Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH:20]([N:6]1[C:5]2[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])[CH3:26])[CH3:25]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccc2c(c1)OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(C)ccc21
Temperature: 70 °C
Yield: 98 %

Procedure:
To a mixture of 7-methyl-4H-benzo[1,4]oxazin-3-one (14.1 g, 86 mmol) and Cs2CO3 (70.4 g, 216 mmol) in DMF (500 mL) was added ethyl 2-bromopropanoate (31.3 g, 173 mmol) at ambient temperature and the reaction mixture was heated to 70° C. for 3 h. The reaction mixture was cooled to ambient temperature and the DMF was removed in vacuo. Water (500 mL) was added to the residue and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 2-(7-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as brown solid (22.2 g, 98%). TLC (eluting with 20% EtOAc/heptane) Rf=0.3.
Reaction SMILES: [CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[NH:13][CH:14]=[N:15]2)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[O:26]1[CH:28]([CH3:29])[CH2:27]1>CS(C)=O>[CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:27][CH:28]([OH:26])[CH3:29])[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: CC1CO1
Reactant: C=CCN(c1ncnc2nc[nH]c12)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCN(c1ncnc2c1ncn2CC(C)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 12.8 g. (50 mmole) 6-[N-allyl-N-cyclohexylamino)-purine (compound of Example 8 j) in 150 ml. dimethyl sulphoxide are added at 40° C. 7.6 g. potassium carbonate. The reaction mixture is stirred for 10 minutes, cooled to ambient temperature, 5.8 g. 1,2-epoxypropane are added dropwise thereto, the reaction mixture is stirred for 5 days at ambient temperature and evaporated and the residue chromatographed on silica gel (elution agent: dichloromethane/methanol 97:3 v/v). After trituration with diethyl ether, there are isolated 5.7 g. of the title compound )36% of theory); m.p. 108°-110° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][NH:19][CH:20]3[C:28]4[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31](OC(=O)C)(=[O:33])C>C(O)=O>[CH:31]([N:19]([CH:20]1[C:28]2[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[O:33]
Reactant: COc1cccc2c1CCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COc1cccc2c1CCC2N(C=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(4,5-diphenyloxazol-2-yl)methylamino-2,3-dihydro-4-methoxy-1H-indene (0.13 g) in formic acid (5 ml) was added acetic anhydride (1 ml) at 0° C. After being stirred for 5 hours at room temperature, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give l-[N-formyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.12 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][S:9]([OH:12])(=[O:11])=[O:10])=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:15]1[S:17][CH2:16]1>O.[N+]([O-])([O-])=O.[Ag+]>[OH-:10].[SH:17][CH2:16][CH2:15][N+:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][S:9]([OH:12])(=[O:10])=[O:11])=[CH:5][CH:6]=1
Reactant: C1CS1
Reactant: O=S(=O)(O)CCc1ccncc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)CCc1cc[n+](CCS)cc1
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
A solution of silver nitrate (1.84 g, 10.6 mmol) in water (5 ml) was added to a stirred aqueous solution (20 ml) of 4-pyridine ethane sulfonic acid (2.00 g, 10.6 mmol) which had been adjusted to pH 7 by the addition of aqueous 2.5N sodium hydroxide (3.0 ml). The solution was cooled in an ice-water bath and ethylene sulfide (0.71 ml, 11.8 mmol) added. The resulting mixture was let stand 45 minutes at ice-bath temperature and the upper clear phase decanted. The gummy solid was mixed with water (20 ml) and vigorously bubbled with hydrogen sulfide for 15 minutes. After stirring an additional 20 minutes, the mixture was filtered through a celite pad to remove silver sulfide and the filtrate was evaporated under vacuum to provide crude title compound as a white semi-solid (1.00 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:25]([NH2:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:25]([NH:33][C:7]([C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])=[O:9])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCCc1ccccc1
Reactant: Cc1nnsc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1nnsc1C(=O)NCCc1ccccc1
Temperature: 5 °C
Yield: 94.6 %

