Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1I)([CH3:6])[CH3:5].[CH2:37]([Sn](CCCC)(CCCC)C=C)[CH2:38]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:36])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH:37]=[CH2:38])([CH3:6])[CH3:5]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OC
Temperature: 80 °C
Yield: 71.7 %

Procedure:
2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-iodo-phenoxy)-2-methyl-propionic acid methyl ester (0.264 g, 0.435 mmole) and tributyl(vinyl) tin (0.207 g, 0.652 mmole) were mixed in toluene (4.0 mL). After bubbled with nitrogen for 15 minutes, tetrakis(triphenylphosphine) palladium(0) (0.050 g, 0.043 mmole) was added. The reaction was heated at 80° C. overnight. The solvent was removed on rota-vapor, and the crude product was purified by column chromatography (silica gel, gradient elution 0-30% acetone in hexane) to provide a colorless oil (0.158 g, 71%). Mass [EI+] 507 (M+H)+.
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)=[CH:4][CH:3]=1.[O:25]=[C:26]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:29][CH2:28][N:27]1[C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][N:47]=1)[C:41]([O:43]C)=O.C(N)C1C=CC=CC=1>>[CH2:6]([NH:7][C:41](=[O:43])[C:40]1[CH:45]=[CH:46][N:47]=[C:38]([N:27]2[CH2:28][CH2:29][N:30]([CH2:31][C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[C:26]2=[O:25])[CH:39]=1)[C:5]1[CH:23]=[CH:24][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccncc3)C2=O)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(N2CCN(Cc3ccncc3)C2=O)c1
Yield: 37 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinate to react with benzylamine, N-benzyl-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 37% yield: mp 154-156° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.25 (t, J=5.9 Hz, 1H), 8.60 (s, 1H), 8.52-8.50 (m, 2H), 8.38 (d, J=5.4 Hz, 1H), 7.37-7.18 (m, 8H), 4.45-4.43 (m, 4H), 3.99 (t, J=7.9 Hz, 2H), 3.42 (t, J=7.9 Hz, 2H); MS (ES+) m/z 387.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:11].[CH:18]1C2N(C=NC=2)C(=S)NN=1>>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[S:11][CH3:18]
Reactant: S=c1[nH]ncc2cncn12
Reactant: Cc1nc(-c2ccccc2)n2c(=S)[nH]ncc12
Product: CSc1nncc2c(C)nc(-c3ccccc3)n12

Procedure:
The procedure of Example 29 is repeated substituting an equimolar amount of 8-methyl-6-phenyl-imidazo-[1,5-d]-as-triazine-4(3H)-thione for the imidazo[1,5-d]-as-triazine-4(3H)-thione employed in that example. There is thus obtained the title compound in equally good yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH:25]=[CH2:26]>CN(C)C=O>[CH2:26]([N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:15])[CH2:25][CH:24]=[CH2:23]
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCn1c(=O)c2c(ncn2CCC)n(C)c1=O

Procedure:
20.8 g of 3-methyl-7-propyl-xanthine, 13.8 g of anhydrous potassium carbonate and 13.5 g of 4-bromo-but-1-ene are refluxed for 8 hours in 150 ml of dimethylformamide, and the solvent is then removed under reduced pressure. The residue is then dissolved in 150 ml of 1 N sodium hydroxide solution and the alkaline solution is extracted with methylene chloride. The residue obtained after evaporation of the methylene chloride is triturated with 100 ml of diisopropyl ether and unreacted 3-methyl-7-propyl-xanthine is removed. 15.6 g (70% of theory relative to 3-methyl-7-propyl-xanthine consumed) of the title compound of melting point 48° C. (from n-hexane) are obtained from the filtrate.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>CC#N>[CH3:22][O:21][C:17]([C:18]1[S:19][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]=1)=[O:20]
Reactant: O=Cc1cccnc1Cl
Reactant: COC(=O)CS
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2cccnc2s1
Yield: 29 %

