Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH2:10][CH:9]1[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.OS(O)(=O)=O>C(#N)C>[CH2:1]([N:8]1[CH2:11][CH2:10][CH:9]1[C:12]([O:14][CH2:15][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCN1Cc1ccccc1
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)C1CCN1Cc1ccccc1
Temperature: 20 °C
Yield: 87 %

Procedure:
To 68.3 g of methyl N-benzylazetidine-2-carboxylate (see Example 4 above; purity 89.8 area % ), acetonitrile (127 mL), K2CO3(s) (23.3 g) and benzyl alcohol (75.6 g) were added. The stirred reaction slurry was heated to between 75 and 80° C., and a modest vacuum (p>700 mbar) was applied. Methanol and acetonitrile were distilled off and, as the reaction slurry became highly concentrated, more acetonitrile was added and the distillation was continued. This procedure was repeated until a conversion of 97% was attained. The concentrated reaction mixture was cooled to 20° C. and diluted with acetonitrile (70 mL). The solid salts were filtered off and the filter cake was washed with acetonitrile (3×50 mL). The solvent was evaporated off at 40° C. To the remaining high-boiling liquid, heptane (1.5 L) and 5% (w/w) NaCl(aq.) (700 mL) were added, giving a mixture of three phases. 2 M H2SO4 (5 mL) was added to give a pH of about 8. After two more extractions of the organic phase with 5% (w/w) NaCl (aq), and water at pH 8, almost all of the third phase (benzyl alcohol) was successfully dissolved. Water (550 mL) was added to the organic phase and the pH was adjusted to 2.6 with 2M H2SO4 (38 mL). After separation, the organic phase was extracted with two more portions of acidified water (150 mL H2O at pH 2.2, followed by 50 mL H2O at pH 2.6). The organic phase was discarded. To the combined aqueous phases (pH 2.5), heptane (1.25 L) was added and pH was adjusted to 4.5 with K2CO3(s). The organic phase was separated off and washed with 10% (w/w) NaCl (aq.) and water. The obtained organic phase was evaporated at 40° C., until a bright yellow to brownish liquid remained (65.1 g, according to titration 94.0% (w/w) product, 4.3% (w/w) benzyl alcohol, purity(GC) 99.5 area % ). A second crop of product was isolated as above by extracting the remaining water phase (pH 4.5) with three more portions of heptane (0.25/0.1/0.1 L heptane at pH 5.8/5.2/4.9). Yield 7.8 g of a slightly more coloured product (assay 90% (w/w) according to titr., purity(GC) 97.9 area %), resulting in a total yield of 87% (68.2 g, 0.242 mol).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=2)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C1COCC1>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(4-Boc-piperazin-1-yl)-(3-nitro-5-trifluoromethyl-phenyl)-methanone (403 mg) was dissolved in THF (6 ml) and BH3Me2S (300 μl) was added and the reaction was stirred for 3 h at 60° C. and 2 h at RT. The reaction was quenched with MeOH (5 ml) and NaOH (100 mg) and stirred at RT for 1 h. The mixture was concentrated and dissolved in CH2Cl2, washed with sat'd NH4Cl/NaHCO2, dried (MgSO4), filtered and evaporated to give the compound as an oil. M+H 390.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][N:32]([C:35](=[O:37])[CH3:36])[CH2:33][CH2:34]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Reactant: CC(=O)N1CCN(CCCN)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCCNc2ccnc(Nc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C
Yield: 10 %

