Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](I)=[C:21]([CH3:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH:32](B1OC(C)(C)C(C)(C)O1)=[CH2:33].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:32]=[CH2:33])=[C:21]([CH3:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(I)c(C)c1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(Oc2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)cc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-1-(4-iodo-3-methyl phenoxy)-2-propylbenzene (265 mg, 0.471 mmol) was dissolved in N,N-dimethylformamide (4.7 mL) and water (0.9 mL). The resultant mixture was sequentially added with vinylboronic acid pinacol ester (280 μL, 1.65 mmol), tetrakis triphenylphosphine palladium (54 mg, 0.0471 mmol), and sodium carbonate (300 mg, 2.83 mmol), and stirred at 80° C. for 1 hour. After completion of the reaction, the reaction solution was filtered using celite and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/chloroform), and 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-1-(3-methyl-4-vinylphenoxy)-2-propylbenzene (218 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.N1C=CC=CC=1>O>[C:5]([O:4][CH2:1][CH2:2][N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)(=[O:7])[CH3:6]
Reactant: OCCn1cccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCn1cccc1
Temperature: 25 °C
Yield: 55 %

Procedure:
The resulting product is reacted with acetic anhydride in accordance with the method of F. F. Blicheand E. S. Blake, J.Am.Chem.Soc.,53, 1015 (1931). A mixture of 1-(2-hydroxyethyl)pyrrole (147 g, 1.32 mole), pyridine (415 ml) and acetic anhydride (139 ml) is heated on a steam bath for 0.5 hours. The reaction mixture is cooled to room temperature, poured into water (one 1) and the product is extracted into ethyl acetate (3×1 l). The extract is washed successively with dilute hydrochloric acid, saturated sodium chloride solution, dilute sodium bicarbonate solution, and again with saturated sodium chloride solution. The extract is dried over sodium sulfate, evaporated in vacuo and the residue (150 g) is subjected to column chromatography on Florisil® activated magnesium silicate. The desired product is eluted with hexane-dichloromethane (1:1) to give 128 g (55%) 1-(2-acetoxyethyl)pyrrole, an oil, identical to an authentic specimen.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][CH2:22][NH:23]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(C1NC=CN=1)(C1NC=CN=1)=[S:29].C([N:42]([CH2:45]C)CC)C.N>C1COCC1.CO>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][CH2:22][N:23]3[C:45](=[S:29])[NH2:42])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: c1cc2c(c(OCCCCCOc3cccc4ccccc34)c1)CCCN2
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=S)N1CCCc2c(OCCCCCOc3cccc4ccccc34)cccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 5-[5-(naphthalen-1-yloxy)-pentyloxy]-1,2,3,4-tetrahydro-quinoline (100 mg, 0.28 mmol) and thiocarbonyl diimidazole (64 mg, 0.36 mmol) in dry THF (3 mL) was added triethylamine (30 mg, 0.3 mmol). After stirred at 50° C. for 3 h, the reaction mixture was treated with excess 2.0 M ammonia in methanol (4 mL). The stirring was continued overnight at 50° C. After removal of the solvent, the residue was purified by silica gel chromatography to give 5-[5-(naphthalen-1-yloxy)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carbothioic acid amide, compound 4 (88 mg, 0.21 mmol, 75%) as a white solid. MS (EI): m/z 421 (M+H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].[C:32](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:31][C:2]([F:1])([F:30])[C:3]([N:5]([C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:32])=[O:4]
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1cccc(NC(=O)C(F)(F)F)c1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
636 mg (1.5 mmol) of (Z)-3-[1-(3-trifluoroacetylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 20 ml of acetone and after the addition of 423 mg (3 mmol) of potassium carbonate and 0.25 g (3 mmol) of methyl iodide stirred for 18 hours at ambient temperature. The reaction solution is freed from the solvent in vacuo after the insoluble matter has been filtered off. The residue is divided between dichloromethane/water, the organic phase is dried and concentrated by evaporation. The residue is triturated with ether, suction filtered and dried.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: C1CCNCC1
Product: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (300 mg, 1.21 mmol) and piperidine in to give 4-chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinoline. Mass Spectrum (ESI) m/e=297.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:5])=[CH:3]Br.[CH3:6][C:7]([OH:11])([CH:9]=[CH2:10])[CH3:8].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:6][C:7]([OH:11])([CH2:9][CH:10]=[CH:1][C:2]([CH3:5])([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:3])[CH3:8]
Reactant: CC(C)=CBr
Reactant: C=CC(C)(C)O
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(O)CC=CC(C)(C)N1CCCCC1
Yield: 31 %

