Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:4])=[O:3].C([Li])CCC.CCCCCC.[CH:42](=O)[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>C1C=CC=CC=1>[N:46]1[CH:47]=[CH:48][C:43]([CH:42]=[CH:7][C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N+:2]([O-:4])=[O:3])=[CH:44][CH:45]=1
Reactant: O=[N+]([O-])c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccccc1C=Cc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
In 120 ml of benzene was suspended 12.00 g of 2-nitrobenzyltriphenylphosphonium bromide and, under argon gas, 20 ml of 1.6M n-butyllithium/n-hexane was added dropwise under ice-cooling with care exercised so that the internal temperature would not rise beyond 20° C. The mixture was then stirred at room temperature for 2 hours, after which 3.05 g of isonicotinaldehyde was added dropwise under ice-cooling and the mixture was stirred at room temperature for another 4 hours. This reaction mixture was poured upon ice-water and extracted with ether. This extract was evaporated under reduced pressure to remove the solvent and the residue was diluted with chloroform and extracted with 2N-hydrochloric acid. The aqueous layer was made basic by adding 30% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the solvent was evaporated off. The residue was purified by silica gel column chromatography (chloroform alone) to provide 2.53 g of the title compound as tan-colored oil. This product was subjected to the next reaction without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]=[C:7]1[O:16][CH3:17])(=[O:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.O>C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:24])[CH:8]=[C:7]1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)COC(C)=O
Agent: CC(C)(C)OOC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(C)=O
Yield: 75.9 %

Procedure:
To a solution of Example 179B (0.15 g, 0.5 mmol) in benzene (5 mL) was added celite (0.15 g), pyridinium dichromate (0.75 g, 2.0 mmol), and a solution of 70% t-butyl peroxide in water (0.25 mL, 2.0 mmol). The heterogenous solution was filtered through celite. The filtrate was diluted with ethyl acetate (10 mL), washed with 5% Na2S2O5 (10 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (5% to 15% ethyl acetate/hexane gradient) afforded the product as colorless oil (0.12 g, 75%). 1H NMR (300 MHz, CDCl3) δ ppm 0.53 (m, 1H), 0.76 (m, 7H), 1.35 (m, 1H), 1.73 (s, 3H), 1.80 (m, 1H), 2.09 (m, 1H), 3.84 (s, 3H), 4.51 (m, 2H), 5.97 (s, 1H), 7.43 (m, 2H), 7.59 (m, 1H), 8.20 (d, J=7.72 Hz, 1H); MS m/z 317.1 (M+H)+.
Reaction SMILES: Br[C:2]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:24])[O:22][CH3:23])[CH3:19])[N:11]=2)[CH2:6][NH:5][C:4]([CH:7]2[CH2:9][CH2:8]2)=[N:3]1.[Cl:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:29]([F:33])=[C:30]([CH:32]=1)[NH2:31].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O1CCOCC1.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>[NH2:31][C:30]1[C:29]([F:33])=[C:28]([C:6]2[N:5]=[C:4]([CH:7]3[CH2:9][CH2:8]3)[NH:3][C:2]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:24])[O:22][CH3:23])[CH3:19])[N:11]=2)[CH:27]=[C:26]([Cl:25])[CH:32]=1
Reactant: COC(=O)N[C@@H](C)CNc1nccc(C2(Br)CNC(C3CC3)=N2)n1
Reactant: CC1(C)OB(c2cc(Cl)cc(N)c2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CC3)nc2-c2cc(Cl)cc(N)c2F)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-methyl 1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (I-1b, 0.59 g, 1.5 mmol) in DME (15 mL) was added a solution of 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (SM-5, (˜12 mL, 0.25 M solution in dioxane; 3.0 mmol) and aqueous Na2CO3 solution (6 mL, 2.0 M, 12.0 mL). The resulting mixture was sparged with nitrogen, and Pd(PPh3)4 (87 mg, 0.075 mmol) was added. The reaction mixture was sealed and subjected to microwave irradiation at 120° C. for about 20 minutes. The reaction was allowed to cool to room temperature and partitioned upon standing. The layers were separated and the organic portion was concentrated, dissolved in EtOAc (150 mL), washed with water (50 mL), followed by extraction with aqueous 0.01 M HCl solution (2×100 mL) and aqueous 0.02 M HCl solution (2×100 mL). The combined acidic aqueous portions were neutralized with saturated aqueous NaHCO3 solution, and extracted with EtOAc (2×225 mL). The combined organic portions were washed with brine, dried (Na2SO4), and concentrated to yield (S)-methyl 1-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (530 mg) which was carried forward without further purification. LCMS (m/z) 460.2 (MH+), tR=0.57 minute.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[CH:26]=O.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:26][C:25]2[CH:24]=[C:23]([Cl:22])[CH:30]=[C:29]([Cl:31])[CH:28]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cc(Cl)cc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)c1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.16 ml of 3,5-dichloro-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 119 mg of expected product is obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN3CCOCC3)cc2C)ncn1
Reaction time: 15 h
Yield: 92.4 %

