Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:23])[NH:15][C:16]2[C:20]([C:21]=1[OH:22])=[CH:19][S:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:23])[NH:15][C:16]3[C:20]([C:21]=2[OH:22])=[CH:19][S:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cscc2[nH]c1=O
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)c1c(O)c2cscc2[nH]c1=O
Temperature: 130 °C
Yield: 29.8 %

Procedure:
Cyclohexylamine (4.6 mL, 40.12 mmol) was added to a solution of 7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (39) (3.2 g, 82.70 mmol) in toluene and heated at 130° C. for 4 h. The solution was cooled and excess solvent was distilled off under vacuum. The residue was taken in CH2Cl2, sonicated briefly, and filtered to yield 3.5 g (89%) of 7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid cyclohexylamide as white solids. MP 244° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.26-1.41 (m, 5H), 1.53 (m, 1H), 1.65 (m, 2H), 1.86 (m, 2H), 3.81 (m, 1H), 6.95 (s, 1H), 8.25 (s, 1H) ppm; MS m/z=293 amu (M++1).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23]OS(C)(=O)=O)[N:11]=1)=[O:9].C(Cl)Cl>O>[F:35][C:33]([F:36])([F:34])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:38])([F:37])[F:1])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23][NH:11][CH2:10][CH2:8][N:7]([CH3:29])[CH3:6])[N:11]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(COS(C)(=O)=O)ncc1-c1ccccc1Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)CCNCc1ncc(-c2ccccc2Cl)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of 0.62 g (1.07 mmol) methanesulfonic acid 4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-5-(2-chloro-phenyl)-pyrimidin-2-ylmethyl ester in 10 ml CH2Cl2 0.29 ml (2.66 mmol) 2-dimethylyminoethylamine were added. The reaction mixture was stirred for 16 hrs. at RT and than poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.22 g (36%) 5-(2-chloro-phenyl)-2-[(2-dimethylamino-ethylamino)-methyl]-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless oil, MS (ISP): 574.1 (M+H+).
Reaction SMILES: C(O[NH:6][N:7]([C:12]1([CH2:22][CH:23]=[CH2:24])[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1)C(NN)=O)(C)(C)C.Cl>CCOC(C)=O.O1CCOCC1>[CH2:22]([C:12]1([NH:7][NH2:6])[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1)[CH:23]=[CH2:24]
Reactant: C=CCC1(N(NOC(C)(C)C)C(=O)NN)CCOC2(CCCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCC1(NN)CCOC2(CCCC2)C1
Temperature: 25 °C
Yield: 112.1 %

Procedure:
A solution of (tert-butoxy)-N′-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]carbohydrazide (0.33 g, 1.06 mmol) in 4 mL of EtOAc was added 4M HCl in dioxane at rt. The solution was stirred at rt until reaction completion, monitored by LC-MS (30 h). The solvent was then removed to give [9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]hydrazine (250 mg). LCMS m/z 211.1 (M+1) observed.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[N:27]([C:28]5[CH:37]=[CH:36][C:31]([C:32](OC)=[O:33])=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:16]([CH2:38][CH3:39])=[N:15]2)[CH2:13][CH2:12]1.CO.C(OCC)(=O)C>C1(C)C=CC=CC=1.O1CCCC1.O>[CH:11]1([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[N:27]([C:28]5[CH:29]=[CH:30][C:31]([CH2:32][OH:33])=[CH:36][CH:37]=5)[N:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:16]([CH2:38][CH3:39])=[N:15]2)[CH2:13][CH2:12]1
Reactant: CCc1nn(C2CC2)c2cc(-c3ccnn3-c3ccc(C(=O)OC)cc3)ccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1nn(C2CC2)c2cc(-c3ccnn3-c3ccc(CO)cc3)ccc12
Temperature: 25 °C

