Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17](Cl)[N:16]=[N:15][C:14]=3[C:20]([NH2:22])=[O:21])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.O>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]4[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:16]=[N:15][C:14]=3[C:20](=[O:21])[NH2:22])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2cccn2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3cccn3)n2)c(C(N)=O)nn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 34.2 %

Procedure:
To a solution of 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (131 mg, 415 μmol) in NMP (5 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) and the mixture stirred at 140° C. for 24 h. A second portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (162 mg, 756 μmol) was added and the mixture heated at 140° C. for a further 24 h. The reaction mixture was cooled, and then diluted with water. The mixture was extracted with ethyl acetate (3×50 mL) then the combined organic phases were washed with brine (50 mL), then concentrated in vacuo, and finally purified by chromatography (silica, 12 g RediSep Gold, 2 to 6% of a 99.5:0.5 methanol:ammonium hydroxide solution in dichloromethane, 20 min) to give tert-butyl (1S,2R)-2-(5-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (70 mg, 142 μmol, 34%) as a beige solid. MS (EI/CI) m/z: 494.3 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1.C(=O)([O-])O.[Na+]>ClCCl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cn2cncn2)CC1
Temperature: -78 °C
Reaction time: 0.02 h
Yield: 35.5 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-piperidin-4-methanol (1.08 g, 5.0 mmol) and diisopropylethylamine (2.6 mL, 15 mmol) in dry dichloromethane (30 mL) was added anhydrous trifluoromethanesulfonic acid (1.0 mL, 6.0 mmol) at −78° C., and the mixture was stirred for 1 minute under iced cooling. The mixture was cooled to −78° C. To the reaction mixture were added 1H-1,2,4-triazole (1.04 g, 15 mmol) and THF (20 mL), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (50 g, ethyl acetate/ethanol=1/0 to 20/1), and recrystallization to give the titled compound as pale yellow crystals (473 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1.[Sb](Cl)(Cl)Cl.C([O-])(=O)C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C1C=CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl[Sb](Cl)Cl
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To 3,4-difluorophenylboronic acid (9.47 g, 60 mmol), cyclopent-2-enone (4.93 g, 60 mmol), antimony trichloride (1.37 g, 6 mmol), sodium acetate, (9.84 g, 120 mmol) and palladium acetate (1.35 g, 6 mmol) are added to acetic acid (300 mL) under an argon atmosphere. The reaction is stirred at room temperature overnight. The reaction mixture is filtered and poured into water. The material is extracted with ethyl acetate (3×), washed with saturated sodium bicarbonate (3×), brine (3×), dried with sodium sulfate, filtered, and concentrated in vacuo. The material is purified using silica gel chromatography eluting with 10% ethyl acetate in pet ether to give the title compound as a yellow oil (6.9 g, 58%). 1H NMR (300 MHz, CDCl3) δ 7.14-6.95 (m, 3H), 3.41-3.37 (m, 1H), 2.64-2.61 (m, 1H), 2.46-2.23 (m, 4H), 1.93-1.84 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([NH:17][CH3:16])=[N:19][CH:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(NC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CNc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N-methyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]([C:7]1[S:16][C:10]2[S:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[CH:8]=1)=[O:6].[I-].[Na+].[CH3:19][S:20][CH2:21][CH2:22]Cl>CS(C)=O.O>[CH3:3][O:4][C:5]([C:7]1[S:16][C:10]2[S:11][CH2:12][C:13](=[O:15])[N:14]([CH2:22][CH2:21][S:20][CH3:19])[C:9]=2[CH:8]=1)=[O:6]
Reactant: CSCCCl
Reactant: COC(=O)c1cc2c(s1)SCC(=O)N2
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc2c(s1)SCC(=O)N2CCSC
Temperature: 50 °C
Reaction time: 6.5 h

Procedure:
Under nitrogen atmosphere, potassium hydroxide (147 mg) in dimethyl sulfoxide (10 ml) was stirred at room temperature for 30 minutes. To the solution were added 2,3-dihydro-6-methoxycarbonyl-2-oxothieno[2,3-b][1,4]thiazine (0.50 g), sodium iodide (0.39 g) and 2-chloroethyl methyl sulfide (0.26 ml), and the mixture was stirred at 50° C. for 6.5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane:ethyl acetate=3:1) to give 2,3-dihydro-6-methoxycarbonyl-1-(2-(methylthio)-ethyl]-2-oxothieno[2,3-b][1,4]thiazine (463 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1.O1CCOCC1>[Si:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:5][C:4]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCCBr
Reactant: COc1ccc(OC)c(N)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(OC)c(NCCCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C)c1
Yield: 50 %

