Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[Br:12])(=[O:3])[CH3:2].C(#N)C.Br[CH2:17][C:18]([CH3:20])=[CH2:19]>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:19][C:18]([CH3:20])=[CH2:17])[C:6]=1[Br:12])(=[O:3])[CH3:2]
Reactant: C=C(C)CBr
Reactant: CC(=O)Oc1cccc(O)c1Br
Solvent: CC#N
Product: C=C(C)COc1cccc(OC(C)=O)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of 2-bromo-3-hydroxyphenyl acetate (Intermediate 38, 3028 mg) in acetonitrile (60 ml) potassium carbonate (3623 mg, 26.2 mmol) and 3-bromo-2-methyl-1-propene (2123 mg, 15.73 mmol) were added. The reaction mixture was stirred at room temperature overnight. The mixture was washed with water (3 times 60 ml). The organic phase was separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a 100 g-SNAP column and cyclohexane/ethyl acetate from 100/0 to 80/20 as eluent to afford the title compound as a colourless oil (2.324 g).
Reaction SMILES: [NH:1]=[C:2]([CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5].[O:11]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[NH:1]=[C:2]([CH3:10])[CH:3]([C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5])[C:21]([NH:20][C:18]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:19])=[S:22]
Reactant: CCCOC(=O)CC(C)=N
Reactant: O=C(N=C=S)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCCOC(=O)C(C(C)=N)C(=S)NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
A warm solution of n-propyl 3-iminobutyrate (18.2 g.) in toluene (75 ml.) was added to a stirred solution of phenoxycarbonyl isothiocyanate (22.8 g.) in toluene (75 ml.). The temperature of the mixture rose from 20° C. to 35° C. The mixture was then stirred for 1.5 hours at the ambient temperature, filtered and the residue washed with light petroleum (b.p. 40°-60° C.) to give 3-imino-2-n-propoxycarbonyl-N-phenoxycarbonylthiobutyramide (36 g.) in the form of an orange solid. This solid was dissolved in ethyl acetate (125 ml.) and treated at 2°-5° C. with a solution of bromine (0.7 ml.) in ethyl acetate (40 ml.) over 15 minutes. The mixture was stirred at the ambient temperature for 1.5 hours and then filtered to give 3-methyl-5-phenoxycarbonylamino-4-n-propoxycarbonylisothiazole hydrobromide (28 g.), m.p. 157°-163° C.
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>C1COCC1.C(Cl)Cl>[C:1]([NH:20][CH:21]([CH2:22][OH:23])[CH2:24][O:25][CH2:41][C:40]1[CH:43]=[CH:44][C:37]([C:29]2[O:28][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=2)=[CH:38][CH:39]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC(COCc1ccc(-c2nc3ccccc3o2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-trityl-1,3-dihydroxy-2-propanamine (3.7 g; 11 mmol) is dissolved in THF (22 ml) and cooled to 0° C. NaH (0.44 g; 11 mmol; 60% in oil) is added and the reaction is warmed to room temperature and allowed to stir for 2 hours. 4-(benzoxazol-2-yl)benzylbromide (1.6 g; 5.5 mmol) is added and the reaction allowed to stir for 15 hours. The reaction is diluted with CH2Cl2 and washed with H2O 2x, dried (Na2SO4), concentrated and purified by column chromatography with basic alumina and eluted with 2% MeOH/98% CH2Cl2 to obtain N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]-3-hydroxy-2-propanamine as a white solid which is used directly in Step E.