Procedure:
A solution of diisobutylaluminum hydride (0.19 mL, 1.5 M in toluene, 0.28 mmol) in toluene (0.19 mL) was added dropwise to a solution of methyl 4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoate (36 mg, 0.093 mmol) in tetrahydrofuran (5 mL) under an atmosphere of argon at −78° C. The reaction was allowed to warm to room temperature over a period of 1 hour. The mixture was then chilled to −40° C. and methanol (4 mL) was slowly added. Again, the reaction was allowed to warm slowly to room temperature, then it was poured into a mixture of ethyl acetate and water. The product was extracted (3×ethyl acetate), and the combined organics were dried and concentrated. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexanes as the eluent to afford 22.6 mg (68%) of 4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}methanol. LC/MS (EI) tR 3.19 (Method A), m/z 359.2 (M++1). 1H NMR (CDCl3) δ 1.0 (m, 4H); 1.2 (t, 3H); 2.5 (m, 1H); 2.8 (m, 2H); 3.2 (m, 1H); 4.5 (s, 2H); 6.5 (s, 1H); 6.9 (t, 1H); 7.0-7.2 (m, 5H); 7.5 (d, 1H); 7.6 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[N:13]=[C:12]([CH2:14][C:15](N)=[O:16])[O:11][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)(C)C>[CH:1]([O:8][C:15](=[O:16])[CH2:14][C:12]1[O:11][N:10]=[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1)([CH3:9])[CH3:2]
Reactant: NC(=O)Cc1nc(C(=O)c2ccccc2)no1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)OC(=O)Cc1nc(C(=O)c2ccccc2)no1
Yield: 185.1 %

Procedure:
A mixture of 9.2 g of (3-benzoyl-1,2,4-oxadiazol-5-yl)acetamide in 300 ml isopropanol was saturated with HCl gas. The resulting mixture was warmed to 70° and maintained there for 11 hours. The resulting cooled mixture was filtered and diluted with 400 ml water. Extraction with Et2O (3×300 ml), washing the organics with a saturated NaHCO3 solution, drying over MgSO4, filtration and concentration gave 10.1 g of an oil. Purification of 9.8 g of this oil by high pressure liquid chromatography with 20% hexane/CH2Cl2 used as an eluent gave 7.0 g (64%) of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:23]([CH3:28])[C:24](=[O:27])[CH:25]=[CH2:26])=[CH:14]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:23]([CH3:28])[C:24](=[O:27])/[CH:25]=[CH:26]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:14]1
Reactant: C=CC(=O)N(C)Cc1c[nH]c2ccccc12
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1c[nH]c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 36.7 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.64 g, 2.80 mmole), N-(1H-indol-3-ylmethyl)-N-methylacrylamide (0.60 g, 2.80 mmole), Pd(OAc)2 (0.06 g, 0.28 mmole), tri-ortho-tolylphosphine (0.17 g, 0.56 mmole) and diisopropylethylamine (0.73 mL, 4.2 mmole) in propionitrile (50 mL) was deoxygenated, then was heated to reflux under N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (250 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3). The title compound (0.37 g, 37%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 361 (M+H)+.
Reaction SMILES: C(O[C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([OH:15])=[CH:12]2)=[CH:7][CH:6]=1)C=C>C1(C2C3C(=CC=CC=3)C=CC=2)C(O)=CC=C2C=1C=CC=C2.C(Cl)(Cl)(Cl)Cl>[CH:6]1[CH:7]=[C:8]2[CH:9]=[CH:10][C:11]([OH:15])=[C:12]([C:12]3[C:13]4[C:8](=[CH:7][CH:6]=[CH:5][CH:14]=4)[CH:9]=[CH:10][C:11]=3[OH:15])[C:13]2=[CH:14][CH:5]=1
Reactant: C=CCOc1ccc2ccc(O)cc2c1
Agent: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A reaction flask described in example 9 was charged with a solution of catalyst 1 c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 7-allyloxy-2-naphthol (40 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0° C. The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether=⅓) to give (R)-BINOL 3i, Yield 99%. [[α]D25=−186.5 (c=0.4 in EtOAc), 1HNMR (300 MHz, CDCl3) δ (ppm) 7.87 (d, J=9.0 Hz, 2H, 2×HC (5)), 7.78 (d, J=9.0 Hz, 2H, 2×HC (4)), 7.21 (d, J=9.0 Hz, 2H, 2×HC (3)), 7.03 (dd, J=9.0 Hz, 3.0 Hz, 2H, 2×HC (6)), 6.49 (s, 2H, 2×HC (8)), 5.08 (s, 2H, 2×OH), 3.66–3.78 (m, 4H, 4×OCH2), 1.58–1.67 (m, 4H, 4×OCH2CH2), 1.20–1.40 (m, 4H, 4×CH2CH3), 0.87–0.89 (t, 6H, 6×CH3). e.e. 95%.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([C:24]#[C:25][CH2:26][OH:27])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1>CO.[Pd]>[F:1][C:2]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][OH:27])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)NCCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Agent: [Pd]
Solvent: CO
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(CCCO)cc2F)cc1=O
Yield: 92 %

