Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.COC(=O)[CH2:26][NH2:27]>CO.[Pd]>[CH2:13]([C@@H:12]1[NH:11][C:9](=[O:8])[CH2:26][NH:27][C:20]1=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)CN
Agent: [Pd]
Solvent: CO
Product: O=C1CNC(=O)[C@H](Cc2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of 23.30 g (62.91 mmol) N-Benzyloxycarbonyl-phenylalanine-glycine-methylester (obtained above) in 650 ml dry methanol was hydrogenated by adding Pd/C-catalyst and stirring the resulting mixture under H2 at r.t. for 3 h. After that, the mixture was filtered through celite and then half of the solvent was evaporated. The remaining solution was refluxed for 17 h. Filtration of the white precipitate and washing it twice with methanol yielded 10.71 g (52.45 mmol, 83.37%) 6-(S)-Benzyl-piperazine-2,5-dione as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O.C(N(C(C)C)CC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (2.1 g, 11.3 mmol) and thionyl chloride (20 mL) was refluxed for 3 h and then cooled to rt. The excess thionyl chloride was removed and the residue dissolved in 10 mL of THF was added to a cooled (0° C.) solution of 2-aminophenol (1.24 g, 11.3 mmol) and diisopropylethylamine (2.4 mL, 13.6 mmol) in anhydrous THF (20 mL). The resulting mixture was refluxed for 4 h and then cooled to rt. The solvent was removed and p-toluenesulfonic acid (8.63 g, 45.4 mmol) and toluene (50 mL) were added to afford a dark mixture that was refluxed overnight. The solvent was removed and the crude was purified by flash chromatography on silica gel eluting with hexanes:CH2Cl2 (1:5) to afford 2-(4-fluoro-3-nitrophenyl)-1,3-benzoxazole as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:13][CH:14]([CH2:16]O)O.O.O=[As](O[As](=O)=O)=O.[OH-].[NH4+]>S(=O)(=O)(O)O.O.C(O)(=O)C>[CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:16][CH:14]=[CH:13]2
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[As](=O)O[As](=O)=O
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2cccnc12
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 2-methyl-3-nitroaniline (10 g), glycerin (20.57 g) and arsenic pentoxide hydrate (As2O5.xH2O, Baker, 88% As2O5, 8.5 g) in concentrated sulfuric acid (9.75 mL) is heated slowly to 150° C. in an open round-bottom flask, then stirred for 6 hours at 150° C. The resulting mixture is cooled to room temperature and diluted with water (200 mL), then basified with ammonium hydroxide (28-30%, 100 mL). After about 10 minutes, the solution is acidified to pH=5 with glacial acetic acid and extracted with methylene chloride (3×200 mL). The combined extracts are washed with water (200 mL) and saturated sodium bicarbonate (200 mL), then dried over magnesium sulfate and rotary evaporated. The crude quinoline is filtered through a short pad of silica gel, using methylene chloride as solvent. The filtrate is rotary evaporated and the residue recrystallized from hexanes/methylene chloride to afford 8-methyl-7-nitroquinoline as a tan solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH2:8][S:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=2)[CH:17]=1)[CH2:13]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH2:8][S:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=2)[CH:17]=1)[CH2:13][Br:42])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CSc2cc(CO)cc(SCc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CSc2cc(CBr)cc(SCc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Temperature: 27.5 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
3,5-Bis(3,5-di-tertiary-butylbenzylthio)benzyl alcohol (49.0 g, 84.9 mmol) and carbon tetrabromide (28.2 g, 85.0 mmol) were dissolved in 300 ml of tetrahydrofuran. To this solution was added with stirring triphenylphosphin (23.5 g, 89.6 mmol), at the temperatures of 10° C. or below. The reaction mixture became clear once, and then colorless crystals separated gradually. After stirring overnight at 25-30° C., the crystals were removed by filtration and the filtrate was concentrated. The residue obtained was purified by means of chromatography with n-hexane:dichloromethane=1:1, giving 34.8 g of 3,5-bis(3,5-di-tertiary-butylbenzylthio)benzyl bromide.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:11]=3[CH:12]=2)[CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:23])([CH3:3])[CH3:2].O1CCOCC1.[Mn]([O-])(=O)(=O)=O.[K+].C=O>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:11]=3[CH:12]=2)[C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)CCO3
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2cc3c(cc21)CCO3