Procedure:
To 2-chloro-3-pyridine carboxaldehyde, compound 147-A, (5.07 g, 35.8 mmol), dissolved in MeCN (30 mL) was added triethylamine (6.5 mL, 46.5 mmol) followed by methyl thioglycolate (3.49 mL, 38.3 mmol) and the reaction was refluxed for 18 h. The reaction mixture was cooled and the solvent evaporated under reduced pressure. The crude residue was partitioned between H2O and EtOAc, the layers separated and the aqueous phase extracted with EtOAc. The organic layers were combined, washed with H2O, brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford compound 147-B as a white solid (2.01 g, 29%). 1H-NMR (DMSO-d6): δ 3.91 (s, 3H), 7.54-7.57 (m, 1H), 8.23 (s, 1H), 8.43-8.46 (m, 1H), 8.72-8.74 (m, 1H); MS: m/z 194.1 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][NH:28][CH2:29][CH3:30]>C(#N)C>[CH3:27][N:28]([CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[CH2:29][CH3:30]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCNC
Solvent: CC#N
Product: CCN(C)CC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), N-methylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 84 (2), 79 (2), 73 (5), 72 (bp).
Reaction SMILES: [CH3:1][C:2]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH:3]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.Cl>[CH3:1][C:2]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]2([CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)[CH:3]=1
Reactant: CC1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1=CC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
tert-Butyl 3-methylspiro[inden-1,4′-piperidine]-1′-carboxylate (0.155 g, 0.518 mmol) obtained in step 3 was dissolved in 4 mol/L hydrogen chloride-1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was suction-filtered to give white crystals. Saturated aqueous sodium hydrogen carbonate solution was added to the white crystals, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.097 g, 94%).
Reaction SMILES: S(OC)(OC)(=O)=O.[CH3:8][N:9]1[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=[C:10]1[CH3:18]>>[CH3:8][N:9]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]1[CH3:18]
Reactant: COC(=O)c1cnc(C)n1C
Solvent: COS(=O)(=O)OC
Product: Cc1ncc(C(=O)O)n1C
Yield: 67 %

Procedure:
In the manner described in Example 1 126 g (1 mol) of 2-methylimidazole-4(5)-carboxylic acid was treated with dimethyl sulfate and the product was converted into its methyl ester for characterization. This gave 103.3 g of methyl 1,2-dimethylimidazole-5-carboxylate, m.p. 38°-40° C., an overall yield of 67%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH:18]1([CH2:21][C:22]2[C:27]([CH2:28]O)=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=[C:24]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:23]=2)[CH2:20][CH2:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:28][C:27]2[C:22]([CH2:21][CH:18]3[CH2:20][CH2:19]3)=[N:23][C:24]([C:34]3[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:38][CH:39]=3)=[CH:25][C:26]=2[C:30]([F:31])([F:33])[F:32])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: OCc1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc2CC2CC2)cc1C

Procedure:
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with [2-cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of N,N,N′,N′-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[F:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][C:13]=1[F:19].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[CH:15]=[CH:14][C:13]=1[F:19]
Reactant: Fc1ccc(I)cc1F
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(F)c2)c1
Temperature: 60 °C
Yield: 93.8 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (110 mg, 0.15 mmol), copper (I) iodide (57 mg, 0.30 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol) to a solution of 1,2-difluoro-4-iodobenzene (0.43 mL, 3.6 mmol) in triethylamine (6.3 mL, 45.0 mmol) and heat at 60° C. for 20 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 65:35 hexanes:ethyl acetate, followed by a second silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane:ethyl acetate, to give the title compound as a white solid (690 mg, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1.C[O-].[Na+].[CH3:16][O:17][CH2:18]Cl>CN(C)C=O>[CH3:16][O:17][CH2:18][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: COCCl
Reactant: Oc1cc(-c2ccccc2)on1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
3-Hydroxy-5-phenylisoxazole (8.05 g) was dissolved in dimethylformamide (80 ml), and sodium methoxide (28% methanol solution, 3.24 g) was added dropwise thereto, followed by stirring of the resulting mixture at room temperature for one hour. While the reaction mixture was cooled to 5° C., chloromethyl methyl ether (4.83 g) was added thereto, followed by stirring of the resulting mixture at the same temperature for one hour. The reaction mixture was poured into ice-cold water (200 ml) and extracted with ether (200 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (6.30 g, 61%) as a colorless oil.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:1]([NH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][C@@H:19]1[CH:20]2[CH2:23][CH2:24][N:17]([CH2:22][CH2:21]2)[CH2:18]1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1ccccc1)C(=O)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.4 %