Procedure:
4-[2-Fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH in the presence of 5% Pd/C for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxypropyl)anilino]-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (92%), m.p. (CH2Cl2/MeOH) 161-164° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.88 (s, 1H), 8.36 (t, J=5.4 Hz, 1H), 8.21 (s, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.17 (dd, J=11.9, 1.7 Hz, 1H), 7.06 (dd, J=8.1, 1.4 Hz, 1H), 5.42 (d, J=0.9 Hz, 1H), 4.48 (t, J=5.0 Hz, 1H), 4.09 (q, J=5.2 Hz, 1H), 3.47 (q, J=5.9 Hz, 2H), 3.41 (q, J=6.0 Hz, 2H), 3.35 (s, 3H), 3.26 (q, J=6.6 Hz, 2H), 2.62 (t, J=7.7 Hz, 2H), 1.75-1.62 (m, 4H). Anal. Calcd for C19H24FN3O4.0.5H2O; C, 59.1; H, 6.5; N, 10.9. Found: C, 59.3; H, 6.4; N, 10.9.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C@@H:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@H:16](O)[CH2:15]3)=[CH:13][C:8]=2[O:7][CH2:6]1>ClCCl>[Cl:3][CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([C:12]2[CH:11]=[CH:10][C:9]3[O:5][CH2:6][O:7][C:8]=3[CH:13]=2)[CH2:15]1
Reactant: O[C@@H]1C[C@H](c2ccc3c(c2)OCO3)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClC1CC(c2ccc3c(c2)OCO3)c2ccccc21

Procedure:
Thionyl chloride (7 mL) was added with stirring and cooling at 15° C. to a solution of cis-3-(benzo[1,3]dioxol-5-yl)-indan-1-ol (10 g) in dichloromethane (300 mL). The mixture was stirred at rt for 40 min. The mixture was washed twice with water, dried (MgSO4) and evaporated in vacuo to give a quantitative yield of 5-(3-chloroindan-1-yl)benzo[1,3]dioxole as an oil, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([NH:24][C:25](=[O:34])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[S:23])[CH:5]=[CH:6][C:7]=1[O:8]C1C2=C(C)C(OC)=CN2N=CN=1.Cl[C:36]1[N:44]=[CH:43][N:42]=[C:41]2[C:37]=1[N:38]=[C:39]([CH2:52][CH3:53])[N:40]2[CH:45]([CH:49]1[CH2:51][CH2:50]1)[CH:46]1[CH2:48][CH2:47]1.N12CCN(CC1)CC2>CC#N>[CH:46]1([CH:45]([CH:49]2[CH2:51][CH2:50]2)[N:40]2[C:39]([CH2:52][CH3:53])=[N:38][C:37]3[C:41]2=[N:42][CH:43]=[N:44][C:36]=3[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:21][C:22]([NH:24][C:25](=[O:34])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[S:23])=[CH:3][C:2]=2[F:1])[CH2:48][CH2:47]1
Reactant: CCc1nc2c(Cl)ncnc2n1C(C1CC1)C1CC1
Reactant: COc1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCc1nc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncnc2n1C(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a mixture 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol, Compound A of Example 3), 6-chloro-9-(dicyclopropylmethyl)-8-ethyl-9H-purine (20.7 mg, 0.075 mmol, PCT Appl. WO 99/01454, U.S. Pat. No. 6,143,743, example 831, the disclosure of which is herein incorporated by reference) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 8.4 mg, 0.075 mmol) was added MeCN (2 mL). The reaction was stirred at RT for 4 h and concentrated in vacuo. The residue was purified by reverse phased preparative HPLC to give the title compound (15.3 mg, 36%) as a white solid. 1H NMR (CDCl3) δ 12.43 (m, 1H), 8.48 (m, 1H), 8.40 (m, 1H), 7.92 (m, 1H), 7.28 (m, 4H), 7.13 (m, 2H), 3.72 (s, 2H), 3.34 (m, 3H), 1.53 (m, 3H), 0.81 (m, 2H), 0.46 (m, 4H), 0.23 (m, 2H), MS(ESI+) m/z 489 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9](=[O:17])[C:8]2=[CH:18][CH:19]=[CH:20][N:7]2[N:6]=1.[CH2:29]([SH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:29]([S:36][CH2:2][CH2:3][C@H:4]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9](=[O:17])[C:8]2=[CH:18][CH:19]=[CH:20][N:7]2[N:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCBr)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H](CCSCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 81.5 %

