Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:5][CH:4]=1.[CH3:24][N:25]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([NH:37][C:36]4[CH:38]=[CH:39][C:33]([CH2:32][N:25]([CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH3:24])=[CH:34][CH:35]=4)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCO3)cc1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
To a solution of 7—(4-dimethylaminophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4—(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.11 g) and triethylamine (0.2 ml) in dimethylformamide (15 ml) was added diethyl cyano-phosphate (0.11 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7—(4-dimethylaminophenyl)-N-(4—((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 149) (0.07 g) as pale brown crystals.
Reaction SMILES: [NH2:1]/[C:2](=[N:4]/[O:5][C:6]([C:8]1[C:9]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:10][C:11]([NH:14][C:15]2[CH:20]=[N:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)=[N:12][CH:13]=1)=O)/[CH3:3]>N1C=CC=CC=1>[C:21]([C:18]1[N:19]=[CH:20][C:15]([NH:14][C:11]2[CH:10]=[C:9]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[C:8]([C:6]3[O:5][N:4]=[C:2]([CH3:3])[N:1]=3)=[CH:13][N:12]=2)=[N:16][CH:17]=1)#[N:22]
Reactant: C/C(N)=N\OC(=O)c1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: c1ccncc1
Product: Cc1noc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 23.5 %

Procedure:
A solution of (E)-tert-Butyl 4-((5-((1-aminoethylideneaminooxy)carbonyl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (40 mg, 0.078 mmol) in pyridine (3 mL) was heated at 120° C. for 8 hr using microwave irradiation. After evaporation of the solvent, the crude product was purified by column chromatography (Biotage), eluting with EtOAc/n-hexane (1/1), to give the title compound as a yellow solid (9 mg, 23%).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].[ClH:27]>>[ClH:27].[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2sc(NC(=N)N)nc2C)cc1
Agent: Cl
Product: Cc1nc(NC(=N)N)sc1C(=O)Nc1ccc(OCC(=O)O)cc1

Procedure:
330 mg of ethyl {4-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate are stirred at RT for 11 hrs. in 6 ml of 25% hydrochloric acid. The reaction mixture is evaporated to dryness in a vacuum and the residue is trituraited in MeCN. There are obtained 293 mg of [4-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy]-acetic acid hydrochloride (1:1); m.p. 273° C., MS: 350 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]2[CH:10]([CH:11]=1)[NH:9][C:8](=[O:12])[CH2:7][CH2:6]2.C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:3]1[C:2]([OH:1])=[CH:11][CH:10]2[CH:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCC2C=CC(O)=CC2N1
Product: O=C1CCC2C=C(Br)C(O)=CC2N1

Procedure:
This intermediate was obtained according to general procedure I from 7-hydroxy-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (370 mg, 2.27 mmol) and NBS (424 mg, 2.38 mmol) after flash chromatography on silica gel (hexanes/ethyl acetate, 1/1, Rf=0.15) as white solid (500 mg, 2.07 mmol, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: O=C1CCCCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
4-Bromo-1-iodobenzene (5 g, 17.7 mmol) in tetrahydrofuran (20 mL) at −40° C. was treated dropwise with isopropyl magnesium chloride (2 M solution in tetrahydrofuran, 23 mmol, 11.5 mL) and following addition was stirred 1 hour. Cyclohexanone (1.5 mL, 14.75 mmol) in tetrahydrofuran (5 mL) was added and the solution was allowed to slowly warm to room temperature over 3 hours. Saturated aqueous ammonium chloride solution was added and the mixture was then diluted with ethyl acetate. The aqueous and organic layers were separated and the organic layer was washed with water (1×) and brine (1×). The combined aqueous layers were extracted with ethyl acetate (3×10 mL), the combined organic layers were dried over magnesium sulfate, were filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (20:1 hexanes-ethyl acetate) to afford 3 g (67% yield) of 1-(4-bromo-phenyl)-cyclohexanol. 13C NMR (100 MHz, CDCl3) □ 148.8, 131.4, 126.8, 120.8, 73.2, 38.9, 25.6, 22.3.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:29][CH3:30])=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[C:6]([O:29][CH3:30])=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: COc1cc(=O)n(CCN2CCC(NC(=O)OC(C)(C)C)CC2)c2cc(F)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(=O)n(CCN2CCC(N)CC2)c2cc(F)ccc12
Yield: 37.6 %

