Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:35][CH2:36][CH3:37])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:28]([N:17]([C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1)[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:38])=[O:5])[C:9]([CH2:35][CH2:36][CH3:37])=[N:10][C:11]=2[CH:16]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(F)c(F)c3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(F)c(F)c3)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(3,4-difluoro-benzoyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.48 (m, 1H), 7.26 (m, 7H), 7.12 (m, 2H), 6.81 (m, 1H), 5.08 (s, 2H), 4.31 (s, 2H), 2.62 (t, 2H), 1.71 (m, 2H), 0.92 (t, 3H). MS calculated for C26H23F2N3O3+H: 464, observed: 464.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH:6]([OH:15])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)(=O)CCCCCCCCCCCCCCCCC.C1(C(C(C2C=CC=CC=2)O)=O)C=CC=CC=1.C(S([O-])(=O)=O)CCCCCCCCCCCCCCC.F[C:76](F)([C:80](F)(F)[C:81](F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)[C:77]([O-:79])=[O:78]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:77]([OH:79])(=[O:78])[CH2:76][CH2:80][CH2:81][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:8][CH2:7][CH2:6][CH2:5][CH2:16][CH2:17][CH2:18][CH2:3][CH3:4].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH:6]([OH:15])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCCCCCS(=O)(=O)[O-]
Agent: COc1cccc(C(O)C(=O)c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
3'-Methoxybenzoin (5 g, 0.021 mol) was dissolved in 200 ml of toluene containing one equivalent of triethylamine. One equivalent of octadecanoyl chloride in 20 ml of toluene was added slowly to the cooled (ice bath) stirred benzoin solution. Stirring was continued with ice bath cooling for one hour. The reaction mixture was then filtered free of precipitated amine salt and the filtrate was evaporated to give an oil which solidified to give a low melting solid. The hexadecanesulfonate (Compound 14) and perfluorooctanoate (Compound 15) (m.p. 55°-58° C.) esters were similarly prepared from the corresponding acid chlorides.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH2:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28]Br)[CH3:25]>O>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][NH:12][CH:10]([CH3:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:25]
Reactant: COc1cccc(CC(C)N)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CNC(C)Cc1cccc(OC)c1)OCC
Temperature: 130 °C
Yield: 68 %

Procedure:
(+)-2-(3-methoxyphenyl)-1-methylethylamine (472.8 g, 2.86 mol), potassium carbonate (sesquihydrate) (1133.8 g, 6.88 mol) and dimethylformamide (2400 ml) were mixed and heated to 130° C. in a reaction flask fitted with an efficient stirrer and a reflux condenser. Bromoacetaldehyde diethylacetal (630 g, 3.20 mol) was added dropwise over a 45 min period while maintaining the temperature at 130° C. The reaction was mildly exothermic. The temperature was maintained at 130° C. for 1 hr. The reaction mixture was cooled to 45° C., and 325 ml of water was added. After stirring at least 1 hr and after the temperature of the mixture reached 30°, it was filtered from the salts and the solvent evaporated under vacuum on a rotatory evaporator. The residual oil was filtered from some inorganic salts and distilled under vacuum; collected fractions boiling at 115°-130° C. at 0.05 mmHg, yield 68% of (+)-N-(2,2-diethoxyethyl)-2-(3-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O)(=O)C.[BH4-]>CO.C(OC)(OC)OC.C(Cl)Cl>[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CCCCCCCN
Agent: [BH4-]
Solvent: CO
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CCCCCCCNCc1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Heptylamine (345.6 mg, 3 mmol) was added into 2,4-difluorobenzaldehyde (440.5 mg, 3.1 mmol) in MeOH (3 ml) and trimethyl orthoformate (2 ml), followed by acetic acid (0.05 ml). The mixture was in microwave oven (Smith Synthesizer) at 150° C. for 10 minutes. DCM (3 ml) was then added and followed borohydride on polymer support (1.2 g, 3 mmol). The mixture was shaken overnight and more of borohydride on polymer support (1.2 g) was added. The mixture was shaken over weekend and then filtered and evaporated. The residue was put on a column ((ISOLUTE®PRS, 10 g) and eluted with MeCN, MeOH and then MeOH(NH3 sat.). 536 mg of oil product was obtained, yield 72%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.B#B.O.Cl>C1COCC1>[CH2:6]1[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:15][C:14]=2[O:13][C:12]2[CH:11]=[C:10]([OH:16])[CH:9]=[CH:8][C:7]1=2
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2c(c1)Oc1cc(O)ccc1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a suspension of 3,6-dihydroxyxanthone (46 g, 201 mmol.) obtained as in Example 1 in 1.6 L of THF was added over 1 hr 800 ml of borane-tetrahydrofuran complex (1.0M in THF, caution very vigorous raction at beginning). This mixture was stirred overnight under argon at room temperature to give a clear yellow solution. The excess diborane was decomposed by careful addition of water followed by 1N HCl to give a clear yellow solution. The tetrahydrofuran was removed by rotary evaporation and the resulting solid filtered, washed with water and redissolved in 10% NaOH. This solution was filtered, cooled and reprecipitated with slow addition of HCl to give a yellow solid which was filtered, washed with water and dried under vacuum to give 40.14 g (93%, mp 207-208) of 3,6-Dihydroxyxanthane. H1NMR (DMSO): 9.41 (s, 2H); 6.97 (d, 2H, J=8.4 Hz), 6.4 (dd, 2H, J=8.4, 2.4 Hz), 6.39 (d, 2H, J=2.4 Hz), 3.765 (s, 2H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[CH3:16]>>[F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Reactant: Fc1cccc(N2CCNCC2)n1
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound can be obtained.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[O:19]([CH2:26][C:27](OC)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(O)(=O)C>[O:28]=[C:27]([CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)COc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)COc1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82608.7 %

