Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:42])([CH2:9][CH2:10][CH2:11]/[C:12](=[N:19]\[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:24][CH:23]=1)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7]C)=[O:6].CO.Cl>O1CCCC1>[CH3:3][C:4]([CH3:42])([CH2:9][CH2:10][CH2:11]/[C:12](=[N:19]\[O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:26][CH:27]=1)/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C)(C)CCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCC(C)(C)C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A 4N aqueous solution of potassium hydroxide (5 ml) was added to a solution of methyl E-2,2-dimethyl-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (340 mg) in tetrahydrofuran (5 ml)-methanol (5 ml), which was heated to reflux for 2 hours and cooled to room temperature. Dilute hydrochloric acid was added to the reaction mixture to neutralize and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain E-2,2-dimethyl-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoic acid (275 mg, yield 83%) as colorless crystals. m.p. 111-112° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:2].Cl[CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N)cc1
Reactant: ClCCNCc1ccccc1
Product: CCOc1ccc(NCCNCc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 29, react 4-ethoxybenzenamine with N-(2-chloroethyl)benzenemethanamine to obtain the title compound.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[C:34](C4C=CC(OC)=C(OC)C=4)=[CH:33][CH:32]=[C:31]([C:45]([N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:46])[CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:52]([C:55]1[CH:60]=[CH:59][C:58](B(O)O)=[CH:57][CH:56]=1)([O-:54])=[O:53]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[C:34]([C:58]4[CH:59]=[CH:60][C:55]([N+:52]([O-:54])=[O:53])=[CH:56][CH:57]=4)=[CH:33][CH:32]=[C:31]([C:45]([N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:46])[CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccc(C(=O)N3CCCC3)cc2-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1OC
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc([N+](=O)[O-])cc4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound (5.2 mg yield) was prepared as described for Compound 419 using 4-nitrophenylboronic acid in place of 3,4-dimethoxyphenylboronic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.Cl.[CH3:12][NH:13][O:14][CH3:15].C([Mg]Cl)(C)C.O>C1COCC1>[CH3:15][O:14][N:13]([CH3:12])[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:9]
Reactant: COC(=O)C1CCOCC1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1CCOCC1
Yield: 57.7 %

Procedure:
Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), and N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) added thereto, then the mixture was stirred. Under an argon atmosphere, THF solution of isopropyl magnesium chloride (2.0 mol/L; 15.0 mL, 30.0 mmol) was added dropwise to the reaction mixture at −30° C., and the mixture was stirred at −5° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by distillation under reduced pressure to give N-methoxy-N-methyltetrahydropyran-4-carboxamide (1.00 g, 58%). Boiling point: 125-129° C./8.0 hPa, 1H NMR (CDCl3, δ ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J=2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J=2.4, 11.9, 11.9 Hz, 2H). Step 2: 2-(Benzoimidazol-2-yl)-4-(2-furyl)thiazole (167 mg, 0.625 mmol) obtained in Reference Example 562 was dissolved in THF (5 mL). To the solution was added n-hexane solution of n-butyl lithium (1.58 mol/L; 1.01 mL, 1.56 mmol) at −78° C. under an argon atmosphere, and the mixture was stirred at −78° C. for 10 minutes. The THF solution (1 mL) of N-methoxy-N-methyltetrahydropyran-4-carboxamide (270 mg, 1.56 mmol) obtained in Step 1 was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give a title compound (191 mg, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.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>O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)cc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(CC(=O)Nc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-N-methylglycine (10 g), 4-chloroaniline (8.8 g), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 25.7 g) and methylene chloride (150 ml) is added dropwise triethylamine (5.9 g) while the temperature of the mixture is kept at 0-5° C. After addition, the mixture is stirred at room temperature for 8 hours, and thereto is added water. The methylene chloride layer is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from diethyl ether to give 2-[N'-(tert-butoxycarbonyl)-N'-methylamino]-N-(4-chlorophenyl)acetamide, m.p. 126-128° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][Zn]C>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:38])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: C[Zn]C
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Product: Cc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (300 mg, 0.529 mmol) and dimethylzinc (529 μl, 1.058 mmol) at 80° C. for 3 hours, the title compound was obtained as a solid (60 mg, 31% yield). MS (ESI): 547.1 [M+H]+
Reaction SMILES: [CH2:1]([NH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:13]=[C:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]1=O)C>>[CH2:1]([N:8]1[C:15]2[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:14]=2[CH:13]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: NNCc1ccccc1
Product: O=C1CCCc2c1cnn2Cc1ccccc1

