Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+].C1C=CC2N(O)N=[N:27]C=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH2:27][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(N)=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98 mmol) in DMF (5 mL) and was added ammonium hydroxide (2.0 mL, excess), and HOBt (645 mg, 4.78 mmol) and the resulting solution stirred at 0° C. for 10 minutes. EDCI (916 mg, 4.78 mmol) was added and the reaction stirred at 25° C. for 18 hours. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate (45 mL), brine (10 mL), and 5% H3PO4 aqueous solution (10 mL), and the layers were separated. The organic layer was washed with 5% H3PO4 aqueous solution (10 mL), twice with saturated aqueous sodium bicarbonate solution (15 mL), water (15 mL), and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light colored solid. The crude material was taken on directly to the next step. (0.990 g, 99% yield) MS (ESI+) m/z=251 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[CH3:39][N:40]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=[N:41]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:39][N:40]1[C:44]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:27][CH2:26]4)[CH:20]=[N:19][CH:18]=2)=[CH:43][CH:42]=[N:41]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 150 °C
Yield: 100 %

Procedure:
(4R)-tert-Butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (158 mg, 0.270 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, St. Louis, Mo.; 84 mg, 0.405 mmol), PdCl2(Amphos) (Aldrich, St. Louis, Mo.; 19.14 mg, 0.027 mmol), and potassium phosphate (172 mg, 0.811 mmol) in a mixture of dioxane (2.5 mL) and water (0.250 mL) was heated by microwave at 150° C. for 5 min. The resulting mixture was heated at 100° C. for 3 h. The mixture was subsequently concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-80% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(5-(1-methyl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (158 mg, 0.270 mmol, 100% yield) as a light-yellow oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.06 (1 H, s), 8.43 (1 H, s), 8.21 (1H, br. s.), 7.76 (1 H, d, J=8.6 Hz), 7.58 (1 H, s), 7.49 (1 H, d, J=8.4 Hz), 6.33 (1H, s), 5.86 (1 H, d, J=7.6 Hz), 4.57 (1 H, br. s.), 4.31-4.40 (1 H, m), 4.19-4.29 (1 H, m), 4.06 (1 H, d, J=11.0 Hz), 3.93 (3 H, s), 3.75-3.87 (1 H, m), 3.15 (1 H, d, J=14.1 Hz), 2.92 (1 H, br. s.), 2.60-2.74 (1 H, m), 2.43 (1 H, br. s.), 2.25 (1 H, m, J=9.0, 4.1 Hz), 2.17 (1 H, d, J=14.9 Hz), 1.76-1.91 (2 H, m), 1.74 (2 H, br. s.), 1.13 (9 H, br. s.), 0.78-0.88 (2 H, m), 0.62-0.73 (2 H, m). MS (ESI, pos. ion) m/z: 586.4 (M+1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=O.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.CCOCC>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:21])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Nc1ccc(F)cc1)c1ccccn1
Yield: 66.2 %

Procedure:
An anhydrous solution of 1,1'-carbonyldiimidazole (13.13 g, 81 mmol) in dimethylformamide (80 mL) was treated with picolinic acid (10.0 g, 81 mmol), and after 1 hour 4-fluoroaniline (8.46 mL, 89 mmol) was introduced. After 27 hours the reaction mixture was poured into saturated sodium bicarbonate solution (900 mL) and ether (400 mL). The aqueous layer was extracted again with ether (3×400 mL) and the ethereal layers were dried and concentrated. The crude solid residue was recrystallized from a mixture of ether and petroleum ether to yield N-(4-fluorophenyl)-2-pyridinecarboxamide (11.6 g, 66%) as beige crystals, m.p. 100°-103° C.
Reaction SMILES: [CH:1]1([C:4](=O)/[CH:5]=[C:6](\O)/[CH:7]([F:9])[F:8])[CH2:3][CH2:2]1.O.[NH2:13][NH2:14].Cl>C(O)C>[CH:1]1([C:4]2[NH:14][N:13]=[C:6]([CH:7]([F:9])[F:8])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(/C=C(\O)C(F)F)C1CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: FC(F)c1cc(C2CC2)[nH]n1
Reaction time: 3 h
Yield: 76.4 %

