Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCCCC1C=CC=[C:32]2[C:33]([NH:35]C(=O)[C:31]=12)=O.O.NN>C(O)C.C(OC(=O)C)C>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:31][CH2:32][CH2:33][NH2:35])=[CH:14][C:13]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OCc2ccccc2)c1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1ccc(Oc2ccc(NCCCN)cc2F)c(OCc2ccccc2)c1
Yield: 18.8 %

Procedure:
To 4-(2-benzyloxy-4-ethylphenoxy)-3-fluoroaniline (500 mg, 1.48 mmol) in 25 ml of ethanol was added 3-bromopropylphthalimide (440 mg, 1.64 mmol). The mixture was refluxed for 2 days. The reaction mixture was diluted with ethylacetate and washed with water, saturated brine solution, dried over anhydrous Na2SO4 and concentrated. The crude obtained was passed through a silica gel column using 15% ethylacetate in petroleum ether as eluant. The LCMS of the obtained mixture showed 53% mass of the coupled product. This was taken in 25 ml of ethanol and added 7 ml of hydrazine hydrate and refluxed overnight. Ethanol was removed in vacuo and added 20% KOH solution (20 ml) to the residue. The aqueous fraction was then extracted with dichlormethane and the combined dichloromethane fraction was dried over anhydrous Na2SO4 and concentrated. The crude product obtained was purified by column chromatography using 5% methanol in dichloromethane as eluant to obtain 110 mg (18.8% after 2 steps) of the N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:28][S:29][CH2:30][CH2:31][CH:32]=O.O.[NH2:35][NH2:36]>C1COCC1.CCO>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:32]([CH2:31][CH2:30][S:29][CH3:28])[NH:36][N:35]=1
Reactant: NN
Reactant: Cc1ccc(C(=O)Cc2ccccc2)c(F)c1
Reactant: CSCCC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CSCCc1[nH]nc(-c2ccc(C)cc2F)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
To a solution of 1-(2-fluoro-4-methylphenyl)-2-phenylethanone (2.0 g, 8.76 mmol) in THF (10 mL) was added LiHMDS (1.0 M in THF) (17.52 mL, 17.52 mmol) slowly via syringe at 0° C. After stirring for 10 min, 1-0H-benzo[d][1,2,3]triazol-1-yl)-3-(methylthio)propan-1-one (2.327 g, 10.51 mmol) was added in one portion. The reaction was stirred at 0° C. for 30 min before quenched with AcOH (2 mL). To the reaction were added EtOH (30 mL), hydrazine hydrate (1.316 g, 26.3 mmol), and brought to reflux for 2 h. After cooled to room temperature, the reaction was concentrated and extracted with EtOAc/H2O, washed with brine, dried over MgSO4, and purified by column chromatography to give the title compound as a clear oil (1.40 g). LCMS m/z=327.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.94 (s, 3H), 2.22 (s, 3H), 2.65 (t, J=7.33 Hz, 2H), 2.88 (t, J=7.58 Hz, 2H), 6.71 (d, J=7.83 Hz, 1H), 6.80 (d, J=11.87 Hz, 1H), 6.97 (t, J=7.96 Hz, 1H) 7.09-7.29 (m, 5H), 9.64 (bs, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:14][C:13]([F:16])([F:15])[CH2:12][CH2:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:9]1=[O:28])(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[F:46][C:47]([F:55])([F:54])[CH2:48][CH2:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[CH2:11][CH2:12][C:13]([F:15])([F:16])[CH2:14][C@@H:8]([NH:7][S:50]([CH2:49][CH2:48][C:47]([F:55])([F:54])[F:46])(=[O:52])=[O:51])[C:9]1=[O:28]
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NC(=O)OC(C)(C)C)C2=O)c(OC)c1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)CCC(F)(F)F)C2=O)c(OC)c1

