Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=O)[CH:4]=1.[C:13]1(N2CCOCC2)[CH2:17][CH2:16][CH2:15][CH:14]=1.Cl.C(=O)(O)[O-:26].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[C:14]2[CH2:15][CH2:16][CH2:17][C:13]2=[O:26])[CH:4]=1
Reactant: O=C([O-])O
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: O=Cc1cc(C(F)(F)F)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCC1=Cc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-(trifluoromethyl)pyridine-2-carbaldehyde (CAS number 132470-83-8; 1.00 g, 5.71 mmol) and 4-(cyclopent-1-en-1-yl)morpholine (CAS number 936-52-7; 0.90 ml, 5.60 mmol) in toluene (15 ml) was heated at 90° C. for 18 hours. The reaction was then cooled to room temperature and concentrated HCl (2 ml) and water (2 ml) was added drop wise. The reaction was stirred at room temperature for 20 minutes and then neutralised with a saturated solution of sodium bicarbonate and then basified with 2 M NaOH (aq). The organics were extracted with ethyl acetate (2×40 ml) and the combined organics were washed with brine (10 ml), dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [N+](C1C=CC(O[C:9]([CH2:11][CH:12]([CH3:26])[CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)=[O:10])=CC=1)([O-])=O.[CH3:29][NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH3:37]>CN(C)C=O>[CH3:29][N:30]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH3:37])[C:9]([CH2:11][CH:12]([CH3:26])[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]2)=[O:10]
Reactant: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC1CCCCC1C
Solvent: CN(C)C=O
Product: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)N(C)C1CCCCC1C

Procedure:
3.8 Grams of 6-[3-(p-nitrophenoxycarbonyl)-2-methylpropoxy]carbostyril is dissolved in 40 ml of dimethylformamide, followed by addition of 1.6 ml of N-methyl-2-methylcyclohexylamine and 12-hour agitation at 60°-70° C. After the reaction, the solvent is distilled off and the obtained residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 20/1 (V/V) chloroform/methanol) and the crude crystals are recrystallized from benzene-ligroin to obtain 1.6 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril in the form of colorless needlelike crystals with melting point of 146°-149° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[O:6][CH3:7].C(N(CC)CC)C.C1(C)C=CC=CC=1.[Br:25][CH:26]([CH3:30])[C:27](Br)=[O:28]>O>[Br:25][CH:26]([CH3:30])[C:27]([N:2]([C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[CH:4]=1)[CH3:1])=[O:28]
Reactant: CNc1cccc(OC)c1
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(N(C)C(=O)C(C)Br)c1
Reaction time: 8 h

Procedure:
A solution of N-methyl-m-anisidine (265 g), triethylamine (269 ml) and toluene (550 ml) was stirred at 0° C. as 2-bromopropionyl bromide (202.6 ml) was added dropwise. The mixture was mechanically stirred overnight at room temperature. Water was added to the reaction and the aqueous layer was collected and extracted with ethyl acetate. All organic phases were combined, washed with 2N HCl, and dried (Na2SO4). The solvent was evaporated to yield an oil which was purified using Kugelrohr distillation. The distillate was dissolved in isopropyl ether. The solid product, 2-Bromo-N-(3-methoxyphenyl)-N-methyl-propanamide, m.p. 55°-56° C., crystallized from this solution.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46](Cl)=[O:47]>>[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:47]
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccccn3)CN2C1=O
Yield: 35.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and picolinoyl chloride (94 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 42 mg (54%) of 18-(picolinoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.8% pure (HPLC), MS m/z 672 (M−H)−, HRMS: calcd. 674.2860 and found 674.2861 (M+H)+, mp 164-166° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][C:32]([C:38]#[N:39])([CH2:35][CH2:36]O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:36][CH2:35][C:32]3([C:38]#[N:39])[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH2:30][CH2:31]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CCO)CC1
Reactant: O=C(OCc1ccccc1)N1CCc2ccc(O)cc2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCOc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (1.1 g), 4-cyano-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1 g) and triphenylphosphine (1.22 g) in tetrahydrofuran (40 ml) was added diethyl azodicarboxylate (2 g) with ice-cooling, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) and dried under reduced pressure to give the title compound (1.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5](F)=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[CH:33]=[N:32]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5]([NH:40][C:35]2[C:34]3[CH:33]=[N:32][N:31]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[C:39]=3[CH:38]=[CH:37][CH:36]=2)=[N:6][CH:7]=1