Procedure:
Prepared analogously to Example 1 starting from benzylhydrazine and 2-(dimethylaminomethylene)-cyclohexane-1,3-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.CCCCCCC.[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2=O)=[CH:20][CH:19]=1.Cl>C1COCC1>[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21](=[CH:20][CH:19]=1)[CH2:22][CH:23]=[C:24]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: Brc1cccc(I)c1
Agent: Cl
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(c1cccc(Br)c1)=CC2
Reaction time: 24 h

Procedure:
To a solution of 1-bromo-3-iodobenzene (339 mmol) in 600 ml of anhydrous THF at −40° C. is added dropwise a 1 M n-dibutylmagnesium solution in heptane (185 mmol). 6-Methoxyindanone (154 mmol) is then added by small portions at −40° C. Stirring continues for 24 hours as the mixture returns to room temperature. After hydrolysis with 300 ml of 1 N HCl, the aqueous phase is extracted 2 times with ethyl acetate. The organic phases are combined, dried on sodium sulfate, concentrated and given form in isopropyl ether to obtain the expected product.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4](N2CCCC2)[CH2:3][CH2:2]1.[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.[O:21]1CCOCC1>>[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][CH:5]1[C:4](=[O:21])[CH2:3][CH2:2][S:1][CH2:6]1
Reactant: C1=C(N2CCCC2)CCSC1
Reactant: C1COCCO1
Reactant: BrCc1ccccc1Br
Product: O=C1CCSCC1Cc1ccccc1Br
Yield: 15 %

Procedure:
In a manner similar to that described in Example 82, 1-(3,6-dihydro-2H-thiopyran-4-yl)-pyrrolidine (25.0 g, 0.15 mole) or as is in dioxane (100 ml) was treated with 2-bromobenzyl bromide (40.0 g, 0.16 mol) to give the title compound as a clear oil (16.3 g, 15%).
Reaction SMILES: [CH2:1]([C:3]1[O:8][C:7](=[O:9])[CH:6]=[C:5]([OH:10])[CH:4]=1)[CH3:2].[C:11](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>>[CH2:1]([C:3]1[O:8][C:7](=[O:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(O)cc(=O)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: CCc1cc(OC)cc(=O)o1
Temperature: 25 °C
Yield: 64 %