Procedure:
1,1-Dimethylethyl (1-{2-[7-fluoro-4-(methyloxy)-2-oxo-1(2H)-quinolinyl]ethyl}-4-piperidinyl)carbamate (0.40 g, 0.95 mmol) was stirred in 1,4-dioxane (15 ml) containing 4M HCl for 5 h, then concentrated. The resulting solid was portioned between ethyl acetate and sodium carbonate solution and the aqueous extracted with ethyl acetate. The organics were dried and concentrated to an oil which contained highly impure product. Analysis of the aqueous by 1 c/ms showed the product to primarily reside in the aqueous fraction. The aqueous was concentrated and the resulting solids washed with dichloromethane containing methanol (10%) which on evaporation provided material which was washed once more with dichloromethane containing methanol (10%). Concentration of the solution provided the title compound (0.114 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[CH:26]([Sn](C=C)(C=C)C=C)=[CH2:27].O.CCOC(C)=O>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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([CH:26]=[CH2:27])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: C=C[Sn](C=C)(C=C)C=C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(NC3CC3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
A solution of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (190 mg, 0.389 mmol) in dioxane (3 mL) was degassed with Ar before being charged with tetravinyltin (0.105 mL, 0.576 mmol) and Pd(Ph3P)4 (41 mg, 0.035 mmol). The mixture was stirred at 100° C. for 3 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 2-chloro-N-cyclopropyl-7-tosyl-5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (39 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].O[C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([O:15]C)=[O:14]>C(Cl)(Cl)(Cl)Cl>[Cl:2][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1sccc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1sccc1Cl

Procedure:
52.1 g. of phosphorus pentachloride are dissolved in 600 ml. of absolute carbon tetrachloride and heated to boiling, whereupon a solution of 15.8 g. of 3-hydroxy-2-methoxycarbonyl-thiophene in 200 ml. of carbon tetrachloride is added dropwise during 3 hours. The mixture is boiled to reflux for 13 hours, the carbon tetrachloride is distilled off and the mixture is evaporated almost to dryness in vacuo. 450 Ml. of water are added dropwise while cooling, whereupon the mixture is heated to boiling and then allowed to cool. The resulting precipitate is filtered off under suction and boiled up with 10 g. of active carbon in a solution of 25 g. of sodium bicarbonate. The active carbon is then filtered off under suction and the cooled solution is acidified with hydrochloric acid. There is obtained 3-chlorothiophene-2-carboxylic acid of melting point 185°-186° C.
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:6]2[C:13]([I:14])=[CH:12][N:11]([CH2:15][C@@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH2:18])[C:7]=2[N:8]=[CH:9][N:10]=1>>[NH2:3][C:5]1[C:6]2[C:13]([I:14])=[CH:12][N:11]([CH2:15][C@@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH2:18])[C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: N
Reactant: C=C[C@@H](Cn1cc(I)c2c(Cl)ncnc21)NC(=O)OC(C)(C)C
Solvent: CO
Product: C=C[C@@H](Cn1cc(I)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 6 h

Procedure:
An 8 N ammonia methanol solution (89.4 ml) was added to the (S)-tert-butyl (1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (20.84 g) obtained in Step 1, and the mixture was stirred in an autoclave at 120° C. for 6 hours. The reaction mixture was cooled with ice, and the solvent was distilled off under reduced pressure. After the resulting residue was diluted with a small amount of methanol, the resulting precipitate was collected by filtration, washed with cold methanol (11 ml), and then dried under reduced pressure to obtain the title compound (8.28 g) as a milky-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O=S(Cl)Cl.[CH3:15]O>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:15])=[O:7])=[CH:9][CH:10]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)nc1