Procedure:
2,5-Dimethoxyaniline (352.3 mg) was dissolved in 20 ml of tetrahydrofuran, and then 2.3 ml of n-butyl lithium (1.0 M solution in hexane), 3 ml of a solution of (16-bromohexadecyloxy)-t-butyldimethylsilane in tetrahydrofuran, and 0.20 ml of 1,4-dioxane were added to this solution at 0° C. The reaction mixture was refluxed for 24 hours while stirring. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic layer was washed with saline solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel chromatography (heptane:ethyl acetate=7:3) gave [16-(t-butyldimethylsilanyloxy)hexadecyl]-(2,5-dimethoxyphenyl)amine as a yellow oil at a 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[Cl:19])=[O:8].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:22]([O:21][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][C:6]=1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[Cl:19])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)ccc1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Oc1ccc(Cl)cc1C(=O)Nc1ccc([N+](=O)[O-])cc1Cl)c1ccccc1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (1.27 g., 3.88 mmol) in pyridine (15 mL) was treated with 4-dimethylaminopyridine (30 mg) and benzoyl chloride (0.49 mL, 4.27 mmol) was introduced dropwise. The suspension was warmed to 50° C. for one hour then cooled to room temperature and stirred for 17 hours. The reaction mixture was partitioned between 1N aqueous HCl and ethyl acetate. The ethyl acetate phase was washed with water, then brine, dried over magnesium sulfate, and concentrated to an off-white solid. This was recrystallized from ethyl acetate/hexanes. 1HNMR (500 MHz, DMSO-d6): δ7.70 (M, 3H), 7.73 (m, 2H), 7.89 (m, 1H), 7.93 (M, 1H), 8.19 (m, 1H), 8.32 (m, 1H), 10.60 (s, 1H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][N:12]([CH3:14])[CH2:11][CH2:10][N:9]1[C:15](OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC[CH2:24][CH2:25][N:26]1[C:34]([O:35]C)=[N:33][C:32]2[C:27]1=[N:28][C:29]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[N:30][C:31]=2[NH2:37].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([CH:8]1[CH2:13][N:12]([CH3:14])[CH2:11][CH2:10][N:9]1[CH:15]([CH2:8][CH2:1][CH2:2][CH3:3])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[NH:33][C:32]2[C:27]1=[N:28][C:29]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[N:30][C:31]=2[NH2:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccccc2)C1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC(CCCC)N3CCN(C)CC3Cc3ccccc3)c2n1

Procedure:
The compound obtained in Step (iii) was reacted with the compound obtained in Example 1, Step (i) in the presence of potassium iodide (166 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol) in DMF to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.C(=O)=O.C([Li])(C)(C)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](F)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1COCC1>[S:29]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)F)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C=O
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)c2cc3ccccc3[nH]2)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of indole (586 mg, 5.0 mmol) in 10 mL THF at −70° C. was added n-butyl lithium (3.7 mL, 5.1 mmol, 1.39 M in hexane) dropwise over 35 min keeping the temperature below −65° C. The reaction was stirred at −70° C. for 30 min, then a saturated solution of CO2 in 20 mL THF added by cannula, the dry ice bath removed and the reaction mixture bubbled with CO2 as the reaction warmed to room temperature. The reaction mixture was concentrated in vacuo then taken up in 10 mL THF and cooled to −70° C. To the solution was added tert-butyl lithium (3 mL, 5.17 mmol, 1.7 M in pentane) dropwise and stirred at −70° C. 1 h, then the reaction mixture added by cannula to a solution of p-toluenesulfonyl fluoride (1.74 g, 10 mmol) in 10 mL THF and stirred at −70° C. 2 h. The reaction was quenched with 1 mL H2O, poured into a solution of ammonium chloride (pH 5), and extracted twice with CHCl3. The combined organic extract was washed successively with a saturated solution of sodium bicarbonate and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 2 to 20% ethyl acetate in hexanes to give a final yield of 199 mg (0.73 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.41 (s, 3H), 7.16-7.26 (m, 2H), 7.27-7.33 (m, 2H), 7.35 (t, J=7.3 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.93 (d, J=8.3 Hz, 2H), 9.31 (s, 1H). 13C NMR (500 MHz, CDCl3, δ): 21.61, 108.87, 112.39, 121.52, 122.62, 125.95, 127.08, 127.35, 130.02, 134.45, 137.16, 138.53, 144.57.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:48]1[CH:53]=[C:52]([NH:54][C:55]2[CH:64]=[CH:63][CH:62]=[CH:61][C:56]=2[C:57]([NH:59][CH3:60])=[O:58])[C:51]([Cl:65])=[CH:50][N:49]=1.[CH3:66][N:67]1[C:71]([NH2:72])=[CH:70][C:69]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[N:68]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:65][C:51]1[C:52]([NH:54][C:55]2[CH:64]=[CH:63][CH:62]=[CH:61][C:56]=2[C:57]([NH:59][CH3:60])=[O:58])=[CH:53][C:48]([NH:72][C:71]2[N:67]([CH3:66])[N:68]=[C:69]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[CH:70]=2)=[N:49][CH:50]=1
Reactant: Cn1nc(-c2ccccc2)cc1N
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Nc2cc(-c3ccccc3)nn2C)ncc1Cl
Temperature: 50 °C

