Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:39]=1[C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=1)=[O:41]
Reactant: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 0.940 g of ethyl 6-(4-aminobenzoyl)-5,6-dihydropyrazolo[4,3-d] [1]benzazepine-2(4H)-acetate in 25 ml of methylene chloride is added 369 μl of triethylamine followed by the dropwise addition of 373 μl of 2,4-dichlorobenzoyl chloride in 3.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO3, brine and the organic layer treated with activated carbon, and filtered through MgSO4. The filtrate is concentrated in vacuo to a residue which is purified by flash chromatography on silica gel using 25% ethyl acetate in methylene chloride to give 380 mg of the desired product as white crystals, m.p. 164°-167° C. The mother liquors are combined, evaporated in vacuo to a residue which is dissolved in 25% ethyl acetate in chloroform to give 535 mg of off-white solid, m.p. 160°-163.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](N)=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[OH-].[Na+].S(=O)(=O)(O)[OH:19]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:19])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1ccc(-c2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
4-(4-Pyridyl)benzamide (0.35 g, 1.8 mmol) was suspended in ethanol (5 mL). 10% w/w aqueous sodium hydroxide solution was added and the reaction mixture refluxed for two hours then allowed to cool to room temperature. The reaction mixture was adjusted to pH 7 with concentrated sulphuric acid. A white precipitate formed which was isolated by filtration to give 4-(4-pyridyl)benzoic acid (238 mg).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:19][NH2:20]>O1CCCC1>[CH3:19][NH:20][S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Oc2ccncc2)cc1

Procedure:
A suspension of 35 g of [4-(4-pyridinyloxy) benzenesulfonyl chloride hydrochloride in 800 ml of tetrahydrofuran was added slowly to 163 ml of 2 M methylamine in tetrahydrofuran. An additional 550 ml of tetrahydrofuran was added and the suspension refluxed for 3 hours. The solvent was removed under vacuum and the residue partitioned between CH2Cl2 and H2O. The organic layer was separated, washed with saturated NaHCO3, brine and dried (Na2SO4). The solvent was removed to give 13.11 g of N-methyl-4-(pyridin-4-yloxy)benzenesulfonamide, m.p. 125-127° C. The aqueous layer was neutralized with 1 N NaOH (solid precipitated) and extracted with CH2Cl2. The extract was washed with brine and dried (Na2SO4). The solvent was removed to give an additional 15.9 g of N-methyl-4-(pyridin-4-yloxy)benzenesulfonamide. A 2.80 g (10.6 mmol) portion of the preceding compound was added to a stirred suspension of 0.424 g (10.6 mmol) of sodium hydride (60% in oil) in 20 ml of dry 1-methylpyrrolidinone. The mixture was stirred until gas evolution ceased and 2.8 g (10.0 mmol) of ethyl 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate was added followed by the addition of 20 ml of dry 1-methylpyrrolidinone. The mixture was heated at 80-90° C. for 58 hours. The solvent was removed under vacuum and the residue extracted with ethyl acetate (100 ml) and the extract washed with 100 ml of H2O. The extract was stirred with 40 ml of 1 N HCl for 1 hour and the aqueous layer separated and neutralized (pH 6-7) with 1 N NaHCO3. The mixture was extracted with ethyl acetate and the extract washed with H2O, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness and the residue crystallized with ethyl acetate-hexane to give 3.43 g of ethyl 4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl] amino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate as pale yellow crystals, m.p. 117-119° C.
Reaction SMILES: [Br-].[CH2:2]([PH3+])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C)([O-])C.[K+].[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH:19]=O>O1CCCC1.COC(C)(C)C>[CH:19](/[C:18]1[CH:21]=[CH:22][C:23]([CH3:24])=[C:16]([OH:15])[CH:17]=1)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1ccc(C=O)cc1O
Reactant: CCCCCC[PH3+]
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCCC/C=C\c1ccc(C)c(O)c1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Under an atmosphere of Argon, to a solution of n-hexylphosphonium bromide (1.07 g) in tetrahydrofuran (10 mL) was added potassium t-butoxide (336 mg) at room temperature and the solution was stirred for 30 minutes. After cooling in ice bath, 3-hydroxy-4-methylbenzaldehyde (136 mg) was added to the reaction solution, which was stirred at room temperature for 1.5 hours. The reaction solution was diluted with t-butyl methyl ether. The solution was washed with dilute hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to give the title compound (180 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][N:16]=[C:15]3[C:10]=2[C:11]2[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=2[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>COCCOC>[O:19]=[C:13]1[C:12]2[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=2[C:10]2[C:15](=[N:16][CH:17]=[CH:18][C:9]=2[NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])=[CH:7][CH:6]=2)[NH:14]1
Reactant: Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: O=c1[nH]c2nccc(Nc3ccc(NS(=O)(=O)c4ccccc4)cc3)c2c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.8 %