Procedure:
(S)-tert-Butyl (3-bromo-1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (45 mg, 0.03 mmol) was treated with benzyl hydrosulfide (7 μl, 0.06 mmol) and potassium carbonate (6 mg, 0.05 mmol) according to the method described in Preparation 31. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 12 mg (81% yield) of the title compound. Purity 70%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)=O.[C:23](=O)([O:25]CC)[NH2:24].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[C:12]([C:11]1[CH:17]=[C:18]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:5]([C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[O:2][CH3:1])[NH:24][C:23]2=[O:25])([OH:14])=[O:13]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccccc2OC)cc1
Reactant: CCOC(N)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COc1ccccc1-c1nc2ccc(C(=O)O)cc2c(=O)[nH]1
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Ethyl 4-(2'-methoxy-benzoylamino)-benzoate (21 g), prepared according to Example 19 is reacted with ethyl carbamate (12 g) and P2O5 (70 g) in xylene (200 ml) for 6 hours at the reflux temperature. After cooling, the precipitate is filtered off, poured in ice-water and treated with NaOH to neutralization. The precipitate (23 g) is collected by filtering and is hydrolyzed by treatment with LiBr (10 moles/mole) in dimethylformamide (150 ml) at the reflux temperature for 2 hours. After cooling, acidify with acetic acid, filter and wash with hot ethanol to obtain 6-carboxy-2-(2'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline (14.7 g; m.p. 296°-297° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[CH2:29]([N:31]([CH2:37][CH3:38])[CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH3:30]>>[CH2:29]([N:31]([CH2:37][CH3:38])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:18]1[N:17]=[C:16]2[N:15]([CH2:26][CH3:27])[C:14](=[O:28])[N:13]([C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])[CH2:22][C:21]2=[CH:20][N:19]=1)[CH3:30]
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reactant: CCN(CC)CCCCN
Product: CCN(CC)CCCCNc1ncc2c(n1)N(CC)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2
Yield: 88.4 %

Procedure:
7-(4-Diethylamino-butylamino)-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 3 using 0.46 g (1.11 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.32 g (2.22 mmol) of 4-diethylamino-butylamine. The crude product was purified using a gradient of 9:1 ethyl acetate/methanol to 9:0.25:0.25 to 9:0.5:0.25 ethyl acetate/methanol/triethylamine to give 0.4833 g (83%) of the title compound: mp 140° C.–141° C. MS (APCI) (m+1)/z 493.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:19])[NH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O.Cl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:19])[N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Reactant: CCOC(=O)CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)ccc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 0.75 h
Yield: 55.5 %

