Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].C(O[C:9](=[O:20])[C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])C>>[CH2:14]([O:13][C:11]([C:10]1[C:9](=[O:20])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][CH:16]=1)=[O:12])[CH3:15]
Reactant: CNC(N)=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c(=O)n(C)c1=O
Reaction time: 12 h
Yield: 35 %

Procedure:
74.08 g (1 mol) of N-methyl urea and 216.2 g (1 mol) diethylethoxymethylenemalonate were heated together at 122° C. for 24 hours, followed by 170° C. for 12 hours, to give the 3-methyluracil-5-carboxylic acid ethyl ester in 35% yield (following recrystallization from ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:29])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:40]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:40]1([C:45]([O:29][C@@H:15]2[C@@H:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:17][CH2:18][CH2:19][C@H:11]([N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:32])[CH2:8][O:9][CH3:10])[C:12](=[O:31])[O:13][C@H:14]2[CH3:30])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](O)[C@H](C)OC1=O
Reactant: O=C(Cl)C1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](OC(=O)C2CCCC2)[C@H](C)OC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A 20 mL vial was charged with tert-butyl((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (200 mg, 0.443 mmol), CH2Cl2 (2215 μl), NEt3 (185 μl, 1.329 mmol) and DMAP (5.41 mg, 0.044 mmol). The reaction mixture was cooled to 0° C. in an ice bath under N2 and cyclopentanecarbonyl chloride (76 mg, 0.576 mmol) was added in one portion. The reaction became dark brownish-yellow. After stirring for 2 h, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3. The mixture was extracted with CH2Cl2 (3×) and the combined organic layers were washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on SiO2 (0→100% EtAOx/hexanes) to provide the title compound as a yellow solid (85 mg, 35.0%): 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=8.5 Hz, 4H), 6.81 (d, J=8.4 Hz, 4H), 5.06-4.85 (m, 3H), 4.77 (d, J=11.6 Hz, 1H), 4.57 (dd, J=10.7, 6.0 Hz, 0H), 4.29-4.17 (m, 1H), 3.78 (s, 3H), 3.38-3.26 (m, 3H), 2.74 (p, J=8.0 Hz, 1H), 2.61 (dd, J=13.7, 3.7 Hz, 1H), 2.31 (dd, J=13.7, 11.1 Hz, 1H), 2.20-2.07 (m, 1H), 1.99-1.52 (m, 8H), 1.51-1.40 (m, 9H), 1.27 (d, J=5.8 Hz, 3H), 1.15-0.96 (m, 1H), 0.97-0.87 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 176.26, 173.56, 157.94, 155.49, 131.94, 129.59, 113.80, 81.21, 75.54, 72.72, 58.52, 55.43, 55.22, 44.32, 44.04, 35.77, 30.09, 30.00, 29.58, 28.20, 26.48, 25.72, 25.70, 19.09, 17.56; ESIMS m/z 570.5 ([M+Na]+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][N:20]=[C:21]=[O:22])[CH:16]=[CH:17][CH:18]=1.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:21]([NH:20][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)=[O:22])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C=NCc1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NCc1cccc(F)c1)NNC(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
553 mg (3.24 mmol) of 4-chlorobenzoic acid hydrazide are placed in 10 ml tetrahydrofuran at room temperature. 500 mg (3.31 mmol) of 3-fluorophenylmethyl isocyanate, dissolved in 5 ml tetrahydrofuran, are rapidly added dropwise to this suspension with stirring. The mixture is further stirred overnight at room temperature. The reaction mixture is treated with 50 ml diethyl ether, and the precipitate is recovered by filtration, then washed with diethyl ether and dried in vacuo. 965 mg (92% of theory) of the target compound are thus obtained