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[CH:27]1([O:33][CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([C:44]#[CH:45])[CH:42]=3)[C:37]([CH3:47])([CH3:46])[CH2:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:33][CH:34]2[CH2:35][CH2:36][C:37]([CH3:47])([CH3:46])[C:38]3[CH:39]=[CH:40][C:41]([C:44]#[C:45][C:14]4[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=4)=[CH:42][C:43]2=3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: C#Cc1ccc2c(c1)C(OC1CCCCC1)CCC2(C)C
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OC2CCCCC2)CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 90 mg (0.3 mmol) of 4-cyclohexyloxy-6-ethynyl-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound N) was converted into the title compound using 88 mg (0.32 mmol) of ethyl 4-iodobenzoate, 70 mg (0.1 mmol) of bis(triphenylphosphine)palladium(II) chloride and 19 mg (0.1 mmol) of cuprous iodide.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[N:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]1[O:13][CH2:12][CH:11]([C@H:20]3[CH2:25][CH2:24][C@H:23]([N:26]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:22][CH2:21]3)[N:10]([CH3:37])[C:9]2=1>C(O)C>[CH3:4][O:5][C:6]1[N:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]1[O:13][CH2:12][CH:11]([C@H:20]3[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]3)[N:10]([CH3:37])[C:9]2=1
Reactant: COc1ccc2ncc3c(c2n1)N(C)C([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2ncc3c(c2n1)N(C)C([C@H]1CC[C@H](N)CC1)CO3
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Hydrazine hydrate (2M solution in methanol, 90 μL, 0.18 mmol, 1.0 eq) is added at room temperature to a stirred solution of 2-[trans-4-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione (105 mg, 0.18 mmol, 1.0 eq) in ethanol (3 mL). After 16 hours stirring at 50° C., solvent is removed to afford trans-4-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexylamine as an orange semisolid (80 mg, 93% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:47])(=[O:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:47])(=[O:46])[CH2:41][CH2:42][C:43]([O-:45])=[O:44]
Reactant: O=C(O)CCC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])CCC(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of succinic acid (0.066 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting solution was stirred for about 4 h and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then a sample (1 mL) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give Nilotinib succinate form II.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:21][CH2:22][CH3:23])(=[O:20])[CH:12]=CC1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6](/[CH:7]=[CH:12]/[C:11]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1
Reactant: Cc1ccc(F)cc1C=O
Reactant: CCOC(=O)C=Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(F)ccc1C

Procedure:
5-Fluoro-2-methylbenzaldehyde (40.58 g; 294 mmol) was converted to the ethyl cinnamate according to step 1 of example 1 to yield 40.81 g. of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S1C2C=CC=CC=2N=C1NC1CCN(CC2C3C(=CC=CC=3)C=CC=2[O:53]CC)CC1.C(=O)([O-])[O-].[K+].[K+].OO.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24](=[O:53])[NH2:25])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccc2ccccc2c1CN1CCC(Nc2nc3ccccc3s2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(C#N)ccc3o2)CC1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(C(N)=O)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
To a suspension of 4-(5-cyano-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.03 g, 3.01 mmol, 1.0 equiv; intermediate T (2-(piperidin-4-ylamino)-benzooxazole-5-carbonitrile)/step 1) and 0.084 g (0.6 mmol) of potassium carbonate in DMSO (5 mL) was added a solution of 35% hydrogen peroxide in water (0.53 mL, 0.59 g, 6.02 mmol, 2.0 equiv) and the reaction mixture stirred at ambient temperature for 24 h. The solution was poured on crashed ice, the reaction mixture extracted with dichloromethane/2-propanol (4:1, 3×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was evaporated under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with a gradient of dichloromethane/methanol (100:0→95:5) containing 33% of NH4OH to yield 1.05 g (97%) of the title compound. MS (ESI): 361.2 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:22]=[CH:21][N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=4)=[CH:14][N:13]3[CH:33]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl.O>[C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:22]=[CH:21][NH:20][CH:19]=4)=[CH:14][N:13]3[CH:33]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cc[nH]c3)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
A solution of 120 mg of N-phenyl-6-(1-triisopropylsilyl-1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in 5 mL of tetrahydrofuran is treated with 262 μL of a molar solution of tetrabutylammonium fluoride in tetrahydrofuran, and stirred for 10 minutes at room temperature. It is then diluted with 15 mL of dichloromethane and 20 mL of water. The organic phase is dried and concentrated to dryness under reduced pressure. The residue is taken up in 2 mL of dichloromethane, and the solid filtered off is washed twice with 1 mL of dichloromethane and then twice with 1 mL of diisopropyl ether, triturated twice with 2 mL of water, filtered off by suction and washed again with 2 mL of dichloromethane and 2 mL of diisopropyl ether and then dried to give 40 mg of N-phenyl-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[C:4]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)#[N:1]
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN)cc1
Yield: 93.5 %

Procedure:
10% Pd-on-C (Aldrich, 800 mg) catalyst was added to a solution of α-azido-4-cyanotoluene (compound 4-2, 8 g, 51 mmol) in EtOAc (150 ml). The reaction mixture was hydrogenated (H2, 45 psi) in a Parr apparatus for 11 hours. Catalyst was removed by filtering and the solvent was removed under vacuum to give the title compound (6.3 g, 93%). 1H NMR (CDCl3): δ 3.85 (s, 2H), 7.45 (d, 2H, J=8.1), 7.60 (d, 2H, J=8.1 Hz), 7.78 (s, 2H, NH2).