Procedure:
[(R)-1-(2,4-Dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (0.85 g, 1.85 mmol) was dissolved in 38 ml dichloromethane. 4 M HCl/1,4-dioxan (20 ml) were added dropwise and the mixture was allowed to react for 1 h. The reaction mixture was concentrated under reduced pressure and concentrated once from acetonitrile. To 291 mg of the resultant hydrochloride salt was added CH2Cl2 (20 ml) followed by the dropwise addition of Hünig's base (0.36 ml, 2.1 mmol). A solution of 3,3,3-trifluoropropane-1-sulfonyl chloride (0.19 g, 0.9 mmol) in CH2Cl2 (5 ml) was added and the reaction mixture (pH 8) was stirred for a further 1.5 h. The reaction mixture was purified over silica gel (heptane-ethylacetate, 95:5-0:100): white solid 0.30 g (77%);
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>C(O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:9]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: Nc1ccc(Br)cc1C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 9.68 g of 5-bromoisatoic anhydride, 5.0 g of 1H-imidazol-1-propanamine and 75 ml of ethanol was stirred at room temperature for 20 hours and concentrated. The residue was washed onto a filter with ethanol and washed with ether for the desired product, mp 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]>>[CH3:20][C:13]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:12][CH2:11][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1].[CH2:20]([OH:9])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:19]=1
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: Oc1ccc(Cl)cc1Cl
Product: CC(C)=CCCC(C)=CCOc1ccc(Cl)cc1Cl
Product: OCc1ccccc1

Procedure:
2,4-dichloro-phenol is reacted with 1-bromo-3,7-dimethyl-octa-2,6-diene to produce 2,4-dichloro-phenyl 3,7-dimethyl-octa-2,-6-dienyl ether (nD25 = 1.5368) and benzyl alcohol is reacted with 1-bromo-3,7-dimethyl-octa-2,6-diene to produce 3,7-dimethyl-octa-2,6-dienyl ether (nD25 = 1.5095).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19]CC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C.CCCCCC>[CH2:25]([O:24][C:22]([CH:16]1[C:17](=[O:19])[C:3]2[C:2](=[C:11]3[C:6](=[CH:5][CH:4]=2)[CH:7]=[CH:8][CH:9]=[N:10]3)[N:1]=[CH:15]1)=[O:23])[CH3:26]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc2cccnc12
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C1C=Nc2c(ccc3cccnc23)C1=O
Temperature: 60 °C
Yield: 84 %

Procedure:
A mixture of 8-aminoquinoline (14.4 g) and diethyl ethoxymethylenemalonate (26 g) in ethanol (100 ml) was heated at reflux for 18 hours. The mixture was cooled, filtered and the solid washed with ethanol. The solid so obtained was added to refluxing diphenyl ether (1000 ml), and the resulting mixture stirred at reflux for 45 minutes. The mixture was cooled to approximately 60° C. and diluted with hexane (500 ml). The mixture was cooled to ambient temperature, filtered and the solid washed with hexane to give 3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline in 84% yield, mp 242-244° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH:10]=1)[CH:8]=O.[O:11]=[C:12]([CH3:15])[CH:13]=[CH2:14].C(=O)([O-])[O-:17].[K+].[K+].CC(=O)CC>O>[CH3:1][O:2][C:3]1[CH:10]=[C:7]2[C:6](=[CH:5][CH:4]=1)[O:17][CH2:14][C:13]([C:12](=[O:11])[CH3:15])=[CH:8]2
Reactant: COc1cccc(C=O)c1
Reactant: O=C([O-])[O-]
Reactant: C=CC(C)=O
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccc2c(c1)C=C(C(C)=O)CO2

