Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: CNC
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N(C)C)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and dimethylamine. LCMS (Method C): 498 (M+H)+, Retention time 11.4 minutes.
Reaction SMILES: [OH-].[NH4+].Br[C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:6][C:5]=1[F:29].O[C@H]1C[NH:34][C@H](C(O)=O)C1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O.O.[Cu]I>[NH2:34][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:6][C:5]=1[F:29]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(Br)c(F)c2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(N)c(F)c2)CC1
Temperature: 85 °C
Yield: 59.4 %

Procedure:
Ammonium hydroxide (14.9 mL, 107 mmol) was quickly added to a solution of tert-butyl 4-((1R,2R)-2-((4-bromo-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step A product, 1.58 g, 3.57 mmol), (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (1.3 g, 7.86 mmol), Copper(I) iodide (1.36 g, 7.14 mmol), and potassium carbonate (1.53 g, 11.1 mmol) in DMSO (12 mL) that had been placed under an inert atmosphere in a sealed tube. The reaction mixture was subsequently heated at 85° C. for 48 hrs in the sealed tube. The solution was cooled to rt and diluted with EtOAc (25 mL) and water (25 mL). The layers were cut and the aqueous phase extracted with EtOAc (25 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto a silica column (KP-Sil 50 g SNAP column, Biotage system) initially eluting with a range of 10-20% EtOAc/Hex over 6 CV, followed by a range of 25-60% EtOAc/Hex over 7 CV to give the desired compound (802 mg, 59%). LC/MS (m/z): 379 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C1C(=O)N([Cl:21])C(=O)C1.O>CN(C=O)C>[Cl:21][C:13]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=12
Reactant: CCc1cc2c(OC)cccn2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn2cccc(OC)c2c1Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 92.1 %

Procedure:
The compound of Example 49 (2.07 g) was dissolved in DMF (60 mL). To this solution, NCS (1.88 g) was added and the mixture was stirred at room temperature for 5.5 hours. Subsequently, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=3:1) afforded the title compound as a gray powder (2.28 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:20])[C:13](=[CH:16]OCC)[C:14]#[N:15])[CH3:10]>C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:20])[C:13]([C:14]#[N:15])=[CH:16][NH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1)[CH3:10]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Cc1ccc(N)cn1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1ccc(C)nc1
Yield: 65.5 %

Procedure:
To a solution of 3-amino-6-picoline (ChemPacific, 15.00 g, 138.70 mmol), in toluene (400 mL) was added ethyl(ethoxymethylene)-cyano-acetate (Aldrich, 98%, 35.88 g, 208.00 mol), and the reaction mixture was refluxed for 4 hrs. The reaction mixture was concentrated and the solid was collected by filtration to give 2-cyano-3-(6-methyl-pyridin-3-ylamino)-acrylic acid ethyl ester (21.0 g). The filtrate was concentrated and the residue was then purified by Biotage column, eluting with a gradient of 30-75% AcOEt in nHex to give 2-cyano-3-(6-methyl-pyridin-3-ylamino)-acrylic acid ethyl ester (7.6 g, total yield: 28.6 g, 89.0%) which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=1[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH3:24]>N1C=CC=CC=1>[CH3:24][N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[CH2:17][CH2:16][C:15]1[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=1[NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCCCC1CCc1ccccc1N
Solvent: c1ccncc1
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Reaction of 4-nitrobenzoyl chloride (6.5 g., 0.035 mole) and 2-(o-aminophenethyl)-1-methylpiperidine (6.0 g., 0.0275 mole) in 35 ml. of pyridine according to the method of Example 25 provides 2'-[2-(1-methyl-2-piperidyl)ethyl]-4-nitrobenzanilide. Crystallization from ethyl acetate provides analytically pure material, m.p. 162°-163.5° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Rh]>[N:1]1([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccnc(CN2CCCC2)c1
Agent: [Rh]
Solvent: CCO
Product: COC(=O)C1CCNC(CN2CCCC2)C1
Yield: 35 %