Procedure:
To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (0.5 g, 2.09 mmol) in THF (13 mL) is added DIPEA (0.73 mL, 4.18 mmol) followed by 1-(4-(3-aminopropyl)-piperazin-1-yl)ethanone, 22, (0.77 g, 4.18 mmol). The resulting mixture is refluxed for 12 hours after which the reaction mixture is cooled to room temperature and the solvent removed in vacuo. To the resulting residue is added water (50 mL) and the solution is washed with EtOAc (3×100 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue which is obtained is purified over silica (10% MeOH in CH2Cl2) to afford 0.173 g (10% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz) δ1.67-1.75 (m, 2H), 1.97 (s, 3H), 2.27-2.40 (m, 6H), 3.37-3.42 (m, 6H), 5.96 (d, J=6.0 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.28 (bs, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.80 (bs, 1H), 8.13 (bs, 1H), 9.19 (s, 1H). MS (ESI, pos. ion) m/z: 389 (M+1). HRMS calcd for C19H25ClN6O, 389.1857 m/z (M+H)+; observed 389.1851 m/z.
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6]C1CCCCO1)[CH:2]=[CH2:3].C([Li])(CC)C.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1COCC1>[CH2:1]([C:4]1[C:5]([OH:6])=[C:13]([B:26]([OH:27])[OH:25])[CH:14]=[CH:15][CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1OC1CCCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C=CCc1cccc(B(O)O)c1O
Reaction time: 0.17 h
Yield: 21 %

Procedure:
2-(2-allylphenoxy)tetrahydropyran (3.5 g, 16.03 mmol) was dissolved in dry THF (120 ml) and the solution cooled to −78° C. sec-Butyl lithium (1.3M in hexanes, 14.7 ml, 19.11 mmol) was added dropwise with stirring over 10 minutes, the reaction was stirred at −78° C. for 2 hours. Triisopropoxy borane (6.7 ml, 28.77 mmol) was added and stirring continued for 4 hours at −78° C. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with ether (2×200 ml). The combined extracts were dried with magnesium sulphate and concentrated under vacuum. The oily solid produced was triturated with cyclohexane and the solid filtered off to give the title compound (600 mg, 21%); MS 177 (M-H)−; HPLC retention time (system 1) 3.09 minutes.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)CO)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:14][CH2:15][C@H:16]([NH:34][C:35](=[O:38])[CH2:36]Cl)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C=O)C>C(OCC)(=O)C>[CH2:7]([O:14][CH2:15][C@H:16]([NH:34][C:35](=[O:38])[CH2:36][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(CCl)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nccn1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
2-Methylimidazole (64 mg, 0.786 mmol) was added to a flask charged with (S)-3-(benzyloxy)-2-(2-chloroacetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (150 mg, 0.393 mmol), prepared as in Example 15, and DMF (3 mL). The mixture was stirred at 40° C. for 30 minutes then diluted with ethyl acetate (20 mL). The dilution was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to provide Compound 160, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methyl-1H-imidazol-1-yl)acetamido)propanamide (100.8 mg, 0.201 mmol, 51% yield) as an off-white solid. 1H-NMR (400 MHz, CDCl3): 8.38 (s, 1H), 7.38-7.21 (m, 7H), 7.05-6.89 (m, 7H), 6.45 (d, 1H), 4.66 (d, 1H), 4.61 (s, 2H), 4.55 (d, 1H), 3.91 (dd, 1H), 3.55 (t, 1H), 2.38 (s, 3H). MS (EI) for C28H27FN4O4. found 502.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)c1

Procedure:
Carboxylic acid (149) (50 mg, 0.21 mmol) was coupled to aniline (60) (41 mg, 0.21 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:8]([C:3]2[CH:4]=[N:5][N:6]([CH3:7])[C:2]=2[Cl:1])=[O:9])=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Cn1ncc(C(=O)Cl)c1Cl
Solvent: ClCCl
Product: Cn1ncc(C(=O)Nc2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 0 °C

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carbonyl chloride (1.0 g, 5.6 mmol) was dissolved in CH2Cl2 (100 mL) under N2 and cooled to 0° C. 4-t-Butylaniline was added and the reaction was stirred with gradual warming to RT overnight. The reaction was quenched with saturated NaHCO3(aq) and extracted 3× with fresh CH2Cl2. The CH2Cl2 extracts were washed with brine, combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure giving 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide as a foamy pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]([OH:18])=O)[C:11](=[O:19])[CH:10]=[N:9]2)=[CH:4][C:3]=1[C:20](=[O:31])[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30].Cl.CN.C[CH2:36][N:37]=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16](=[O:18])[NH:37][CH3:36])[C:11](=[O:19])[CH:10]=[N:9]2)=[CH:4][C:3]=1[C:20]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[O:31]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCCc3ccccc3Cl)c2)c1=O
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCCc3ccccc3Cl)c2)c1=O
Reaction time: 5 h
Yield: 27.3 %

