Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13](=O)[O:14]C(=O)[NH:16][C:11]=2[CH:10]=1.O>C(O)(=O)C>[C:2]1([NH:1][C:13](=[O:14])[C:12]2[C:11](=[CH:10][C:9]([F:8])=[CH:20][CH:19]=2)[NH2:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(F)ccc1C(=O)Nc1ccccc1

Procedure:
A solution of aniline (1.77 g) in acetic acid (50 ml) was added to a solution of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (1 g) in acetic acid (100 ml) and the mixture heated at 100° for 20 minutes. It was then poured into water and the precipitate collected, dried and recrystallised from toluene to give N1 -phenyl-4-fluoroanthranilamide, m.p. 120°-122°. (Compound 4).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23](=[O:26])[NH:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[C:18]([O:22][C:23]([NH:24][NH:25][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 4-oxopiperidine-1-carboxylate (4.08 g, 17.5 mmol) in 50 mL of methanol was added tert-butylcarbazate (2.31 g, 17.5 mmol). The mixture was stirred at room temperature for 3 h and then was concentrated in vacuo to afford a white foam. This residue was taken up in 50 mL of 50% glacial acetic acid. To the resulting suspension was added sodium cyanoborohydride (1.1 g, 17.5 mmol) portionwise with vigorous stirring at room temperature. After the addition was complete the mixture was stirred for 3 h at room temperature. The mixture was neutralized with 1N NaOH/solid NaOH and then extracted twice with methylene chloride. The combined organics were washed with sat'd aq sodium bicarbonate and brine, dried (Na2SO4), filtered through a pad of silica gel and concentrated in vacuo to afford Example 12A, benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate, as a solid (6.0 g) which was pure enough to be used without purification. LRMS (ESI): 350.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.[NH2:12]O.Cl.CCO>O>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][CH:5]([NH2:12])[CH2:6]2
Reactant: NO
Reactant: CN1C2CCCC1CC(=O)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C2CCCC1CC(N)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a 250 mL RB flask were added 9-methyl-9-azabicyclo[3.3.1]nonan-3-one (10 g), NH2OH.HCl (5.26 g), NaOAc.3H2O (10.26 g), EtOH (56 mL), and H2O (26 mL). The mixture was refluxed for 1.5 h and cooled to RT. Solvents were removed and the residue was partitioned between aqueous K2CO3 (3M) and CHCl3. The organic phase was separated and the aqueous phase extracted twice with CHCl3. The combined CHCl3 solution was washed once with brine, dried over Na2SO4, filtered, and evaporated to a brownish oil, which solidified upon standing. The solid was transferred to a 500 mL Parr flask. To this were added Raney-Ni (6.2 g, wet) and NH3 solution in MeOH (150 mL), made by bubbling NH3 into MeOH for 20 min. This mixture was hydrogenated under a pressure of 40-45 psi of H2 at RT for 18 h. The mixture was filtered through a pad of Celite. All volatiles were removed on a rotary evaporator. EtOH (50 mL) was added to the residue and then evaporated to give an I-1 as an oil (9.5 g, 94%). This crude product contained two isomers, and was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:32]
Reactant: COc1ccc(N2CCOCC2)cc1NC(=O)c1ncc[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCOCC2)cc1NC(=S)c1ncc[nH]1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
To a suspension of 1.0 g of imidazole-2-carboxylic acid (8.9 mmol) in 15 ml DMF was added 1.6 g of CDI (9.8 mmol) and stirred at ambient temperature for 1 h. Then the mixture was refluxed for 30 min. After cooling to ambient temperature, 2.0 g of 2-methoxy-5-morpholin-4-yl-phenylamine (9.8 mmol) were added and the reaction mixture was heated to reflux for 16 h. The mixture was evaporated and the residue taken up in water (40 ml) and extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 2:1). 0.25 g 1H-imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (9%) were obtained as a white solid; M.p.: 227–230° C. 0.2 g of 1H-Imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.66 mmol) were taken up in toluene (8.0 ml) and treated with 0.8 g of Lawesson reagent (2.0 mmol). The reaction mixture was heated to reflux for 22 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 1:1). 0.125 g of 1H-imidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (59%) was obtained as a yellow foam; MS (ISP): m/e=319 (M+H+).
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Cl>CN(C)C=O.O>[CH3:10][C:2]([O:1][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)([CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: BrCCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)OCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (22 mL) of tert-butyl 2-hydroxy-2-methylpropanoate (1.0 g) in N,N-dimethylformamide was added sodium hydride (250 mg) under an ice bath, and the mixture was stirred at room temperature for 1 hour. Thereafter, under an ice bath, 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.88 mL) was added dropwise, and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and 1N hydrochloric acid under an ice bath, followed by extraction with t-butyl methyl ether. The organic layer was sequentially washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound having the following physical property values, as a mixture (400 mg) with tert-butyl 2-hydroxy-2-methylpropanoate.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:5])C.[CH2:41]([NH2:43])[CH3:42]>CO.C1COCC1>[CH2:41]([NH:43][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:20]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:5])[CH3:42]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Reactant: CCN
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 8-indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 27 (b), 20 mg, 0.037 mmol) in 1 mL methanol was added a solution of ethylamine in THF (2N, 2 mL). The mixture was stirred at 80° C. for 16 hours. The solvent was removed by vacuum to leave a yellow solid (12.7 mg, 64%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.60 (br, 1H), 9.29 (s, 1H), 8.78 (s, 1H), 7.75 (s, 1H), 7.60 (br, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.20 (m, 2H), 7.12 (d, J=7.6 Hz, 1H), 6.87 (br, 2H), 3.69 (br, 4H), 3.42(q, J=7.1 Hz, 2H), 3.01 (t, J=7.3 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.65 (br, 2H), 2.49 (br, 6H), 2.17 (m, 2H). 1.08 (t, 7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H34N6O3: 539.27 (M+H), Found 539.0.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].C([Mg]Br)C(C)C.[C:35](=O)=[O:36]>O1CCCC1>[OH:36][CH2:35][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: O=C=O
Agent: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(CO)c(Cc3ccccc3C(F)(F)F)sc21
Reaction time: 2 h

