Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5](=[O:12])[N:6]([CH:8]2[CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[F:14][C:15]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:8]1([N:6]2[C:5](=[O:12])[C:4]([CH3:13])=[CH:3][C:2]([C:23]3[CH:22]=[C:21]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=[CH:19][C:18]=3[O:17][C:16]3[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:15]=3[F:14])=[CH:7]2)[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(Br)cn(C2CCC2)c1=O
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C2CCC2)c1=O
Yield: 31.6 %

Procedure:
The title compound of Example 483, step 3 (27 mg, 0.11 mmol), N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide (55 mg, 0.13 mmol), K2CO3 (46 mg, 0.33 mmol) and Pd(dppf)2Cl2 (8 mg, 0.011 mmol) in DMF (2 mL) were reacted and purified in a manner similar to Example 483, step 4 to give the title compound (16 mg, 32%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.65 (s, 1H), 7.42 (s, 1H), 7.26-7.27 (m, 1H), 7.13 (dd, J=8.8, 2.8 Hz, 1H), 6.97-6.89 (m, 2H), 6.83 (d, J=9.2 Hz, 2H), 6.54 (s, 1H), 5.09-5.18 (m, 1H), 3.04 (s, 3H), 2.53-2.46 (m, 2H), 2.23-2.18 (m, 2H), 2.16 (s, 3H), 1.87-1.81 (m, 2H). LCMS: 461 (M+H)+
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1)[C:2]#[CH:3].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].F[C:33](F)(F)[C:34](O)=O>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.[Cu]I.C(#N)C.O>[C:34]1([C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][N:7]2[C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=[C:11]([NH2:20])[C:10]=3[N:9]=[CH:8]2)[CH:33]=[CH:18][CH:19]=[CH:10][CH:11]=1
Reactant: C#CCOCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Nc1nc2ccccc2c2c1ncn2CCOCC#Cc1ccccc1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a mixture of 1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (10 g, 37.6 mmol), anhydrous N,N-dimethylformamide (150 mL) and potassium carbonate (6.23 g, 45.1 mmol) was heated to 70° C. lodobenzene (4.43 mL, 39.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.53 g, 0.75 mol), and copper(I) iodide (0.29 g, 1.50 mmol) were added and the mixture was allowed to stir for 0.5 hour. The temperature was raised to about 85° C. After 1.5 hours analysis by HPLC (reverse phase, acetonitrile/water with 0.1% trifluoroacetic acid) indicated that the reaction was complete. The mixture was allowed to cool to ambient temperature and then it was filtered. The filtrate was concentrated under reduced pressure. The residue was purified twice by flash chromatography (95/5 dichloromethane/methanol) to provide 2.7 g of 1-{2-[(3-phenyl-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 196-197° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][CH:28]([CH3:31])[CH2:29][OH:30]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:30][CH2:29][CH:28]([CH3:31])[CH3:27])[CH:7]=1
Reactant: CC(C)CO
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CC(C)COc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 2-methylpropan-1-ol (74 μl; 0.789 mmol), example 58 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:6]=[C:7]([CH3:11])[S:8][C:9]=1[CH3:10].O.[NH2:14][NH2:15]>C(O)CCC>[CH3:11][C:7]1[S:8][C:9]([CH3:10])=[C:5]([CH2:4][C:3]([NH:14][NH2:15])=[O:2])[N:6]=1
Reactant: NN
Reactant: COC(=O)Cc1nc(C)sc1C
Solvent: CCCCO
Solvent: O
Product: Cc1nc(CC(=O)NN)c(C)s1
Yield: 68 %

Procedure:
As described for example 112a, (2,5-dimethyl-thiazol-4-yl)-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was then heated under reflux for 20 h. Evaporation of all volatiles and crystallization from n-butanol and toluene afforded the title compound as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.31 (s, 3H), 2.51 (s, 3H), 3.37 (s, 2H), 4.20 (s, 2H), 9.10 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: CCc1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:30][CH3:31])(=[O:29])[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:31][O:30][C:20](=[O:29])[C@H:21]([O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@H](O)c1ccccc1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Oc1ncc(C(=O)Nc2ccc(F)cc2)cn1)c1ccccc1
Yield: 34.2 %