Procedure:
A slurry of (2-{4-Chloro-3-[2-(2-chloro-phenyl)-ethylcarbamoyl]-phenyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-acetic acid (71.4 mg, 0.154 mmol), methylamine HCl (15.6 mg, 0.231 mmol), EDCI (44.4 mg, 0.231 mmol), and DMAP (75.5 mg, 0.616 mmol) in DMF (1.0 mL) were stirred at ambient temperature for 20 hours. The reaction was diluted with 1N HCl, and let stir for 5 hours. The crude was filtered and triterated from hexane to give the title compound (20 mg). LCMS (m/z) 476.1 M+1.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[C:17](=[O:18])[CH:16]=[CH:15][C:13](=[O:14])[C:10]=3[C:11](=[O:12])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH2:19]=[CH:20][C:21]([Cl:23])=[CH2:22]>C(O)(=O)C.CCOCC>[Cl:23][C:21]1[CH2:22][CH:16]2[CH:15]([C:13](=[O:14])[C:10]3[C:11](=[O:12])[C:4]4[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=4[C:7](=[O:8])[C:9]=3[C:17]2=[O:18])[CH2:19][CH:20]=1
Reactant: O=c1ccc(=O)c2c(=O)c3ccccc3c(=O)c1=2
Reactant: C=CC(=C)Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1C2=C(C(=O)c3ccccc31)C(=O)C1CC(Cl)=CCC1C2=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 72 %

Procedure:
Quinizarinquinone (I) (1.0 g, 4.2 mmol) and chloroprene (1.12 g, 12.6 mmol) were dissolved in acetic acid (6 ml, glacial) and stirred at ambient temperature under nitrogen for 2.5 days. The reaction mixture was then diluted with ether (25 ml), the reaction mixture filtered, the retained precipitate washed with ether and dried under reduced pressure in the presence of phosphorus pentoxide to yield 9-chloro-6a,7,10,10atetrahydro-5,6,11,12-naphthacenetetraone (II) (988 mg, 72%). Recrystalization (chloroform-ether) gave the foregoing compound in analytical purity m.p. 221°-222° C.,
Reaction SMILES: CC[O:3]C(C[NH3+])=O.[Cl-].C([O-])(=O)C.[Na+].[OH:14][C:15]1[N:20]=[CH:19][NH:18][C:17]2=[C:21]([C@@H:24]3[NH:31][C@H:28]([CH2:29]O)[C@@H:26]([OH:27])[CH2:25]3)[CH:22]=[N:23][C:16]=12>CO>[OH:14][C:15]1[N:20]=[CH:19][NH:18][C:17]2=[C:21]([C@@H:24]3[NH:31][C@H:28]([CH3:29])[C@@H:26]([OH:27])[C@H:25]3[OH:3])[CH:22]=[N:23][C:16]=12
Reactant: OC[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)C[C@@H]1O
Reactant: CCOC(=O)C[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Glycine hydrochloride ethyl ester (0.76 g) and sodium acetate (0.9 g) were added to a stirred solution of the product from Example 1.3 (0.51 g) in methanol (10 ml). The mixture was stirred at room temperature for 16 h and then concentrated to dryness. Chromatography of the residue gave the (1S)-N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1-C-[1-cyano-2-(ethoxycarbonylmethylamino)ethenyl]-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol (4) (0.48) g as a diastereomeric mixture.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].O=S(Cl)Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>>[C:13]1([NH:12][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)=CC(=O)O
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)=CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A mixture of 3-methyl-but-2-enoic acid (100 g, 1 mol) and SOCl2 (119 g, 1 mol) was heated at reflux for 3 h. The excess SOCl2 was removed under reduced pressure. CH2Cl2 (200 mL) was added followed by the addition of aniline (93 g, 1.0 mol) in Et3N (101 g, 1 mol) at 0° C. The mixture was stirred at room temperature for 1 h and quenched with HCl (5%, 150 mL). The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with water (2×100 mL) and brine (100 mL), dried over Na2S O4 and concentrated to give 3-methyl-but-2-enoic acid phenylamide (120 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25]Br)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25][NH:12][CH2:11][CH2:10][CH2:9][CH:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: CCOC(=O)CCBr
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCNCCCC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
26.1 g (0.1 mol) of 4,4-di(p-fluorophenyl)butylamine and 18.1 g of 3-bromopropionic acid ethyl ester are refluxed with 21.0 g of potassium carbonate in 200 ml of 2-butanone for 24 hours while stirring. The reaction mixture is filtered and the filtrate is concentrated by evaporation under reduced pressure, yielding crude 3-[4,4-di(p-fluorophenyl)-butylamino]-propionic acid ethyl ester in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH:31][C:19]([C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[CH:12][N:11]=2)=[O:21])[O:27][N:26]=1
Reactant: O=C(O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid (example T) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 454.0901 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].O[NH:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[NH:9].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][CH2:2][C:3]1[O:4][N:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[N:7]=1
Reactant: O=C(Cl)CCl
Reactant: N=C(NO)c1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCc1nc(-c2nccs2)no1
Temperature: 100 °C
Yield: 25.6 %