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: N#Cc1ccccc1N1CCNCC1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 89 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 3.30 (s, 4H), 3.84 (s, 3H), 4.14 (s, 3H), 7.02-7.10 (m, 2H), 7.35-7.89 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:30])([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1C(=O)C(C)(c1ncnn1C)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (100 mg, 0.25 mmol) and potassium carbonate (70 mg, 0.51 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 hr. Then the solution was cooled to 0° C. and a solution of iodomethane (0.1 mL) in N,N-dimethylformamide (1 mL) was added dropwise at 0° C. over 1 hr, stirred at room temperature overnight. The mixture was quenched with water (30 mL), extracted with ethyl acetate, washed with brine, and then the extraction was evaporated to get the crude product, which was used in next step without further purification (80 mg, yield 77%). LC-MS (ESI) m/z: 409 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]3=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=[CH:21][N:7]3[N:6]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[C:22]1([C:19]2[CH:20]=[CH:21][N:7]3[C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:5]([C:2]2([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:3][CH2:4]2)=[N:6]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a stirred solution of 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.168 mmol)) in DCM (15 mL) was added pyridine (0.0200 mL, 0.253 mmol) followed by methanesulfonylchloride (0.0200 mL, 0.253 mmol) and the reaction stirred at RT for 2 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-94 as described in general methods) to give N-(1-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)methanesulfonamide (26.0 mg, 35.5%) as white solid. LCMS Condition B-34: retention time 2.32 min, [M+1]=435.0. HPLC Condition B-31: retention time 7.72 min, Purity 99.61%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.31 (m, 2H), 1.36-1.42 (m, 2H), 2.99 (s, 3H), 4.71 (d, J=4.8 Hz, 2H), 6.71 (d, J=2.7 Hz, 1H), 7.07 (t, J=4.8 Hz, 1H), 7.27 (ddd, J=6.8 Hz, J=5.5 Hz, J=1.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.41-7.45 (m, 1H), 7.47-7.57 (m, 4H), 7.72-7.77 (m, 2H), 8.06 (s, 1H), 8.35-8.40 (m, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[C:21]([C:23]1[C@@H:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[N:27]2[N:37]=[C:38]([NH:40][C:41](=[O:50])[O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:39]=[C:26]2[N:25]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)[C:24]=1[CH3:61])#[N:22]>CN(C1C=CN=CC=1)C.ClCCl>[C:21]([C:23]1[C@@H:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[N:27]2[N:37]=[C:38]([N:40]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[C:41]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:50])[N:39]=[C:26]2[N:25]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)[C:24]=1[CH3:61])#[N:22]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(C(=O)OCc3ccccc3)C(=O)Oc3ccc([N+](=O)[O-])cc3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
Under an atmosphere of argon protective gas and at 0° C., 4-nitrophenyl chloroformate (27.2 mg, 135 μmol, 2.5 eq.), triethylamine (11.1 mg, 140 μmol, 2.6 eq.) and DMAP (0.7 mg, 5.4 μmol, 0.1 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 μmol; Example 38) in dry dichloromethane (2 ml), and the mixture was then stirred for 5 h. This reaction solution was used as such without further purification for subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:13]=[C:12]([CH3:26])[C:11]=2[C:10](=O)[CH2:9]1.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:13]=[C:12]([CH3:26])[C:11]=2[C:10](=[N:32][NH:31][C:28]([NH2:30])=[NH:29])[CH2:9]1
Reactant: Cc1nn(CCCc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(CCCc2ccccc2)c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 175.4 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-1-(3-phenylpropyl)-4,5,6,7-tetrahydroindazol-4-one (0.11 g), aminoguanidine hydrochloride (0.048 g), concentrated hydrochloric acid (0.073 ml), water (0.073 ml) and ethanol (10 ml) was refluxed for 8 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-1-(3-phenylpropyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 153) (0.12 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[OH-].[Na+]>O.ClC(Cl)Cl>[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([N:1]1[CH2:3][CH2:2]1)=[O:13]
Reactant: C1CN1
Reactant: O=C(Cl)c1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1O)N1CC1
Temperature: -5 °C