Procedure:
The following is based on the procedure disclosed in Deshpande, V. H. et al. Indian Journal of Chemistry, 35, pp. 790-793 (1996). Compound V (57.65 g, 411 mmol) was placed in an oven dried 2000 mL three-neck flask and dissolved in dry acetone (1500 ml). To this solution was added potassium carbonate (74 g, 540 mmoles) and dimethylsulfate (51 ml, 540 mmoles). The flask was equipped with a water condenser and mechanical stirrer. The mixture was heated to reflux for 3.5 hours. Analysis by LCMS showed reaction to be complete. Therefore the reaction was cooled to room temperature and the solids removed by filtration. The solvent of the filtrate was removed by rotary evaporation. The yellow oily residue left behind was purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate in hexanes. The appropriate fractions were collected and concentrated by rotary evaporation to yield compound W (40.55 g, 61%) as a yellow solid. 1H NMR CDCl3 δ: 5.78 (s, 1H), 5.42 (s, 1H), 3.80 (s, 3H), 2.51 (q, 2H, J=8.0 Hz), 1.22 (t, 3H, J=8.0 Hz). ESMS m/z: 155 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([NH:23][C:22]3[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:28])=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Reactant: Nc1c(Cl)cccc1Cl
Product: O=C(Nc1c(Cl)cccc1Cl)C1c2ccccc2COc2ccc(Br)cc21
Yield: 18.4 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.67 g of 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 46 (Compound H) in place of Compound A and 0.76 g of 2,6-dichloroaniline in place of aniline to obtain 0.40 g of Compound 39.
Reaction SMILES: Br[C:2]1[CH:23]=[N:22][C:5]2[NH:6][C:7](=[O:21])[CH2:8][N:9]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])[CH2:10][C:4]=2[CH:3]=1.[C:24]([O:28]C(C)(C)C)(=[O:27])[CH:25]=[CH2:26].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(Cl)[Cl:65]>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[ClH:65].[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:9]2[CH2:10][C:4]3[CH:3]=[C:2](/[CH:26]=[CH:25]/[C:24]([OH:28])=[O:27])[CH:23]=[N:22][C:5]=3[NH:6][C:7](=[O:21])[CH2:8]2)[CH2:15][CH2:16]1
Reactant: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(Br)cc3C2)CC1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: ClCCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(/C=C/C(=O)O)cc3C2)CC1
Product: Cl
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A suspension of 7-Bromo-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (1.39 g, 3.64 mmol) in propionitrile (32 mL) and DMF (8 mL) was de-oxygenated with Ar for 15 min. The mixture was treated with tert-butyl acrylate (2.1 mL, 14 mmol) and (i-Pr)2EtN (1.3 mL, 7.4 mmol) and then was de-oxygenated with Ar for 10 min. Pd(OAc)2 (83 mg, 0.37 mmol) and P(o-tol)3 (0.22 g, 0.73 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 10 min. The mixture was heated to reflux overnight, then allowed to cool. The resulting precipitate was isolated by filtration and dissolved in CH2Cl2. The solution was filtered through Celite and the solvent was removed in vacuo to give the title compound (1.13 g, 72%) as an off-white solid: MS (ESI) m/e 430 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([CH:16]=[O:17])=[C:4]([N:18](CC2C=CC(OC)=CC=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.C1(CO)CCCCC1.C(#N)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([CH:16]=[O:17])=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(N)nc(OCC3CCCCC3)c2C=O)cc1
Agent: OCC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(CNc2nc(N)nc(OCC3CCCCC3)c2C=O)cc1

Procedure:
The mixture of 2-Amino-4-cyclohexylmethoxy-6-di(4-methoxybenzyl)amino-5-pyrimidine carbaldehyde and cyclohexylmethanol obtained previously was stirred in trifluoroacetic acid (2 ml) for 18 h. Excess trifluoroacetic acid was removed, and the residue extracted with ethyl acetate and water (50 ml each) Further ethyl acetate was added to the aqueous layer, and the organic components combined, dried and evaporated. The residual brown oil was applied to a silica column, eluting with 20% EtOAc/petrol (40:60). A pale yellow oil was obtained. Addition and removal of acetonitrile gave a solid which was recrystallised from a petrol/ethyl acetate mixture (0.091 g; 0.34 mmol) M.p. 97° C.
Reaction SMILES: ClCCl.[NH2:4][C@@H:5]1[C:23](=[O:24])[N:7]2[C:8]([C:20]([OH:22])=[O:21])=[C:9]([CH2:12][O:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])[CH2:10][S:11][C@H:6]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:37][C:38]1[S:42][N:41]=[C:40](/[C:43](=[N:47]/[O:48][CH2:49][CH3:50])/[C:44](Cl)=[O:45])[N:39]=1>CC(N(C)C)=O>[NH2:37][C:38]1[S:42][N:41]=[C:40](/[C:43](=[N:47]/[O:48][CH2:49][CH3:50])/[C:44]([NH:4][C@@H:5]2[C:23](=[O:24])[N:7]3[C:8]([C:20]([OH:22])=[O:21])=[C:9]([CH2:12][O:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])[CH2:10][S:11][C@H:6]23)=[O:45])[N:39]=1
Reactant: CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
In 200 ml off dichloromethane is suspended 11 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To the suspension is added 14 g of bistrimethylsilylacetamide and the mixture is stirred at room temperature until complete dissolution and cooled in an ice-water bath. To this solution, 14 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetyl chloride is added and the mixture is stirred for a while, to which 6 g of dimethylacetamide is added. The whole mixture is stirred with ice-cooling for 60 minutes. The dichloromethane is evaporated off and the residue is dissolved in methyl ethyl ketone. The solution is washed with water and dried. The solvent is then evaporated off and diethyl ether is added to the residue to give a fine precipitate, which is collected by filtration, giving 12.5 g of the above-identified compound.
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.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1)#[N:20].[NH2:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:43][OH:44]>>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][C@@H:37]2[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]2[CH2:43][OH:44])=[O:18])=[O:7])=[CH:31][CH:32]=1)#[N:20]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@@H]1CCCC[C@H]1CO
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)N[C@@H]2CCCC[C@H]2CO)N(C(=O)c2ccc(-c3ccccc3C#N)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=475.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=3)(=[O:33])=[O:32])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1N
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1NS(=O)(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 129.7 %