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 80 mg; 0.23 mmol) in DCM was treated with morpholine (40 mL; 0.46 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 15 hours the mixture was filtered and washed with water. The organic fraction was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an of-white solid (90 mg, 92%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][C:37]2[N:45]=[CH:44][CH:43]=[CH:42][C:38]=2[C:39]([OH:41])=O)=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH2:57]([NH2:61])[CH:58]([CH3:60])[CH3:59]>CN(C=O)C>[CH2:57]([NH:61][C:39](=[O:41])[C:38]1[CH:42]=[CH:43][CH:44]=[N:45][C:37]=1[O:36][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[CH:47][CH:46]=1)[CH:58]([CH3:60])[CH3:59]
Reactant: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (178 mg, 0.469 mmol) was added to a mixture of 2-(4-(pyridin-2-ylamino)phenoxy)nicotinic acid (131 mg, 0.426 mmol) and diisopropylethylamine (148 μL, 0.853 mmol) in DMF (1 mL) and the mixture was stirred at rt for 10 min. Isobutylamine (63.5 μL, 0.639 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was purified by chromatography on silica gel to deliver N-isobutyl-2-(4-(pyridin-2-ylamino)phenoxy)nicotinamide as a white solid. MS (ESI, pos. ion) m/z: 363.1 (M+1). IC50 (uM) 0.09344.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:17]=[CH:16][S:15][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1C(=O)N([Br:29])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:17]=[C:16]([Br:29])[S:15][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2c3sccc3CC2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC2c3sc(Br)cc3CC2C1

