Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](=[O:22])[NH:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCC[C@@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 3-[(2S)-2-methylpiperidin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (98 mg, 0.33 mmol) in dichloromethane (30 mL) was added pyridine (104 mg, 1.31 mmol), and then Tf2O (186 mg, 0.66 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice-water (20 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (200 mg, crude).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH2:19])[CH2:6][CH2:7][C:8](=[O:18])[NH:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11]O)[CH3:2].S(Cl)([Cl:23])=O>ClCCl>[Cl-:23].[Cl:23][CH2:11][CH:10]([NH:9][C:8]([CH2:7][CH2:6][CH:5]([NH3+:19])[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(N)CCC(=O)NC(CO)C(=O)OCC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C([NH3+])CCC(=O)NC(CCl)C(=O)OCC
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of alcohol (5) (0.29 g, 1 mmol) in dichloromethane (10 ml) was treated with thionyl chloride (1 g) and stirred at room temperature under nitrogen overnight. The solvent was removed on a rotary evaporator (bath temperature below 28° C.). Dichloromethane (10 ml) was added and stripped under the same conditions twice. The solid residue was taken in water (8 ml) and washed with MTBE (2×15 ml). The resulting aqueous solution contains pure (6) (LCMS) and was used as such in the next step.
Reaction SMILES: [Li+].CCC[CH2-].[CH3:6][C:7](=[N:9][OH:10])[CH3:8].CO[C:13](=[O:32])[C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20](=[O:30])[C:21]2C(C)=CC(C)=CC=2C)[CH2:16][N:15]1[CH3:31].[OH-:33].[Na+]>C1COCC1.O>[C:20]([OH:19])(=[O:30])[C:21]([OH:10])=[O:33].[CH3:8][C:7]1[CH:6]=[C:13]([C@H:14]2[CH2:18][C@H:17]([OH:19])[CH2:16][N:15]2[CH3:31])[O:32][N:9]=1
Reactant: CC(C)=NO
Reactant: [OH-]
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)c2c(C)cc(C)cc2C)CN1C
Agent: [CH2-]CCC
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([C@H]2C[C@H](O)CN2C)on1
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
N-butyllithium (1.70 mL, 2.5 M, 4.26 mmol) was added dropwise at 0° C. to a solution of acetone oxime (155.5 mg, 2.13 mmol)in anhydrous THF (10.0 mL). The resulting solution was stirred at the same temperature for two hours. trans-1-Methyl-4-(2,4,6-trimethylbenzoyloxy) proline methyl ester (21c, 500.0 mg, 1.64 mmol)in anhydrous THF (5.0 mL) was slowly added to the solution through syringe. The resulting mixture was further stirred at 0 ° C for eight hours and slowly warmed to room temperature overnight. THF was then evaporated in vacuo. A THF-sulfuric acid solution (10.0 mL, prepared in a ratio of sulfuric acid: THF: H2O=8.2 g: 40 mL: 10 mL) was added and the mixture was refluxed for two hours. The mixture was made basic with 10% NaOH and extracted with ethyl acetate (30 mL 4X). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1:1 and 2:1) to give 112.5 mg (21% yield) of the title compound (21 d) as an oil. TLC Rf =0.63 (ethyl acetate:hexane=2:l ). MS (DCl/NH3) m/e 329 (M+H)+. 1H NMR (CDCl3) δ: 6.86 (s, 2H, 2ArH), 6.03 (s, 1 H, isoxazole H), 5.48-5.54 (m, 1 H, OCH), 3.76 (dd, J =9.6, J=6.3 Hz, 1H, ArCHN), 2.38-2.61 (m, 4H, 2CH2), 2.44 (s, 3H, NCH3), 2.31 (s, 6H, 2ARCH3), 2.30 (s, isoxazole-CH3), 2.29 (s, 3H, ARCH3).
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH3:8][NH:9][O:10][CH3:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:11][O:10][N:9]([CH3:8])[C:1](=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of butanoic acid (1.01 g, 0.0115 mol) and N,O-dimethylhydroxylamine hydro-chloride (1.12 g, 0.0115 mol) in DCM (50 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (5.6 g, 0.013 mol) and TEA (3.2 mL, 0.023 mol). The mixture was stirred overnight at room temperature. The solution was then washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash column chromatography (ether/hexanes). The solvent was removed (235 mbar/40° C.) to afford the product (1.33 g, 88%). 1H NMR (300 MHz, CDCl3): δ 3.68 (s, 3H), 3.18 (s, 3H), 2.40 (t, 2H), 1.74-1.59 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:28]=[C:29]=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl.C(OCC)C>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:29]([NH:28][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:30])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CC(c3csc(C4CCNCC4)n3)=NO2)cc1
Reactant: CCCCCN=C=O
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCNC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1