Procedure:
A mixture of 10 mmoles 2-methyl-1-bromo-1-propene, 12.5 mmoles 2-methyl-3-buten-2-ol, 30 mmoles piperidine, 0.20 mmole palladium acetate and 0.40 mmole triphenylphosphine was reacted at 100° C. There was produced 61% of a mixture of nonadienols, 31% 2,6-dimethyl-6-piperidino-4-hepten-2-ol and 6% of what is believed to be 2,6-dimethyl-4-piperidino-5-hepten-2-ol.
Reaction SMILES: N[C@@H](CC)[C@H](O)[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[NH2:13][C@@H:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O.[CH3:21]NC1CC1>>[NH2:13][C@@H:14]([CH2:18][CH2:19][CH3:20])[C@H:15]([OH:17])[C:4]([N:6]([CH:7]1[CH2:9][CH2:8]1)[CH3:21])=[O:5]
Reactant: CCC[C@H](N)C(=O)O
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CNC1CC1
Product: CCC[C@H](N)[C@H](O)C(=O)N(C)C1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using (S)-2-aminopentanoic acid in the first step (step B1), and N-methylcyclopropanamine in the seventh step (step B7).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:53])[C@H:47]([CH2:49][C:50](=[O:52])[NH2:51])[NH2:48])(C)(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([NH:48][C@H:47]([C:46]([OH:45])=[O:53])[CH2:49][C:50](=[O:52])[NH2:51])=[O:34])=[CH:36][CH:37]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)O)cc2)cc1

Procedure:
The product from Example 95C and L-aspargine tert-butyl ester hydrochloride were processed as described in Example 251A and 258B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.18-13.09 (br.s, 1 H), 8.94 (s, 1 H), 8.28 (d, 1 H), 7.39 (s, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.91 (s, 1 H), 6.84 (d, 2 H), 4.60 (dd, 1 H), 4.49 (s, 2 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 2.91 (s, 3 H), 2.60 (d2 H), 2.39 (s, 3 H); MS ((ESI+) m/z 661 (M+H)+.
Reaction SMILES: NC1N(CC2C=CC=CC=2Cl)N=NC=1C(N)=O.N1C=CC=CC=1.C(Cl)(=O)C(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][N:39]1[C:43]([NH:44][C:45](=O)[C:46]([CH3:49])([CH3:48])[CH3:47])=[C:42]([C:51]([NH2:53])=[O:52])[N:41]=[N:40]1>CN(C)C(=O)C.O>[C:46]([C:45]1[NH:44][C:43]2[N:39]([CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[N:40]=[N:41][C:42]=2[C:51](=[O:52])[N:53]=1)([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)C(=O)Nc1c(C(N)=O)nnn1Cc1ccccc1Cl
Agent: CC(C)(C)C(=O)Cl
Agent: NC(=O)c1nnn(Cc2ccccc2Cl)c1N
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3Cl)c2[nH]1
Temperature: 155 °C