Procedure:
5-Bromo-1-isobutyl-3-methyl-6-[2-(trifluoromethyl)benzyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.6 g, Example 1c)) was dissolved in tetrahydrofuran (150 ml) at room temperature under an atmosphere of nitrogen. To this solution was added isobutyl magnesium bromide (4.9 mls, 2M in tetrahydrofuran). After 30 mins carbon dioxide gas was passed through the reaction and stirred for 2 hrs. The reaction mixture was then concentrated in vacuo and redissolved in ethanol (100 ml). Concentrated HCl (1 ml) was added and the reaction was heated at reflux for 36 hrs. The reaction was then concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The resultant gum was purified via chromotography eluting with 3:2 isohexane/diethyl ether to yield the sub title compound as a brown oil (2.3 g)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:18](=[O:17])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
To 150 g (735 mmol) (S)-1-(4-bromophenyl)ethylamine in 2 L DCM are added 459 mL (918 mmol) of an aq. Na2CO3 solution (c=2 mol/L). To this mixture a solution of 164 g (749 mmol) BOC2O in 350 mL THF is added dropwise at r.t. and stirring is continued for 1 h. Then the mixture is poured onto water and stirred for additional 20 min. The layers are separated, the org. layer is washed with water (2×), dried over Na2SO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[CH:27][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2ccccc2-n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 90 °C