Procedure:
To a solution of 2-benzamido-3-methylbutanoic acid (780 mg, 3.53 mmol) in THF (25 ml), were added (R)-quinuclidin-3-ol (538 mg, 4.23 mmol), DCC (873 mg, 4.23 mmol) and HOBt (572 mg, 4.23 mmol), and the reaction was stirred at RT for 15 hours. The solvent was evaporated. EtOAc was added, and the insoluble was removed by filtration. The organic solution was washed twice with 1N Na2CO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=99/1 to 8/2) to obtain (R)-quinuclidin-3-yl 2-benzamido-3-methylbutanoate (436 mg, 37.4% yield).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=[O:27])[N:11]([C:18]1([CH3:26])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:12]2=[O:17])=[O:6])=[N+]=[N-].O.[ClH:29]>CO.[Pd]>[ClH:29].[NH2:1][CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=[O:27])[N:11]([C:18]1([CH3:26])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:12]2=[O:17])=[O:6]
Reactant: CC1(N2C(=O)c3cccc(NC(=O)CN=[N+]=[N-])c3C2=O)CCC(=O)NC1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1(N2C(=O)c3cccc(NC(=O)CN)c3C2=O)CCC(=O)NC1=O
Reaction time: 5 h
Yield: 35 %

Procedure:
A mixture of 2-azido-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-acetamide (1.4 g, 3.8 mmol) and 10% Pd/C (0.2 g) in methanol (100 mL) and 4N HCl (20 mL) was hydrogenated in Parr Shaker for 5 hours. H2O (10 mL) was added, and the mixture was filtered through celite. The filtrate was concentrated, and the residue was evaporated with ethanol (3×20 mL). The solid was slurried with hot methanol (30 mL) to give 2-amino-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-acetamide hydrochloride (0.5 g, 35%) as a yellow solid: mp 111-113° C.; 1H NMR (DMSO-d6) δ 1.90 (s, 3H, CH3), 2.04-2.09 (m, 1H), 2.50-2.72 (m, 3H), 3.97 (s, 2H, CH2), 7.64 (d, J=7.2 Hz, 1H, Ar), 7.86 (t, J=7.7 Hz, 1H, Ar), 8.32 (d, J=8.2 Hz, 1H, Ar), 8.40 (s, 3H, NH3), 10.30 (s, 1H, NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.05, 28.55, 29.10, 41.11, 58.83, 117.98, 118.92, 127.13, 131.76, 134.74, 135.99, 166.18, 167.22, 167.75, 172.04, 172.18; Anal. calcd. for C16H17N4O5Cl: C, 50.47; H, 4.50; N, 14.71; Cl, 9.31. Found: C, 50.35; H, 4.40; N, 14.54; Cl, 9.01.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH2:55]([N:62]=[C:63]=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH2:55]([NH:62][C:63]([N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1)=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)NCc2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and benzyl isocyanate as starting materials in 35% yield. LCMS for C32H34ClN8O2 (M+H)+: m/z=597.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:16]([OH:18])=O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)[CH2:3][CH2:2]1.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[F:29][C:30]1([F:34])[CH2:33][N:32]([C:16]([C:15]([NH:14][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:23]3[CH2:24][C:25]([F:28])([F:27])[CH2:26]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:13])([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:18])[CH2:31]1
Reactant: FC1(F)CNC1
Reactant: CCC(CC)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O
Product: CCC(CC)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)N1CC(F)(F)C1