Procedure:
4-(1-Benzyl-pyrrolidin-3-yl)-2-methoxy-phenylamine (220 mg, 0.78 mmol) and 4-isopropylphenylsulfonyl chloride (170 mg, 0.78 mmol) were dissolved in tetrahydrofuran (20 ml). Triethylamine (0.32 ml, 2.34 mmol) was added and the reaction mixture stirred over night at room temperature (10% conversion) and subsequently refluxed for 4 h (70% conversion). One small portion of 4-isopropylphenylsulfonyl chloride and triethylamine were added and the reaction mixture was stirred 15 min at 150° C. in the microwave (CEM). The solvent was evaporated under reduced pressure, the residue treated with ethyl acetate (50 ml) and extracted twice with slightly acidic water. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give an oil (470 mg). The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-100%). Fractions containing the product were combined the solvent evaporated to yield an oil (143 mg, 40%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([OH:15])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.Cl.Cl.[C:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.O1CCCC1>[C:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([C:13]([CH:5]2[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2](=[O:1])[CH2:3][CH2:4]2)=[O:15])[CH2:36][CH2:35]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(O)[C@@H]1CCC(=O)N1c1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To an ice-cold stirred solution of 5-oxo-1-phenylproline (Reference Example 12, 0.22 g, 1.08 mmol) and N,N-dimethylformamide (3 drops) in tetrahydrofuran (10 mL) was added oxalyl chloride (0.14 g, 1.10 mmol). The mixture was stirred at 0° C. for 30 min, and then allowed to warm to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in pyridine (10 mL). To this mixture was added 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.30 g, 1.03 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% NaHCO3 solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to give an orange solid. This solid was recrystallized from hexane-ethyl acetate to give the title compound (0.26 g, 59%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](O)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1.CN(C)C=O.[C:28](=[N:31]O)([NH2:30])[CH3:29]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][N:31]=[C:28]([CH3:29])[N:30]=4)=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CC(N)=NO
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(F)ccc1-2
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2cc(F)ccc2-3)n1
Reaction time: 1.5 h

Procedure:
8.60 g (28.5 mmol) of (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid, 30 ml of N,N-dimethylformamide and 6.16 g (38 mmol) of N,N'-carbonyldiimidazole are stirred at room temperature for 45 minutes and at 55° for 1 hour. 2.44 g (33 mmol) of acetamidoxime are subsequently added and the mixture is stirred at 75° for a further 1.5 hours. The mixture is poured into 200 ml of water, stirred for 20 minutes, suction filtered and the filter residue is dried. 8.60 g of the thus-obtained product are stirred at 115° for 2.5 hours in 50 ml of glacial acetic acid. The solution is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization of the residue from ethyl acetate there is obtained (S)-7-fluoro-11,12,13,13a-tetrahydro-1-(3-methyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 248°-249°.