Procedure:
340 (40 mg, 0.13 mmol), DIEA (34 mg, 0.26 mmol), and benzenesulfonyl chloride (47 mg, 0.26 mmol) were suspended in DME (2 mL), and stirred for 4 h at room temperature. The precipitate formed during the reaction was filtered, washed with EtOAc, and dried under vacuum to provide 341 (20 mg, 34% yield) as a solid. LC-MS (M+H=443, obsd.=443).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([O:29][C@@H:30]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]2)[CH:26]=[CH:25][N:24]=1.CC(O)=O>O1CCOCC1.C(=O)(O)[O-].[Na+]>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:23]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)[CH:26]=[CH:25][N:24]=2)[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccnc(Cl)n2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a stirred solution of the 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 165 mg, 0.55 mmol) and tert-butyl (3R)-3-[(2-chloropyrimidin-4-yl)oxy]pyrrolidine-1-carboxylate (164 mg, 0.55 mmol) in dioxane (2.7 ml) was added AcOH (66 μl, 1.15 mmol). The mixture was heated to 120° C. for 5 h, treated with additional portion of AcOH (66 μl, 1.15 mmol), and left to stir overnight. Additional AcOH (66 μl, 1.15 mmol) was then added and the resultant mixture was left to stir overnight. The mixture was then cooled to room temperature, diluted with saturated sodium bicarbonate solution, and extracted with ethyl acetate (×3). The combined organics were washed with brine, dried over sodium sulfate, concentrated, and purified by Combiflash. (ethyl acetate/hexanes) to afford 80 mg (0.14 mmol, 26% yield) of tert-butyl (3R)-3-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}pyrrolidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C@H:8]2[CH2:12][O:11]C(C)(C)[O:9]2)=[CH:4][CH:3]=1.Cl.CC(=O)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@H:8]([OH:9])[CH2:12][OH:11])=[CH:15][CH:16]=1
Reactant: CC1(C)OC[C@H](COc2ccc(F)cc2)O1
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: OC[C@@H](O)COc1ccc(F)cc1
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A mixture of 26 parts of (S)-4-[(4-fluorophenoxy)methyl]-2,2-dimethyl-1,3-dioxolane, 35 parts of a hydrochloric acid solution 2N and 80 parts of 2-propanone was stirred for 2 hours at reflux temperature. The mixture was stirred overnight at room temperature, diluted with 240 parts of ethanol and evaporated. The residue was dissolved in trichloromethane. The organic layer was washed twice with water, dried, filtered and evaporated. The residue was crystallized from tetrachloromethane. The product was filtered off and dried, yielding 11 parts (50.4%) of (-)-(R)-3-(4-fluorophenoxy)-1,2-propanediol; [α]D =-10.08° (c=0.5% in methanol) (146).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14](Br)=[N:13][C:12]=3[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:13][C:12]=3[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=c1c2[nH]c(Br)nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: O=c1c2[nH]c(N3CCCCC3)nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1

Procedure:
The title compound was prepared from 1,3-di-cyclohexylmethyl-8-bromo xanthine (0.7 g, 0.0017 mol) and piperidine (0.28 g, 0.003 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. 266° C.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)([C:13](O)=[O:14])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)([CH2:10][OH:11])[CH2:13][OH:14])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CC(CO)(CO)Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 19 h