Procedure:
In analogy to the procedure described in Example 293, 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-2-ethylbutanoic acid and 3,3-difluoroazetidine (CAN 679431-52-8) were condensed to the title product. MS (EI): m/e=471.4 [M−H]−.
Reaction SMILES: C[Si](Br)(C)C.C[O:7][P:8]([C:12](=[O:17])[CH2:13][CH2:14][NH:15][OH:16])(=[O:11])[O:9]C>C(#N)C>[OH:16][NH:15][CH2:14][CH2:13][C:12]([P:8](=[O:7])([OH:11])[OH:9])=[O:17]
Reactant: COP(=O)(OC)C(=O)CCNO
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=C(CCNO)P(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.2 mol trimethylsilylbromide are slowly added to a solution of 0.1 mol 3-(N-hydroxyamino)-propionylphosphonic acid dimethylester in 100 ml of absolute acetonitrile. After 3 hours of stirring at room temperature the solution is concentrated and taken up in 50 ml methanol. After stirring for 30 minutes it is concentrated again. 3-(N-hydroxyamino)-propionylphosphonic acid may be further be converted without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:19])[C:11]=1[O:12][CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([O:26]C)=[O:25])=[CH:5]2.[OH-].[Na+].Cl>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:19])[C:11]=1[O:12][CH2:13][CH:14]([CH2:15][CH3:16])[CH2:17][CH3:18])[O:8][CH:7]([C:20]([F:23])([F:21])[F:22])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2
Reactant: CCC(CC)COc1c(Cl)cc2c(c1C)OC(C(F)(F)F)C(C(=O)OC)=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)COc1c(Cl)cc2c(c1C)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
The ester from Step 3 (0.55 g, 1.35 mmole) was dissolved in 3.5 mL methanol and 3.5 mL THF. Sodium hydroxide (2.5 N) (1.6 mL, 4 mmole) was added to above solution and stirred at room temperature overnight. The reaction mixture was acidified with 1.5 N HCl. The compound was extracted with EtOAc. The organic layer was washed with water and dried over anhydrous MgSO4. The filtrate was evaporated and dried in vacuo, after recrystalization with EtOH and water to afford a yellow solid (0.31 g, 59%): ESHRMS m/z391.0884 (M−H, C18H19O4F3Cl, Calc'd 391.0918). 1H NMR (acetone-d6/400 MHz) 7.84 (s, 1H), 7.45 (s, 1H), 5.88 (q, 1H, J=7.0 Hz), 3.92 (m, 2H), 2.17 (s, 3H), 1.71 (m, 1H), 1.61 (m, 2H), 1.53 (m, 2H), 0.971 (t, 6H, J=7.2 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:4]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:5]2[CH:6]=[N:7][C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])=[N:4]2)=[O:30])[N:17]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cnc(CN)n1)c1csc(N)n1)C(=O)O
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cnc(CNC(=N)N)n1)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
To a solution 2-(((Z)-(2-(((2R,3S)-2-((3-(aminomethyl)-1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (25 mg, 0.047 mmol) and pyrazole-1-carboxamidine hydrochloride (10.9 mg, 0.099 mmol) in DMF (470 μL) was added DIPEA (33 μL, 0.188 mmol). After stirring at rt for 12 h the solution was concentrated in vacuo. Toluene was added and it was reconcentrated (3×). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (16 mg, 52%) as a white powder. LCMS: Rt=0.31 min, m/z=574.3 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.45 (br s, 1H), 8.47 (s, 1H), 7.86 (br s, 1H), 7.31 (br s, 3H), 6.74 (br s, 1H), 6.55 (s, 1H), 5.22 (br s, 1H), 4.69-4.59 (m, 1H), 4.60-4.50 (m, 1H), 4.45-4.36 (m, 2H), 4.34-4.26 (m, 1H), 1.35 (s, 3H) 1.41 (s, 3H).
Reaction SMILES: [N+:1](=C)=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N>CCOCC.CO>[NH2:1][C:12]1[C:11](=[CH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:15][C:14](=[O:16])[C:13]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C1NC(=Cc2ccccc2)C(O)=C1[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Agent: N
Solvent: CO
Solvent: CCOCC
Product: NC1=C([N+](=O)[O-])C(=O)NC1=Cc1ccccc1
Yield: 75 %

Procedure:
An excess of diazomethane in ether is added to a suspension of 0.46 g (2 mmol) benzylidene-4-hydroxy-3-nitro-3-pyrrolin-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 20 ml methanol. When the evolution of nitrogen has subsided, the solvent is stripped off, the residue is dissolved in methanol and the solution is heated under reflux with an excess of ammonia solution for five minutes, whereupon yellow crystals precipitate out, which are filtered off with suction and washed with methanol. 4-Amino-5-benzylidene-3-nitro-1,5-dihydropyrrol-2-one obtained with a melting point of >260° C. in a yield of 75%.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:6][CH3:7])=[O:5].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[C:15]([C:14]1[C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=[CH:18][C:17]=1[O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:6][CH3:7])=[O:5])#[N:16]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CNC(=O)C(C)(C)CO
Product: CNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 77 %

Procedure:
Prepared as in Example 215c from 3-hydroxy-N,2,2-trimethylpropanamide (Example 221d) and 2,6-dinitrobenzonitrile in 77% yield as a pale yellow solid. MS 378 (MH+).