Procedure:
To a degassed solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 0.84 mmol), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (328 mg, 1.27 mmol) and K3PO4 (445 mg, 0.706 mmol), in DMF (6 mL)-water (0.6 mL) was added dichlorobis (triphenylphosphine) palladium (II) (30 mg, 0.042 mmol). The reaction mixture was heated at 90° C. for 95 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2′-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methylbiphenyl-4-carboxamide. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.57-7.78 (m, 5H), 7.4 (dd, 1H), 7.25 (s, 1H), 6.92-7.2 (m, 4H), 4.6 (m, 1H), 4.2 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.1 (m, 1H), 2.83 (m, 6H), 2.5 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:18])[CH:7]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH:19](I)([CH3:21])[CH3:20]>O1CCCC1>[CH2:11]([O:10][C:8](=[O:9])[C:7]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)([CH:19]([CH3:21])[CH3:20])[C:6]([O:5][CH2:3][CH3:4])=[O:18])[CH3:12]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccco1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(c1ccco1)C(C)C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
24 g (1 mol) of sodium hydride were suspended in 100 ml of absolute tetrahydrofuran. A solution of 218.4 g (0.97 mol) of 2-furylmalonic acid diethyl ester in 200 ml of absolute tetrahydrofuran was added dropwise. The temperature rose to 30° (blue suspension). After stirring at 30° for 30 minutes, 340 g (200 ml; 2 mol) of isopropyl iodide were added dropwise within 30 minutes. The reaction mixture was heated to reflux overnight, thereafter evaporated under reduced pressure, and dissolved in ether. After evaporation of the solvent, the remaining oily residue was distilled in a high vacuum, to obtain 240.6 g (92.5%) of 2-furyl-2-isopropylmalonic acid diethyl ester (purity 93.6%) in the form of a yellowish oil, boiling point 85°-88°/13 Pa.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([O:30][CH3:31])=[CH:21][C:22]([O:28][CH3:29])=[C:23]([N:25]=[C:26]=[O:27])[CH:24]=1>C(#N)C>[Cl:18][C:19]1[C:20]([O:30][CH3:31])=[CH:21][C:22]([O:28][CH3:29])=[C:23]([NH:25][C:26](=[O:27])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[CH:6][CH:7]=2)[CH:24]=1
Reactant: COc1cc(OC)c(N=C=O)cc1Cl
Reactant: Nc1ccc(NC(=O)c2ccccc2F)cc1
Solvent: CC#N
Product: COc1cc(OC)c(NC(=O)Nc2ccc(NC(=O)c3ccccc3F)cc2)cc1Cl
Reaction time: 12 h

Procedure:
A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) in acetonitrile (4 mL) is treated with 5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture becomes a solution and is allowed to stand for 12 hours. A white solid forms and is collected by filtration (0.79 g). [M+H]444.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:17])[CH:25]([N+:26]([O-:28])=[O:27])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: Cc1ccccc1/C=C/[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1C1CN(Cc2ccccc2)CC1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (3.93 g, 16.55 mmol) in CH2Cl2 (60 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-methyl-2-((E)-2-nitro-vinyl)-benzene (2.70 g, 16.55 mmol) and trifluoroacetic acid (0.13 ml, 1.65 mmol) in CH2Cl2 (30 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:6) afforded 1.01 g (21%) of the title compound as a light yellow oil. ES-MS m/e: 297.4 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].S(=O)(=O)(O)O.[C:16](O)(=[O:18])[CH3:17]>C(OC(=O)C)(=O)C>[C:16]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([CH3:3])=[CH2:2])=[CH:5][CH:6]=1)(=[O:18])[CH3:17]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: C=C(C)c1ccc(OC(C)=O)cc1
Temperature: 200 °C

Procedure:
134 g of dimeric p-isopropenyl phenol are dissolved under nitrogen in 150 g of acetic acid anhydride, followed by the addition of 0.5 g of concentrated sulphuric acid. The reaction begins with a slight heat effect under which the temperature of the reaction mixture rises to around 50° C and then falls again. When the reaction temperature has fallen to around 30° C, the reaction mixture is slowly heated until, finally, acetic acid distils off under normal pressure. The temperature is regulated in such a way that distillation is continuous. When no more acetic acid distils over, the remaining acetic acid and the excess acetic acid anhydride are distilled off in a water jet vacuum, after which the reaction mixture is cooled. Another 5 g of concentrated sulphuric acid are then added, followed by heating in a high vacuum until p-acetoxy-α-methyl styrene distils off. The temperature of the reaction mixture is regulated in such a way that the reaction mixture distils off continuously; it is in the range from 70° to 120° C and is ultimately increased to 200° C. The reaction product which has distilled over is then redistilled; 119 g (68% of the theoretical) of p-acetoxy-α-methyl styrene are obtained in the boiling range from 80° to 82° C/0.1 Torr.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:37])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])(C(C)(C)C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O>[OH:8][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:37]
Reactant: CCCCCC/C=C\COC(=O)CCCCCCCC(CCCCCCCC(=O)OC/C=C\CCCCCC)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC/C=C\COC(=O)CCCCCCCC(O)CCCCCCCC(=O)OC/C=C\CCCCCC
Reaction time: 48 h
Yield: 39 %