Procedure:
4.00 g (10.69 mmol) 2,2-bis(4-nitrobenzyl)malonic acid were dissolved in 40 ml tetrahydrofuran and added dropwise in a the course of 2 hours to 64.1 ml (64.1 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in tetrahydro-furan. After 19 hours at 25° C., 50 ml water were carefully added. The reaction mixture was then partitioned between ethyl acetate and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue, 3.77 g (97%) of a white powder was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:57])([F:56])[C:46]1[CH:47]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:49]=[CH:50][CH:51]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:53](=[O:54])[CH2:52][C:48]3[CH:49]=[CH:50][CH:51]=[C:46]([C:45]([F:56])([F:44])[F:57])[CH:47]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cccc(C(F)(F)F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-(trifluoromethyl)phenylacetic acid (0.6 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-trifluoromethyl-phenyl)-acetamide (0.7 g, 70%) as a white solid: mp 156-158° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=5.36 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.09 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.67 (s, 2H), 4.74 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.52-7.82 (m, 7H), 8.77 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.84, 41.53, 48.83, 121.94, 123.12 (123.17, 123.22), 125.50 (125.56, 125.60, 125.66), 127.15, 128.68, 129.09, 129.23, 131.53, 133.19, 133.31, 134.61, 137.51, 138.99, 166.88, 167.40, 179.77, 170.00, 172.72; Anal. Calcd. for C23H18N3O5F3: C, 58.35; H, 3.83; N, 8.88; F, 12.04. Found: C, 58.13; H, 3.53; N, 8.83; F, 11.69.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:11]=1[CH3:20])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1>CCCCCC.[Li]CCCC.C1COCC1>[Si:5]([O:8][CH2:9][C:10]1[C:11]([CH3:20])=[CH:12][CH:13]=[C:14]([O:16][CH2:17][O:18][CH3:19])[C:15]=1[C:21]1([OH:25])[CH2:24][CH2:23][CH2:22]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: O=C1CCC1
Reactant: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1C1(O)CCC1
Reaction time: 2 h
Yield: 13.7 %

Procedure:
To a solution of tert-butyl-[[5-(methoxymethoxy)-2-methyl-phenyl]methoxy]-dimethyl-silane (Intermediate 174, 0.3 g, 1 mmol) in hexane (5 ml), BuLi (1.6M in hexane, 0.9 ml, 1.4 mmoli) was added at room temperature. The reaction mixture was stirred for 2 h and then added dropwise at −30° C. to a suspension of CeCl3 (0.37 g, 1.5 mmoli) in dry THF (5 ml) that was previously stirred at room temperature overnight. After 45 min at −30° C., cyclobutanone (0.07 g, 1 mmoli) dissolved in THF (1 ml) was added. The reaction was stirred at the same temperature for and then quenched with ammonium chloride (20 ml) and extracted with Ethyl Acetate (2×20 ml). Combined organic layers were dried over Na2SO4 and evaporated under vacuum to afford a colorless oil that was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 75:25 as eluents affording the title compound (0.05 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3]C=O)C.CC[O-].[Na+].[CH3:10][C:11]([CH3:24])([C:13](=[O:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH3:12].Cl>C(O)C>[OH:3][CH:1]=[C:14]([O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[C:13](=[O:23])[C:11]([CH3:24])([CH3:10])[CH3:12]
Reactant: CCOC=O
Reactant: CC(C)(C)C(=O)COc1ccc(F)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)C(=CO)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 35.7 %

Procedure:
163 g (2.2 mols) of formic acid ethyl ester were added dropwise to a solution of 136 g of sodium ethylate in 1,500 ml of ethanol at 0° C. 420 g (2 mols) of 2,2-dimethyl-4-(4-fluorophenoxy)-butan-3-one were then slowly stirred in at 0° C. After a reaction time of 24 hours at 0° C., the mixture was allowed to warm to room temperature and was subsequently stirred at this temperature for a further 96 hours. The reaction mixture was poured into 5,000 ml of ice-water and the organic phase was separated off by extraction with chloroform. Unreacted starting material could be isolated from this chloroform solution and could be employed again. The aqueous phase was acidified with 10% strength hydrochloric acid, while cooling, and the oil which separated out was taken up in chloroform. The chloroform phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The oil which remained was distilled in vacuo. 170 g (83% of theory, relative to reacted material) of 1-hydroxy-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one of boiling point 101°-102° C./0.6 mm Hg (nD20 =1.5132) were obtained. ##STR50##
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([OH:13])=O)=[CH:4][C:3]=1[Cl:14].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>CN(C)C=O.ClCCl>[NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][CH2:29][O:28][CH3:27])[CH2:33][CH2:34]2)=[O:13])=[CH:4][C:3]=1[Cl:14]
Reactant: COCCCN1CCC(N)CC1
Reactant: Nc1c(Cl)cc(C(=O)O)c2nccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCN1CCC(NC(=O)c2cc(Cl)c(N)n3ccnc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
To a suspension of the 5-amino-6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 1, METHOD A, Step 4, 210 mg, 0.99 mmol) in N,N-dimethylformamide (5 mL) was added 1,1′-carbonyldiimidazole (177 mg, 1.09 mmol) and stirred at room temperature for 20 min. To this resulting solution was added 1-(3-methoxypropyl)-4-piperidinamine (A. Karasawa et al., WO 9950264, 188 mg, 1.09 mmol) and the mixture was stirred overnight under nitrogen at room temperature. The mixture was concentrated in vacuo, chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% aqueous ammonia (95:5:0.5) to afford a yellow oil, which was dissolved in dichloromethane (300 mL), washed with water (75 mL×3), brine (75 mL) and dried over magnesium sulfate. After treatment with charcoal, removal of solvent gave a cream solid, which was recrystallized from diethyl ether to afford 175 mg (48%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])[CH2:7][S:8][C@H:3]12.[CH3:19][O:20][N:21]=[C:22]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:23]([O-])=[O:24].[Na+].N1CCC1=O>O1CCOCC1>[C:11]([O:10][CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[C@H:2]([NH:1][C:23](=[O:24])[C:22](=[N:21][O:20][CH3:19])[C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[C:17](=[O:18])[N:4]2[C:5]=1[C:14]([OH:16])=[O:15])(=[O:13])[NH2:12]
Reactant: CON=C(C(=O)[O-])c1cccs1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C1CCN1
Agent: [Na+]
Solvent: C1COCCO1
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1cccs1
Yield: 50.4 %