Procedure:
Intermediate 62 (390 mg, 2.4 mmol) dissolved in ethanol (2 ml), added hydrazine hydrate (0.13 ml, 2.65 mmol) and HCl (0.18 ml). This mixture was refluxed for 3 h. After 3 h, ethanol was removed on rotavapour and work up (H2O/AcOEt) afforded the title compound (290 mg) which was used in the next step without further purification. 1H-NMR (δ ppm, CDCl3, 400 MHz): 12.96 (s, 1H), 6.84 (t, J 54.8, 1H), 6.15 (s, 1H), 1.95-1.87 (m, 1H), 0.99-0.91 (m, 2H), 0.74-0.66 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: NCC(O)CO
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCC(O)CO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 3-amino-1,2-propanediol (45 ml) and triethylamine (150 mg) were added to pyridine (500 mg), and the mixture was stirred at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (60 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1.5 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (107 mg) as a colorless powder.
Reaction SMILES: [C:1]([NH:7][NH2:8])([C:3]([NH:5][NH2:6])=[O:4])=[O:2].[C:9](Cl)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]>CC(N(C)C)=O>[C:9]([N:5]([C:3](=[O:4])[C:1]([NH:7][NH2:8])=[O:2])[NH:6][C:9](=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12])(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]
Reactant: O=C(Cl)c1ccccc1O
Reactant: NNC(=O)C(=O)NN
Solvent: CC(=O)N(C)C
Product: NNC(=O)C(=O)N(NC(=O)c1ccccc1O)C(=O)c1ccccc1O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
35.4 g of oxalic acid bis-hydrazide are suspended in 1000 ml of dimethyl acetamide, the suspension is briefly heated to 100° C and cooled to room temperature, and 93.5 g of salicylic acid chloride are slowly added in such a way that the reaction temperature does not exceed 40° C. After a further 15 minutes' stirring a largely homogeneous, yellowish solution has been obtained. After filtering off the undissolved constituents, the solution is mixed with 1.2 liters of ice water, whereupon the reaction product precipitates. The substance is filtered off, washed with water and purified by again precipitating it from dimethyl acetamide solution by means of water. After isolation and intensive drying at 130° C in vacuo, N,N'-bis-(salicyloyl)-oxalic acid dihydrazide (Stabiliser No. 2) is obtained as a white powder of melting point>320° C (decomposition).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH2:31])[CH3:30])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH:31][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:30])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-9H-purine (0.077 g, 0.39 mmol), 1-[4-chloro-1- (3-fluorophenyl)-2-naphthyl]ethanamine (0.058 g, 0.19 mmol), and N,N-diisopropylethylamine (0.067 mL, 0.39 mmol) in ethanol (0.6 mL) was heated at 100° C., in a sealed tube overnight. The volatiles were removed under reduced pressure. The residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H18ClFN5(M+H)+: m/z=418.1; Found: 418.1.
Reaction SMILES: C(O[CH2:4][CH:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:13][C:11]1[C:22]2[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOCC(C(=O)OCC)C(=O)OCC
Reactant: Cc1cccc(N)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(C)ccc2c1O
Temperature: 100 °C
Yield: 76.3 %

Procedure:
Diethyl ethoxymethylmalonate (37.8 mL, 187 mmol) and m-toluidine (20.0 mL, 187 mmol) were combined and heated at 100° C. for about 3 hours. The reaction mixture was allowed to cool to ambient temperature and it solidified. Dowtherm A (350 mL) was added and the reaction mixture was heated at reflux for about 30 minutes. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, rinsed with acetone and dried to provide 33 g of ethyl 4-hydroxy-7-methyl-3-quinolinecarboxylate as a tan powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([CH3:9])([OH:8])[CH2:4][CH2:3]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32](O)=[O:33])=[C:25]2[N:24]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32]([NH:1][CH:2]3[CH2:7][CH2:6][C:5]([OH:8])([CH3:9])[CH2:4][CH2:3]3)=[O:33])=[C:25]2[N:24]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: CC1(O)CCC(N)CC1
Product: CC1(O)CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Yield: 48 %