Reactant: Nc1cccc2c1cnn2C1CCCCO1
Reactant: Cc1nc(-c2cc(Br)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(Br)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-(5-bromo-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.250 g, 0.637 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (0.138 g, 0.637 mmol) in THF (10 mL) was stirred at 0° C. and treated dropwise with lithium bis(trimethylsilyl)amide, 1.0 M solution in THF (1.912 mL, 1.912 mmol) (Aldrich catalog number 225770) and stirred at 0° C. for 30 minutes. The mixture was quenched with water (10 mL), diluted with water (50 mL) and extracted with dichloromethane. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (40 g), eluting with a gradient of 5% to 10% 2 M NH3/MeOH in dichloromethane to give N-(5-bromo-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine as yellow crystals. This was treated with dichloromethane (5 mL) and trifluoroacetic acid (5 mL) (Aldrich, St. Louis, Mo.) to give N-(5-bromo-3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-1H-indazol-4-amine, m/z (ESI, +ve) 421/423 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br. s., 1H); 13.25 (br. s., 1H); 12.85 (br. s., 1H); 8.69 (br. s., 1H); 8.48 (br. s., 1H); 7.99 (br. s., 1H); 7.32 (br. s., 1H); 7.23 (br. s., 1H); 2.93 (s, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.C(N(CC)CC)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([N:11]=[C:21]=[O:23])[CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc(N=C=O)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
1.46 g (7 mmol) of N1,N1-dimethylbenzene-1,3-diamine dihydrochloride, followed by 9.9 cm3 (71.64 mmol) of triethylamine, are added, at a temperature in the region of 5° C., under an argon atmosphere, to 2.82 g (9.5 mmol) of triphosgene in solution in 150 cm3 of dichloromethane. After stirring for 20 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), to give a residue which is triturated in 50 cm3 of tetrahydrofuran. After filtration, a solution of 3-dimethylaminophenyl isocyanate in approximately 0.14 N tetrahydrofuran is obtained, which solution is used directly in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6]P(=O)(OCC)OCC.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[Br:39][C:40]1[N:45]=[C:44]([CH:46]=O)[CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[Br:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44](/[CH:46]=[CH:6]/[C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:45]=1
Reactant: CCOP(=O)(Cc1cccc(OC)c1)OCC
Reactant: O=Cc1cccc(Br)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2cccc(Br)n2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 3-methoxybenzylphosphonate (0.5 g, 1.94 mmol) in dimethylformamide (5 mL) at room temperature was added sodium methoxide (0.209 g, 3.87 mmol) and 18-Crown-6 (0.205 g, 0.77 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0° C. and treated with a solution of 6-bromopicolinaldehyde (0.432 g, 2.32 mmol) in dimethylformamide (2 mL) dropwise. When addition was complete, the ice bath was removed and the reaction stirred at room temperature for 1 h. The reaction was heated to 120° C. and held there for 2 h. The reaction was cooled to room temperature and stirred overnight. The resulting suspension was poured into water (70 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether (2×), washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was suspended in ethanol (ca. 10 ml). The resulting solution was placed in the freezer and held there for 3 h. The resulting precipitate was collected by filtration to give 150 mg (27%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 7.61 (d, J=15.9, 1H), 7.49 (dd, J=7.6, 7.6, 1H), 7.22-7.36 (m, 3H), 7.16 (d, J=7.6, 1H), 7.10 (m, 1H), 7.07 (d, J=15.9, 1H), 6.87 (dd, J=8.2, 2.1, 1H), 3.84 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.0, 157.1, 142.3, 138.9, 137.7, 134.4, 129.8, 126.7, 126.3, 120.7, 120.1, 114.8, 112.3, 55.4. Mass spec.: 290.01 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[S:37]([NH:40][C:41]1[C:42]([O:56][CH3:57])=[N:43][CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)(=[O:39])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([C:31]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=3[F:29])(=[O:39])=[O:38])[C:42]([O:56][CH3:57])=[N:43][CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 52.2 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.34 mmol) was treated with 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (280 mg, 0.51 mmol), 2M cesium carbonate (350 μl, 0.70 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.04 mmol) according to the method described in Example 3 to give 117 mg (50% yield) of the title compound. Purity 97%.