Procedure:
A suspension of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.36 mmol) and (R)-(−)-methyl mandelate (86 mg, 0.52 mmol) in 3.6 mL of THF was treated dropwise with DBU (80 μL, 0.54 mmol) at ambient temperature. The reaction mixture clarified and turned yellow over the course of 5 min. The reaction was quenched after 24 hours by the addition of 5 mL of 1 M HCl. The mixture was extracted with 2×25 mL portions of ethyl acetate. The organic extracts were combined, dried using Na2SO4 and concentrated in vacuo. The crude material was dissolved in 30% (v/v) ethyl acetate/hexanes and filtered though a 10 g plug of silica gel. The eluent was concentrated to dryness and triturated with 3×5 mL portions of hexane followed by 3×10 mL portions of 10% (v/v) portions of ethyl acetate/hexanes. The residue was dried to yield 47 mg (34%) of the titled compound as a white solid. ESI-MS m/z 382 (MH+), 380 (M−H−).
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH2:25][C:26]#[N:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH2:25][CH2:26][NH2:27])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1cc(Br)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NCCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.6 %

Procedure:
To a mixture of NaBH4 (6.0 g) in THF (100 ml) was added dropwise trifluoroacetic acid (18 ml) at 0° C. (ice bath). 4-Bromo-2-cyanomethylphenyl benzyl ether (10 g) was added and the mixture stirred at ambient temperature for 18 hours. The reaction was quenched with water (100 ml), the pH adjusted to 13 with 2N aqueous NaOH solution, and extracted with diethyl ether. The diethyl ether extracts were dried (MgSO4) and evaporated to give 2-(2-aminoethyl)-4-bromophenyl benzyl ether (11.0 g) as a yellow gum.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][CH2:33][OH:34].O[C:36]1[CH:45]=[CH:44][C:39]([C:40](OC)=O)=[CH:38][CH:37]=1>C1(C)C=CC=CC=1>[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][CH2:33][O:34][C:36]1[CH:45]=[CH:44][C:39]([CH3:40])=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 0.25 h

Procedure:
Di-t-butylazodicarboxylate (9.46 g, 41.08 mmol) is added to a stirred solution of triphenylphosphine (10.77 g, 41.08 mmol), 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (7.35 g, 36.15 mmol) and methyl 4-hydroxybenzoate (5.0 g, 32.86 mmol) in toluene (120 mL) at 0° C. After stirring for 15 min, the ice-water bath is removed. Stirring is continued for 1 h at RT, 1 h at 40° C., and overnight at RT. The reaction is then concentrated under vacuum, and the residue is crystallized from EtOAc to give 5-methyl-2-phenyl-4-(2-p-tolyloxy-ethyl)-oxazole as a white solid.
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.S1C=CC(S(Cl)(=O)=O)=C1>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: O=S(=O)(Cl)c1ccsc1
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (235 mg, 1.0 mmol) and 3-thienylsulfonyl chloride (208 mg, 1.1 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give benzamide I-5 (259 mg, 67%) as a white powder: mp (EtOAc) 207-210° C.; 1H NMR δ 10.40 (s, 1H, CONH), 8.93 (d, J=2.2 Hz, 1H, H-2″), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6″), 8.23 (br t, J=6.3 Hz, 1H, NHSO2), 8.17-8.21 (m, 2H, H-2′, H-4″), 7.92 (dd, J=8.3, 1.7 Hz, 2H, H-2, H-6), 7.75 (dd, J=5.1, 1.3 Hz, 1H, H-5′), 7.42 (br d, J=8.4 Hz, 2H, H-3, H-5), 7.39 (dd, J=8.2, 4.7 Hz, 1H, H-5″), 7.35 (dd, J=5.1, 1.3 Hz, 1H, H-4′), 4.13 (d, J=6.3 Hz, 2H, CH2N); 13C NMR δ 165.5, 144.5, 141.9, 141.8, 140.5, 135.7, 132.9, 130.4, 129.0, 127.6 (2), 127.3 (2), 127.2, 125.1, 123.4, 45.7; MS m/z 374.6 (MH+, 100%). Anal. calcd for C17H15N3O3S2: C, 54.67; H, 4.05; N, 11.25. Found: C, 54.86; H, 3.95; N, 11.06%.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[N:10]=[N:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH:15]1([CH2:20][CH2:21][CH2:22]I)[CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C)C=O>[CH:15]1([CH2:20][CH2:21][CH2:22][N:10]2[C:11](=[O:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: ICCCC1CCCC1
Reactant: O=c1nn[nH]n1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1n(CCCC2CCCC2)nnn1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
To a solution of 600 mg of 1-phenyl-5-tetrazolone (for the synthesis of this compound see: Horwitz, J. P.; Fisher, B. E.; Tomasewski, A. J. J Amer Chem Soc 1959, 81, 3076) in 2 mL of N,N-dimethylformamide (DMF) was added 280 mg of powdered 85% potassium hydroxide followed by 870 mg of 3-cyclopentyl-1-iodopropane from Step A. The mixture was stirred at 80° C. for 18 h and then quenched by addition of water. The product was extracted with dichloromethane and purification by flash chromatography on silica gel (9:1 hexane:ethyl acetate) afforded 830 mg of the title compound: 1H NMR (CDCl3) δ7.96 (d, 2H, J=8.5 Hz), 7.50 (t, 2H, J=7.5 Hz), 7.37 (t, 1H, J=7.5 Hz), 4.02 (t, 2H, J=7.1 Hz), 1.90 (m, 3H), 1.79 (m, 2H), 1.61 (m, 2H), 1.53 (m, 2H), 1.41 (m, 2H), 1.10 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[C:31]([CH2:32][CH3:33])=[CH:30][N:29]=[CH:28][N:27]=1.Cl.C[O-].[Na+].CO>C(O)C>[CH2:32]([C:31]1[C:26]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:24][CH:23]=2)=[N:27][CH:28]=[N:29][CH:30]=1)[CH3:33]
Reactant: CCc1cncnc1Cl
Reactant: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCc1cncnc1Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Yield: 58.9 %