Procedure:
A solution of 6-methyl nicotinic acid, 2-1 (5 g, 36.5 mmol) in 100 ml of anhydrous methanol was placed in a 250 ml three neck flask equipped with a dropping funnel vertical condenser and CaCl2 drying tube. The reaction solution was cooled to -15° in an ice acetone bath and SOCl2 (5 ml, 69.1 mmol) was added dropwise. The solution was then heated at reflux for 3 h then cooled and the solvent removed at reduced pressure. The resulting white solid was treated with 60 ml of saturated NaHCO3 and extracted into CH2Cl2 (3×50 ml). The pooled extracts were dryed (Na2SO4 ), filtered and evaporated at reduced pressure. The resulting oil crystallized on standing giving 2-2 as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[C:16](=O)([O-])O.[Na+]>CO>[OH:1][C:2]1[C:3]([C:8]([O:10][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ncccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncccc1O
Yield: 64 %

Procedure:
3-Hydroxypicolinic acid (1.0 g) was suspended in methanol (10 ml) and concentrated sulfuric acid (1.0 ml) was added. The mixture was refluxed under heating for 5 hr. The reaction mixture was ice-cooled, neutralized with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (711 mg, yield 64%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[C:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[N:15]=[CH:16][CH:17]=2)[N:12]=[C:11](C(O)=O)[CH:10]=1.C1(P([N:44]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[C:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[N:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([NH2:44])[CH:10]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)c2ccnc(-c3c(F)cccc3F)c2n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Nc1cc(-c2ccc(F)cc2F)c2ccnc(-c3c(F)cccc3F)c2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 114.8 %

Procedure:
To a suspension of the title compound from Example 1 (100 mg, 0.25 mmol) in tert-butanol (2.4 mL) were added diphenylphosphoryl azide (DPPA) (0.07 mL, 0.32 mmol) and triethylamine (0.045 mL, 0.32 mmol). The mixture was heated at 100° C. for 75 minutes. The solvent was evaporated and the mixture redissolved in HCl (4M in dioxane, 2 mL) and stirred at room temperature for 2.5 hours. Subsequently, 4% aqueous sodium bicarbonate (40 mL) was added to the mixture and the reaction was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to give 106 mg of a yellowish oil. The mixture was purified by column chromatography (C-18 silica from Waters©, reverse phase water/(acetonitrile/methanol 50:50) as eluent [0.1% v/v ammonium formate buffered] 0% to 100%). The organic solvent from the appropriate fractions was evaporated and the aqueous phase basified to pH 10 with ammonium hydroxide. This was extracted with ethyl acetate, dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a white solid (55 mg, 60%).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:20][CH:19]=1.O.Cl>O1CCCC1.CO>[CH3:4][C:5]1[S:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)sc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Lithium hydroxide monohydrate (83.6 mg) was added to a solution of methyl E-4-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (500 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (8 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (2.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (363 mg, yield 75%) as colorless crystals. m.p. 99-100° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:35][CH:34]=2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:33]2[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH2:39][N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (62 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(4-(2-morpholinoethoxy)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=451).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:39]([NH:41][NH2:42])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:12][C:13]2[O:15][CH:39]=[N:41][N:42]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc(C(Cc2nnco2)N2C(=O)c3ccccc3C2=O)cc1OC