Procedure:
The minor isomer from Step A (45.1 mg, 0.197 mmol) was dissolved in DCM (1.0 mL) and 4N HCl in dioxane (492 μL, 1.97 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour and was concentrated to afford 4-amino-1-methylcyclohexanol (minor isomer). The 4-amino-1-methylcyclohexanol was reacted with (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C) according to the procedure outlined in Example 1 to provide the title product as a white solid (14 mg, 48% yield). MS (apci) m/z=456.1 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].OC(C(F)(F)F)=O.[NH2:37][CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41].C[O-].[Na+]>CCO>[F:29][C:27]1[CH:28]=[C:23]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:9]=3)[C:14]([OH:15])=[C:5]([C:3]([NH:37][CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41])=[O:4])[N:6]=2)[CH:24]=[N:25][CH:26]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A mixture of 1-(5-fluoro-pyridin-3-yl)-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (51 mg, 0.13 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (121 mg, 0.52 mmol) and NaOMe (56 mg, 1.05 mmol) in EtOH (3 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water (20 mL) and EtOAc (20 mL). 1 M HCl was added with vigorous stirring until pH was ˜3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-35% EtOAc/hexanes+2% AcOH) to give 30 mg of the title compound as a yellow solid. MS: (+) m/z 476.14 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(N1CCN(c2ccccc2)CC1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(N1CCN(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Temperature: 155 °C
Yield: 72 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(4-phenylpiperazin-1-yl)ethanone (1.0 g, 3.9 mmol) and chlorosulfonic acid (6 mL) was heated at 155° C. for 15 min. After cooling to RT, the mixture was poured into ice water and extracted with EtOAc. The organic layer was concentrated and purified via silica gel chromatography using 7/3 hexanes/EtOAc to obtain 4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride as a yellow solid (1.0 g, 72%). 1H NMR (400 MHz, CDCl3) δ 7.93-7.89 (m, 2H), 6.96-6.92 (m, 2H), 3.88 (t, J=5.3 Hz, 2H), 3.83 (t, J=5.1 Hz, 2H), 3.55-3.52 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]>CN(C(OC)OC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[C:10]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])=[CH:10][N:11]([CH3:19])[CH3:12]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl
Agent: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)N1C(=O)c2ccccc2C1=O

Procedure:
1 mmol of 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione was heated to 80° C. in neat N,N-dimethylformamidedimethyl acetal for six hours. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether to obtain 2-{2-(2,4-dichlorophenyl)-1-[(dimethylamino)methylene]-2-oxoethyl}isoindoline 1,3-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7](Cl)=[O:8])([O-:3])=[O:2].N1C=CC=CC=1.[CH:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7]([O:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: OC1CCCCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(OC1CCCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 88 %