Procedure:
To 10 ml of ethanol were added 0.23 g of 4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.13 g of 4-chloro-5-ethylpyrimidine, and after adding 2 ml of an ethanol solution of hydrochloric acid (containing 0.071 g of hydrochloric acid), the mixture was reacted under reflux for 2 hours. After cooling, a 28% sodium methylate-methanol solution was added to the reaction mixture to make it alkaline, and then the mixture was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.18 g of the title compound as pale yellow crystal.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:40])[CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]([F:39])([F:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CO.[Pd]>[F:39][C:31]([F:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[OH:40]
Reactant: O=c1ccc2c([C@@H](O)CNCCCCCCOCC(F)(F)c3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Solvent: CO
Product: O=c1ccc2c([C@@H](O)CNCCCCCCOCC(F)(F)c3ccccc3)ccc(O)c2[nH]1
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To Intermediate (II) (1.10 g, 2.0 mmol) in methanol (50 mL) was added 20% palladium on charcoal (300 mg). The mixture was hydrogenated at 2 bars for 3 hours. The catalyst was filtered through Celite and the solvent concentrated. The resulting oil was purified by column chromatography with silica gel eluting with methylene chloride/methanol (95:5) to give the title compound (0.50 g, 54%) as oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH:9]=2)[N:4]=1.O.[SH:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[NH:29][CH:30]=[N:31]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2cc3ccccc3cc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc3ccccc3cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 48.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2n (200 mg, 0.563 mmol), 6-mercaptopurine monohydrate (105 mg, 0.619 mmol), K2CO3 (86 mg, 0.619 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 128 mg of a dark yellow solid (48%), mp 247.8-254.4° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.90 (s, 1H); 8.50 (s, 1H); 8.46 (s, 1H); 8.34 (s, 1H); 8.27 (d, J=8.2 Hz, 1H); 8.16 (d, J=8.2 Hz, 1H); 7.81 (dd, J=1.6, 7.3 Hz, 1H); 7.70 (t, J=7.5 Hz, 1H); 7.61-7.74 (m, 2H); 7.49 (t, J=7.5 Hz, 1H); 7.44-7.53 (m, 1H); 4.44-4.56 (m, 2H). 13C NMR (DMSO-d6) ppm: 161.3, 151.6, 151.5, 143.9, 142.2, 136.7, 134.4, 132.5, 131.8, 131.6, 130.5, 129.7, 129.3, 128.8, 128.6, 128.3, 128.3, 127.1, 125.2, 119.5, 32.4. MS (ES): m/z 471.0 (M+). Anal. calcd. for C24H15ClN6OS.0.2C2H6O.0.05KCl: C, 60.57; H, 3.37; Cl, 7.69; N, 17.37; S, 6.63. Found: C, 60.24; H, 3.46; Cl, 7.50; N, 17.34; S, 6.69.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].I[C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])/[C:11](=[O:20])[NH:12]2>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.CN(C=O)C.CCN(CC)CC>[OH:6][CH:3]([CH2:4][CH3:5])[C:2]#[C:1][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])/[C:11](=[O:20])[NH:12]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (52.6 mg, 0.63 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (100 mg, 0.25 mmol) (Starting Material 4 supra) using (Ph3P)2PdCl2 (17.5 mg) and Cul (4.8 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 12 mg, 14%).
Reaction SMILES: [C:1]([N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([NH:18][O:19]C3CCCCO3)=[O:17])=[CH:11][CH:12]=2)[CH2:7]1)(=[O:5])[C:2]#[C:3][CH3:4].Cl>CO>[C:1]([N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([NH:18][OH:19])=[O:17])=[CH:11][CH:12]=2)[CH2:7]1)(=[O:5])[C:2]#[C:3][CH3:4]
Reactant: CC#CC(=O)N1CCc2ccc(C(=O)NOC3CCCCO3)cc2C1
Agent: Cl
Solvent: CO
Product: CC#CC(=O)N1CCc2ccc(C(=O)NO)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 124 mg 2-but-2-ynoyl-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 6 ml methanol and 6 ml 0.1 N aqueous hydrochloric acid is stirred overnight at ambient temperature. The mixture is evaporated and the residue is treated with water and acetone. A colorless solid separates. After drying, 73 mg of the title compound are obtained. MH+=275.7
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24].[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[C:37]([C:40](O)=[O:41])=[CH:36][N:35]([CH:43]([CH3:45])[CH3:44])[C:34]2=[O:46])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:40]([C:37]2[C:38](=[O:39])[N:33]([C:30]3[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=3)[C:34](=[O:46])[N:35]([CH:43]([CH3:45])[CH3:44])[CH:36]=2)=[O:41])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C(C)C)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3C(C)C)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=165-167° C.; LCMS m/z=613 (M+1); 1H NMR (CDCl3) δ: 10.86 (s, 1H), 8.72 (s, 1H), 8.46 (d, 1H, J=5.5 Hz), 7.66 (dd, 1H, J=2.5, 8 Hz), 7.63 (d, 1H, J=2 Hz), 7.60 (s, 1H), 7.44 (s, 1H), 7.27-7.25 (m, 3H), 7.05 (d, 1H, J=9 Hz), 6.37 (d, 1H, J=5.5 Hz), 4.98 (p, 1H, J=8 Hz), 4.06 (s, 6H), 3.09 (p, 1H, J=8 Hz), 1.5 (d, 6H, J=7 Hz), 1.18 (d, 6H, J=7 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[N:18]=[C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=[C:15]([NH2:27])[N:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CCO>[CH3:26][N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]1[N:16]=[C:15]([NH2:27])[N:14]=[C:13]([C:10]2[N:9]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH:31][CH:28]([CH3:30])[CH3:29])=[CH:3][CH:4]=3)[O:12][N:11]=2)[N:18]=1
Reactant: CC(C)N
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(Cl)nc3)n2)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Yield: 27.3 %