Procedure:
2-[1-(3,4-Dimethoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindoline-1,3-dione was prepared by the procedure of Example 8 from 3-(3,4-dimethoxyphenyl)-3-(1,3-dioxoisoindolin-2-yl)propanoic acid (2.0 g, 3.6 mmol), carbonyidiimidazole (1.0 g, 6.2 mmol), formic hydrazide (0.41 g, 6.8 mmol), and phosphorus oxychloride (1.3 mL, 14 mmol) in acetonitrile (20 mL). The product was obtained as a white solid (730 mg, 34% yield): mp, 83.0-85.0° C.; 1H NMR (CDCl3) δ 3.82 (dd, J=6.0, 16.0 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 3.90 (s, 3H, CH3), 4.39 (dd, J=10.3, 15.7 Hz, 1H, CHH), 5.84 (dd, J=6.0, 10.3 Hz, 1H, NCH), 6.81-6.85 (m, 1H, Ar), 7.16-7.19 (m, 2H, Ar), 7.68-7.73 (m, 2H, Ar), 7.77-7.83 (m, 2H, Ar), 8.30 (s, 1H, CH); 13C NMR (CDCl3) δ 27.66, 51.76, 55.79, 55.89, 111.00, 111.07, 120.29, 123.3,8, 130.16, 131.55, 134.07, 149.03, 149.11, 152.96, 163.90, 167.86; Anal Calcd for C20H17N3O6+0.3 Et2O: C, 63.22; H, 5.20; N, 10.32. Found: C, 63.40; H, 5.02; N, 10.46. (1H NMR showed that the sample contained 30% of ether).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([CH:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH2:27][CH2:26]3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1>ClCCl.C(N(CC)CC)C>[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([CH:25]3[CH2:26][CH2:27][CH:28]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:36][CH2:37][N:38]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:39][CH2:40]4)[CH2:29][CH2:30]3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCNCC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.57 mg, 0.005 mmol) in dichloro-methane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=557.4
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].[CH3:24][O:25][CH2:26][C:27]#[C:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]2[O:36][CH2:37][O:38][C:30]=12.[ClH:39].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.C(#N)C>C(O)CC.C(OCC)C>[ClH:1].[ClH:39].[C:22]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:33][C:32]1[CH:34]=[CH:35][C:29]([C:28]#[C:27][CH2:26][O:25][CH3:24])=[C:30]3[O:38][CH2:37][O:36][C:31]=13)=[C:10]([O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH:9]=[C:8]([O:20][CH3:21])[CH:7]=2)#[N:23]
Reactant: COCC#Cc1ccc(N)c2c1OCO2
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)c(C#N)cnc2c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCCO
Solvent: CCOCC
Solvent: CC#N
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OC)cc(OC4CCN(C)CC4)c23)c2c1OCO2

Procedure:
A mixture of 4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline (165 mg) and 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (123 mg) in 1-propanol (10 ml) was treated with a 1.0M solution of hydrogen chloride in diethyl ether (0.5 ml) then stirred and heated at reflux for 2 hours. On cooling a solid precipitated from the reaction mixture. The resulting suspension was basified with aqueous ammonia and evaporated to a gum. This residue was purified by multi-injection preparative RP HPLC [Kromasil C18 5 μm silica column, 100 mm×10 mm; eluted with a mixture of acetonitrile (55%) and 0.1% aqeous ammonia solution (45%)]. After isolation, the major product was converted to its dihydrochloride salt in acetonitrile using two equivalents of a 1.0M solution of hydrogen chloride in diethyl ether. The title compound was thus obtained as a yellow solid (81 mg); NMR Spectrum: (DMSOd6 & CD3COOD, 373K) 2.17 (m, 2H), 2.38 (m, 2H), 2.77 (s, 3H), 3.30 (m, 4H), 3.37 (s, 3H), 3.96 (s, 3H), 4.33 (s, 2H), 5.04 (m, 1H), 6.12 (s, 2H), 6.92 (d, 1H), 6.97 (m, 2H), 7.08 (s, 1H), 8.63 (s, 1H); Mass Spectrum: M+H+ 501.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15]([CH2:23][C:24]([O:26]CC)=[O:25])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:23]([C:24]([OH:26])=[O:25])[N:3]=[N:2]2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
4-Azido-N-ethylbenzamide (267 mg, 1.40 mmol) and ethyl benzoylacetate (0.316 ml, 1.75 mmol, 1.25 eq.) were dissolved in ethanol (8 ml), sodium ethoxide (122 mg, 1.75 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 13 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (3:1, 40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and stood still at 0° C. The precipitate was collected by filtration, washed with water and dried to give the title compound as a pale-yellow powder (465 mg, 1.38 mmol, 98.8%).