Procedure:
A suspension of 9.65 g of 4-methyl-[1,2,3]thiadiazol-5-carboxylic acid in 70 ml of dichlormethane was cooled to 5° C. while stirring, treated with 0.15 g of 4-dimethylamino-pyridine and subsequently with 13.8 g of N,N'-dicyclohexyl-carbodiimide at such a rate that the internal temperature <10° C. could be maintained. After completion of the addition, the mixture was cooled to 5° C. and 8.92 g of phenethylamine were added at such a rate that the internal temperature of <37° C. could be maintained. After completion of the addition, the mixture was stirred for a further 1 h., then the precipitate was filtered off under suction, rinsed well with dichloromethane and the filtrate was evaporated. The residual yellow oil was subjected to chromatography on silica gel with hexane/ethyl acetate 50:50. There were obtained 15.66 g (92%) of 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid phenethylamide as a colorless crystallizate of m.p. 64°-68° C. Recrystallization of a sample from tert.-butyl methyl ether gave colorless crystals of m.p. 64.5°-66° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>C(OCC)C>[F:15][C:4]([F:3])([F:14])[CH:5]([O:6][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OC(c1ccc(F)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OC(c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A dried 50 mL of flask was charged sodium hydride, 60% dispersion in mineral oil (624 mg, 15.6 mmol) under N2 and then washed with dried hexane (20 mL) twice. Dried ethyl ether (10 mL) was added and a solution of 2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethanol (90% ee) (2.5 g, 12.89 mmol) in ethyl ether (10 mL) was added at 0° C. After completion of addition, the reaction mixture was allowed to warm up to room temperature and stirred for 1 h. A solution of trifluoromethanesulfonyl chloride (3.28 g, 19.5 mmol) in ethyl ether (10 mL) was added at 0° C. After completion of addition, the reaction was allowed to warm up to room temperature and stirred for 1 h. The solvent was removed under rot-vap and diluted with hexane (150 mL) and washed with a saturated NaHCO3 n and brine. After drying with MgSO4, the organic solvent was removed to give trifluoro-methanesulfonic acid 2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethyl ester (3.15 g) (90% ee) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:15])([F:14])/[C:10](/Br)=[N:11]/[OH:12].[CH2:16]([OH:19])[C:17]#[CH:18]>C1(C)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[C:10]1[CH:18]=[C:17]([CH2:16][OH:19])[O:12][N:11]=1
Reactant: O/N=C(\Br)C(F)(F)F
Reactant: C#CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCc1cc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.3 %

