Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.CC1C2[O:18][CH:17]=[CH:16]C=2C=CC=1.C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[C:7]([S:8][C:17](=[O:18])[CH3:16])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cccc2ccoc12
Reactant: Cc1cnc(C)c(S)n1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Sc1nc(C)cnc1C

Procedure:
2,5-Dimethyl-3-acetylthio-pyrazine was prepared by acetylating 2,5-dimethyl-3-mercapto-pyrazine [compound (2) a.] with acetic anhydride in an alkaline medium according to the method described in Houben-Weyl, 4th ed., vol. 9, 753 (1955). The product has a m.p. of 36°-42°C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:14][CH2:13][C@H:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11]2)=[N:7][CH:6]=1)[NH2:4].[C:26](OCC)(=O)[CH2:27][OH:28].[O-]CC.[Na+]>C(O)C.O>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:8]2[S:9][C:5]([C:3]3[N:4]=[C:26]([CH2:27][OH:28])[O:1][N:2]=3)=[CH:6][N:7]=2)[CH2:11]1
Reactant: CCOC(=O)CO
Reactant: NC(=NO)c1cnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1nc(-c2cnc(N3CC[C@H](Oc4ccccc4C(F)(F)F)C3)s2)no1
Temperature: 25 °C

Procedure:
A mixture of N′-hydroxy-2-{(3S)-3-[2-(trifluoromethyl)phenoxy]-pyrrolidin-1-yl}-1,3-thiazole-5-carboximidamide (373 mg, 1 mmol), ethyl glycolate (380 μL, 4 mmol) and sodium ethoxide, (21 wt. % solution in ethyl alcohol, 1.6 mL, 4.2 mmol) in ethanol (10 mL) was refluxed for 30 min. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. The residue was triturated with Et2O to give the title compound as a pale yellow powder. 1H NMR (500 MHz, acetone-d6): δ 7.83 (s, 1 H), 7.69-7.65 (m, 2 H), 7.41 (d, 1 H), 7.16 (t, 1 H), 5.52 (m, 1 H), 5.05 (s, 1 H), 4.87 (s, 2 H), 3.98 (m, 1 H), 3.85-3.69 (m, 3 H), 2.60-2.44 (m, 2 H).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH:18]=[CH:19][C:20]([F:32])([F:31])[O:21][C:22]3[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]>C1(C)C=CC=CC=1.C(O)C.[C].[Pd]>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]([F:32])([F:31])[O:21][C:22]3[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=3)[CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=CC(F)(F)Oc3cc(F)c(F)c(F)c3)CC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC(F)(F)Oc3cc(F)c(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In a nitrogen-purged 1-L stainless steel autoclave, 7.7 g (16.8 mmol) of 1-(3-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)-1,1-difluoro-2-propenyloxy)-3,4,5-trifluorobenzene obtained in Example 3 was dissolved in 200 ml of a mixed solution of equal amount of toluene/ethanol. 0.8 g of 5% palladium carbon catalyst was added thereto, and the mixture was stirred at room temperature under a hydrogen pressure of 0.1 to 0.2 MPa for 10 hours. The catalyst was separated from the reaction mixture by filtration, and then the solvent was distilled off under reduced pressure. The concentrated residue was purified by means of a silica gel column chromatography with heptane as a developing solvent and further recrystallized from a mixed solution of equal amount of heptane/ethanol to obtain 4.9 g of 1-(3-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)-1,1-difluoropropoxy)-3,4,5-trifluorobenzene as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:31]([F:32])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[CH2:33][CH3:34].CCN(C(C)C)C(C)C.[Cl:44][CH2:45][C:46](Cl)=[O:47].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:12]1[C@@H:11]2[C@H:15]([C@H:7]([CH2:6][C:5]3[CH:30]=[C:31]([F:32])[C:2]([NH:1][C:46](=[O:47])[CH2:45][Cl:44])=[C:3]([CH2:33][CH3:34])[CH:4]=3)[CH2:8][S:9](=[O:28])(=[O:29])[CH2:10]2)[O:14][C:13]1=[O:16])([CH3:26])([CH3:27])[CH3:25]
Reactant: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1NC(=O)CCl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of (3aR,7S,7aS)-7-(4-amino-3-ethyl-5-fluoro-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (0.245 g, 0.5 mmol) and DIPEA (0.52 mL, 3 mmol) in CH2Cl2 was slowly added a solution of 2-chloroacetylchloride (0.226 g, 2.0 mmol) dissolved in CH2Cl2 (2 mL) at 0-5° C. After stirring for 1 h at 0-5° C. the reaction mixture was poured onto cold saturated NaHCO3 solution and extracted with CH2Cl2. Combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was dissolved in MeOH, stirred for 0.5 h at 25° C., and evaporated again. The title compound was obtained after chromatographic purification (Combi Flash, 12 g silica gel, hexane-EtOAc) as a light yellow solid: TLC (toluene-EtOAc 1:1) Rf=0.44; UPLC RtD=1.799 min; ESIMS [M+NH4]+=582; 1H NMR (600 MHz, DMSO-d6): δ 9.70 (s, 1H), 7.39 (s, 1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.13 (d, 1H), 6.98 (d, 1H), 6.95 (s, 1H), 4.42 (d, 1H), 4.28 (s, 2H), 4.21 (d, 1H), 4.19 (t, 1H), 3.72 (m, 2H), 3.48 (t, 1H), 3.14 (dd, 1H), 2.98 (m, 2H), 2.55 (m, 4H), 1.26 (s, 9H), 1.08 (t, 3H).
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-].[C:4]([OH:12])(=[O:11])[CH:5]([CH2:7][C:8]([OH:10])=[O:9])[OH:6]>O>[C:4]([O:12][OH:1])(=[O:11])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[Ca+2:2].[Ca+2:2].[OH:1][O:11][C:4](=[O:12])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[OH:1][O:11][C:4](=[O:12])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[OH:1][O:11][C:4](=[O:12])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6]
Reactant: [OH-]
Reactant: O=C(O)CC(O)C(=O)O
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
A dicalciumhydroxy malate granular product was prepared by mixing two molar equivalents of particulate calcium hydroxide with one molar equivalent of particulate malic acid (totaling 45 kg for the entire composition) in a Ribbon Blender for 15 minutes at normal speeds. A water jacket was used to ensure that the product would not over react when small amounts of water were added to the batch. Next, about 1 L of water was slowly sprayed into the particulate mixture product. After about 10 minutes of reaction time (where the product became spongy and had risen, and then dropped back to a more granular state), an additional 1 L of water was added. This was repeated several times until no further reaction appeared to be occurring upon addition of water. The end result was a granular product. Once a fully reacted granular product was formed, no additional water was added. The resulting composition was then dried in a cool room and ground to a predetermined particle size.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:4]=1[C:5]([NH:7][C:8]1[C:17]2[N:16]=[CH:15][C:14]3[C:18](=[O:22])[NH:19][N:20]([CH3:21])[C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:3]([Cl:2])[C:4]=1[C:5]([NH:7][C:8]1[C:17]2[N:16]=[CH:15][C:14]3[C:18](=[O:22])[N:19]([CH2:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[N:20]([CH3:21])[C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: Cn1[nH]c(=O)c2cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc3c21
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c2c(cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc32)c(=O)n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-one hydrochloride (85 mg), 4-chloromethylpyridine hydrochloride (40 mg) and potassium carbonate (111 mg) in dimethylformamide (1 ml) was stirred for 3 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1-methyl-2-(pyridin-4-ylmethyl)-1H-pyrazolo[4,3-c]quinolin-3-one.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:29])CC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 20 h
Yield: 39.8 %