Reaction SMILES: [CH:1]1[C:23]2=[C:24]3[C:4]4[C:5]([CH:17]=[CH:18][C:19]3=[C:20](S([O-])(=O)=O)[CH:21]=[C:22]2[OH:25])=[C:6](S([O-])(=O)=O)[CH:7]=[C:8](S([O-])(=O)=O)[C:3]=4[CH:2]=1.[Na+:30].[Na+].[Na+].[S:33](=O)(=[O:36])([OH:35])[OH:34]>>[OH:25][C:22]1[CH:21]=[CH:20][C:19]2[C:24]3=[C:4]4[C:5]([CH:6]=[CH:7][CH:8]=[C:3]4[C:2]([S:33]([O-:36])(=[O:35])=[O:34])=[CH:1][C:23]=13)=[CH:17][CH:18]=2.[Na+:30]
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)([O-])c1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34
Agent: [Na+]
Product: O=S(=O)([O-])c1cc2c(O)ccc3ccc4cccc1c4c32
Yield: 10 %

Procedure:
Scheme 1 shows steps used to synthesize compound 3. Reaction of HPTS with 30% sulfuric acid at 150° C. for 20 min gave sodium 3-hydroxypyrene-5-sulfonate 1 in 10% yield. Acetylation of 1 followed by chlorination of 2 gave intermediate 3, which is analogous to our HPTS-Cl but with only one sulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][NH:13][C:12](=[O:15])[C@H:11]([NH:16]C(=O)OCC3C=CC=CC=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>[Pd].C1(C)C=CC=CC=1.CO>[NH2:16][C@@H:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:14][NH:13][C:12]1=[O:15]
Reactant: O=C(N[C@@H]1CC=C(c2ccc(O)cc2)CNC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: N[C@@H]1CCC(c2ccc(O)cc2)CNC1=O
Reaction time: 18 h

Procedure:
10% Palladium on carbon (10 mg) was added to a solution of benzyl (3R)-6-(4-hydroxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (15 mg, 0.043 mmol) in toluene (5 mL) and methanol (1 mL). The reation vessel is evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated. MS 221 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=1)=[O:27])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CC(C(=O)O)C(=O)NCc1cccc(C(F)(F)F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=523.4 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3-trifluoromethyl-benzyl)-malonamic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Li+].CS[C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=2[N:17]=1.[ClH:35]>O1CCCC1.O.C(#N)C>[ClH:35].[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[N:13]=[CH:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=3[N:17]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 88 g (0.93 mol) of 4-aminopyridine in 1 L of tetrahydrofuran was added 21.2 g (2.67 mol) of lithium hydride. The reaction mixture was heated to 50° C. for 1 hour. To the stirred reaction mixture was added a solution of 318 g (0.89 mol) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one in 1.8 L of tetrahydrofuran. The reaction solution was heated at reflux for 24 hours, and then cooled to 50° C. The reaction mixture was diluted by the slow addition of a mixture of 500 mL of water and 1 L of 6N hydrochloric acid. The reaction mixture was cooled to 24° C. and stirred for 16 hours. The reaction mixture was further diluted by addition of 250 mL of acetonitrile and 200 mL of water, and stirring was continued for an additional 2 hours. The mixture was then filtered, and the filter cake was dried at 45° C. in vacuo for 12 hours to provide 360 g (92%) of 2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride, mp 295–300° C. (dec). HPLC established the purity at 98%. Mass Spec (APCI) 439.89 m/z.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([O-])([O-])[O:16][CH2:17][CH3:18].C(OC(=O)C)(=O)C>O>[C:1]([C:9](=[CH:15][O:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC([O-])[O-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Ethyl benzoylacetate (17.0 g, 88.4 mmol) and ethyl orthoformate (106 mL, 637 mmol) were dissolved in acetic anhydride (60.2 mL, 637 mmol) and stirred at 140° C. overnight. The reaction solution was returned to room temperature, then added with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (20.7 g, yield 94%) was obtained as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][CH2:22][C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH:3]=1.[C:33](OC(=O)C)(=[O:35])C>C(O)=O>[F:20][C:8]1[CH:9]=[C:10]([CH3:19])[C:11]([S:13][CH2:14][C:15]([F:17])([F:18])[F:16])=[CH:12][C:7]=1[N:6]1[C:2]([NH:1][CH:33]=[O:35])=[CH:3][C:4]([O:21][CH2:22][C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:26])([F:27])[F:28])=[N:5]1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)C(F)(F)F)cc2N)cc1SCC(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)C(F)(F)F)cc2NC=O)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.18 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,4,4,4-heptafluorobutoxy)pyrazole was dissolved in 15 mL of formic acid, and 8mL of acetic anhydride was added under cooling with ice, followed by stirring at room temperature for 12 hours. Then, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.92 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-formylamino-3-(2,2,3,3,4,4,4-heptafluorobutoxy)pyrazole.