Procedure:
Following the procedure of Example 2, the title compound (888 mg., 50%) was prepared from (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylic acid (1.09g., 4 mmole) and sodium 2-methoxyimino-2-(thien-2-yl)acetate (syn -isomer) (923mg., 4.8 mmole). Its properties are: m.p. 157° to 163° , [α]D20° + 57.3° (c 1.0 in dioxan), RPAC 0.8* Solvent system A*,λmax. (pH6 buffer) 262.5 nm (ε 15,550), and inflexion at 235 nm (ε 10,350), τ (DMSO-d6) 0.20 (d, J 8 Hz, NH), 2.29 (dd, J 2 and 5 Hz, thienyl C5 -H), 2.7 to 2.9 (m, thienyl C3 -H and C4 -H), 3.40 (s, CONH2), 4.13 (dd, J 5 and 8 Hz, C7 -H), 4.75 (d, J 5 Hz, C6 -H), 5.01 and 5.34 (AB-q, J 13 Hz, C3 -CH2), 6.08 (s, NOCH3), and 6.42 (collapsed AB-q, C2 -H2), νmax. (Nujol) 3700 to 2100 (CO2H), 3480, 3440, 3365, and 3255 (NH and NH2), 1760 (azetidin-2-one), 1722 (CO2H), 1709 (OCONH2) and 1652 and 1530 cm-1 (amide).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O.O>[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]5[S:21][CH:22]=[CH:23][N:24]=5)=[O:18])[C:10]=4[N:9]=3)=[CH:4][CH:3]=2)[CH2:26][CH2:27]1
Reactant: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Reactant: C1COCCN1
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(N4CCOCC4)nc3)nc12
Temperature: 140 °C
Reaction time: 0.42 h
Yield: 57.1 %

Procedure:
A mixture containing 2-(6-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (7; 20 mg, 0.056 mmol) and morpholine (48; 49 mg, 0.56 mmol) in DMSO (1.5 mL) was stirred at 140° C. in a microwave reactor for 25 min. The reaction mixture was cooled to room temperature and diluted with water. The precipitated solids were collected by filtration and dried. The solids were redissolved in EtOAc and enough petroleum ether was added to precipitate the product out again. The solids were collected by filtration, washed with MeOH and dried to afford 2-(6-morpholinopyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 247) as a pale yellow solid (13 mg, 57%). MS (ESI) calcd for C20H18N6O2S: 406.12; found: 407 [M+H].
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.O>ClCCCl>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1F
Reactant: Nc1ccc(I)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: O
Product: Fc1ccccc1CNc1ccc(I)cc1
Yield: 109.5 %

Procedure:
A solution of 4-iodoaniline (1 g, 4.5 mmol), 2-fluorobenzaldehyde (0.48 ml, 0.566 g, 4.5 mmol) and triacetoxyborohydride (1.9 g, 9.0 mmol) in 1,2-dichloroethane (20 ml) was stirred for 4 days at room temperature. After addition of water the mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and evaporated to give the title compound (1.612 g, quant.). The crude material was used without further purification. MS: (ES/+) m/z: 328 [MH+], C13H11FIN requires 327; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.4-7.1 (m, 6H), 6.4 (d, 2H), 4.3 (m, 1H), 2.5 (m, 2H).