Procedure:
To a stirred solution of 4.6 g. of 1-isopropyl-3,4,7,8-tetrahydro-4-phenyl-furo[2,3-g]quinazolin-2(1H)-one in 200 ml. of dioxane cooled to 5°±5°C. is added dropwise a solution of 3.0 g. of potassium permanganate in 140 ml. of water. After the addition is completed 1.5 ml. of formalin solution is added. The resulting precipitated solids are removed by filtration and the filtrate concentrated in vacuo to obtain an oil of 1-isopropyl-7,8-dihydro-4-phenyl-furo[2,3-g]quinazolin-2(1H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[CH2:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCCCCC>[CH2:31]([N:30]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:17])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C(Nc1cccc(Br)c1)Oc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)c1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of 1.46 g. of phenyl N-(3-bromophenyl)carbamate in 15 ml. of tetrahydrofuran is added to a solution of 2.32 g. of dibenzylamine in 20 ml. of tetrahydrofuran and the mixture is stirred under reflux for 24 hours. The mixture is diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane affords 1,1-di-benzyl-3-(3-bromophenyl)urea, m.p. 102°-103° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:29])[N:17]([CH3:28])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:20]=2)=[CH:11][C:10]=1[F:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:30][C:10]1[CH:11]=[C:12]([C:15]2[C:16](=[O:29])[N:17]([CH3:28])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:20]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Yield: 100 %

Procedure:
A solution of 5-(4-(benzyloxy)-3-fluorophenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.133 g, 0.331 mmol) in TFA (1.5 mL) was stirred at 40° C. for 3.5 hours. The reaction mixture was concentrated to dryness and then purified by flash column chromatography, eluting with 20:1 dichloromethane/MeOH. The desired product (0.103 g, 100%) was obtained as a foamy white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.81 (br s, 1H), 8.96 (br s, 1H), 7.86 (s, 1H), 7.56-7.45 (m, 3H), 7.37 (t, J=7.4 Hz, 2H), 7.27 (m, 1H), 7.15 (t, J=7.2 Hz, 1H), 6.92 (t, J=9.0 Hz, 1H), 3.54 (s, 3H). LRMS (APCI pos) m/e 312 (M+1).
Reaction SMILES: [CH2:1]([O:4][CH:5](OCC#C)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:2]#[CH:3].C([Cl:20])(=O)C.S(Cl)(Cl)=O>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([Cl:20])[O:4][CH2:1][C:2]#[CH:3])=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: C#CCOC(OCC#C)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: C#CCOC(Cl)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 125 %

Procedure:
1-(Bis-prop-2-ynyloxy-methyl)-4-chloro-benzene (11.7 g) is added to acetyl chloride (19.9 g) and thionyl chloride (0.2 ml) over 1 hour. The temperature is maintained at 20° C. by occasionally cooling. The reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is evaporated at 20-30° C. using vacuum. 1-Chloro-4-(chloro-prop-2-ynyloxy-methyl)-benzene (13.4 g) is obtained as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[CH2:11](N(CC)CC)[CH3:12].C[Si](C#C)(C)C.C(=O)([O-])O.[Na+]>C1COCC1.[Cu]I.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.O>[CH2:9]([O:8][C:5]1[CH:4]=[CH:3][C:2]([C:11]#[CH:12])=[CH:7][N:6]=1)[CH3:10]
Reactant: CCN(CC)CC
Reactant: CCOc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(OCC)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 5-bromo-2-ethoxypyridine (5.00 g, 24.8 mmol) in THF (50 mL)-triethylamine (25 mL) were added trimethylsilylacetylene (5.3 mL, 37.2 mmol), copper(I) iodide (237 mg, 1.24 mmol) and bis(triphenylphosphine)palladium(II) chloride (870 mg, 1.24 mmol), and the mixture was stirred under an argon stream at 60° C. for 1 hr. Water was added to the reaction mixture, the mixture was extracted twice with hexane, and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=19:1) to give an oil. To a solution of the oil in THF (50 mL) was added 1 M tetrabutylammonium fluoride THF solution (26.0 mL, 26.0 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=19:1) to give the title compound (690 mg, yield 19%) as an oil.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)CCC.Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C1(C)C=CC=CC=1.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>[N:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1
Reactant: Brc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(-c3ccccn3)c2)cc1
Yield: 77.9 %