Procedure:
A solution of the product of stage (iv) (50 mg) in ethanol (2 ml) was hydrogenated at 70 psi and 70° over 5% rhodium on carbon (35 mg) for 14 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue (0.1 g) was purified by flash chromatography eluting with dichloromethane/methanol/ammonia 200:10:2 to give the title compound as an oil (0.018 g). T.l.c. (Silica/dichloromethane/methanol/ammonia 75:10:2) Rf 0.6.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)=[CH:6][CH:5]=1.[H][H]>CO.[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COc1ccc(C2=CCNCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCNCC2)cc1
Yield: 66 %

Procedure:
To a stirred solution of 4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine, HCl (3 g, 13.3 mmol) (from step B) in methanol (20 mL) was added 10% palladium on carbon (1.4 g) and the reaction mixture was stirred at 20 psi of hydrogen for 12 h. The reaction mixture was filtered through a pad of celite, which was washed with ethyl acetate, and the combined organic fractions were concentrated to obtain a white solid (2 g, 70% yield). LCMS (ES-API), m/z 192.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 9.13-8.36 (m, 2H), 7.14 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 3.73 (s, 3H), 3.07-2.87 (m, 4H), 2.87-2.65 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:12][O:13]C(=O)C)[C:5]([CH:21]([CH3:23])[CH3:22])=[C:4]([Cl:24])[N:3]=1.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:12][OH:13])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:5]([CH:21]([CH3:22])[CH3:23])=[C:4]([Cl:24])[N:3]=1
Reactant: CC(=O)OCc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reaction time: 23 h
Yield: 65.9 %

Procedure:
To a stirred solution of (67) (5 g, 13.54 mmol) in THF (20 ml) at room temperature, was added lithium hydroxide (649 mg, 27 mmol) followed by distilled water (20 ml). After stirring for 23 hr., THF was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic layer was taken, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:4 to 1:1)) to afford 2.92 g (66%) of a white solid. m.p. 140-141° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.4 Hz), 1.76 (1H, t, J=5.6 Hz), 2.39 (3H, s), 3.58 (1H, m), 4.69 (2H, d, J=5.6 Hz), 6.84 (1H, s), 6.95 (1H, s), 7.09 (1H, s).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:10]=2)[O:5][C:4]([CH3:18])([CH3:17])[CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH3:17])([CH3:18])[CH2:3][CH:2]2[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1ccc2c(c1)C(N)CC(C)(C)O2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1ccc2c(c1)C(NS(C)(=O)=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
A reaction mixture of 3.0 g (12 mmol) of 4-amino-6-butoxy-2,2-dimethylchroman, 4.9 g (48 mmol) of triethylamine and 1.65 g (14.4 mmol) of methanesulfonyl chloride in 25 ml of THF was stirred at RT for 3 h. After concentrating, the residue was taken up in water and extracted with EA. After drying and concentrating, the product was crystallized using PE and 2.25 g of 6-butoxy-4-(methylsulfonyl)amino-2,2-dimethylchroman were obtained; m.p. 123-127° C.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[C:9]([NH:20][C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[CH:30]4)[CH:28]=3)=[O:22])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[C:9]([NH:20][C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[CH:30]4)[CH:28]=3)=[O:22])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cncc(-n2cccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cncc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-phenyl-2-(5-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoate and stirred an room temperature for 2 hours. The solvent was evaporated under reduced pressure, ethyl acetate and water were added and pH was adjusted to pH 7.0 with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 23 mg of 4-phenyl-2-(5-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoic acid as white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:11]1([C:9]2[N:8]=[C:7]3[C:3]([NH:4][CH:5]=[N:6]3)=[CH:2][N:10]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C1CNCCN1
Product: c1nc2nc(N3CCNCC3)ncc2[nH]1