Procedure:
(1,4-Dibenzylpiperazin-2-yl)methanol (15 g, 50.5 mmol) in DCM (50 mL) was added dropwise to a stirred solution of DAST (7.42 mL, 60.6 mmol) in DCM (150 mL) cooled to −78° C. The reaction mixture was maintained below −30° C. for 24 h before warming to room temperature and stirring for an additional 20 h. The reaction was quenched by the addition of water (100 mL). The organic phase was separated, the aqueous basified with NaOH (aq.) to pH 10 and extracted with DCM (3×75 mL). The combined organics were washed with water (2×100 mL), brine (2×100 mL), dried (Na2SO4) and concentrated under reduced pressure. The resultant oil was purified by chromatography on silica gel with EtOAc:heptane (1:9, v/v) as eluent to afford 1,4-dibenzyl-2-fluoromethylpiperazine (6.0 g, 20.1 mmol, 40%). A biproduct of the reaction was also isolated, 1,4-dibenzyl-6-fluoroperhydro-1,4-diazepine (1.0 g, 3.35 mmol, 7%).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]2[CH2:35][CH2:34]2)=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N-:36]=[N+:37]=[N-:38].[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:31]([CH:33]3[CH2:35][CH2:34]3)=[N:38][N:37]=[N:36]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)C1CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(COc2ccc(-n3nnnc3C3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
Trifluoromethane sulfonic anhydride (9.42 ml) was added dropwise over 10 min to a solution of cyclopropanecarboxylic acid(4-benzyloxy-phenyl)-amide (15 g) and sodium azide (3.64 g) in acetonitrile (250 ml) at 0°. The reaction mixture was stirred at room temperature under nitrogen for 16 h. 10% Aqueous sodium hydrogen carbonate (80 ml) was added and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (2×100 ml). The combined organic pads were dried over anhydrous sodium sulphate and concentrated in vacuo to give a brown oil. Purification by chromatography with ethyl acetate:isohexane (1:1) as eluant afforded the title compound (2.4 g) as a yellow solid, m.p. 118°.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14]1[NH:15][CH2:16][CH2:17][CH2:18][C:19]=1[N+:20]([O-:22])=[O:21]>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]1[NH:15][CH2:16][CH2:17][CH2:18][C:19]=1[N+:20]([O-:22])=[O:21]
Reactant: CSC1=C([N+](=O)[O-])CCCN1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC1=C([N+](=O)[O-])CCCN1
Yield: 74 %