Procedure:
A solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperidine (i.e. the product of Example 1, Step B) (0.10 g, 0.32 mmol) and pentyl isocyanate (0.036 g, 0.32 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight, then filtered and concentrated under reduced pressure to provide a white solid. The solid was slurried in diethyl ether, filtered and air-dried to provide the title compound, a compound of the present invention, as a white powder (0.081 g), melting at 132-134° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]=[C:20]1[C:25](C(O)=O)=[CH:24][CH:23]=[C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:21]1.[CH2:34]([N:36]1[C:48]2[CH:47]=[CH:46][C:45]([NH2:49])=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35]>>[CH2:34]([N:36]1[C:48]2[CH:47]=[CH:46][C:45]([NH:49][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6]([C:25]3[C:20](=[O:19])[O:21][C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:24]=3)=[O:7])=[O:18])=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCCCCc1ccc(C(=O)O)c(=O)o1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCCCCc1ccc(C(=O)N2CC(=NOC)C[C@H]2C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)c(=O)o1

Procedure:
Following the general method as outlined in Example 2, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained after column chromatography as an off-white solid as a mixture of E/Z-isomers. The isomers were separated by column chromatography.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=1)[CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]

Procedure:
The preparation of begins with the known methyl 3-(bromomethyl)benzoate. This halide is heated in xylene solution with triphenylphosphine to yield (3-methoxycarbonylbenzyl)triphenylphosphonium bromide. The phosphonium salt is converted to the ylide with sodium ethoxide and the ylide caused to react with acetaldehyde to yield ethyl 3-(1-propenyl)benzoate. (Note that the ethyl ester has been obtained as a result of transesterification with solvent ethanol.) The ester is heated with N-bromosuccinimide in carbon tetrachloride for an extended period to yield ethyl 3-(3-bromo-1-propenyl)benzoate. This compound is treated with the anion derived from methyl methylthiomethyl sulfoxide as described in section (b) above. The resulting dimethylmercaptal S-oxide is hydrolyzed with acid catalysis to ethyl 3-(4-oxo-1-butenyl)benzoate. Hydrogenation of this olefinic aldehyde over a palladium catalyst affords the aldehyde intermediate XXIII.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][CH:14]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:15](OC)(OC)[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:14]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[NH:13][C:11]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)(c1ccncc1)C(NC(=O)NCCCc1ccccc1)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(-c2ccc(F)cc2)c(-c2ccncc2)n1CCCc1ccccc1
Temperature: 25 °C