Procedure:
A mixture of 6-[5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-triazine-2,4-diamine (Intermediate 135, 0.100 g, 0.263 mmol), isopropylamine (0.087 mL, 1.052 mmol), DIPEA (0.091 mL, 0.525 mmol) in EtOH (1 mL) was heated 3 times under microwave conditions (first treatment: 100 W, 130 C, 40 min; second treatment: 100 W, 130 C, 45 min; third treatment: 100W, 130 C, 45 min). The reaction mixture was cooled down and concentrated under vacuum. The resulting dark oil was purified by preparative HPLC, to afford the title compound (29 mg, 27%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].O=S(Cl)[Cl:16]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,4-dimethoxybenzoic acid (0.25 g, 1.4 mmol) in 5 mL of SOCl2 was warmed to reflux and was allowed to stir for 2 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude material was diluted with 5 mL of toluene and concentrated under reduced pressure. This dilution with toluene and concentration was repeated two additional times to give the crude title compound which was used without additional purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)(=[O:12])=[O:11])=[CH:5][C:4]=1[CH3:22]>[Pd].C(O)C.CCOC(C)=O>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[C:4]([CH3:22])[CH:5]=1)(=[O:11])=[O:12]
Reactant: COc1ncc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ncc(NS(=O)(=O)c2ccccc2N)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 106.5 %

Procedure:
A mixture of N-(6-methoxy-5-methylpyridin-3-yl)-2-nitrobenzenesulfonamide (2.69 g, 8.32 mmol) and 10% palladium on charcoal (1.35 g) in ethanol/EtOAc (1:1, 100 mL total reaction volume) was stirred at rt under an atmosphere of H2 for approximately 2.5 h. Filtration and concentration in vacuo yielded the crude title compound (2.60 g).