Procedure:
5-amino-1-(2-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide (10.80 g, 42.9 mmol, Eq: 1.00) was suspended in N,N-dimethylacetamide (50.2 g, 54.0 ml). Pyridine (5.1 g, 5.19 ml, 64.4 mmol, Eq: 1.5) was added followed by pivaloyl chloride (7.84 g, 8.00 ml, 64.4 mmol, Eq: 1.5) and the reaction mixture was heated to ca 80° C. After 3 h reaction (and complete conversion of the starting material to the intermediate), KHCO3 (21.6 g, 215 mmol, Eq: 5.00) was added and the suspension was heated to Tj=155° C. for 24 h to convert the 1-[(2-chlorophenyl)methyl]-5-(2,2-dimethylpropanoylamino)triazole-4-carboxamide intermediate to the product. The reaction mixture was cooled to RT and water (254 g, 254 ml) was added dropwise over 30 min. The brown suspension was cooled to 0° C., stirred for 1 h30 min and was filtered. The filter cake was washed with water (43.2 g, 43.2 ml) and dried at 500° C./5 mbar to give 11 g of the title compound as an off-white powder. MS(m/e): 318.0 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16](O)[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:15]2=[C:16]([Cl:28])[N:17]3[C:21]([N:22]=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[N:18]3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(O)c2CC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(Cl)c2CC1
Temperature: 25 °C

Procedure:
To a suspension of 3.0 g (8.86 mmol) 10-hydroxy-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester in 6 mL toluene was added 7 mL (74.06 mmol) of phosphorus oxychloride and 1.28 mL (7.35 mmol) of DIPEA, and the reaction was heated at reflux for 40 minutes. The mixture was cooled to room temperature and poured into ice. The aqueous phase was extracted with DCM (3×20 mL) and the combined organic layers were dried over MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1 to 7:3).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]([CH3:31])[CH3:30].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH:29]([CH3:31])[CH3:30])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)I
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(C)n(C(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.00 g) and 2-iodopropane (2.8 mL) in N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.34 g), and the mixture was stirred at room temperature for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.23 g, 10%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)[OH:45])C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH2:18][OH:45])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: OB(O)c1cncnc1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@H]5CO)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 74A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.02 (d, J=8.81 Hz, 1H) 7.77 (d, J=1.36 Hz, 1H) 7.45 (d, J=7.80 Hz, 1H) 7.40 (dd, J=8.48, 1.70 Hz, 1H) 7.07 (d, J=7.80 Hz, 1H) 3.83-4.00 (m, 1H) 3.52-3.75 (m, 2H) 3.32-3.47 (m, 1H) 2.99-3.17 (m, 1H) 2.63-2.80 (m, 3H) 2.59 (s, 3H) 2.50 (s, 3H) 1.70-2.08 (m, 5H) 1.46-1.65 (m, 2H). MS: (M+H)+=394.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:27][C:28]1[CH:51]=[CH:50][C:31]([C:32]([NH:34][CH2:35][CH:36]([N:40]2[CH2:45][CH2:44][N:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:42][CH2:41]2)[C:37](O)=[O:38])=[O:33])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].Cl.[C:53]([O:57][NH2:58])([CH3:56])([CH3:55])[CH3:54].C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:53]([O:57][NH:58][C:37]([CH:36]([N:40]1[CH2:45][CH2:44][N:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:42][CH2:41]1)[CH2:35][NH:34][C:32](=[O:33])[C:31]1[CH:50]=[CH:51][C:28]([O:27][CH2:23][C:24]#[C:25][CH3:26])=[CH:29][CH:30]=1)=[O:38])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)ON
Reactant: CC#CCOc1ccc(C(=O)NCC(C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC#CCOc1ccc(C(=O)NCC(C(=O)NOC(C)(C)C)N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 0.33 h
Yield: 101.1 %