Procedure:
N-(3-phenylpropyl)-N′-[(2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethyl)] urea (224 g, 0.45 mol) was mixed with 4N HCl (800 g) and heated under reflux for 4–5 h (95–100° C.). Upon completion, the reaction was cooled to room temperature and adjusted to pH 13 with 8N NaOH solution (480 g), resulting in precipitation of a solid product. The pH of the suspension was controlled to pH≧13 for 30 min, with addition of sodium hydroxide as needed. The suspension was centrifuged and the aqueous phase removed and discarded. The solid was resuspended in 2N NaOH solution (1000 g), centrifuged a second time and then re-suspended in water (2×1000 g, water phase pH 7). The solid product was dried at 45–50° C., under vacuum (for about 4–5 days), to a final water content of <2%, to yield the product as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:34][CH:35]=1)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Reactant: CC(C)(C)C(=O)Cl
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(NC(=O)C(C)(C)C)cc1
Yield: 91.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (200.0 mg, 0.42 mmol) and pivaloyl chloride (0.062 ml, 0.51 mmol), the procedure of Inventive Example 94 was repeated to obtain 214.6 mg (91.2%) of the title compound in a colorless amorphous form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Br[CH2:35][CH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([O:21][CH2:35][CH2:36][OH:37])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(OCCO)c([N+](=O)[O-])c(N2CCN(c3ccc(F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.5 %

Procedure:
0.180 g (0.540 mmol) of the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) and 0.142 g (1.1 mmol) of N-ethyldiisopropylamine, dissolved in 5.0 ml of N,N-dimethylformamide, were slowly added between −5° C. and 0° C. to a suspension of 0.923 g (7.0 mmol) of 2-bromo-ethanol and 0.897 g (6.5 mmol) of potassium carbonate in 5.0 ml of N,N-dimethylformamide. The reaction mixture was then stirred at room temperature for 48 hours. It was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 to 1:1 v/v gradient of hexane and ethylacetate as the eluent giving 0.039 g (0.10 mmol, 19.1% of theory) of the 2-{6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-pyrimidin-4-yloxy}-ethanol as a light yellow amorphous solid; MS: [M+H]+=378; and 0.091 g (0.241 mmol, 44.7% of theory) of the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-(2-hydroxy-ethyl)-2-methyl-5-nitro-3H-pyrimidin-4-one as yellowish amorphous solid; MS: [M+H]+378.
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])=[S:14])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.Br[CH2:21][C:22](=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:22]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])/[C:13](=[N:12]/[C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:11])/[S:14][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)CBr
Reactant: COCCNC(=S)NC(=O)C12CC3CC(CC1C3)C2
Product: COCCn1c(C(C)(C)C)cs/c1=N\C(=O)C12CC3CC(CC1C3)C2

Procedure:
A mixture of Example 14B (57 mg, 0.20 mmol) and 1-bromo-3,3-dimethylbutan-2-one (36 mg, 0.027 mL, 0.20 mmol, Aldrich) was processed according to the method described in Example 14C. Purification by column chromatography (SiO2, 30-45% ethyl acetate/hexanes gradient) afforded title compound. 1H NMR (dimethylsulfoxide-d6, 300 MHz) δ 1.37 (s, 9H), 1.56-1.63 (m, 4H), 1.69-1.79 (m, 4H), 2.07-2.18 (m, 2H), 2.24-2.30 (m, 2H), 2.53-2.60 (m, 1H), 3.26 (s, 3H), 3.75 (t, J=6.78 Hz, 2H), 4.40 (t, J=6.95 Hz, 2H), 6.57 (s, 1H); MS (DCI/NH3) m/z 363 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7](=[O:13])[CH2:8][NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=[CH:3]1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:9]1[CH2:8][C:7](=[O:13])[C:6]2[N:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:10]1(=[O:12])=[O:11]
Reactant: ClCCCBr
Reactant: Cn1ccc2c1C(=O)CNS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ccc2c1C(=O)CN(CCCCl)S2(=O)=O
Yield: 45.2 %