Procedure:
A solution of the product from step h) (722 mg, 2.88 mmol) in AcOH (7.2 ml) and CHCl3 (7.2 ml) was treated with NBS (529 mg, 2.97 mmol) at 22° C. for 30 minutes. Next, the reaction was carefully quenched with sat. NaHCO3 (10 ml), extracted with EtOAc (2×75 ml) and the combined organic extracts were dried (MgSO4) and solvent evaporated in vacuo leaving the crude product that was purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (10% to 50% ethyl acetate) to give the subtitle compound. MS calculated for C15H20BrNO2S+H 358, observed M-tBu 302, 304.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:68][C:69]1[CH:78]=[CH:77][CH:76]=[C:75]2[C:70]=1[CH:71]=[C:72]([NH:79]C(=O)OC(C)(C)C)[N:73]=[CH:74]2>C1COCC1>[NH2:79][C:72]1[N:73]=[CH:74][C:75]2[C:70]([CH:71]=1)=[C:69]([CH2:68][N:14]1[C:13]3[CH:18]=[C:19]([F:20])[C:10]([S:7]([NH:6][C:21]4[S:25][N:24]=[CH:23][N:22]=4)(=[O:9])=[O:8])=[CH:11][C:12]=3[O:16][C:15]1=[O:17])[CH:78]=[CH:77][CH:76]=2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(CO)cccc2cn1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc2c(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)cccc2cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (50 mg, 0.107 mmol), (E)-di-tert-butyl diazene-1,2-dicarboxylate (49.4 mg, 0.214 mmol) and triphenylphosphine (56.2 mg, 0.214 mmol) were added to a 5 mL RB flask. Then THF was added and r×n mixture was stirred at 0° C. for 10 min before addition of tert-butyl (5-(hydroxymethyl)isoquinolin-3-yl)carbamate (29.4 mg, 0.107 mmol) in THF. After stirring at 0° C. for 2 h, the reaction was filtered and concentrated in vacuo. Residue was dissolved in 1 mL of DCM and treated with 0.25 mL of TFA. After stirring at RT for 30 minutes, the solvent and TFA were removed in vacuo. Purified by reverse phase chromatography (10-95% MeCN in water w/0.1% TFA, C18 column) to yield 26-5. 1H NMR δ (ppm)(CH3 OH-d4): 9.02 (1H, s), 8.38 (1H, s), 7.95 (2H, d, J=8.72 Hz), 7.76 (1H, d, J=5.33 Hz), 7.55 (1H, d, J=7.15 Hz), 7.43 (1H, t, J=7.69 Hz), 7.01 (1H, d, J=9.05 Hz), 5.47 (2H, s). HRMS [M+H]C19H13FN6O4S2 calc'd 473.0496. Found 473.0500.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cc1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-(4-methylbenzyl)-1H-indole (Step 1 of Example 25) and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 382. 1HNMR (300 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.76 (d, 2H, J=8.8 Hz), 7.52 (s, 1H), 7.53 (d, 2H, J=8.1 Hz), 7.41-7.38 (m, 3H), 7.11 (m, 4H), 6.54 (d, 1H, J=3 Hz), 5.39 (s, 2H), and 2.23 ppm (s, 3H). Elemental Analysis for C23H18F3NO: Calculated: C, 72.43; H, 4.76; N, 3.67. Found: C, 72.38; H, 4.70; N, 3.59.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:17][CH:16]=[N:15][C:14]=2[CH3:18])/[C:6](=[O:11])[NH:7]3)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(F)ccc3c2/C(=C/c2[nH]cnc2C)C(=O)N3)cc1OC

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3,4-dimethoxyphenylboronic acid (61.7 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 2 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-1,3-Dihydro-4-(3,4-dimethoxyphenyl)-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 19 mg, 37%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])[CH3:2].[NH:17]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1)[NH2:18]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:17]([C:19]2[CH:24]=[N:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:18]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccn1
Reactant: COc1ccc(NN)cn1
Solvent: CCO
Product: CCOC(=O)C1=NN(c2ccc(OC)nc2)C(O)(c2ccccn2)C1

Procedure:
4-(2-Pyridyl)-2,4-dioxobutanoic acid ethyl ester (1.10 g) obtained from Referential Example 31 and 5-hydrazino-2-methoxypyridine (0.692 g) obtained from Referential Example 2 were dissolved in ethanol (22 mL). The resultant mixture was refluxed under heat for 14 hours, followed by cooling in air. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), followed by purification through silica gel column chromatography (toluene-acetone), to thereby give 5-hydroxy-1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)-4,5-dihydropyrazole-3-carboxylic acid ethyl ester as a solid substance (0.575 g, 34%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: Clc1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@H]1O
Yield: 33.8 %

Procedure:
The title compound (76 mg, 34%) was prepared using (2S,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (129 mg, 0.46 mmol) and 4-chlorophenyl-1H-imidazol-2-ylmethylamine (95 mg, 0.46 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1cccc(N)c1Cl
Product: Cc1cccc(Nc2ccccc2CC(=O)O)c1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-chloro-3-methylaniline to yield 2-[(2-chloro-3-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH3:15].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24]O)=[CH:19][N:18]=1.C(O)(=O)C.[ClH:30]>CC(C)=O>[ClH:30].[ClH:30].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24][C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH2:1])=[C:3]([O:14][CH3:15])[CH:4]=2)=[CH:19][N:18]=1
Reactant: COc1ccc2ccc(OC)c(N)c2c1
Reactant: Nc1ncc(CO)c(N)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: COc1ccc2c(Cc3cnc(N)nc3N)cc(OC)c(N)c2c1
Yield: 78 %

