N:5]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[C:36](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[OH:1][C:2]1[C@H:11]2[C@H:6]([C@H:7]3[CH2:12][C@@H:10]2[CH2:9][CH2:8]3)[N:5]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:29]([CH3:36])[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
(1R,2S,7R,8S)—N-{3-[6-Hydroxy-3-(3-methyl-butyl)-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 22, 90 mg, 0.172 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL). Potassium carbonate (0.04 g, 0.344 mmol) was added followed by iodomethane (0.027 g, 0.189 mmol). The mixture was stirred at 25° C. for 5 h. The reaction mixture was extracted with ethyl acetate (2×100 mL) and water (100 mL). The organic layer was washed with saturated aqueous brine solution (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (Teledyne Isco RediSep column; 40% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)—N-{3-[6-hydroxy-3-(3-methyl-butyl)-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.052 g, 0.097 mmol, 56.4%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.92 (6H, d, J=6.4 Hz), 1.21-1.26 (1H, m), 1.28-1.33 (1H, m), 1.39-1.63 (7H, m), 2.54 (1H, bs), 2.63-2.67 (1H, m), 3.00 (3H, s), 3.06-3.17 (1H, m), 3.29 (3H, s), 3.63-3.72 (2H, m), 7.62 (1H, d, J=8.5 Hz), 7.70-7.73 (1H, m), 7.85 (1H, s). LC-MS (ESI) calcd for C24H32N4O6S2 536.18, found 537.6.6 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]=[C:10]([C:21]3[C:22]([CH3:29])([CH3:28])[O:23][C:24]([CH3:27])([CH3:26])[CH:25]=3)[CH:9]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]=[C:10]([CH:21]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]3([CH3:29])[CH3:28])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1-n1nc(C2=CC(C)(C)OC2(C)C)cc1-c1ccc(Cl)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC2(C)C)cc1-c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A solution of 5-(4-chlorophenyl)-1-(2-methoxyphenyl)-3-(2,2,5,5-tetramethyl-2,5-dihydrofuran-3-yl)-1H-pyrazole (162 mg, 0.4 mmol, 1 eq) (Example 67) and PtO2 (9 mg, 0.04 mmol, 0.1 eq) in ethyl acetate (10 mL) was put under a balloon of H2 and stirred overnight. Additional PtO2 (9 mg) was then added and the reaction stirred for 3 more days under a balloon of H2. The reaction was filtered through Celite, and concentrated. Purification by HPLC eluting with 30 to 100% acetonitrile/H2O gave the title compound (70 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH:8]([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:27]=[CH:26][C:20](/[CH:21]=[C:22](\[CH3:25])/[CH:23]=O)=[CH:19][CH:18]=1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C@@H:8]2[CH2:11][O:12][C@@H:23](/[C:22](/[CH3:25])=[CH:21]/[C:20]3[CH:26]=[CH:27][C:17]([C:16]([F:15])([F:28])[F:29])=[CH:18][CH:19]=3)[O:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: C/C(C=O)=C\c1ccc(C(F)(F)F)cc1
Reactant: OCC(CO)SCc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C/C(=C\c1ccc(C(F)(F)F)cc1)[C@H]1OC[C@H](SCc2ccc(Cl)cc2)CO1

Procedure:
In 12 ml of benzene were dissolved 341 mg (1.46 mmol) of 2-[(4-chlorobenzyl)thio]-1,3-propanediol and 375 mg (1.75 mmol) of (E)-4-(trifluoromethyl)-α-methylcinnamaldehyde, and 3 mg of p-toluenesulfonic acid were added to the solution, followed by heating of the resulting mixture with reflux under nitrogen atmosphere for 2 hours. After cooling, the reaction mixture was washed with an aqueous sodium hydrogencarbonate solution. The residue obtained by evaporation of the solvent was subjected to column chromatography using 15 g of silica gel. The fractions eluted with a mixed solvent of hexane-ethyl acetate (9:1) were collected and the thus obtained solid was washed with hexane to obtain 370 mg (yield: 59%) of the title compound having a melting point of 93 to 95° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:26])=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(N(CC)CC)C.[C:34]1([C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37](Br)[O:36]1)=[O:35].O>CN(C)C=O>[C:34]1([C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]([O:19][C:18]([C:14]2[N:13]3[C:21](=[O:22])[C@@H:11]([NH:10][C:8](=[O:9])[C:7]([C:5]4[N:6]=[C:2]([NH2:1])[S:3][C:4]=4[Cl:26])=[N:23][O:24][CH3:25])[C@H:12]3[S:17][CH2:16][CH:15]=2)=[O:20])[O:36]1)=[O:35]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC3OC(=O)c4ccccc43)=CCS[C@H]12)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a solution of 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (209 mg) in N,N-dimethylformamide (5 ml) are added triethylamine (0.07 ml) and phthalidyl bromide (128 mg), and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is poured into water and the separated precipitate is collected by filtration. The solid material is dissolved in ethyl acetate, washed with water, diluted aqueous sodium hydrogen carbonate solution, water, diluted aqueous phosphoric acid and water, dried, and evaporated. Purification of the residue by silica gel column chromatography gives 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid phthalidyl ester (220 mg).
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38]([N:3]1[CH2:4][CH2:5][C@@H:6]2[C@@H:1]([N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7]2)[CH2:2]1)=[O:39]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)quinoxaline (Intermediate 3) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C23H20FN7O, 429.46; m/z found 430.2 [M+H]+. 1H NMR (CD3OD): 8.42-7.97 (m, 2H), 7.88-7.44 (m, 5H), 7.39-6.20 (m, 3H), 5.08-4.67 (m, 1H), 4.41-3.44 (m, 6H), 3.25-3.07 (m, 1H), 2.39-1.86 (m, 2H).
Reaction SMILES: Br.Br[C:3]1[C:8](=[O:9])[CH:7]=[CH:6][N:5]([CH3:10])[CH:4]=1.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][N:5]1[CH:6]=[CH:7][C:8](=[O:9])[C:3]([C:18]2[CH:19]=[CH:20][C:15]([C:13]([O:12][CH3:11])=[O:14])=[CH:16][CH:17]=2)=[CH:4]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cn1ccc(=O)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2cn(C)ccc2=O)cc1
Temperature: 100 °C
Yield: 20.4 %