Procedure:
The crude 4-tributylstannyl-1-trityl-1H-imidazole (1.37 g) in toluene (10 mL) was treated sequentially with 2-bromopyridine (0.33 mL, 3.43 mmol) and Pd(PPh3)4 (0.26 g, 0.23 mmol). The reaction mixture was heated at reflux under an argon atmosphere for 4 hours. After cooling, the reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (50 mL) and sequentially washed with aqueous saturated potassium fluoride (75 mL), water (75 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in-vacuo to afford 0.69 g of crude 4-(2-pyridyl)-1-trityl-1H-imidazole.
Reaction SMILES: C(O[CH2:4][NH:5][C:6]1[N:27]=[CH:26][CH:25]=[CH:24][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[S:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:9])C.[BH4-].[Na+].O>CS(C)=O>[CH3:4][NH:5][C:6]1[N:27]=[CH:26][CH:25]=[CH:24][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[S:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:9]
Reactant: CCOCNc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 2-(ethoxymethyl-amino)-N-(5-phenoxy-thiophene-2-ylmethyl)-nicotinamide described in Preparation Example A+-6 (148 mg, 0.385 mmol) in dimethylsulfoxide (3 mL) was added sodium borohydride (44 mg, 1.15 mmol), and the solution was stirred for 30 minutes at 100° C., followed by stirring for 20 minutes at 110° C. Furthermore, sodium borohydride (35 mg, 0.925 mmol) was added thereto, followed by stirring for 20 minutes at 110° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, and then, concentrated in vacuo. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (86 mg, 0.26 mmol, 67%) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:3]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N:20]1([C:27]([NH:29][C@@H:30]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:31](O)=[O:32])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)Cl>[C:6]([NH:5][C:3]([CH:2]([NH:1][C:31]([CH:30]([NH:29][C:27]([N:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:28])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:4])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)NC(C)(C)C
Reaction time: 1 h

Procedure:
The crude product from Example AK ((S)-2-Amino-3-(4-nitrophenyl)-N-tert-butylpropionamide) (1.34 g, 5.25 mmol) and the product from Example Z (1.35 g, 5.25 mmol) were dissolved in DMF (40 mL), then HBTU (1.99 g, 5.25 mmol) and diisopropylethylamine (4.3 g, 33 mol) were added and stirred for 1 hour. The mixture was poured into CH2Cl2 (100 mL); the CH2Cl2 solution was washed with aqueous sodium bicarbonate (3×) and dried over sodium bicarbonate. The crude reaction mixture was further purified by column chromatography (SiO2, EtOAc) to yield the title compound (2.5 g), mp 194-195° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:7]1[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH2:1][CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccccc2Cl)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 2-chloro phenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C21H19ClNO3 (M+H): 368.1048. Found 368.1015
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2=[O:21])#[N:2].[C@@H:24]12[CH2:32][NH:31][CH2:30][C@@H:29]1[CH2:28][CH2:27][CH2:26][NH:25]2.C(N(CC)CC)C>C(#N)C>[C:1]([C:3]1[C:4]([N:31]2[CH2:32][C@@H:24]3[C@@H:29]([CH2:28][CH2:27][CH2:26][NH:25]3)[CH2:30]2)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2=[O:21])#[N:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(F)c(F)cc2c1=O
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(N3C[C@@H]4CCCN[C@@H]4C3)c(F)cc2c1=O
Yield: 81.7 %