Procedure:
50 mg (0.4 mmol) of 1-hydroxybenzotriazole then 70 mg (0.4 mmol) of 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride are added to a solution of 100 mg (0.2 mmol) of 3-(4-but-2-ynyloxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoic acid in 2 ml of dichloromethane and 2 ml of dimethylformamide. The reaction medium is stirred for 20 min before adding a mixture containing 30 mg (0.3 mmol) of O-tert-butylhydroxylamine hydrochloride and 40 μl (0.3 mmol) of triethylamine. The mixture is then stirred at ambient temperature for 20 h. Dichloromethane is added, the organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate then with water, dried over magnesium sulphate, filtered and concentrated under vacuum. 100 mg (85%) of N-[2-tert-butoxycarbamoyl-2-(4-methanesulphonylpiperazin-1-yl)ethyl]-4-but-2-ynyloxy benzamide are obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1.[CH3:16][NH:17][CH3:18].[O:19]1[CH2:23]CCC1>>[Br:1][C:2]1[C:3]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:23](=[O:19])[N:17]([CH3:18])[CH3:16])=[CH:11][CH:10]=2)=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1
Reactant: CCn1cc(Br)c(-c2ccc(N)cc2)n1
Reactant: CNC
Reactant: C1CCOC1
Product: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described in Example 5a with 4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)aniline and 2 M dimethylamine in tetrahydrofuran provided the title compound. ESMS [M+H]+: 337.2
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.C1(C)C=CC=CC=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(N(CC)CC)C>[C:16]([NH:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCc1nnc(N)s1
Reactant: CCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nnc(CC)s1
Yield: 80.4 %

Procedure:
2-Amino-5-ethyl-1,3,4-thiadiazole (0.5 g) was added to a mixture of toluene (5 ml) and triethylamine (0.4 g). With stirring, butyryl chloride (0.5 g) was added to the suspension at room temperature. After stirring for 2 hours, aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with water several times. The precipitated crystals and the organic layer were combined and the solvent was concentrated to 5 ml. The precipitated crystals were filtrated and dried. The title compound (0.62 g) was obtained.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][S:5]1(=O)=O)[CH3:3].[CH2:17]([N:19]([CH2:23][CH3:24])[C:20](Cl)=[O:21])[CH3:18]>C(N(CC)CC)C>[CH2:17]([N:19]([CH2:23][CH3:24])[C:20]([N:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9](=[O:10])[N:4]([CH:2]([CH3:3])[CH3:1])[S:5]1)=[O:21])[CH3:18]
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N1SN(C(C)C)C(=O)c2ccccc21
Yield: 80.8 %

Procedure:
In a similar manner 12 g of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide was caused to react with 7.28 g of diethylcarbamoyl chloride in the presence of 14 ml of triethylamine. The crude product was crystallized from methanol to afford 12.4 g of N,N-diethyl-3,4-dihydro-3-(1-methylethyl)-4-oxo-1H-2,1,3-benzothiadiazine-1-carboxamide, m.p. 103°-104.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:30]=[N:29][C:28]2[N:13]([C@@H:14]3[O:27][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:16]=[CH:15]3)[CH:12]=[N:11][C:10]=2[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].CO>[CH2:1]([N:8]1[CH:30]=[N:29][C:28]2[N:13]([C@@H:14]3[O:27][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH:12]=[N:11][C:10]=2[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1c2ncn([C@H]3C=C[C@@H](COCc4ccccc4)O3)c2ncn1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1c2ncn([C@H]3CC[C@@H](COCc4ccccc4)O3)c2ncn1Cc1ccccc1
Yield: 90 %