Procedure:
1.52 g (10 mmol) of 2-hydroxy™5-methoxybenzaldehyde, 0.66 g of 3-oxo-1-butene and 1.4 g (10 mmol) of potassium carbonate are added at room temperature and with magnetic stirring to 40 ml of 2-butanone. The mixture is brought to reflux with stirring and this temperature is maintained for 2 hours. After being cooled, the reaction medium is poured into 100 ml of water and extracted 3 times with 100 ml of diethyl ether. The organic phases are combined, washed to neutrality with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the organic phase is evaporated on a water bath under vacuum and the product recrystallized.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([NH:17]N)=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:19])(=[O:5])=[O:4]>[Ni].C(O)C>[OH2:4].[CH3:1][N:2]([CH3:20])[S:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([NH2:17])=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:19])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1c(N)nc2cc(C(=O)NN)ccc21
Agent: [Ni]
Solvent: CCO
Product: CN(C)S(=O)(=O)n1c(N)nc2cc(C(N)=O)ccc21
Product: O

Procedure:
Two grams of 1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxylic acid hydrazide, 8 g. of Raney nickel and 100 ml. of 2B ethanol were refluxed for 4 hours. The cooled mixture was filtered and the catalyst was washed with ethanol. The ethanol washings were combined with the filtrate. The ethanol solution was evaporated to dryness in vacuo. The residue was dissolved in methanol and the solution was filtered through a fritted glass funnel having 4 mm. layer of alumina. The methanol filtrate was concentrated in vacuo to provide 1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxamide hydrate, m.p. about 208°-209° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C@@H:16]([CH3:25])[C:17](N1CCOCC1)=[O:18].[Mg].[Cl-].[NH4+]>O1CCCC1.O>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:18])[C@@H:16]([O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1)[CH3:25]
Reactant: Fc1ccccc1Br
Reactant: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](OC1CCCCO1)C(=O)c1ccccc1F
Temperature: 35 °C
Yield: 103.6 %

Procedure:
1-Bromo-2-fluorobenzene (15 g) and 40 g of 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine was dissolved in 200 ml of tetrahydrofuran, to which 44 g of magnesium turnings was added, and the mixture was vigorously stirred. The reaction vessel was cooled when a temperature of the reaction solution was raised to 35° C., and 16.7 g of 1-bromo-2-fluorobenzene was added dropwise to the reaction solution at 35° to 37° C. over the period of 10 minutes. After stirring at 30° to 35° C. for 2 hours, the reaction solution was ice-cooled, to which 100 ml of a saturated aqueous solution of ammonium chloride and 100 ml of water were added. The mixture was extracted with ethyl acetate (200 ml×2, 100 ml). Then, the extract was washed with water and an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=10:1 to 5:1) to give 22.4 g of (2S)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone as a pale yellow oil.
Reaction SMILES: CNCC1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[O:10][C:9](=[O:15])[C:8]([CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28])=[O:18])=[C:7]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH2:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])C.C(Cl)(=[O:46])C.O>C1COCC1>[C:40]([N:39]([CH2:42][C:43]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[O:10][C:9](=[O:15])[C:8]([CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[C:27]([F:29])([F:30])[F:28])=[O:18])=[C:7]2[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:37])(=[O:46])[CH3:41]
Reactant: CNCc1cc2c(-c3ccccc3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1cc2c(-c3ccccc3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 2-[6-[(methylamino)methyl]-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (Example 180)(0.20 g) in THF (5 ml) was combined with triethylamine (0.11 ml) and acetyl chloride (0.033 ml), and stirred for 3 hours. The reaction solution was combined with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate followed by a saturated brine, and then dried over magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by column chromatography (packing: silica gel, eluent: ethyl acetate-hexane=1:4), and further recrystallized from ethyl acetate-diisopropyl ether to obtain the title compound as a colorless crystal (105 mg, 48%). Melting point: 199-201° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][CH2:7][S:6]1(=[O:14])=[O:13].[CH3:25][NH:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[C:31]([O:32][CH3:33])[CH:30]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[ClH:1].[CH3:33][O:32][C:31]1[CH:30]=[C:29]([CH:38]=[CH:37][C:34]=1[O:35][CH3:36])[CH2:28][CH2:27][N:26]([CH3:25])[CH2:2][CH2:3][CH2:4][C:5]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][CH2:7][S:6]1(=[O:14])=[O:13]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: COc1ccc(C2(CCCCl)S(=O)(=O)CCCS2(=O)=O)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCC2(c3ccc(OC)c(OC)c3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Product: Cl
Temperature: 120 °C