Procedure:
A solution of triethylamine (5.35 ml, 38.6 mmol) in toluene (15 ml) was added dropwise over 10 minutes to a solution of (Z)-2,2,2-trifluoro-N-hydroxyacetimidoyl bromide (71) (5.35 g, 19.3 mmol) and prop-2-yn-1-ol (72) (3.25 g, 57.9 mmol, TCI_JP) in toluene (37.5 ml) and stirred for 10 hours at room temperature. The reaction was quenched with H2O (30 ml), extracted with ethyl acetate (50 ml), washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude product of (3-(trifluoromethyl)isoxazol-5-yl)methanol (73) (1.88 g, yield 47%) as a brown oil.
Reaction SMILES: Cl.[CH3:2][O:3]/[N:4]=[C:5](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:6]([OH:8])=O.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:48][C@@H:49]1[C:77](=[O:78])[N:51]2[C:52]([C:65]([O:67][CH2:68][C:69]3[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=3)=[O:66])=[C:53]([C@H:56]3[C:60](=C=O)[CH2:59][C@@H:58](OC)[O:57]3)[CH2:54][S:55][C@H:50]12>CN(C)C=O.N1C=CC=CC=1>[CH3:68][O:67][C:65]([C@H:58]1[O:57][C@@H:56]([C:53]2[CH2:54][S:55][C@@H:50]3[C@H:49]([NH:48][C:6](=[O:8])/[C:5](=[N:4]\[O:3][CH3:2])/[C:9]4[N:10]=[C:11]([NH:14][C:15]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[S:12][CH:13]=4)[C:77](=[O:78])[N:51]3[C:52]=2[C:65]([O:67][CH2:68][C:69]2[CH:70]=[CH:71][C:72]([O:75][CH3:76])=[CH:73][CH:74]=2)=[O:66])[CH2:60][CH2:59]1)=[O:66]
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3O[C@H](OC)CC3=C=O)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@H]3CC[C@@H](C(=O)OC)O3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A stirred solution of 2-(Z)methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid hydrochloride (148mg) and N,N-diisopropylethylamine (0.107ml) in dimethylformamide (1ml) was cooled to -55 to -60° C. and methanesulphonyl chloride (0.024ml) was added. The mixture was stirred at the same temperature for 0.5h and then a solution of 4-methoxybenzyl (6R,7R)-7-amino-3-[(2R,5S)-5-methoxy-carbonyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (126mg) in dimethylformamide (1ml) was added followed by pyridine (0.023ml). The mixture was then stirred at 0° C. for 1h and then at room temperature for 0.5h. The mixture was partitioned between ethyl acetate and aqueous citric acid solution, and the organic phase was washed with water, then brine, dried over magnesium sulphate and evaporated. The title compound (100mg) was isolated by column chromatography of the residue (silica gel, 3:7 hexane:ethyl acetate as eluent); vmax (CHCl3) 3403, 1786, 1732 and 1681cm-1 ; δH (CDCl3) 1.66-2.36 (4H, m), 3.58 (1H, d, J 18.0Hz), 3.73 (3H, s), 3.81 (3H, s), 4.02 (1H, d, J 18.0Hz), 4.08 (3H, s), 4.53 (1H, dd, J 3.34, 8.91Hz), 5.02 (1H, d, J 4.8Hz), 5.18 (1H, d, J 11.8Hz), 5.24 (1H, d, J 12.0Hz), 5.30 (1H, dd, J 5.7, 9.9Hz), 5.86 (1H, dd, J 4.6, 8.6Hz), 6.72-6.83 (2H, m), 6.89 (2H, d, J 8.54Hz), 7.01 (1H, s) and 7.25-7.4 (17H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][C:11]=3[CH:10]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:32][CH2:33][CH2:34][N:35]1[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:36]1=[O:43].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][C:11]=3[CH:10]=2)=[N:4][C:5]([NH:32][CH2:33][CH2:34][N:35]2[C:39]([CH3:40])([CH3:41])[C:38](=[O:42])[NH:37][C:36]2=[O:43])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2sc(-c3nc(Cl)ncc3Br)cc2c1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2sc(-c3nc(NCCN4C(=O)NC(=O)C4(C)C)ncc3Br)cc2c1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A mixture of (2S)-tert-butyl 2-((2-(5-bromo-2-chloropyrimidin-4-yl)benzo[b]thiophen-5-yloxy)methyl)pyrrolidine-1-carboxylate (524 mg, 1.00 mmol) in toluene (25 mL) was treated with 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione (205 mg, 1.20 mmol) and triethylamine (121 mg, 1.2 mmol) and then heated to reflux in an oil bath for 3 h. The reaction was cooled to room temperature, diluted with ethyl acetate (25 mL) and washed in turn with a saturated aqueous solution of sodium bicarbonate (15 mL), deionized water (15 mL), and a saturated aqueous solution of sodium chloride (15 mL). The organic layer was separated, dried over sodium sulfate (300 mg), filtered through a coarse frit (to remove the sodium sulfate), and condensed in vacuo to give a white solid (450 mg). The crude material was purified by flash chromatography (EtOAc/hexane v/v) to yield the title compound as a white solid (325 mg, 50%). MS (M+H)+ 659/661.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[F:21][C:22]([F:31])([F:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:29][C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:30])[F:31])=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCCCN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCCCN1CCN(C(=O)c2ccc(CNc3ccc(C(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared from the product of Example 13 and 4-trifluoromethyl-phenylamine.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li][CH2:16]CCC.CI>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH3:16])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: [Li]CCCC
Reactant: Cc1cccc(-n2c(C)ccc2C)n1
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cccc(-n2c(C)ccc2C)n1
Temperature: -30 °C
Yield: 60 %

Procedure:
To a solution of 2-(2,5-Dimethyl-pyrrol-1-yl)-6-methyl-pyridine (6.82 g, 36.6 mmol) in 75 mL of dry THF cooled to −40° C. under a N2 atmosphere was added dropwise n-BuLi as a 2.5M solution in hexanes (16 mL, 40 mmol). The resulting solution was stirred at low temperature for thirty minutes then treated with CH3I (2.4 mL, 38.6 mmol). On completion of the addition the mixture was allowed to warm to −30° C. and after 20 min to room temperature. The reaction was subsequently quenched by pouring into brine solution, the product isolated by extraction with EtOAc. Dried over MgSO4, filtered and concentration under vacuum. Purified by silica gel column chromatography eluting with EtOAc/hexane gave the title compound (4.42 g, 60%).
Reaction SMILES: [C:1]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]1[C:22](Cl)=[N:21][C:19](Cl)=[N:18][C:16]=1Cl>N1C=CC=CC=1>[C:1]1(=[N:13][O:14][C:16]2[N:18]=[C:19]([O:14][N:13]=[C:1]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:21]=[C:22]([O:14][N:13]=[C:1]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=C1CCCCCCCCCCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: c1ccncc1
Product: C1CCCCCC(=NOc2nc(ON=C3CCCCCCCCCCC3)nc(ON=C3CCCCCCCCCCC3)n2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.4 %

