Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8](Cl)[N:7]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[N:7]=1
Reactant: Nc1cccc(CCCO)c1
Reactant: COc1ccc(Br)c(CNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Br)c(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 80 °C
Yield: 82.8 %

Procedure:
To a solution of N-(2-bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine (4.0 g, 11 mmol) and 3-(3-aminophenyl)propan-1-ol (2.3 g, 15 mmol, prepared according to Example 12, Step B) in 1,4-dioxane (90 mL) was added p-toluenesulfonic acid monohydrate (0.31 g, 1.6 mmol). The mixture was heated at 80° C. over two days and the reaction was complete. After cooling, the mixture was filtered under vacuum. The cake was washed with cold EtOAc to give the desired product as an off-white powder (4.35 g, 83%). LCMS for C21H22BrClN4O2 (M+H)+: m/z=477.0, 479.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1.[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[N:32][C:27]2=[C:26]([C:33](Cl)=[O:34])[CH:25]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:11]=[CH:10][C:9]=2[NH:21][C:33]([C:26]2[CH:25]=[N:24][N:28]3[CH:29]=[CH:30][CH:31]=[N:32][C:27]=23)=[O:34])[CH:7]=1
Reactant: O=C(Cl)c1cnn2cccnc12
Reactant: COc1ccc(F)cc1-c1c(N)cnn1CCOC[Si](C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1CCOC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine (580 mg, 1.72 mmol) in tetrahydrofuran (40 mL) was added of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (320 mg, 1.72 mmol) in THF (5 mL) at 0° C. After the addition, the mixture was warmed to room temperature, and then stirred overnight at this temperature. The mixture was concentrated to give 330 mg (40%) of N-(5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification. LCMS (ESI) m+H=483.1. 1H NMR (400 MHz, CDCl3) δ: 9.63 (s, 1H), 8.82 (m, 1H), 8.76 (s, 1H), 8.52 (m, 1H), 8.42 (s, 1H), 7.38 (dd, 1H), 7.31 (d, 1H), 7.22 (m, 1H), 7.06 (m, 2H), 5.42 (d, 2H), 3.86 (s, 3H), 3.72 (m, 2H), 0.92 (q, 2H), 0 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[N:9]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2c(n(C(=O)c3ccc(Cl)cc3)c3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5.5 g. of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester in 40 ml. of dimethylformamide was added 0.9 g. of 54.5 percent sodium hydride in mineral oil. After the mixture had stirred 1 hour at room temperature, 3.5 g. of p-chlorobenzoyl chloride in 10 ml. of dimethylformamide was added dropwise over the course of 10 minutes. The mixture was then stirred for 5 hours between 60°-70° and then poured onto ice (500 g.). The mixture was extracted with ether (3 × 150 ml.) and the ether was in turn extracted with water (5 × 100 ml.). After drying the ether solution over sodium sulfate, the desiccant was removed by filtration and the ether was evaporated. Upon recrystallization of the residue with ethyl acetate, 3.8 g. of product was obtained, m.p. 129°-132° . Following two further recrystallizations from methanol, a yield of 2.3 g. of 6-chloro-9-(p-chlorobenzoyl)-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester was obtained, m.p. 136°-137°.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:14])[C@H:11]([CH3:13])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:29]([N:36]([CH3:42])[C@H:37]([C:39](O)=[O:40])[CH3:38])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CN1CCOCC1>C1(C)C=CC=CC=1.O.CN(C)C=O>[C:32]([O:31][C:29]([N:36]([CH3:42])[C@@H:37]([CH3:38])[C:39]([NH:12][C@@H:11]([CH3:13])[C:10]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:14])=[O:40])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.81 g (22.3 mmol) of L-alanine benzyl ester hydrochloride, 3.32 g (24.6 mmol) of HOBt and 4.92 g (25.7 mmol) of EDC are introduced into 10 ml of anhydrous dimethylformamide under argon. At 0° C., 4.54 g (22.3 mmol) of N-Boc-N-methyl-L-alanine and 14.7 ml (133.9 mmol) of N-methylmorpholine are added, and the reaction mixture is stirred overnight with slow warming to RT. The reaction solution is treated with water and toluene and extracted with shaking. The aqueous phase is extracted twice with toluene, and the combined organic phases are dried over sodium sulfate and concentrated to dryness after filtration. The product is purified chromatographically by silica gel chromatography on about 1500 ml of silica gel using MeOH/dichloromethane 10/1. 7.9 g (97% of th.) of the product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:22](O)([CH3:24])[CH3:23])[CH:5]=[C:6]([CH2:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH3:10])[CH:7]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>N1C=CC=CC=1>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:9]([CH2:8][C:6]2[CH:5]=[C:4]([C:22]([CH3:24])=[CH2:23])[CH:3]=[C:2]([Br:1])[CH:7]=2)[CH3:10])=[CH:17][CH:16]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cc(Br)cc(C(C)(C)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C)c1cc(Br)cc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
Compound 140 (3.11 g; 7.69 mmol) was dissolved in pyridine (50 ml). While the solution was stirred at room temperature, phosphorus oxychloride (11.8 g; 76.9 mmol) was added dropwise. After completion of the addition, the mixture was stirred for 3 hours at 120° C. The mixture was brought to room temperature, and poured into ice/water. The mixture was alkalinized with sodium hydroxide, and extracted with chloroform (150 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 1.83 g of the target compound as pale yellow oily matter (yield: 61.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([NH:15][C:16]([NH:18]C(=O)C3C=CC=CC=3)=[S:17])[CH:14]=2)[CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([NH:15][C:16]([NH2:18])=[S:17])[CH:14]=2)[CH:4]=1
Reactant: COc1ccnc(-c2ccc(C)c(NC(=S)NC(=O)c3ccccc3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccnc(-c2ccc(C)c(NC(N)=S)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a suspension of N-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)-N′-benzoylthiourea (0.27 g) in methanol (5 ml) was added an aqueous sodium hydroxide solution (IN, 0.89 ml) dropwise. The mixture was stirred at ambient temperature for 4 hours, and the pH was adjusted to 8.0 with 1N hydrochloric acid. The mixture was diluted with water (50 ml) and extracted with dichloromethane-methanol (4:1) three times. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give N-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)thiourea (176 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([OH:14])[CH:12]=[CH2:13].C(=O)(O)[O-].[Na+].CN(C)C=O>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OC)(C)(C)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:13][CH2:12][CH:11]=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C=CCO
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=CCCc1ccc([N+](=O)[O-])cc1
Temperature: 35 °C