Procedure:
A 50-mL sealed tube was charged with Pd(OAc)2 (18 mg, 0.08 mmol) and 2,2′-bis (diphenylphosphino)-1,1′-binaphthyl (BINAP, 50 mg, 0.08 mmol) in 1,4-dioxane (10 mL). The mixture was degassed using bubbling nitrogen for 40 min and heated at 50° C. for 1 h. Then the mixture was cooled to room temperature whereupon 2-[(2,5-dichloro-4-pyridinyl)amino]-N-methyl-benzamide (300 mg, 1.01 mmol), 2-methyl-5-phenyl-2H-pyrazol-3-ylamine (704 mg, 4.06 mmol) and cesium carbonate (960 mg, 2.96 mmol) were added under an inert atmosphere. The tube was sealed and heated at 120° C. overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel, eluted with dichloromethane-methanol (DCM-MeOH) 99:1 followed by purification by preparatory TLC to afford the desired compound as a off white solid (25 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ 2.76 (d, 3H, J=4.52 Hz), 3.68 (s, 3H), 6.69 (s, 1 H), 6.85 (s, 1H), 7.07-7.14 (m, 1 H), 7.25-7.31 (m, 1H), 7.36-7.42 (m, 2H), 7.46-7.53 (m, 1 H), 7.63 (d, 1H, J=8.08 Hz), 7.69 (d, 1H, J=7.4 Hz), 7.75 (d, 2 H, J=7.16 Hz), 8.04 (s, 1H), 8.69 (brs, 1H), 8.81 (s, 1H), 10.13 (s, 1H). LC-MS calculated for C23H21ClN6O (M+H) 433.15. found 433.3. HPLC purity 96% at λ=200 nm and 99% at λ=260 nm.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nccc2ccccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1nccc2c([N+](=O)[O-])cccc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution D8 (1 g, 7 mmol) in sulfuric acid (2.5 ml) was cooled (<4° C.) and concentrated nitric acid (1 ml) added over 10 min. Reaction was stirred for 30 min and then heated at 60° C. for 2 h. After cooling the reaction mixture was poured into ice water slurry (100 ml) and basified using solid potassium carbonate followed by extraction using DCM. Organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:35]3[NH:34][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:49][CH2:48]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)c(OC)c1OC
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Agent: I
Product: COc1ccc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)c(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (1.1 g, 2.3 mmol) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (1.21 g, 2.6 mmol). Purify by chromatography on silica gel eluting 28% methanol/ethyl acetate containing 20 mL concentrated aqueous ammonia solution/3L to give the title compound: mp; 112-119° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[NH3:14]>C(O)(C)C>[CH3:12][S:11][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[CH:3][C:2]([NH2:14])=[N:13][C:6]=2[N:7]=1
Reactant: N
Reactant: CSc1ncc2ccc(Cl)nc2n1
Solvent: CC(C)O
Product: CSc1ncc2ccc(N)nc2n1
Temperature: 40 °C
Yield: 74.2 %

Procedure:
A suspension of 2.95 g (13.9 mmol) of 7-chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (Example 6) in 200 mL of isopropanol saturated with ammonia is sealed and heated at 40° C. for 65 hours. The suspension is resaturated with ammonia and heated for another 18 hours at 40° C. The solid is collected by filtration and triturated with water to give 1.98 g (74.2%) of the product, mp>250° C.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=O>C(OS([O-])(=O)=O)CCCCCCCCCCC.[Na+]>[C:1]([C:9]1[CH2:14][CH2:13][CH2:12][C:11]2[C:10]=1[O:15][C:16](=[O:20])[C:17]=2[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: CC(=O)C(=O)O
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1=C2CCCC(C(=O)c3ccccc3)=C2OC1=O
Yield: 25.5 %