Procedure:
The silyl protected diester 8 (0.3 g, 0.44 mmol) was dissolved in 1 M solution of TBAF in THF (6 mL) and the solution was kept at 40° C. for two days after which the TLC showed the completion of the reaction. The reaction mixture was diluted with water (60 mL) and extracted with ether (2×50 mL). The combined organic layers were concentrated and the thus obtained crude product was purified by column to isolate the pure product (0.097 g, 39%). 1H NMR (400 MHz, CDCl3) δ 5.64 (dt, J=10.9, 7.4 Hz, 2H), 5.52 (dt, J=11.0, 6.8 Hz, 2H), 4.61 (d, J=6.8 Hz, 4H), 3.57 (s, 1H), 2.30 (t, J=7.5 Hz, 4H), 2.09 (q, J=7.1 Hz, 4H), 1.75-1.53 (m, 4H), 1.53-1.06 (m, 36H), 0.88 (t, J=6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.98, 135.64, 123.57, 77.54, 77.22, 76.91, 72.14, 60.41, 37.69, 34.54, 31.89, 29.70, 29.60, 29.44, 29.29, 29.07, 27.76, 25.80, 25.15, 22.82, 14.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([CH:49]=1)[C:46]([NH2:48])=[O:47]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:40][C:41]4[CH:42]=[N:43][CH:44]=[C:45]([CH:49]=4)[C:46]([NH2:48])=[O:47])=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3cnc(O)nn23)cn1
Reactant: NC(=O)c1cncc(N)c1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(-c2ccc3cnc(Nc4cncc(C(N)=O)c4)nn23)cn1
Yield: 40 %

Procedure:
The titled compound was prepared in analogous fashion as Example 522 using 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol, N-phenylbis(trifluoromethanesulphonimide) and 5-amino-nicotinamide to give 5-[7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-nicotinamide as a light brown solid (23.9 mg, 40% yield). M.p.=>250° C. LCMS (E/I+) 361 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.05 (s, 1H), 8.92 (s, 1H), 8.83 (s, 1H), 8.60 (m, 3H), 8.09 (s, 1H), 7.62 (s, 1H), 7.25 (d, 1H, J=4.7 Hz), 7.02 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [CH2:1]([Mg]I)[CH3:2].[Mg].C(I)C.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([F:18])[CH:11]=1>C(OCC)C>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:1][CH3:2])=[C:12]([F:18])[CH:11]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC[Mg]I
Agent: [Mg]
Solvent: CCOCC
Solvent: CCI
Product: CCC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a ice-cold solution of ethyl magnesium iodide prepared from magnesium (2.39 g, 98.51 mmoles) and ethyl iodide (7.88 ml, 98.51 mmoles) in diethyl ether (50 ml), 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmoles) in diethyl ether (10 ml) was added and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with dilute HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as red colour liquid (5.8 g, 99% yield) which is used as such for step.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>C(Cl)Cl.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: ClCCl
Product: Clc1ncc2ccccc2n1

Procedure:
A two-phase mixture of a solution of 2,4-dichloroquinazoline (5 g) in methylene chloride (100 mL) covered with 100 mL of saturated brine containing 9% NH4OH is treated with powdered zinc (5 g) and the resultant mixture is then refluxed for 4 h, cooled and filtered through celite. The organic layer is removed, diluted with ethyl acetate (100 ml), washed with 1 N HCl solution, dried and concentrated.