Procedure:
In Step 3, a 6-chloropurine (4) undergoes a displacement reaction with a piperazine (5) to provide a piperazinyl purine of Formula (I). The reaction can proceed in the presence of a suitable base, such as triethylamine or diisopropylethylamine, in a solvent such as methanol, ethanol, or isopropanol, at an elevated temperature such as about 50 to 100° C. Alternatively the reaction can be accomplished using microwave irradiation.
Reaction SMILES: C(O[C:4](=[O:14])[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:6]O)C.[NH:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1)[NH2:16].C([O-])C.[Na+].Cl>C(O)C>[CH3:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([N:15]2[C:4](=[O:14])[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:6][NH:16]2)[CH:22]=1
Reactant: CCOC(=O)C(=CO)c1cccnc1
Reactant: Cc1ccnc(NN)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.53 g (7.90 mmol) of the compound from Example 2A and 2.92 g (23.7 mmol) of the compound from Example 1A are dissolved 2 ml anhydrous ethanol under argon and the mixture is stirred at RT for 16 h. 537 g (7.90 mmol) sodium ethanolate are added, the reaction solution becoming dark red in color. The mixture is subsequently stirred at RT for 30 min and 7.9 ml 1 M hydrochloric acid are then added. The solution is partly concentrated, a precipitate separating out. This is filtered off, washed with water (twice with 5 ml each time) and with MTBE (5 ml) and dried in vacuo. 435 mg (22% of th.) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:1][C:2]1[C:10]2[C:9]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: Oc1cccc2scc(CCc3ccccc3)c12
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3scc(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 4-hydroxy-3-(2-phenylethyl)benzo-[b]thiophene (80 mg), 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.17 g) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.044 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-3/2) to give the title compound (75 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl.[NH2:35][C:36]1[S:40][N:39]=[C:38](/[C:41](=[N:45]/[O:46][CH3:47])/[C:42](Cl)=[O:43])[N:37]=1.P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[NH2:35][C:36]1[S:40][N:39]=[C:38](/[C:41](=[N:45]/[O:46][CH3:47])/[C:42]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:43])[N:37]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CO/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

Procedure:
In 240 ml of dichloromethane is suspended 9.06 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To the suspension is added 28.9 g of bistrimethylsilylacetamide and the mixture is stirred at room temperature until complete dissolution and cooled in an ice-water bath. To this solution, 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetyl chloride hydrochloride prepared from 5.83 g of 2-(5-amino-1,2,4-thiadiazol-3yl)-2(Z)-methoximinoacetic acid and 6.02 g of phosphorus pentachloride in 90 ml of dischloromelthane is added and the mixture is stirred for a while. The whole mixture is stirred with ice-cooling for 60 minutes. The dichloromethane is evaporated off and the residue is dissolved in melthyl 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 precipiate, which is collected by filtration, giving 11.8 (82% yield) g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][CH:11]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[N:3]([CH2:10][CH:11]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(Cn1cc([N+](=O)[O-])nc1Br)OC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn(CC(CO)OC2CCCCO2)c(Br)n1
Yield: 88.9 %