Procedure:
To 690 parts of a solution of aziridine in water 0.875M are added 42 parts of sodium hydrogen carbonate while cooling in an ice-salt bath at -5° C. While stirring vigorously, there is added dropwise, during a 30 minutes period, a solution of 78.8 parts of 2-hydroxybenzoyl chloride in 150 parts of trichloromethane at a temperature below 5° C. The reaction mixture is allowed to reach 25° C while stirring, and a diluted sodium hydroxide solution is added to pH 8. The product is extracted three times with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated, yielding 56 parts of 1-(2-hydroxybenzoyl)aziridine as a residue.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12].[Li+].CC([N-]C(C)C)C.CN([CH:29]=[O:30])C1C=CC=CC=1>C1COCC1>[F:1][C:2]1[C:10]([CH:29]=[O:30])=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12]
Reactant: Cn1ncc2c(F)cc(F)cc21
Reactant: CN(C=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc2c(F)c(C=O)c(F)cc21
Reaction time: 2 h

Procedure:
A solution of 4,6-difluoro-1-methyl-1H-indazole ((xvi), 168 mg, 1 mmol) in dry THF (1 mL) was added dropwise to a freshly prepared solution of LDA (n-BuLi 1.25 mL and diisopropylamine 0.285 mL, 2 mmol, in 10 mL THF) at −78° C. The solution was stirred at this temperature for 2 h, and then N-methylformanilide (0.247 mL, 2 mmol) was added dropwise at −70° C. After stirring 2 additional hours at −78° C. the RM was quenched with glacial acetic acid, diluted with water, and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and the solvent was removed. The residue was purified by flash chromatography to afford the title compound as a yellowish crystalline powder (tR 4.49 min (conditions 5), MH+=197, 1H-NMR in DMSO-d6: 10.2 (s, 1H); 8.42 (s, 1H); 7.61 (d, 1H); 4.04 (s, 3H)).
Reaction SMILES: [O:1]=[C:2]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[B:22]1[O:26][C@@H]2CC3CC([C@]2(C)[O:23]1)C3(C)C)[CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:6].Cl.C1(OB(O)O)C=CC=CC=1.COC(C)(C)C>O>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:5]([NH:4][CH2:3][C:2]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[B:22]([OH:26])[OH:23])=[O:1])=[O:6])=[CH:8][CH:9]=1
Reactant: CC1(C)C2CC1[C@]1(C)OB([C@@H]3CCCN3C(=O)CNC(=O)c3ccnc4ccccc34)O[C@@H]1C2
Agent: Cl
Agent: OB(O)Oc1ccccc1
Solvent: COC(C)(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC[C@H]1B(O)O)c1ccnc2ccccc12
Yield: 62.2 %

Procedure:
To a stirred solution of the N-(2-oxo-2-((2R)-2-((3aS,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)ethyl)quinoline-4-carboxamide (0.27 g, 0.585 mmol) in water (8 mL) at pH=3 (adjusting as necessary with 2N aq HCl) was added phenylboric acid (0.143 g, 1.17 mmol) and methyl-tert-butylether (7 mL). The mixture was stirred for 2 days (pH was 4) water and organic layer were separated, the water layer was adjusted to pH 3, and the water layer was extracted with a mixture 4-1 of DCM-isopropanol. The DCM layer was dried over sodium sulfate, filtrated evaporated and further purified using column chromatography (DCM-MeOH 0-10% MeOH) to yield a clear oil of 0.119 g (79%) (R)-1-(2-(quinoline-4-carboxamido)acetyl)pyrrolidin-2-ylboronic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)=[C:4]([CH2:13][CH3:14])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([C:4]1[CH:3]=[C:2]([C:20](=[O:22])[CH3:21])[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)[CH3:14]
Reactant: CCc1cc(Br)ccc1-c1cscn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1cc(C(C)=O)ccc1-c1cscn1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a stirred solution of 4-(4-bromo-2-ethylphenyl)-1,3-thiazole (2.35 g, 8.76 mmol) in dioxane (45 ml) was added tributyl(1-ethoxyvinyl)tin (3.48 g, 9.64 mmol), tetrakis(triphenylphosphine)palladium (1010 mg, 0.876 mmol), lithium chloride (928 mg, 21.9 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was concentrated in vacuo. To the residue was added THF (15 ml), 2N HCl aqueous solution (15 ml), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (1.51 g, 74% yield).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:12])[CH:3]=1.[Cl-].[Li+].C(N(CC)CC)C.[CH2:22]([OH:25])[CH:23]=[CH2:24]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O-:12][N+:4]1[CH:3]=[C:2]([CH2:24][CH2:23][CH:22]=[O:25])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: [O-][n+]1cc(Br)c2ccccc2c1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=CCCc1c[n+]([O-])cc2ccccc12
Temperature: 100 °C