Procedure:
Dimethyl methylphosphonate (18 ml, 0.166 mol) was addded to anhydrous THF (150 ml) under argon atmosphere and cooled to -78° C. After 20 min. a solution of n-butyl lithium in hexane (1.59N, 108.8 ml, 0.173 mmol) was added to the mixture. After being stirred for 30 min. a solution of methyl phenoxyacetate (10 ml, 0.069 mmol) in 10 ml of anhydrous THF was added, and the reaction mixture was stirred successively for 30 min. at -78° C. and for 30 min. at room temperature, and acidified with acetic acid. After confirming a weakly acidic pH of the solution thus obtained, THF was distilled out. Water (50 ml) was added to the residue, and the resulting mixture was extracted with ethyl acetate (150 ml×3). The combined organic layers were washed with 100 ml of water and with 100 ml of brine, dried over anhydrous sodium sulfate, and concentrated. The oily product was distilled under reduced pressure to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (14.65 g, 0.057 mol, yield: 82.3%). B.p.: 145°-147° C./0.1 mmHg. The product was identified by the following data.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].C(O[C:30](=O)[CH2:31][C:32]([OH:43])([C:37]1[S:41][C:40]([SH:42])=[N:39][CH:38]=1)[C:33]([F:36])([F:35])[F:34])C.CCOCCO>CC(O)C.CCOC(C)=O.O.[Cu](I)I>[F:36][C:33]([F:34])([F:35])[C:32]([C:37]1[S:41][C:40]([S:42][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]2[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:13][N:14]=[C:7]2[CH:6]=[CH:5]3)=[N:39][CH:38]=1)([OH:43])[CH2:31][CH3:30]
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Reactant: CCOC(=O)CC(O)(c1cnc(S)s1)C(F)(F)F
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCCO
Product: CCC(O)(c1cnc(Sc2ccc3c(ccc4nnc(-c5ccccc5)n43)c2)s1)C(F)(F)F
Temperature: 90 °C

Procedure:
7-Iodo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (10c, 140 mg, 0.38 mmol), copper iodide (14 mg, 0.08 mmol), and potassium carbonate (105 mg, 0.76 mmol) were suspended in iPrOH (1 mL). 10b (92 mg, 0.38 mmol) in iPrOH (1 mL) was added, followed by ethyl glycol (0.04 mL, 0.76 mmol), and the reaction was heated to 90° C. overnight. The reaction was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (5% MeOH in CH2Cl2), and the isolated product was precipitated from CH2Cl2 to give the desired product, 10d.
Reaction SMILES: C(B)(C(C)C)(C)C.C1COCC1.[CH:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:13]([OH:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CC=Cc1ccccc1
Agent: BC(C)(C)C(C)C
Solvent: C1CCOC1
Product: OCC=Cc1ccccc1
Yield: 70 %

Procedure:
The reduction of aldehydes and ketones with TBDA to the corresponding alcohol proceeds at rates comparable to those of thexylborane-THF. Cinnamaldehyde may be completely reduced by excess TBDA, but treatment with 1 molar equivalent at 0° C. for 15 minutes produces cinnamyl alcohol (70% yield) as the sole product. Similarly, only the aldehyde group of campholenic aldehyde is reduced to give the corresponding alcohol in 80% isolated yield.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[CH:2]1.N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>CN(C=O)C>[Si:17]([O:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)([C:14]([CH3:16])([CH3:15])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1c[nH]cn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 97.1 %