Procedure:
To tetrahydrofuran (120 ml) solution of 2-bromo-1-[3-(t-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl)-4-nitroimidazole (12.7 g) prepared in Example 28, was added 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (30 ml) under stirring and ice-cooling condition, the reaction mixture was stirred at a room temperature overnight. The reaction mixture was concentrated under a reduced pressure and the residue was diluted with ethyl acetate, washed with water and an aqueous solution being saturated with sodium chloride. After being dried over anhydrous magnesium sulfate, the residue was concentrated under a reduced pressure, thus obtained residue was purified by use of a silica gel column chromatography (eluent: dichloromethane/ethyl acetate=10/1), there was obtained 2-bromo-1-[3-hydroxy-2-(tetrahydropyran-2-yloxy)propyl]-4-nitroimidazole (8.51 g, yield: 89%) as colorless liquid product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].[H][H]>C1COCC1.O>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:13][OH:14])([CH3:27])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCC(CO)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
To a stirred solution of 2-benzyloxycarbonylamino-6-tert-butoxycarbonylamino-hexanoic acid (Cbz-Lys(Boc)-OH) (Chem-Impex International, 3.8 g, 10 mmol) in THF (25 mL) in a 100 mL round flask was added 1,1′-carbonyldiimidazole (CDI) (1.7 g, 10.5 mmol) at room temperature. After 20 minutes, the THF solution was transferred via a Teflon cannula (+=2 mm) to a stirred solution of sodium borohydride (0.75 g, 20 mmol) in water (10 mL) in a 1 L round flask immersed in a water bath at 5-10° C. The addition caused a strong evolution of hydrogen gas and the mixture was stirred for a couple of hours. The volatiles were then removed on a rotovap, and the residue was dissolved in ethyl acetate (150 mL). The ethyl acetate solution was extracted successively with cold 1 N HCl (2×50 mL), saturated sodium bicarbonate solution (2×50 mL), brine (100 mL), and was dried with anhydrous sodium sulfate. The dried ethyl acetate solution was then pass through a one inch flash pad of silica gel, and concentrated to provide a colorless solid (3.3 g, 91%), TLC Rf=0.24 (95:5:2 EtOAc:MeOH:H2O).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[N:19]=[C:20]([Cl:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:22][C:20]1[CH:21]=[C:16]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][N:12]=2)[C:17](=[O:24])[N:18]([CH3:23])[N:19]=1
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 90 °C
Yield: 74 %

Procedure:
A solution of 5-(4-methylpiperazin-1-yl)pyridin-2-amine (172 mg, 0.90 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol) cesium carbonate (1.02 g, 3.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (77.7 mg, 0.13 mmol) in dioxane (10 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) was added and the resulting solution was heated at 90° C. for 18 h. The mixture was cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined, dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was triturated with methanol and dichloromethane and filtered, washed with ether and dried to give 6-chloro-4-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one (223 mg, 74%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:36]([O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:34])[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)=[CH:10][C:2]=1[Cl:1])[CH3:37]
Reactant: CCOC(=O)CCN
Reactant: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Agent: Cl
Product: CCOC(=O)CCNC(=O)c1cc(Cl)c(Oc2cc(C)ncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 29, from 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid and beta-alanine ethylester hydrochloride (commercially available, CAS RN 4244-84-2). Colorless foam (73%). MS (ESI): m/z=597.169 [M+H]+.
Reaction SMILES: [CH2:1]1[O:12][C:4]2[CH:5]=[C:6]([N+:9]([O-])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2]1.O.NN>O1CCCC1.[Rh].O.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH2:1]1[O:12][C:4]2[CH:5]=[C:6]([N:9]=[O:10])[CH:7]=[CH:8][C:3]=2[O:2]1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Agent: Cl[Fe](Cl)Cl
Agent: [Rh]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: O=Nc1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
1,2-Methylenedioxy-4-nitrobenzene (8.3 g, 0.05 mol) was dissolved in tetrahydrofuran (150 ml) with rhodium on carbon catalyst (0.2 g) at 0° C. and was treated dropwise with hydrazine hydrate (2.8 g, 0.055 mol). On completion of the addition, the mixture was stirred for 1 hour and then filtered through a HYFLO (Trade Mark) filter. The resulting solution was added dropwise to a chilled, stirred solution of iron (III) chloride hexahydrate (27.5 g, 0.1 mol) in water (150 ml). On completion of the addition, water (220 ml) was added and the green precipitate was filtered off, washed with water and dried overnight under high vacuum. 1,2-Methylenedioxy-4-nitrosobenzene was obtained as a green solid (3.7 g, 50% yield) by column chromatography eluting on silica with dichloromethane. M.p. 90°-92° C. M+ (CI):152 (M+ +H)