Procedure:
A mixture of 10 g of 2-benzoyl-cyclohexanone, 5.8 g of pyruvic acid and 0.2 g of sodium dodecylsulfate is heated at 150° for 15 hours. After cooling, the raw reaction product is extracted with ethyl ether and the ether solution is washed with an aqueous solution of sodium bicarbonate, then with water and then dried. The residue which is obtained after removing the solvent (9 g) is chromatographed on an SiO2 column using as an eluent cyclohexane: ethyl ether 7:3. There are obtained 3.2 g of 7-benzoyl-3-methyl-2,4,5,6-tetrahydro-benzo[b]furan-2-one. After recrystallization from hexane-ethyl acetate m.p. is 79°-81°.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:18]=2[NH:19][C:20]2[C:21]([CH3:30])=[C:22]3[C:26](=[C:27]([Cl:29])[CH:28]=2)[NH:25][CH:24]=[CH:23]3)[C:16]#[N:17])=[CH:7][CH:6]=1.[CH3:31][NH:32][CH3:33]>C1COCC1.COCCOC>[Cl:29][C:27]1[CH:28]=[C:20]([NH:19][C:18]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:32]([CH3:33])[CH3:31])=[CH:6][CH:7]=2)[C:21]([CH3:30])=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2
Reactant: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCCl)cc2)cc(Cl)c2[nH]ccc12
Reactant: CNC
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCN(C)C)cc2)cc(Cl)c2[nH]ccc12
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 5-[4-(2-chloroethoxy)phenyl]-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile (144 mg, 0.3 mmol) and dimethyl amine (1.7 mL of a 2.0 M solution in THF, 3.4 mmol) in DME (3 mL) in a sealed tube was stirred at 110° C. for 48 h and cooled to room temperature. After the resulting solution was concentrated, 1 N aqueous HCl was added and the aqueous phase was extracted with ethyl acetate and the aqueous solution was adjusted to pH of 10 by adding sodium carbonate and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, and concentrated to give 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-{4-[2-(dimethylamino)ethoxy]phenyl}nicotinonitrile as a yellow solid (109 mg, 74%). HPLC retention time: 5.1 min.(g); MS: 446.3 (M+H); and HRMS: 446.1743.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)[CH:5]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1nc(-c2cccc(CCO)c2)cs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1nc(-c2cccc(CCOS(C)(=O)=O)c2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-{4-[3-(2-hydroxyethyl)phenyl]-1,3-thiazol-2-yl}acetamide (300 mg) in CH2Cl2 (10 ml) were added methansulfonyl chloride (106 μl) and triethylamine (207 μl) at 5° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Resulting residue was purified by silica gel column chromatography with n-hexane and ethyl acetate (1:1) as an eluent to give 2-{3-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl methanesulfonate (388 mg) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:8](O)=[O:9]>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:8]=[O:9])=[CH:3][CH:4]=1
Reactant: O=CO
Reactant: Nc1ccncc1
Product: O=CNc1ccncc1

Procedure:
Was prepared according to Example 2 from 4-aminopyridine and formic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:39][O:40][CH2:41][C:42]([O:44]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:43])[C:15]([NH:17][CH:18]2[C:37](=[O:38])[N:20]3[C:21]([C:26]([O:28][CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[S:27])=[C:22]([CH3:25])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>ClCCl>[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:39][O:40][CH2:41][C:42]([OH:44])=[O:43])[C:15]([NH:17][CH:18]2[C:37](=[O:38])[N:20]3[C:21]([C:26]([O:28][CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])=[S:27])=[C:22]([CH3:25])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CC1=C(C(=S)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CC1=C(C(=S)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
Trifluoroacetic acid (4.7 g) was added to a solution of pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (3.1 g) in dichloromethane (12.4 ml) and anisole (0.9 g) with ice-cooling and the mixture was stirred for an hour at ambient temperature. To the resulting solution was added isopropyl ether and stirred. The precipitates were collected by filtration, washed with isopropyl ether. The precipitates were added to a mixture of ethyl acetate and water and adjusted to pH 7.5 with saturated aqueous potassium carbonate. The separated aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were filtrated off, washed with water and dried over phosphorus pentoxide in vacuo to give pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (1.69 g).