Procedure:
A solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.51 g, 0.003 mol) and 2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.49 g, 0.003 mol) in ethanol (50 ml) was refluxed for 6 hours. The mixture was cooled, and the solvent was removed in vacuo. The residue was dissolved in hot propan-2-ol and the product crystallised on cooling. Recrystallisation of the product from propan-2-ol/methanol gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-1,4,5,6-tetrahydropyridine (0.66 g, 82%) m.p. 205.5°-206.5°. Found: C, 48.6; H, 6.5; N, 23.6; S, 10.8; C12H19N5O2S requires: C, 48.5; H, 6.4; N, 23.55; S, 10.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[O:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:16]3[O:17][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)o1
Yield: 97.2 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (3.2 g, 19.1 mmol) (Alfa) was reacted with 5-chloro-2-furaldehyde (2.5 g, 19.1 mmol) (Aldrich) and piperidine (1.89 mL, 19.1 mmol) in methanol to give E/Z-6-chloro-3-(5-chloro-furan-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 5.2 g, 97%)
Reaction SMILES: [CH3:1][CH:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:12]([N:5]([CH:2]([CH3:1])[CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCBr
Reactant: CCC(C)Nc1ccccc1
Product: CCCCCCCN(c1ccccc1)C(C)CC

Procedure:
N-n-heptyl-N-(1-methylpropyl)aniline was prepared from N-(1-methylpropyl)aniline and 1-n-heptylbromide using the same method as in Example 2ii).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=2[Cl:23])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].CN.[NH:26]1[CH:30]=CC=N1.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:23])=[CH:14][C:15]([Cl:22])=[C:16]([S:18]([NH:26][CH3:30])(=[O:20])=[O:19])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: Cn1nc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: c1cn[nH]c1
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 4-chloro-3-(5-chlorosulfonyl-2,4-dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole (0.43 g, 1 mmole) in 2 ml tetrahydrofuran was added dropwise to a 40% aqueous methylamine solution dissolved in 20 ml tetrahydrofuran to react the pyrazole derivative with methylamine. After the addition was finished, the reaction was continued further for 30 minutes at room temperature. Then ethyl acetate was added to the reaction product solution to extract the objective product. The extract solution was washed with water, dehydrated, and evaporated to dryness, giving the title compound (0.42 g) in paste form, yield 100%.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH3:5][CH:6]([CH2:9]O)[CH2:7][OH:8]>>[CH:3]([CH:1]1[O:8][CH2:7][CH:6]([CH3:9])[CH2:5][O:2]1)=[CH2:4]
Reactant: C=CC=O
Reactant: CC(CO)CO
Product: C=CC1OCC(C)CO1