Procedure:
A mixture of 1-amino-2,7-dimethoxynaphthalene (2.03 g, 10.00 mmol) [O. Fischer and W. Kern, J. Prakt. Chem., 94, 34(1916)], 2,4-diamino-5-hydroxymethylpyrimidine (1.40 g, 10.0 mmol), glacial acetic acid (20 mL) and concentrated hydrochloric acid (1.4 mL) was refluxed for 2 hr. The cooled reaction mixture was diluted with acetone and the resulting precipitate was collected and dried giving the title compound as a grey solid (3.40 g, 78%). Recrystallization from aqueous ethanol with concentrated HCl gave an analytical sample, mp >210° dec. Anal. Calcd for C17H19N5O2.2HCl.2H2O: C, 47.01; H, 5.80; N, 16.12; Cl, 16.32. Found: C, 47.19; H, 5.90; N, 16.05; Cl, 16.37.
Reaction SMILES: [CH2:1]([C:24]([OH:26])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O.[CH3:27][Li]>C1COCC1.CCOCC>[O:23]=[C:21]([CH3:27])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[C:11][C:10]#[C:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:24]([OH:26])=[O:25]
Reactant: O=C(O)CCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)CCCCCCCCC#CC#CCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.08 g (3mmol) Icosa-9,11-diyne-1,20-dicarboxylic acid was suspended in 55 mL anhydrous THF and dissolved with slight warming. To this solution, 11.2 mL, 1.4 M methyl lithium in ether (8 mmol) was slowly added with the aid of syringe. A total of 2 mol equivalent of methyl lithium in ether were used per carboxylic acid to convert acid into ketone. The reaction turned into a viscous slurry from a free flowing suspension. The reaction was left stirring at room temperature overnight. The purplish colored suspension was treated with ice to quench the reaction. The product was extracted with ether, after acidifying the solution. The yellowish waxy product was characterized by NMR and found to contain the desired product as well as one byproduct tertiary alcohol due to additional reaction of methyl lithium present in the reaction mixture at the time of quenching. This problem was alleviated by addition of trimethyl silyl chloride in an amount enough to react with excess methyl lithium. This step provided clean reaction product.
Reaction SMILES: CCN(CC)CC.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:12].[CH2:22]([O:24][C:25](=[O:29])[C:26](Cl)=[O:27])[CH3:23]>CCOC(C)=O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11](=[O:12])[CH2:10][NH:9][C:26](=[O:27])[C:25]([O:24][CH2:22][CH3:23])=[O:29])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: NCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)NCC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 59 %

Procedure:
Et3N (8.88 ml) was added to a solution of 2-amino-1-(4-nitrophenyl)ethanone hydrochloride (step B product, 11.5 g) in EtOAc (115 ml). This was followed by drop wise addition of Ethylchlorooxoacetate (7.11 ml). The reaction mixture was refluxed for 2 hours. It was then cooled and quenched with water. The organic layer was separated, dried over Na2SO4 and the solvent was concentrated to get dark brown oil which was purified by column chromatography in 3:7 Ethyl acetate:Pet ether to get yellow solid. The solid was crystallized in ethyl acetate/pet ether to yield 8.9 g (59%) of the title compound. 1HNMR (DMSO-d6, 300 MHz): δ 9.21 (t, 1H), 8.35 (d, 2H), 8.24 (d, 2H), 4.78 (d, 2H), 4.29 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=2)O1>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:29]3[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Product: N#Cc1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cn1
Yield: 24 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (1.0 g) was reacted with 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine-2-carbonitrile as in General Procedure 4A to give the title compound as a bright yellow solid (24% yield). M.p. 200° C. (dec), LCMS: m/z=364.53 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.46-3.52 (m, 2H), 3.62-3.72 (m, 2H), 4.50 (s, 2H), 5.12 (s, 1H), 6.70 (s, 1H), 6.92-7.00 (m, 2H), 7.03-7.12 (m, 1H), 7.62-7.69 (m, 2H), 7.67 (s, J=3.0 Hz, 1H), 7.75 (m, 1H), 8.73 (d, J=1.5 Hz, 1H).