Procedure:
A solution of (1H-imidazol-4-yl)methanol (14.6 g, 108 mmol) in DMF (100 mL) was treated with imidazole (22.16 g, 325 mmol) and TBDPSCl (29.8 g, 108 mmol) and the mixture was stirred and heated to 50° C. for 6 h. It was then allowed to cool to RT, poured onto H2O and extracted with DCM. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, DCM/MeOH 100:0 to 90:10) afforded the title compound (35.3 g). UPLC-MS: MS 337.2 (M+H+); UPLC rt 1.04 min.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH3:14][CH:15]1[O:20][C:19]2[CH:21]=[CH:22][C:23]([O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][C:18]=2[NH:17][C:16]1=[O:32]>>[CH:1]1([NH:4][C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([N:29]3[CH2:30][CH2:31][CH:26]([O:25][C:23]4[CH:22]=[CH:21][C:19]5[O:20][CH:15]([CH3:14])[C:16](=[O:32])[NH:17][C:18]=5[CH:24]=4)[CH2:27][CH2:28]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC1Oc2ccc(OC3CCNCC3)cc2NC1=O
Reactant: O=C(NC1CC1)c1ccc(F)cc1
Product: CC1Oc2ccc(OC3CCN(c4ccc(C(=O)NC5CC5)cc4)CC3)cc2NC1=O
Yield: 35.5 %

Procedure:
Using N-cyclopropyl-4-fluorobenzamide as the alkylating agent, the reaction with 394E was carried out as described for 395 providing the title compound as a tan solid (0.0308 g, 35.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.57 (m, 2H) 0.62-0.70 (m, 2H) 1.35-1.43 (m, 3H) 1.59-1.73 (m, 2H) 1.92-2.05 (m, 2 H) 2.80 (tq, J=7.34, 3.95 Hz, 1H) 3.11-3.22 (m, 2H) 3.56-3.69 (m, 2H) 4.38-4.49 (m, 1 H) 4.54-4.62 (m, 1H) 6.50 (d, J=2.78 Hz, 1H) 6.57 (dd, J=8.84, 2.78 Hz, 1H) 6.88 (d, J=8.84 Hz, 1H) 6.96 (d, J=9.09 Hz, 2H) 7.70 (d, J=8.84 Hz, 2H) 8.14 (d, J=4.29 Hz, 1H) 10.57 (s, 1H). ESI-MS: m/z 422.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C1COCC1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([C:3]2[C:4](=[O:14])[O:5][C:6]3[C:11]([C:2]=2[CH3:1])=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=3)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)c2ccc(Cl)cc2)c(=O)oc2cc(C#N)ccc12
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (170 mg, 0.918 mmol) in dry THF (5 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (1 mL). After 30 minutes 4-chloro-benzoyl chloride (160 μL) was added slowly and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30% ethyl acetate in hexanes to yield the title compounds as a white foam and a white solid, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([CH:22]=1)[O:7][C@@H:8]([CH2:19][O:20][CH3:21])[CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C.[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27]>Cl.O1CCOCC1>[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27].[NH2:11][CH2:10][CH2:9][C@@H:8]([O:7][C:6]1[CH:22]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:23]#[N:24])[CH2:19][O:20][CH3:21]
Reactant: COC[C@@H](CCNC(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Product: COC[C@@H](CCN)Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
The product from step (e) (140 mg, 0.39 mmol) was dissolved in 4M hydrochloric acid in dioxan and stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and aqueous saturated sodium bicarbonate solution. The organic layer was separated and washed with water (2×20 ml), dried (magnesium sulphate) and evaporated in vacuo. The residue was dissolved in ethyl acetate (5 ml) and treated with one equivalent of oxalic acid. The precipitated solid was filtered off and dried to give the title compound (30 mg, 22%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[C:10](=[O:20])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:41](O)[CH2:42][OH:43]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]2([O:43][CH2:42][CH2:41][O:20]2)[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(=O)c2c1[nH]c1ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC2(OCCO2)c2c1[nH]c1ccccc21

Procedure:
A mixture of 3-(4-fluorobenzoyl)-1-oxo-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (39 mg, 10.1 mmol) and TsOH (10 mg) and ethylene glycol (0.2 mL) in toluene (10 mL) was heated to reflux overnight under nitrogen. After cooling, the reaction was diluted with DCM. It was then washed with saturated aqueous NaHCO3 and water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluted with MeOH-DCM (2:98) to give the title compound (7.5 mg); 1H-NMR (CDCl3): δ 9.68 (1H, s), 8.24 (1H, d), 7.08 (2H, m), 7.57 (1H, s), 7.41 (2H, m), 7.12 (2H, m), 4.77 (2H, m), 4.55 (2H, m), 4.46 (2H, q), 1.46 (3H, t). MS (ES): 437 (MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1cc(F)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(F)ccc2Cl)CC1
Temperature: 80 °C
Yield: 55.4 %