Procedure:
Acrolein and 2-methyl-1,3-propanediol were condensed to produce 2-vinyl-5-methyl-1,3-dioxane in accordance with the procedure of Example I.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:18][C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:13](=[O:17])[NH:14][CH2:15][CH3:16])[N:10]=[CH:9]2)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH2:15]([NH:14][C:13]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([O:18][C:19](=[O:21])[CH3:20])[C:4]=2[CH2:1][CH:2]2[CH2:3][O:30]2)[CH:9]=[N:10]1)=[O:17])[CH3:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(OC(C)=O)ccc2cnn(C(=O)NCC)c12
Solvent: ClCCl
Product: CCNC(=O)n1ncc2ccc(OC(C)=O)c(CC3CO3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step D (2.70 g, 9.4 mmol) in dichloromethane (15 mL) was added 3-chloro-perbenzoic acid (2.31 g, 10.3 mmol, 77% pure) and the mixture stirred at ambient temperature for 1 h. Additional 3-chloro-perbenzoic (0.2 g, 0.9 mmol) was added and the reaction continued for 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (50 mL). The extract was dried (MgSO4) and evaporated to a white solid (1.59 g, 56%): mp 110-111° C.; LC/MS (+APCI) m/z 304 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5].COCCOC.[OH-].[Na+].Cl[CH:20]([F:22])[F:21]>O>[F:21][CH:20]([F:22])[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(O)cccc1F
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(F)cccc1OC(F)F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
150 g (1.1 mol) of 2-fluoro-6-hydroxybenzonitrile were introduced into 2000 ml of ethylene glycol dimethyl ether. Then, 262.8 g (3.3 mol) of concentrated NaOH were added dropwise. The reaction mixture was heated to 65° C. and 95 g (1.1 mol) of chlorodifluoromethane were passed in. The mixture was stirred at 65° C. for one hour and at room temperature overnight. Then, the reaction mixture was stirred into 3 l of water, followed by extraction repeated three times with a total of 800 ml of methyl tert.-butyl ether. The combined organic phases were washed twice with 500 ml of water, once with 250 ml of sodium chloride solution and dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 211 g (99% of theory) of the desired product with a purity of 97% according to GC. 1H NMR (in CDCl3): δ=6.5-6.9 ppm (t, 1H, OCF2H), 7.15 ppm (m, 2H, arom. H), 7.65 ppm (m, 1H, arom. H).
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46]C(C)(C)C)=[O:45])[C:11]([NH:13][C@@H:14]2[C:39](=[O:40])[N:16]3[C:17]([C:36]([O-:38])=[O:37])=[C:18]([CH2:21][N+:22]4([CH3:35])[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O.Cl.C(OCC)(=O)C>CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([OH:46])=[O:45])[C:11]([NH:13][C@@H:14]2[C:39](=[O:40])[N:16]3[C:17]([C:36]([O-:38])=[O:37])=[C:18]([CH2:21][N+:22]4([CH3:35])[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)OC(C)(C)C)CC3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4csc(N)n4)[C@H]3SC2)CCNCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 26.7 %

Procedure:
To a suspension of 7β-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-(1-methyl-4-tert-butoxycarbonyl-1-piperazinio)methyl-3-cephem-4-carboxylate hydrochloride (syn isomer) (4.02 g) in methanol (12 ml) was added conc. hydrochloric acid (4.4 ml) at 10° C. The resulting solution was warmed to room temperature and stirred for 4.5 hours. The mixture was pulverized with ethyl acetate (800 ml) and the powder was collected by filtration, washed with ethyl acetate and dried in vacuo. The powder (3.68 g) was suspended in a mixture of dichloromethane (12 ml) and anisole (4 ml), and trifluoroacetic acid (8 ml) was added thereto. After being stirred at room temperature for 3.5 hours, the mixture was pulverized with diisopropyl ether (800 ml) and the powder was collected by filtration and washed with diisopropyl ether. The powder was suspended in a mixture of water (100 ml) and ethyl acetate (30 ml) and adjusted with a saturated aqueous solution of sodium bicarbonate. After removal of the insoluble materials, the aqueous layer was separated, adjusted to pH 4 with 1N hydrochloric acid and chromatographed on Diaion HP-20 (250 ml). The elution was carried out with 10% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-[2-(2-aminothiazol- 4-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (763 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=[O:8].O.[OH-].[Li+]>CCO.O>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(-c2ccncc2)sc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1sc(-c2ccncc2)cc1C(=O)O
Temperature: 80 °C
Yield: 82.2 %

Procedure:
To a solution of ethyl 2-amino-5-(pyridin-4-yl)thiophene-3-carboxylate (400 mg, 1.53 mmol) in EtOH (50 mL) was added a solution of lithium hydroxide monohydrate (256 mg, 6.1 mmol) in water (5 mL). The reaction mixture was heated to 80° C. for 2 hour. After removal of the solvent, the residue was dissolved in water and the organic materials were extracted with AcOEt (50 mL). The organic layer was discarded, and the aqueous layer was neutralized with 2N HCl aqueous solution to pH=5 or 6, upon with a precipitate formed. The solid was collected by filtration and dried to give the title compound (277 mg, 77%) as an orange solid:
Reaction SMILES: [CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][CH:19]=[C:20](C3C=CC=CC=3)[CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:28]([CH3:29])[CH3:30])[C:3]1[C:4]([C:17]2[O:18][C:19]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:20][CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3cc(-c4ccccc4)co3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 172.1 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(4-phenylfuran-2-yl)quinoxaline-6-carboxylate (50 mg, 0.12 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (19.9 mg, 0.50 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3 N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (40 mg, 83%).