Procedure:
10.4 g of 2-(3-chloropropyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide are treated with 5.11 g of N-methyl-homoveratrylamine, 30 ml of N-ethyl-N,N-diisopropylamine and 70 ml of dimethylformamide. The solution is heated at 120° C for 6 hours. After evaporation, the residue is worked-up in a manner analogous to that described in Example 5. There is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride of melting point 167°-169° C.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCOCCCCCCCCCC(O)=O.[CH:42]1([N:48]=[C:49]=[N:50][CH:51]2[CH2:56][CH2:55][CH2:54]CC2)CCCCC1>O1CCCC1>[CH3:1][N:48]([C:49]1[CH:54]=[CH:55][CH:56]=[CH:51][N:50]=1)[CH3:42]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: COCOCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 595 mg of 10-(methoxymethoxy)decanoic acid, 6 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 739 mg of the title compound were obtained.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.[CH2:12]1[O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@@H:14]2[C@@H:13]1O>C(Cl)Cl>[N+:1]([O-:4])([O:3][C@@H:13]1[CH2:12][O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@H:14]12)=[O:2]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a solution of fuming nitric acid (0.92 mL, 22.2 mmol) in CH2Cl2 (44 mL) and acetic anhydride (2.10 mL, 22.2 mmol) cooled to −20° C., 1,4:3,6-dianhydro-D-mannitol (2.50 g, 17.1 mmol) was added as solid. After the reaction mixture was stirred at 0° C. for 3 hours, it was slowly poured into ice/NaHCO3. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (Biotage SP1, column SNAP 100, EtOAc/n-hexane from 30 to 100%), affording the title product as a white solid (1.35 g, yield 41%). 1H-NMR (300 MHz, CDCl3); δ 5.39 (1H, q), 4.89 (1H, t), 4.49 (1H, t), 4.35-4.27 (1H, m), 4.10-4.04 (2H, m), 3.58 (2H, t), 2.40 (1H, d).
Reaction SMILES: N1([C:6](C2C=CN=C2)=[O:7])C=CN=C1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][N:23]3[C:26]([C:29]4[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=4)=[CH:27][N:28]=[C:22]3[CH:21]=2)=[CH:16][CH:15]=1.[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH2:45])([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH:45][C:6]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:26]2[N:23]3[CH:24]=[CH:25][C:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)=[CH:21][C:22]3=[N:28][CH:27]=2)[CH:30]=1)=[O:7])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(C1C=CN=C1)n1ccnc1
Reactant: Nc1cccc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1cccc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Reaction time: 2 h
Yield: 11.6 %