Procedure:
A mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (2, 1.10 g, 3.3 mmol), 2-chloro-5-fluorophenyl boronic acid (0.58 g, 3.3 mmol), Pd(PPh3)4 (0.38 g, 0.33 mmol), and 2 M Na2CO3 (20 mL) in DME (50 mL) was heated at 80° C. for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4×50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes) to provide tert-butyl 4-(2-chloro-5 fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (15) as a clear oil (0.57 g, 55%): 1H NMR (300 MHz, DMSO-d6) δ 7.53-7.46 (m, 1H), 7.23-7.14 (m, 2H), 5.79-5.74 (m, 1H), 4.00-3.92 (m, 2H), 3.52 (t, J=5.7 Hz, 2H), 2.40-2.32 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH2:13])=[O:11])=[CH:6][C:5]=12.[C:14](=S)=[S:15].[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]>C(O)C>[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18].[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[O:11][C:14]([SH:15])=[N:13][N:12]=3)=[CH:6][C:5]=12
Reactant: NNC(=O)c1ccn2ncnc2c1
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: Sc1nnc(-c2ccn3ncnc3c2)o1
Temperature: 90 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 1,2,4-triazolo[1,5-a]pyridine-7-carbohydrazide (450 mg, 2.54 mmol), carbon disulfide (0.38 mL, 6.35 mmol), triethylamine (0.44 mL, 3.18 mmol) and ethanol (30 mL) was stirred at 90° C. for 18 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (814 mg, yield 100%) as brown crystals.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH2:11]([O:13][C:14](=[O:46])[CH2:15][C:16]1([CH2:19][CH2:20][C:21]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][CH:37]=2)(C(OCC=C)=O)[C:22]([O:24]CC=C)=[O:23])[CH2:18][CH2:17]1)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:13][C:14](=[O:46])[CH2:15][C:16]1([CH2:19][CH2:20][CH:21]([CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:41]=2)[C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)[CH3:12]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(CCC1(CC(=O)OCC)CC1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CC1(CCC(CCc2ccc(C(=O)OC)cc2)C(=O)O)CC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
At room temperature a solution of 0.6 ml (4.3 mmol) of triethylamine and 0.12 ml (3.25 mmol) of formic acid in 15 ml of dioxane is added to a solution of 650 mg (1.3 mmol) of diallyl {2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}{2-[4-(methoxycarbonyl)phenyl]ethyl}malonate, 24 mg (0.09 mmol) of triphenylphosphine and 6 mg (0.026 mmol) of palladium acetate in 15 ml of dioxane. The reaction mixture is then stirred at 100° C. for 12 hours. After complete conversion, the reaction solution is cooled and the solvent is removed under reduced pressure. The residue is then taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid, and the organic phase is removed. The aqueous phase is extracted three more times with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated under reduced pressure and the residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gives 406 mg (83% of theory) of a yellow oil.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O>P([O-])([O-])([O-])=O.CN(C)C=O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C@@H:7]([C:16]([OH:18])=[O:17])[C:6](=[CH2:5])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C=C1CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
40 g of aluminium amalgam are added to a solution of 21.8 g (80 mmols) of 7β-aminocephalosporanic acid in 900 ml of 0.5 M phosphate buffer (pH 7) and 100 ml of dimethylformamide. The mixture is stirred for 1 hour at pH 6.0 and 45° C. After cooling, the reaction mixture is washed with cold ethyl acetate and the aqueous phase is filtered through celite. The filtrate is adjusted to pH 3.5 and evaporated in vacuo and the residue is taken up in 200 ml of methanol-water, 7:3. The portion filtered off (27.5 g) still contains considerable amounts of inorganic salts in addition to the product. 7β-Amino-3-methylene-cepham-4α-carboxylic acid is obtained as an almost colourless powder by shaking with 150 ml of water, leaving the mixture to stand for 3 hours at 0° C, and filtering. Thin layer chromatogram on silica gel: Rf (system 52/n-butanol-glacial acetic acid-water 75:75:21 ) = 0.20, Rf (system 100/ethyl acetate-pyridine-glacial acetic acid-water, 60:20:6:11) = 0.13, Rf (system 200/n-butanol-carbon tetrachloride-methanol-formic acid-water, 30:40:20:5:5) = 0.34.