Procedure:
To a methanol solution (1 mL) of N1,5′-O-dibenzyl-2′,3′-didehydro-2′,3′-dideoxyinosine (207 mg, 0.5 mmol), 5% palladium-carbon (20 mg) was added, and the mixture was stirred at room temperature for 2 hours in an atmosphere of hydrogen (1 atm). The palladium catalyst was removed from the obtained reaction mixture by filtration, and the resultant filtrate was concentrated under reduced pressure. After purification by chromatography (using 15 g of silica gel and ethyl acetate as an eluting solution), 187 mg of the intended product was obtained in a yield of 90% as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][C:11](=C3C(=O)C4C(=CC=CC=4)C3=O)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:25][NH2:26].CC[O:29][CH2:30][CH3:31]>>[C:1]1([C:7]2[C:12]([CH2:5][C:4]3[C:3]4[C:31](=[CH:12][CH:7]=[CH:1][CH:2]=4)[C:30](=[O:29])[NH:26][N:25]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: NN
Reactant: O=C1C(=C2C=CN=C(c3ccccc3)C2)C(=O)c2ccccc21
Solvent: O
Product: O=c1[nH]nc(Cc2cccnc2-c2ccccc2)c2ccccc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A mixture of 2-(2-phenyl-pyridin-4-ylidene)-indan-1,3-dione (3.1 g, 10.4 mmol) and hydrazine hydrate (9.7 mL) was stirred at 130° C. under argon for 5 h. The reaction mixture was cooled and filtered. The resultant tacky solid was dissolved in ethyl acetate (250 mL) and then washed with water (2×50 mL) and brine (1×50 mL). The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. Trituration from ether afforded the title compound as a beige solid (2.82 g, 9.0 mmol, 86% yield). 1H-NMR (DMSO-d6) 12.59 (broad s, 1H), 8.52 (d, J=4.6, 1H), 8.24 (dd, J=7.7, 1.0,1H), 7.95 to 8.03 (m, 4H), 7.78 to 7.91 (m, 2H), 7.40 to 7.49 (m, 3H), 7.21 (d, J=6.5, 1H), 4.39 (s, 2H); MS ES 314 (M+H)+, calc.313; TLC (1:2:8 v/v methanol-acetone-dichloromethane) Rf=0.40.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9](O)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25].CN(C)C=[O:30]>>[N+:24]([C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=1[O:30][C:10]1[CH:11]=[C:6]([C:2]([CH3:5])([CH3:1])[CH2:3][CH3:4])[CH:7]=[CH:8][CH:9]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Reactant: CCC(C)(C)c1ccc(O)cc1
Reactant: CN(C)C=O
Product: CCC(C)(C)c1cccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Temperature: 150 °C

Procedure:
A mixture of 4-(1,1-dimethylpropyl)phenol (821 mg, 0.005 mol), 4-bromo-3-nitrobenzotrifluoride (1.35 g, 0.005 mol) potassium carbonate (1.38 g, 0.010 mol) and cuprous oxide (143 mg, 0.001 mol) in dimethylformamide (25 ml) was stirred under argon at 150 ° C. for sixteen hours. The solvent was evaporated and the residue partitioned between ethyl acetate and water, the layers separated, dried over MgSO4 and evaporated. The crude product flash chromatographed (silica gel, ethyl acetate/hexane) to give the title compound as a yellow oil. 1H NMR (250 MHz, CDCl3) ∂ 8.20 (d, 1H), 7.70 (dd, 1H), 7.45 (m, 2H), 7.05 (m, 3H), 1.65 (q, 3H), 1.30 (s, 6H), 0.65 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11].Cl.Cl[CH2:19][CH2:20][NH2:21]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][C:6]1[C:10]([CH3:11])=[N:9][N:8]([CH2:19][CH2:20][NH2:21])[C:7]=1[CH3:12]
Reactant: Cc1n[nH]c(C)c1Cc1cc(Cl)cc(Cl)c1
Reactant: NCCCl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nn(CCN)c(C)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 120 °C
Yield: 19.3 %

Procedure:
A stirred suspension of the pyrazole (200 mg, 0.78 mmol) of Example 23 and 2-chloroethylamine hydrochloride (136 mg, 1.18 mmol) in toluene (1 ml) was heated at 120° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. After cooling, the mixture was diluted with dichloromethane (30 ml), washed with 2M aqueous sodium hydroxide solution (20 ml), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with methanol:dichloromethane:ammonia (5:95:0.5, by volume) to afford the title compound (45 mg) as white crystals, m.p. 70–72° C.