Reaction SMILES: O[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[N:5]=[N:4]1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH3:12][C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:2][NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:4]=[N:5][C:6]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)nnn2CO
Reactant: Nc1ccccc1
Solvent: CCO
Product: Cc1ccc2c(c1)nnn2CNc1ccccc1

Procedure:
5.0 g (0.03 mol) of 1-hydroxymethyl-5-methylbenzotriazole and 2.9 g (0.03 mol) of aniline were suspended in ethanol and refluxed for 1 hour. The insoluble substance was removed by filtration while it was still hot and the filtrate was cooled to obtain crude crystals. By recrystallization of the crude crystals from ethanol 4.2 g of the desired compound having a melting point of 149° to 152° C. was obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH3:19][O:20][C:21]1[C:22]([C:38](OC)=[O:39])=[N:23][N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:25](=[O:27])[CH:26]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:38]([C:22]1[C:21]([O:20][CH3:19])=[CH:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=2)[N:23]=1)=[O:39]
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)c(=O)cc1OC
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (1.58 g, 16.2 mmol) and iPr2NEt (2.82 mL, 16.2 mmol) in CH2Cl2 (13 mL) was added AlMe3 (1.8 M solution in toluene, 9.0 mL, 16.2 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 4-methoxy-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridazine-3-carboxylate (1.77 g, 5.4 mmol) in CH2Cl2 (15 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and crystallized from hexane/AcOEt to give the title compound (1.48 g, 83% yield) as a white solid: mp 127-129° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.37 (3H, s), 3.64 (3H, s), 3.91 (3H, s), 6.30 (1H, s), 7.55-7.60 (1H, m), 7.62-7.65 (1H, m), 7.82-7.86 (1H, m), 7.88 (1H, s). Anal. Calcd for C15H14F3N3O4: C, 50.42; H, 3.95; N, 11.76. Found: C, 50.47; H, 3.99; N, 11.83.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2.O.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][C:16]1[O:15][C:14]([CH2:13][NH:12][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([C:21]#[N:22])=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(CNc2ccc3c(I)cccc3n2)o1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1ccc(CNc2ccc3c(C#N)cccc3n2)o1
Temperature: 160 °C
Yield: 91 %

Procedure:
A stirred mixture of (5-iodo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (example 50, step A) (500 mg, 1.37 mmol), zinc cyanide (177 mg, 1.5 mmol) and tetrakis-(triphenylphosphine)-palladium (159 mg, 0.14 mmol) in DMF (5 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield 2-[(5-methyl-furan-2-ylmethyl)-amino]-quinoline-5-carbonitrile as light brown solid (346 mg, 91%).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:32])=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3[O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:21]=O)[CH:16]=2)[C:11]([CH3:34])([CH3:33])[CH2:10][C:9]1=[O:35])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:32])=[C:15]([C:18]3[CH:19]=[C:20]([CH:21]=[CH2:1])[CH:23]=[CH:24][C:25]=3[O:26][CH2:27][C:28]([F:30])([F:31])[F:29])[CH:16]=2)[C:11]([CH3:34])([CH3:33])[CH2:10][C:9]1=[O:35])[CH3:7]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OCC(F)(F)F)cc21
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(OCC(F)(F)F)c(-c2cc3c(cc2C)C(C)(C)CC(=O)N3CC)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In accordance with Scheme 16, to a suspension of methyltriphenylphosphonium bromide (3.27 mmol, 1.17 g) in 7.5 mL THF was added a solution of n-butyllithium in hexanes (1.6 M, 3.27 mmol, 2.04 mL) at −40° C. The reaction was warmed to −10° C. and stirred for 30 min. The reaction mixture was cooled to −60° C. and then Compound 1D (0.14 mmol, 0.06 g), in 7.5 mL THF, was added dropwise. The yellow suspension was allowed to stir at r.t. overnight and then quenched by adding 1 mL H2O. It was extracted with EtOAc and was washed with brine. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo. The yellow oil thus obtained was then purified by column chromatography (3.5:1 hexanes/EtOAc) to obtain 1-ethyl-4,4,6-trimethyl-7-[2-(2,2,2-trifluoro-ethoxy)-5-vinyl-phenyl]-3,4-dihydro-1H-quinolin-2-one as a colorless thick gum (0.61 g, 94% yield).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:18]([O:20]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:13][CH2:14][C:15]([NH2:17])=[O:16])=[O:10])=[CH:3][CH:2]=1.[NH2:30][C@H:31]([C:36]([NH:38][C@H:39]([C:47]([O:49][CH3:50])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])[CH2:32][C:33](=[O:35])[NH2:34].Cl>CN(C)C=O.C(N(CC)CC)C>[NH:11]([C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10])[C@H:12]([C:18]([NH:30][C@H:31]([C:36]([NH:38][C@H:39]([C:47]([O:49][CH3:50])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])[CH2:32][C:33](=[O:35])[NH2:34])=[O:20])[CH2:13][CH2:14][C:15](=[O:16])[NH2:17]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1