Procedure:
4-bromoisoquinoline 2-oxide (5-2) (500 mg, 2.23 mmol, 1.0 equiv), lithium chloride (95 mg, 2.23 mmol, 1.0 equiv) and palladium(II) acetate (20.04 mg, 0.089 mmol, 0.04 equiv) were dissolved in anhydrous DMF (8.6 mL). To this orange solution, was added triethylamine (933 μl, 6.69 mmol, 3.0 equiv) and allyl alcohol (308 μl, 4.46 mmol, 2.0 equiv). The reaction mixture was heated at 100° C. for 1.5 hours. Black precipitate was formed. And LCMS showed the starting material was completely consumed. The reaction mixture was filtered, and washed with EtOAc, then concentrated. The crude was purified with silica gel chromatography (MeOH/EtOAc=0->20%) to afford the compound (5-3). LRMS m/z (M+H) 202.1 found, 202.2 required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[C:26](OC(=O)CC)(=O)[CH2:27][CH3:28]>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[N:19]=[C:26]2[CH2:27][CH3:28])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Reactant: CCC(=O)OC(=O)CC
Agent: [Na+]
Agent: [OH-]
Product: CCC1=Nc2c(OC)c(OC)cc3ncnc(c23)N1c1cccc(Br)c1

Procedure:
A solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (120 mg, 0.32 mmol) (from Example 6, Step B, supra) in propionic anhydride (3 mL) (Aldrich) was heated at 170° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was extracted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.05) as eluent to give the desired 3-(3-bromo-phenyl)-2-ethyl-8,9-dimethoxy-3H-1,3,4,6-tetraaza-phenalene as a brown solid. (Yield 50 mg, 38%).
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:54]([OH:55])[CH:41]6[CH:42]([C:43]([O:45][NH:46][CH2:47][C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[O:44])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:56]([CH3:58])[CH3:57])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:47]([NH:46][O:45][C:43]([CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:56]([CH3:58])[CH3:57])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:54]([OH:55])[CH:41]1[O:40]3)[O:36]2)=[O:44])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(C(=O)ONCc6ccccc6)C5O2)C4O)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(C(=O)ONCc6ccccc6)C5O2)C4O)C13C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
27 mg of compound (78) was dissolved in 2 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with chloroform-methanol (20:1). The fraction containing the desired product was concentrated to dryness to give 18.4 mg of compound (79).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].Br[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: Brc1ncccn1
Product: COC(=O)c1cc(COc2ccc(-c3ncccn3)cc2)c(C)o1

Procedure:
Compound (136) was prepared from compound (119) and 2-bromo-pyrimidine by adapting the procedure of Example 30(a). LC/MS System A; Rt=3.43 mins, m/z (ES+)=325 (M+H for C18H16N2O4).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:7]1[C:11]([C:12]#[N:13])=[C:10]([C:14]([O:16]CC)=[O:15])[N:9]=[C:8]1[N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[C:4]#[C:5][CH3:6]>C(O)C>[CH2:3]([N:7]1[C:11]([C:12]#[N:13])=[C:10]([C:14]([OH:16])=[O:15])[N:9]=[C:8]1[N:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)OCC)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)O)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
16 ml of a 5N aqueous sodium hydroxide solution was added to a 500 ml ethanol solution of 25.1 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-ethoxycarbonyl-1H-imidazol-2-yl]piper azine-1-carboxylate, and the mixture was stirred at room temperature for two hours. Then, the solvent was concentrated under reduced pressure. The residue was dissolved in a mixture consisting of 1 L of ethyl acetate and 500 ml of water. 50 ml of 2N hydrochloric acid was added to the solution. The organic layer was washed with 200 ml of a saturated sodium chloride solution, and dried over magnesium sulfate. The organic liquid was concentrated under reduced pressure to give 23.2 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:26])=[C:4]([CH:22]=[C:23]([Br:25])[CH:24]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]([F:21])([F:20])[F:19])=[O:6].[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[C:3]([O:26][C:33]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:34])=[C:4]([CH:22]=[C:23]([Br:25])[CH:24]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[CH:10][C:9]=1[C:18]([F:19])([F:20])[F:21])=[O:6]
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)cc(Br)c1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)cc(Br)c1OC(=O)N1CCOCC1
Yield: 70.6 %

Procedure:
Using 3,5-dibromo-2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.