Procedure:
Chloroacetyl Chloride (5.0 mL, 44.5 mmol) was added to N-Hydroxy-thiazole-2-carboxamidine (0.50 g, 3.49 mmol) and K2CO3 (1.0 g, 7.20 mmol). The reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (0.18 g, 25%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([Mg]Br)([CH3:13])=[CH2:12].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:11]([CH3:13])=[CH:12]2
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cccc(Br)c2[nH]1
Temperature: -55 °C
Reaction time: 1 h

Procedure:
27.0 g of 2-bromonitrobenzene are placed in 400 ml of THF. The medium is placed under nitrogen and is cooled to −55° C. and then 800 ml of 0.5M isopropenylmagnesium bromide in THF are added dropwise. The medium is left stirring for 1 hour and then it is poured into a saturated NH4Cl solution. Extraction is carried out with ether, the extract is evaporated and then the residue is taken up in DCM. Washing is carried out with a saturated NaCl solution. The organic layer is dried and evaporated and then the residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (1/9, v/v) mixture. 10.7 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17](O)=[O:18])=[C:12]([CH2:15][OH:16])[CH2:13][S:14][C@H:9]12)=[O:6].Cl>CC(C)=O.O>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[CH:9]2[S:14][CH2:13][C:12]3[CH2:15][O:16][C:17](=[O:18])[C:11]=3[N:10]2[C:20]1=[O:21])=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C3=C(COC3=O)CSC12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
A solution of 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5 ml) was adjusted to pH 2 with 6 N hydrochloric acid and stirred for 4 hours at ambient temperature. After the acetone was distilled off, to the residue was added water (1 ml). The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and ice-cooled for 1 hour. Precipitating crystals were collected by filtration, washed with water and dried to give 6-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazine-1,7(4H)-dione (syn isomer) (0.23 g), mp 210° to 215° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccccc1C(=O)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (200 mg, 0.76 mmol) was dissolved in dichloromethane (5 mL) at -78° C. and treated with 4-methylmorpholine (0.17 mL, 1.55 mmol, 2 eq.) and 2-methoxy-benzoyl chloride (0.11 mL, 0.74 mmol). The solution was allowed to warm to 0° C. and stir for 1 hour. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 3% methanol in dichloromethane to give 268 mg (90%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[NH:13][CH:12]=2)=[C:6]([O:23][CH3:24])[CH:5]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]([C:34](=[O:35])[NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)[CH:12]=2)=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C(=O)Nc3ccc(F)cc3)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a stirred solution of 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.30 grams, 3.82 mmol) and 4-dimethylaminopyridine (0.58 mL, 4.77 mmol) in methylene chloride (60 mL) was added 4-fluorophenylisocyanate (0.70 mL, 5.73 mmol). The resulting solution was stirred for 18 hours, at room temperature, and then diluted with methylene chloride. The solution was washed with 1 M hydrochloric acid, water and brine, then dried over magnesium sulfate. Concentration in vacuo followed by trituration in diethylether gave 4-[1-(4-fluoro-phenylcarbamoyl)-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.60 grams, 88% yield).