Reaction SMILES: CO.[O-2].[Ba+2].O.[NH2:6][NH2:7].C(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCO[CH2:19][CH3:20]>>[C:9]1([C:19](=[N:6][NH2:7])[CH3:20])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: NN
Reactant: CCOCC
Agent: [Ba+2]
Agent: [O-2]
Solvent: CO
Solvent: O
Product: CC(=NN)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 1 L flask equipped with a mechanical stirrer, thermometer, and addition funnel was charged with 300 mL of methanol and cooled to 0° C. Barium oxide (8.4 g, 55 mmol) was added portion-wise with exotherm. The reaction was cooled again to 0° C., and hydrazine monohydrate (54.6 g, 1.09 mol) was slowly added. The reaction mixture was stirred for 10 minutes, after which benzaldehyde (131.5 g, 1.09 mol) was added drop-wise over a 30 minute period. The reaction was then stirred for 1 hour, while maintaining a temperature below 8° C. 1H NMR indicated the absence of ketone and a complete reaction. Ether (200 mL) was added, and the BaO was filtered through a bed of silica gel. The resultant clear filtrate was liberated of methanol on a rotary evaporator at or below room temperature. The remaining concentrate was distilled at ca. 1 torr and the intended (1-phenyl-ethylidene)-hydrazine was collected at 91-94° C. in a 50 g quantity. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.65 (m, 2H), 7.35 (m, 3H), 5.37 (br, 2H), 2.13 (s, 3H). During the distillation, a bright yellow solid of N,N′-bis-(1-phenyl-ethylidene)-hydrazine appeared in the distillation vessel. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.95 (m, 4H), 7.45 (m, 6H), 2.32 (s, 6H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19](=[O:44])[NH:20][C:21]3[S:22][C:23]([N:32]4[CH2:37][CH2:36][N:35]([CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)[CH2:34][CH2:33]4)=[C:24]([C:26]4[S:27][CH:28]=[C:29]([Cl:31])[CH:30]=4)[N:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[ClH:18].[Cl:18][C:17]1[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[N:13][CH:14]=[C:15]([C:19](=[O:44])[NH:20][C:21]2[S:22][C:23]([N:32]3[CH2:37][CH2:36][N:35]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:34][CH2:33]3)=[C:24]([C:26]3[S:27][CH:28]=[C:29]([Cl:31])[CH:30]=3)[N:25]=2)[CH:16]=1
Reactant: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(N4CCN(C5CCCCC5)CC4)s3)cc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(Nc1nc(-c2cc(Cl)cs2)c(N2CCN(C3CCCCC3)CC2)s1)c1cnc(N2CCC(C(=O)O)CC2)c(Cl)c1
Reaction time: 24 h
Yield: 131.7 %

Procedure:
To a solution of 30 mg of the compound of Example 13 in 1 ml of MeOH, 0.12 ml of 1M NaOH aq. was added at room temperature, and the mixture was stirred for 24 hours. After the solvent was evaporated under reduced pressure, the obtained residue was dissolved in 5 ml of EtOAc, 0.2 ml of 1M HCl was added thereto, and the mixture was stirred for a while. Then, the solvent was evaporated under reduced pressure and washed with diethylether to obtain 20 mg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid hydrochloride.