Procedure:
Add 1-iodo-4-nitrobenzene (100 g, 400 mmol), allyl alcohol (40 mL, 590 mmol), sodium bicarbonate (80 g, 940 mmol), palladium acetate (4.5 g, 0.05 mmol), tetra-N-butylammonium chloride (110 g, 390 mmol) and dimethylformamide (500 mL) to a 2 L flask and stir. Degas the reaction by pump purging with nitrogen, then heat to 35° C. for 30 hours. Cool the reaction to 0° C. and add methyl tert-butyl ether and water. Stir for 30 minutes then filter over Hyflo Super Cel®. Separate the layers and add tetrahydrofuran to the organic layer and wash with lithium chloride (5% aqueous) and brine. Dry the organic phase over MgSO4, filter over silica gel and concentrate under reduced pressure to give an oily residue. The title compound was used without purification. 1H NMR (CDCl3, 500.0 MHz): δ 9.81-9.85 (m, 1H), 8.10-8.18 (m, 2H), 7.34-7.40 (m, 2H), 3.00-3.10 (m, 2H), 2.80-3.10 (m, 2H).
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[C:19]([N:26]1[CH2:33][C:32](=[O:34])[CH2:31][C@@H:27]1[C:28]([OH:30])=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])=[CH:38][CH:37]=1.COC(C)(C)C>C1(C)C=CC=CC=1>[O:34]=[C:32]1[CH2:33][N:26]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:27]([C:28](=[O:30])[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][CH:37]=2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1C(=O)O
Reactant: Nc1ccc(-n2ccccc2=O)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.2 742 mg (3.00 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 459 mg (2.00 mmol) of Boc-4-keto-D-proline and 372 mg (2.00 mmol) of 1-(4-aminophenyl)-1H-pyridin-2-one in 25 ml of toluene, and the mixture is stirred at room temperature for 18 hours. 200 ml of tert-butyl methyl ether are added, and the precipitate formed is filtered off. 200 ml of petroleum ether are added to the filtrate, and the resultant precipitate is filtered off, giving tert-butyl (R)-4-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a brownish solid; ESI 398.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]#[N:17]>>[N:1]1([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:15][C:16]#[N:17])[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: N#CCBr
Product: N#CCN1CCN(CCN2CCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(2-Pyrrolidin-1-yl-ethyl)-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless solid; ES-MS: M+H=223.3.
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH2:5][S:6][C@@H:7]2[C@H:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:13](=[O:24])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11].Cl.[CH3:28][O:29][NH2:30]>O1CCCC1.O>[CH3:28][O:29][N:30]=[CH:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:13](=[O:24])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CON
Reactant: COC(OC)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 10 h
Yield: 83.8 %