Procedure:
Twelve grams (0.055 mole) fo crude 3-nitro-4-chlorobenzoyl chloride were dissolved in 200 ml. of benzene. Eight milliliters of pyridine were added to the reaction mixture. Six milliliters of cyclohexanol were dissolved in 50 ml. of benzene and the solution was added dropwise to the acid chloride-pyridine mixture. The reaction mixture was refluxed for 4 hours and filtered. The benzene filtrate was washed successively with dilute acid, dilute base and water. The washed benzene solution was dried and evaporated in vacuo to yield 12.5 g (88 percent) of cyclohexyl 3-nitro-4-chlorobenzoate, mp 57°-58° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]([F:69])([F:68])[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[N:63]=[C:62]([NH2:67])[CH:61]=[CH:60]2>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([NH:67][C:62]3[CH:61]=[CH:60][C:59]4[C:64](=[CH:65][CH:66]=[C:57]([C:56]([F:68])([F:55])[F:69])[CH:58]=4)[N:63]=3)=[O:21])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:24])([F:23])[F:25])([O-:3])=[O:2]
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: Nc1ccc2cc(C(F)(F)F)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)Nc1ccc2cc(C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (30 ml) was added EDAC.HCl (81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and triethylamine (85 mg, 0.84 mmol). After 15 minutes 6-(trifluoromethyl)quinolin-2-amine (68 mg, 0.32 mmol) was added and the resulting solution was stirred overnight at room temperature. The contents were then quenched with water (100 ml) and extracted with dichloromethane (3×50 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 3% methanol in dichloromethane to afford 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]-oxy]-N-[6-(trifluoromethyl)quinolin-2-yl]acetamide as a yellow solid (80.6 mg, 52%). (ES, m/z): [M+H]+ 557.20; 1H NMR (300 MHz, CD3OD): δ 8.51-8.47 (m, 2H), 8.29 (s, 1H), 8.05-7.99 (m, 2H), 7.93 (dd, J=1.8, 9.0 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.83 (dd, J=2.4, 9.0 Hz, 1H), 4.27 (s, 2H), 3.63-3.45 (m, 2H), 2.27-2.14 (m, 4H), 1.70-1.56 (m, 2H), 1.46-1.34 (m, 2H).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.CN.[CH3:33][N:34](C)C=O>CO>[CH3:33][NH:34][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12](=[O:30])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: O=C(Nc1ccc(C(=O)N2CCC(=O)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: CN
Solvent: CO
Product: CNC1CCN(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-oxo-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline(0.5 g) are added 40% solution of methylamine in methanol (5 ml), molecular sieves 4A (1 g) and dimethylformamide (6 ml), and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is filtered and to the filtrate is added sodium borohydride (80 mg), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated and water is added to the resulting residue, and extracted with ethyl acetate. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give 4-methylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.2 g) as colorless amorphous.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH:17](O)[CH3:18])[C:12]=1[CH3:20]>ClCCl>[Cl:10][C:11]1[C:12]([CH3:20])=[C:13]([CH:17]([F:7])[CH3:18])[N:14]=[CH:15][N:16]=1
Reactant: Cc1c(Cl)ncnc1C(C)O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1c(Cl)ncnc1C(C)F
Temperature: -78 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
DAST (0.436 mL, 3.30 mmol) was added to dichloromethane (DCM) (11 mL), cooled to −78° C. and treated dropwise with a solution of 1-(6-chloro-5-methyl-4-pyrimidinyl)ethanol (Intermediate 44, 380 mg, 2.201 mmol) in DCM (4 mL) under argon. The resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched by adding water (7 ml) and extracted with DCM (×2). The DCM layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 Biotage column chromatography eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (153 mg);
Reaction SMILES: [C:1]1([N:11]=[C:12](Cl)[C:13]([F:16])([F:15])[F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:18]=[N+:19]=[N-:20].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([N:11]2[C:12]([C:13]([F:16])([F:15])[F:14])=[N:20][N:19]=[N:18]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C(Cl)=Nc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Four grams (15.5 mmol) of N-(naphthalen-1-yl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 13, 1.84 g (27.9 mmol) of sodium azide, 1.08 g (7.76 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 14 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was precipitated for 1 hour in 18 ml of n-hexane while being cooled using an ice bath, followed by filtration and drying, thereby giving 3.86 g of 1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-tetrazole as a white powder (yield: 94.1%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1cccc(Br)c1
Product: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Temperature: 190 °C
Reaction time: 2.5 h

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (107 mg, 0.87 mmol) (described in a previous experimental) and 3-bromoaniline (0.75 mL, 7.8 mmol) is stirred under N2 at 190° C. for 2.5 h, and the precipitate which appears on cooling is recrystallized from PriOH. 1H NMR (DMSO) δ 9.91 (1H, brs), 9.34 (1H, s), 8.45 (1H, s), 8.19 (1H, s), 7.84 (1H, d, J=8.0 Hz), 7.34 (1H, t, J=8.0 Hz), 7.29 (1H, d, J=8.2 Hz), 6.68 (2H, brs), 6.45 (1H, s).