Procedure:
3-Bromo-1-methylpyridin-4(1H)-one hydrobromide (640 mg) was suspended in toluene (10 ml) and water (5 ml), and [4-(methoxycarbonyl)phenyl]boronic acid (642 mg), sodium carbonate (757 mg) and tetrakis(triphenylphosphine)palladium(0) (138 mg) were added, followed by stirring under heating in an oil bath at 100° C. for 3 hours. The reaction mixture was filtered through Celite, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL Ltd., the same shall apply hereinunder) (chloroform:methanol=90:10) to obtain methyl 4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoate (118 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:20][C:21](=[O:30])[CH2:22][C:23](=O)[C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:23]([C:24]4[CH:28]=[CH:27][S:26][CH:25]=4)[CH2:22][C:21](=[O:30])[NH:20][C:9]=3[CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1ccsc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccsc2)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 66.6 %

Procedure:
Prepared from [3-(3-oxo-3-thiophen-3-yl-propionylamino)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example K14) (110 mg, 0.25 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (53 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([S:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:38])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]([S:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:17])[CH3:16].Br[CH2:60][CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65]>CC#N>[CH3:38][C:8]([S:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([CH3:7])[CH2:9][N:10]([CH2:11][CH2:12][NH:13][CH2:14][C:15]([S:18][C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH3:16])[CH3:17])[CH2:60][CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65]
Reactant: CC(C)(CNCCNCC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCN(CCNCC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 65.7 %

Procedure:
K2CO3 (1.92 g, 13.9 mmol, 100 mol %) was added to N,N′-bis(2-methyl-2-triphenylmethylthiopropyl)ethylenediamine (10.03 g, 13.9 mmol) in CH3CN (60 mL), followed by ethyl 5-bromovalerate (3.30 mL, 20.8 mmol, 150 mol %). The reaction was heated at reflux under argon overnight. The solution was then concentrated to a paste and partitioned between 0.25 M KOH (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (1×50 mL) and the combined ethyl acetate layers were washed with 50 mL water and NaCl solution (2×50 mL), dried with Na2SO4 and concentrated to an orange oil. Purification by flash chromatography (300 g flash silica, 100% CHCl3 to 5% MeOH/CHCl3) gave pure title compound (7.75 g, 66% yield). FABMS analysis yielded an (MH+) of 849 (compared with a calculated molecular weight of 849.24 for the compound C55H64N2O2S2).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH3:17])[CH2:15]O)([O-:7])=[O:6].N1C=CC=CC=1.C(Cl)[Cl:25]>C1(C)C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH3:17])[CH2:15][Cl:25])([O-:7])=[O:6]
Reactant: ClCCl
Reactant: CC(CO)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(CCl)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 98 %

Procedure:
12.16 g thionyl chloride (7.5 ml, 102 mmol) in 10 ml toluene (abs.) are added quickly in a drop-wise manner to 6.2 g 2-(2-nitrophenyl)propanol (34 mmol) in 90 ml abs. toluene and 2 ml pyridine. The reaction solution is heated 1 h under reflux. After cooling, this is poured onto 100 g ice and mixed with 80 ml CH2Cl2. The H2O phase is extracted 2× each with 80 ml CH2Cl2. The combined organic phases are neutralized with 120 ml saturated bicarbonate solution, dried over Na2SO4 and rotary evaporated. 6.62 g (33 mmol, 98%) 2-(2-nitrophenyl)propyl chloride are obtained as a brown oil.