Procedure:
The compound of Example 13 (1.80 g, 7.0 mmole) was added to a stirred suspension of sodium hydride (0.33 g, 8.4 mmole) in dry dimethylformamide (50 mL). After 45 minutes, ethyl iodoacetate (1.43 g, 6.7 mmole) was added, and the mixture was stirred overnight, diluted with 10% hydrochloric acid (300 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was washed with brine (twice), dried and evaporated. The resulting yellow, waxy solid was chromatographed, eluting with 3% ethyl acetate in dichloromethane, to give the title compound (1.28 g, 53% yield). Rf=0.52 (silica gel, 5:95 methanol:dichloromethane). Fast atom bombardment mass spectrometry confirmed the theoretical molecular weight of 344.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=2[C:20]([F:23])([F:22])[F:21])[CH2:6][CH2:5]1.[I-].ClC1C=CC=C[N+]=1C.[CH3:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=1[NH:41][C:42]1[N:47]=[C:46]([C:48]2[CH:49]=[N:50][CH:51]=[N:52][CH:53]=2)[CH:45]=[CH:44][N:43]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([CH3:33])=[C:35]([NH:41][C:42]4[N:47]=[C:46]([C:48]5[CH:53]=[N:52][CH:51]=[N:50][CH:49]=5)[CH:45]=[CH:44][N:43]=4)[CH:36]=3)=[O:16])=[CH:13][C:12]=2[C:20]([F:23])([F:21])[F:22])[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(CN2CCN(CCF)CC2)c(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncnc2)n1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(CCF)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cncnc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
Under an argon atmosphere, 1.71 g of 4-[4-(2-fluoroethyl)piperazin-1-ylmethyl]-3-trifluoromethylbenzoic acid (Reference Example 14) was dissolved in 14 ml of anhydrous N,N-dimethylformamide and 1.56 g of 2-chloro-1-methylpyridinium iodide was added, followed by stirring at room temperature for 10 minutes. 1.50 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) and 1.13 ml of N,N-diisopropyl-N-ethylamine were added in turn, followed by stirring at room temperature for 1 hour. 300 ml of water was added to the reaction solution, followed by extraction with ethyl acetate. Two hundred ml of saturated sodium hydrogen carbonate was added to the aqueous layer and the mixture was further extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography and the crude crystals were washed with diethyl ether-ethyl acetate to obtain 1.68 g of the objective compound as pale yellow crystals.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:36][N:35]=1
Reactant: Cc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(OC(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methylphenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (521 mg, 1.1 mmol) produced in Synthesis Example 30 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 183 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methylbenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (496 mg, yield 96%).
Reaction SMILES: [C:1]1([C:11]2[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[C:27]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][C:24]([NH2:25])=[C:23]([N+:34]([O-:36])=[O:35])[CH:22]=1.C(Cl)CCl.CN(C=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:25][C:24]1[C:23]([N+:34]([O-:36])=[O:35])=[CH:22][C:21]([Cl:20])=[C:27]([N:28]2[CH2:33][CH2:32][N:31]([C:16]([C:15]3[C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[N:12][O:13][C:14]=3[CH3:19])=[O:17])[CH2:30][CH2:29]2)[CH:26]=1
Reactant: Nc1cc(N2CCNCC2)c(Cl)cc1[N+](=O)[O-]
Reactant: Cc1onc(-c2cccc3ccccc23)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1onc(-c2cccc3ccccc23)c1C(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1

Procedure:
A mixture of 3-(1-naphthyl)-5-methylisoxazole-4-carboxylic acid (394 mg, 1.558 mmol), 4-chloro-2-nitro-5-(piperazin-1-yl)aniline (400 mg, 1.558 mmol, prepared as described in [El-Abadelah, M. M.; Nazer, M. Z.; El-Abadla, N. S.; Awadallah, A. M. Asian Journal of Chemistry 1999, 11(4), 1463-1468.]), EDC (448 mg, 2.337 mmol), and DMAP (571 mg, 4.67 mmol) in DCM (5 mL)/DMF (3 mL) was stirred overnight.