Procedure:
A suspension of 200 mg (1 mmol) of Compound 13, 189 mg (1.2 mmol) of 1-bromo-3-chloropropane and 345 mg (2.5 mmol) of potassium carbonate in 5 ml of acetone was refluxed for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate/methylene chloride=1/30), whereby 125 mg of the title compound were obtained (yield: 45%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]3[N:24]=[N:25][N:26]=[C:16]3[C:15]=2[NH2:27])[CH:2]=1.[C:28](OCC)(OCC)(OCC)[CH3:29].C(Cl)(Cl)Cl.CO>ClCCCl>[CH3:28][C:29]1[N:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]3[N:24]=[N:25][N:26]=[C:16]3[C:15]=2[N:27]=1
Reactant: Nc1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Reactant: CCOC(C)(OCC)OCC
Solvent: CO
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(c3ccccc3n3nnnc23)n1CCOCCCc1cccnc1
Yield: 98.1 %

Procedure:
Under an atmosphere of nitrogen, N5-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine (0.70 g, 1.92 mmol) was dissolved in 1,2-dichloroethane (15 ml). Triethyl orthoacetate (0.53 ml, 2.88 mmol) was added via syringe and the reaction was heated to reflux for 3 hours. Analysis by thin layer chromatography (95/5 chloroform/methanol) showed complete consumption of the diamine. The reaction was quenched by the addition of water (15 ml). The phases were separated and the aqueous fraction was extracted with dichioromethane (3×10 ml). The combined organic fractions were washed with brine (15 ml), dried (Na2SO4), filtered and concentrated in vacuo to yield 0.73 g of 5-methyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a red oil. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]3([CH2:15][CH2:14][CH2:13]3)[S:11](=[O:27])(=[O:26])[CH2:10]2)[C:5]([F:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:39](Br)[CH:40]=[CH2:41]>C1COCC1>[CH2:41]([C@@H:10]1[C@:9]([C:4]2[C:5]([F:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)([CH3:28])[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[C:12]2([CH2:13][CH2:14][CH2:15]2)[S:11]1(=[O:27])=[O:26])[CH:40]=[CH2:39]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)CS(=O)(=O)C12CCC2
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C2(CCC2)S1(=O)=O
Reaction time: 0.67 h
Yield: 37.2 %

Procedure:
A solution of (R)-tert-butyl (7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (5.0 g, 10.50 mmol) in THF (100 mL) was brought to −78° C. followed by the dropwise addition of potassium bis(trimethylsilyl)amide, 1 m in tetrahydrofuran (63.0 ml, 63.0 mmol). The resulting mixture was stirred at this temperature for 40 min then neat allyl bromide (2.72 ml, 31.5 mmol) was added dropwise. The mixture was kept at this temperature for 40 min. Then, it was quenched with saturated NH4Cl at −78° C. and brought to rt, and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-25% Et2O/heptane to afford a white solid as tert-butyl ((6R,7R)-6-allyl-7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (2.02 g, 3.91 mmol, 37.3% yield). LC/MS (ESI+) m/z=537.8 (M+H) and tert-butyl ((6S,7R)-6-allyl-7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (1.06 g, 2.053 mmol, 19.56% yield). LC/MS (ESI) m/z=537.8 (M+H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene at 23° C. was treated sequentially with 50% sodium hydroxide (1.3 g) and benzoyl chloride (0.728 g). The mixture was stirred overnight. The solids were removed by filtration and washed with water to afford N'-t-butyl-N-(2-pyridinecarbonyl)-N'-benzoylh-ydrazine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:40][O:41][CH2:42][C:43]1[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH2:42][C:43]2[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCc4nc(=O)c(O)c[nH]4)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (25 mg) (0.042 mmol), 8.6 mg (0.055 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 10.5 mg (0.055 mmol) of p-toluenesulphonic acid hydrate are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the solvent is removed in a high vacuum at room temperature and the residue is treated with 3 ml of water. The precipitated product is filtered off and washed in succession with water and diethyl ether. After drying in a high vacuum there are obtained 20 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl] thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([F:30])[F:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]([F:29])[F:30])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2cc(C(F)F)ccc2OCC2CC2)OC1(C)C
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (example B.c16) the title compound is obtained as off-white solid.