Procedure:
Imidazol-1-yl-(3H-pyrrol-3-yl)-methanone (240 mg, 1.5 mmol) was added to a stirred solution of 3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]phenylamine (450 mg, 1.5 mmol) in THF (10 ml) at 0° C. under N2. The mixture was stirred at this temperature for 2 hours and then at RT for 3 hours. Half of the reaction mixture was transferred to a separate flask and treated with (2-amino-ethyl)-carbamic acid tert-butyl ester (320 mg, 2 mmol). The mixture was stirred at RT for 16 hours. The volatiles were removed in vacuo and the residue was purified using silica chromatography (2→4% 2M NH3-MeOH/CH2Cl2) to give the title compound (85 mg, foam). MS: [M+H]+ 490.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C1(N=C=NC2CCCCC2)CCCCC1.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46]([CH2:48][C:49](O)=[O:50])=[O:47]>C1C=CC=CC=1>[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46]([CH2:48][C:49]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:50])=[O:47]
Reactant: O=C(O)CS(=O)c1cccs1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)CS(=O)c3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
154 mg of t-butyl 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate and 83 mg of dicyclohexylcarbodiimide were dissolved in 5 ml of benzene, and 76 mg of 2-thienylsulfinylacetic acid ([α]D22° :+11.0°, C=1.00, ethanol) was added to the solution. This liquid reaction mixture was agitated at 25° C. for 2 hours. The mixture was filtered, made adsorbed on 2 g of silica gel and subjected to chromatography using benzene-ethyl acetate (50:50) on 20 g of silica gel to obtain 145 mg of t-butyl 7-(2-thienylsulfinylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. The so obtained ester was dissolved in 1 ml of trifluoroacetic acid, and the solution was agitated at 25° C. for 5 minutes. Then, the solution was added dropwise to 70 ml of ether. The resulting precipitate was collected and dissolved in 5% aqueous sodium bicarbonate solution to form 100 ml of a solution. Then, the solution was extracted with ethyl acetate, and the pH of the aqueous layer was adjusted to 2.0 and the aqueous layer was further extracted with ethyl acetate. The organic layer was dried and concentrated until the volume was reduced to 5 ml. The resulting residue was mixed with a 30% solution of sodium 2-ethylhexanoate in propanol, and ether was added to the mixture. The precipitated salt was collected, recrystallized from methanolether and dried under reduced pressure to obtain 51 mg of sodium 7-(2-thienylsulfinylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate of the R form optically active in the sulfoxide. The NMR spectrum was found to be in agreement with that of the intended product. The bacterium-inhibiting activity of the so obtained compound was much superior to that of the product derived in the same manner by using 2-thienylsulfinylacetic acid having [α]D22° of -9.2° as the starting compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=O.[CH3:10][O:11][NH:12][CH3:13].Cl.C([O-])([O-])=O.[K+].[K+]>S(Cl)(Cl)=O>[CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([N:12]([O:11][CH3:10])[CH3:13])=[O:7]
Reactant: COCC(C)(C)C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: COCC(C)(C)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
A solution of 3-methoxy-2,2-dimethyl-propionic acid (1.0 g, 7.6 mmol) in thionyl chloride (5 ml) was heated to 50° C. for 16 hours. The reaction mixture was concentrated to a yellow residue and then dissolved in DCM (15 ml). O,N-Dimethyl-hydroxylamine-hydrogen chloride (886 mg, 9.1 mmol) and powdered K2CO3 (2.2 g, 16 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a filter funnel, and the filtrate was collected and concentrated giving a white semisolid. The crude product was purified by silica gel chromatography using 20-50% EtOAc in hexanes as eluant providing 260 mg (20%) of 3,N-dimethoxy-2,2,N-trimethyl-propionamide as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]=2[CH:17]=1.O[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].[O:28]1[CH2:33]CC(=O)C[CH2:29]1.[O-]S([O-])(=O)=O.[Mg+2]>ClCCl.O.CN(C)C(=O)C>[CH3:1][C:2]1[C:3]([C:18]([F:19])([F:21])[F:20])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][N:14]([C:23]4([C:24]#[N:25])[CH2:27][CH2:33][O:28][CH2:29][CH2:26]4)[CH2:15][CH2:16]3)[C:6]=2[CH:17]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCNCC1
Reactant: CC(C)(O)C#N
Reactant: O=C1CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCN(C2(C#N)CCOCC2)CC1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
6-Methyl-1-(4-piperidinyl)-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (free base of D60, 0.473 g, 1.47 mmol), 2-hydroxy-2-methylpropanenitrile (2 eq., 2.94 mmol, 0.268 ml), tetrahydro-4H-pyran-4-one (2 eq., 2.94 mmol, 0.27 ml), MgSO4 (880 mg) and N,N-dimethylacetamide (4 ml) were heated at 60° C. under argon for 24 hours. The mixture was subsequently cooled to room temperature and dichloromethane/water (70 ml/70 ml) were added and the biphasic mixture obtained was sonicated at room temperature for 20 minutes. The two phases were separated and the organic phase was dried by hydromatrix cartridge. The organic solvent was subsequently evaporated and the solid obtained was triturated with diethyl ether to afford the title compound (440 mgs, 70%).