Procedure:
To a solution of 3-dimethoxymethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (76 mg) in tetrahydrofuran (4 ml) is added a solution of O-methylhydroxylamine hydrochloride (23 mg) in water (1 ml), and the mixture is kept at room temperature for 10 hours. The reaction mixture is evaporated to remove tetrahydrofuran, and the separated solid material is collected by filtration. Recrystallization of the solid from a mixture of ethyl acetate and ether gives 3-methoxyiminomethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (61 mg). m.p. 186°-189° C. Yield: 80%.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:16]=1)[CH3:4].Cl.[CH3:18][O:19][C:20](=O)[O:21]C>>[CH3:18][O:19][C:20]([CH:13]1[CH2:12][CH2:11][O:10][C:9]2[CH:16]=[C:5]([CH2:3][CH3:4])[CH:6]=[CH:7][C:8]=2[C:14]1=[O:15])=[O:21]
Reactant: CCc1ccc2c(c1)OCCCC2=O
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCc1ccc2c(c1)OCCC(C(=O)OC)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A suspension of sodiumhydride in paraffin (0.42 g, 60%) was added to 4 ml of dimethylcarbonate. To this suspension 8-Ethyl-3,4-dihydro-2H-benzo[b]oxepin-5-one (5.3 mmol) dissolved in 2 ml dimethylcarbonate was added dropwise at room temperature. The mixture was refluxed for two hours, cooled to room temperature and stirred overnight. 25 ml of 2 mol/l hydrochloric acid were added to the mixture. The resulting solution was extracted by ethyl acetate. The organic phase was dried over sodiumsulfate and the solvent removed in vacuo. 8-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester was obtained as a brown oil in a yield of 87%. LC-MS: 2.2 min, 249.0 (MH+), 2.7 min, 249.0 (MH+)
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[CH2:21][C:20]2[CH:22]=[C:23]3[O:28][CH2:27][O:26][C:24]3=[CH:25][C:19]=2[C:18]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[N:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]1(=[O:67])[NH:61][C:60](=[O:62])[C:59]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:58]12>C1COCC1>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([C:18]2[C:19]3[CH:25]=[C:24]4[O:26][CH2:27][O:28][C:23]4=[CH:22][C:20]=3[CH2:21][C:15]([CH2:14][N:61]3[C:60](=[O:62])[C:59]4=[CH:63][CH:64]=[CH:65][CH:66]=[C:58]4[C:57]3=[O:67])=[N:16][N:17]=2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccc(C2=NN=C(CO)Cc3cc4c(cc32)OCO4)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reaction time: 24 h

Procedure:
A solution of 1.25 ml (8.05 mmol) of diethyl azodicarboxylate in 7 ml of THF is added in drops to a stirred solution of 2.60 g (7.66 mmol) of 8-hydroxymethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine (starting compound III.), 2.11 g (8.05 mmol) of triphenylphosphine and 1.18 g (8.05 mmol) of phthalimide in 130 ml of dry THF at room temperature. The mixture is stirred for 24 hours at this temperature. Then, the precipitated product is suctioned off and washed with ethanol. 2.87 g (80%) of the title compound, which can be further processed without further purification, is obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]2[CH2:30][CH2:29][CH2:28][CH:27]2[CH3:31])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]3[CH2:30][CH2:29][CH2:28][CH:27]3[CH3:31])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1CCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To a solution of potassium tert-butoxide (0.68 g) in DMF (5 mL) was added dropwise a solution of 2-(benzyl{[3-chloro-5-(2-methylpyrrolidin-1-yl)pyrazin-2-yl}methyl]amino)ethanol (1.82 g) in DMF (5 mL) at 0° C., and the mixture was stirred for 1.5 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→33% ethyl acetate/hexane) to give the title compound (1.38 g, 85%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][CH:7]=1.[Cl:29]NC(=O)CCC(N)=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23][C:24]([CH3:25])([CH3:27])[CH3:26])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][C:7]=1[Cl:29]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Reactant: NC(=O)CCC(=O)NCl
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)c(Cl)n2)c(F)c1
Temperature: 60 °C
Yield: 52.4 %