Procedure:
To a cold (0° C.) solution of cyclododecanone oxime (7.89 g, 0.04 mol) in dry pyridine (30 ml) is added cyanuric chloride (1.84 g, 0.01 mol). An exothermic reaction occurs and the temperature rises to 20° C. The solution is then stirred 20 h at room temperature and then poured into 300 ml of ice-cold water. The precipitated solid is filtered off and chromatographed (silica gel, CH2Cl2—C2H5O(CO)CH3 95:5). The pure fraction is recrystallized from ethylacetate-hexane to afford 2.36 g of the title compound as a white solid, m.p. 104-107° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10](O)([CH3:13])([CH3:12])[CH3:11].C(OCC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:10]([O:8][C:7]([CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)=[O:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(=O)C1
Temperature: 2 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a cold (ice bath) solution of 3-oxo-1-cyclopentanecarboxylic acid (1.50 g), tert-butylalcohol (1.05 g) and 4-dimethylaminopyridine (140 mg) in dichloromethane (9 mL) was added a solution of dicyclocarbodiimide in dichloromethane (9 mL). The mixture was stirred 3 hours at ca. 2° C. then diethylether (30 mL) was added and the precipitate was filtered off and discarded. The solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (9:1 v/v) as eluant to afford the title compound (1.80 g, 96%) as colorless oil. MS (EI): 111 (M-OtBu.)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:34])[N:12]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)c1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Yield: 103.1 %

Procedure:
5-Chloro-2-(4-fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)imidazo[4,5-b]pyridine (372 mg 1 mmol) is dissolved in CH2Cl2/HOAc (7 ml 5/2) and treated with MCPBA (270 mg 70% 1.1 mmol) at 0° C. for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (ethyl acetate) to yield the title compound (400 mg 100%) as yellow foam.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[NH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([C:52]([O:54][CH3:55])=[O:53])=[CH:44]1>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]([C:52]([O:54][CH3:55])=[O:53])=[CH:44]2)=[CH:37][CH:38]=1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: COC(=O)c1cn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c2ccccc12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and methyl 1H-indole-3-carboxylate. M/e+ 430 for C25H21ClN3O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.24 (dd, J=5.8, 2.5 Hz, 1H), 7.74 (d, J=9.1 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.64 (m, 1H), 7.51 (s, 1H), 7.48 (m, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.31 (m, 2H), 7.29 (t, J=5.8 Hz, 1H), 6.80 (t, J=6.9 Hz, 1H), 5.67 (s, 2H), 3.83 (s, 3H) ppm.
Reaction SMILES: F[C:2]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:16])[CH:3]=1.[F:17][C:18]1([F:23])[CH2:21][CH:20]([OH:22])[CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.C([O-])(O)=O.[Na+]>[F:17][C:18]1([F:23])[CH2:21][CH:20]([O:22][C:2]2[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:16])[CH:3]=2)[CH2:19]1
Reactant: OC1CC(F)(F)C1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(OC2CC(F)(F)C2)cc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
370 mg of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate, 297 mg of 3,3-difluorocyclobutanol and 1.47 g of Cs2CO3 were dissolved in 10 ml of anhydrous NMP and stirred at 60° C. for 4 h. The reaction mixture was then diluted with 125 ml of a 50% concentrated aqueous NaHCO3 solution and extracted 3 times with 100 ml of EA each time. It was dried over Na2SO4, and the solvent was removed in vacuo. Chromatography on silica gel with DIP resulted in 380 mg of a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=[O:3].[CH2:21](O)[CH2:22][OH:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[CH2:21]1[CH2:22][O:23][CH2:4][CH:2]([CH2:1][C:5]2[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[O:3]1
Reactant: OCCO
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc(C2=C(CC3COCCO3)C(=O)NCCC2)c1

Procedure:
The starting material is prepared as follows: The solution of 27.2 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 31 g of ethylene glycol and 0.2 g of p-toluenesulfonic acid hydrate in 200 ml of benzene is refluxed with a water separator for 7 hours. It is cooled to 0°, 100 ml of 5% aqueous sodium bicarbonate are added and the benzene layer separated. It is washed with water, dried, evaporated and the residue crystallized from diethyl ether to give the 3-(2-ethylenedioxypropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 132°-134°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:35]1[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4ccc(F)cc4nc3OC)CC2)cc(OC)c1OC
Yield: 83 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 83%).