Procedure:
14.5 g of Z-Gln-ONP and 10.8 g of H-Asn-Phe-OCH3, hydrochloride (Ann. 688, 259 [ 1965]) are dissolved together in 100 ml of dimethylformamide and to the solution 4.55 ml of triethylamine are added slowly. A thick paste forms which is diluted with 50 of dimethylformamide. After a reaction period of 24 hours at room temperature, the batch is filtered and the residue washed with dimethylformamide. The resulting Z-Gln-Asn-Phe-OMe can be recrystallized from much hot dimethylformamide. Melting point, 261°-265° C. (decomp.). [α]D20 = + 11° (c = 0.94 in hexamethylphosphoric acid triamide).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:10][CH3:11])[C:5]=1[C:12]1[NH:25][C:15]2=[CH:16][C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[C:21]=3[CH:22]=[C:14]2[N:13]=1.[CH3:26]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:10][CH3:11])[C:5]=1[C:12]1[N:13]([CH3:26])[C:14]2=[CH:22][C:21]3[C:20](=[O:23])[NH:19][C:18](=[O:24])[C:17]=3[CH:16]=[C:15]2[N:25]=1
Reactant: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)NC3=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc(Cl)c1-c1nc2cc3c(cc2n1C)C(=O)NC3=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
NaH (0.12 g, 3.04 mmol) was added in portions to a solution of 2-(4-chloro-2-methoxypyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.0 g, 3.04 mmol) in 30 mL of anhydrous DMF at 0° C. under argon. The reaction mixture was then stirred at rt for 3 h. MeI (2.16 g, 15.2 mmol) was added dropwise via a syringe at rt under argon. The resulted mixture was stirred for 6 h at rt, hydrolyzed by adding 100 mL of water. The brown precipitate was isolated, washed with water and dried under vacuum. The solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=49/1 v/v) to give a white solid product, 0.68 g, 65.4% yield. MS: 343.0 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 11.27 (s, 1H), 8.42 (d, 1H, J=5.5 Hz), 8.23 (s, 1H), 8.08 (s, 1H), 7.43 (d, 1H, J=5.5 Hz), 3.89 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.Cl.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:31][C:30]3[CH:29]=[N:28][N:27]([CH3:32])[C:26]=3[NH:25][C:24]3[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:23]2=3)=[O:21])=[CH:16][C:15]=1[F:38].O>C(Cl)(Cl)Cl>[CH3:32][N:27]1[C:26]2[NH:25][C:24]3[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:23]=3[N:22]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH2:13][NH:12][CH:1]=[O:3])=[C:15]([F:38])[CH:16]=3)=[O:21])[CH2:31][C:30]=2[CH:29]=[N:28]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Reactant: O=CO
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Formic acid (0.85 ml, 22.5 mmol) and acetic anhydride (1.4 ml, 13.5 mmol) were combined and stirred for 1 h at room temperature. (4-Aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (113 mg, 0.3 mmol) was added and the mixture was stirred for 1 h. Water (20 ml) was added and the mixture was stirred for 1 h. It was diluted with chloroform, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield a white solid identified as the title compound (48 mg, 40%).
Reaction SMILES: [OH-].[Na+].[CH:3](=[CH:12][C:13](=[O:15])[CH3:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(O)C>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH:14][C:13](=[O:15])[CH:12]=[CH:3][CH:4]=[CH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)C=CC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=CC=Cc1ccccc1)C=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 92.2 %

Procedure:
16.2 g of a 10% strength NaOH solution were added dropwise, while cooling slightly, to a mixture of 46.5 g of cinnamalacetone, 45.4 g of p-nitrobenzaldehyde and 160 ml of ethanol at 25° C. The reaction mixture became clear after a short time, and a yellow solid subsequently separated out. The mixture was stirred for one hour, after which the solid was filtered off under suction, washed with diethyl ether, and dried under reduced pressure to give 76 g (91% of theory) of 1-(4-nitrophenyl)-7-phenyl-1,4,6-heptatrien-3-one of melting point 168°-170° C.