Procedure:
To a 25 mL round-bottomed flask were added a stirbar, 52 mg (0.13 mmol) 4′-(5-aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide, 27 mg (0.20 mmol) N-chlorosuccinamide, and dry DMF (2.0 mL). The flask was sparged with nitrogen and heated at 60° Celsius for 18 hours before cooling to rt and subjecting the reaction mixture (after syringe filtration) to HPLC purification to give the title compound (29.6 mg, 52%). MS (ESI): mass calcd. for C20H20ClFN4O2S, 434.10; m/z found, 435.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.44 (d, J=2.0, 1H), 8.06 (dd, J=8.1, 1.5, 1H), 7.85 (dd, J=9.4, 6.8, 1H), 7.70-7.64 (m, 1H), 7.64-7.57 (m, 1H), 7.43-7.27 (m, 3H), 7.13 (s, 2H), 6.98 (d, J=3.7, 1H), 1.02 (s, 9H).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]3[CH:15]([C:16](=[O:19])[NH:17][N:18]=2)[CH2:14]3)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cu][C:27]#[N:28].[C-]#N.[K+]>O.Cl.C1(C)C=CC=CC=1>[C:27]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]3[CH:15]([C:16](=[O:19])[NH:17][N:18]=2)[CH2:14]3)=[CH:8][CH:7]=1)#[N:28]
Reactant: N#C[Cu]
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2=NNC(=O)C3CC23)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89.8 %

Procedure:
A cold solution of 2.4 g (34.8 millimoles) of sodium nitrite in 20 ml of water is added to a solution of 7.0 g (34.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 8a) in 26 ml of concentrated hydrochloric acid and 260 ml of water whilst stirring at 0° C. The mixture is then stirred for a further 10 minutes, at 0°-5° C., after which it is neutralized with sodium carbonate at the same temperature. The resulting solution is added dropwise, whilst stirring, to a cold (0°-5° C.) solution of 3.9 g (43.5 millimoles) of copper-(I) cyanide and 7.0 g (107.5 millimoles) of potassium cyanide in 175 ml of water, covered with a layer of 85 ml of toluene. The mixture is then stirred for 30 minutes at 5° C., followed by 20 hours at room temperature. After filtering off the product and drying it under reduced pressure at 50° C., 6.6 g (90% of theory) of 2-(p-cyanophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as brown crystals, of melting point 265°-266° C. after recrystallization from acetonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[NH:12][C:11]3=[O:17])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[NH:12][C:11]3=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NC(=O)C2(c3cccc([N+](=O)[O-])c3)CC12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C23CC2C(=O)NC3=O)c1

Procedure:
Following the procedure of Example 1, 600 mg of 1-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione are dissolved in 30 ml of ethanol and reduction is carried out with hydrogen in the presence of 60 mg of 5% palladium/carbon. When the hydrogenation is complete, the mixture is diluted with ethanol and the catalyst is removed by filtration over HYFLO-Super-Cel®. The solvent is stripped off in vacuo and the residue is recrystallised from a mixture of ethyl acetate/petroleum ether, affording the title compound in the form of pale pink crystals with m.p. 135°-137° C. and an Rf value of 0.47 on thin-layer silica gel plates in the system methylene chloride/methanol (10:1), or 0.52 in methylene chloride/methanol/glacial acetic acid (40:5:1).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]=1[CH3:14])=O.[N+]([O-])(O)=O.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[NH:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.CC#N>C(O)(C(F)(F)F)=O>[CH3:13][N:9]1[C:8]([CH3:14])=[C:7]([C:5]2[CH:4]=[CH:3][N:36]=[C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[CH:32][CH:31]=3)[N:35]=2)[S:11][C:10]1=[O:12]
Reactant: Cc1c(C(=O)C=CN(C)C)sc(=O)n1C
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Solvent: CC#N
Solvent: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)sc(=O)n1C

Procedure:
This compound was prepared by condensation between 5-(3-dimethylamino-acryloyl)-3,4-dimethyl-3H-thiazol-2-one and N-[4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine nitrate. Pale solid. Anal. RP-HPLC: tR=10.9 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>97%). 1H-NMR (CDCl3) δ: 2.42 (m, 4H, CH2), 2.53 (s, 3H, CH3), 3.04 (m, 4H, CH2), 3.28 (s, 3H, CH3), 6.84 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 6.86 (d, 2H, J=9.0 Hz, Ph-H), 7.54 (d, 2H, J=9.0 Hz, Ph-H), 8.35 (d, 1H, J=5.5 Hz, pyrimidinyl-H), and 9.33 (s, 1H, NH).