Procedure:
14.32 g (45 mmol) of ethyl 8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 6.31 g (50 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and 10.22 g (101 mmol) of triethylamine are boiled under reflux in 270 ml of acetonitrile for 4 hours. The reaction mixture is left to stand at room temperature for some hours and the solid which has crystallized out is filtered off with suction, rinsed with acetonitrile and dried. 15.6 g of a beige solid are obtained (82% of theory).
Reaction SMILES: [NH2:1][C:2]([CH:7]([OH:26])[CH:8]([OH:25])[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH2:5][OH:6])[CH2:3][OH:4]>CO.[C].[Pd]>[NH2:1][C:2]([CH:7]([OH:26])[CH:8]([OH:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH2:3][OH:4])[CH2:5][OH:6]
Reactant: CCCCCCCCCCCCCC=CCC(O)C(O)C(N)(CO)CO
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCC(O)C(O)C(N)(CO)CO
Yield: 50.2 %

Procedure:
2-Amino-2-(1,2-dihydroxy-4-octadecenyl)-1,3-propanediol (68.0 mg) was dissolved in 14 ml of methanol and 6.8 mg of 5% palladium-carbon was added thereto. The catalytic reduction was conducted at ordinary temperature and at atmospheric pressure day and night. After the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 34.3 mg of the subject compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>CN(C=O)C>[CH2:29]([N:31]([CH2:17][C@@H:15]([OH:16])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1])[CH2:32][CH3:33])[CH3:30]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C[C@@H](O)COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2cc1OC
Temperature: 70 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
A mixture of (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.79 mmol), (prepared as described for the starting material in Example 269), and diethylamine (0.25 ml, 2.38 mmol) in DMF (10 ml) was stirred at 70° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, dichloromethane/methanol/0.88 ammonia (100/8/1)) to give (2R)-7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (288 mg, 81%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH:39]1[CH3:44])=O)(C)(C)C>>[CH3:20][C:18]([CH3:21])([CH3:19])[C:17]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:41]4[CH2:42][CH2:43][NH:38][CH:39]([CH3:44])[CH2:40]4)[CH:3]=3)[N:9]=2)[NH:14][CH:15]=1)=[O:22]
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Product: CC1CN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)CCN1

Procedure:
2,2-Dimethyl-1-{2-[3-(3-methyl-piperazin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2-methyl-piperazine-1-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=378.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([NH:23][C@@H:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])[N:15]=1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].CO>C1COCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH:23][C@@H:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])[N:15]=1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])c(N[C@H](C)c3cccnc3)n2)c(OC)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(N[C@H](C)c3cccnc3)n2)c(OC)c1
Reaction time: 0.5 h

Procedure:
A solution of (R)-tert-butyl 2,4-dimethoxybenzyl(5-nitro-6-(1-(pyridin-3-yl)ethylamino)pyridin-2-yl)carbamate (500 mg) in THF (25 mL) was treated with an aqueous solution comprised of 2 g of Na2S2O4 and 1 g NaHCO3 in 20 mL of water followed by 1 mL of methanol. The mixture was stirred for 30 minutes, then diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to provide the intermediate (R)-tert-butyl 2,4-dimethoxybenzyl(5-amino-6-(1-(pyridin-3-yl)ethylamino)pyridin-2-yl)carbamate (66). The intermediate was dissolved in THF (50 mL) and treated with 1,1′-carbonyldiimidazole (0.5 g) at 50° C. for 20 h. The mixture was concentrated and purified by column chromatography (2→5% MeOH in methylene chloride) to provide 413 mg of (R)-tert-Butyl 2,4-dimethoxybenzyl(2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)carbamate (67).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[O:21][CH3:20])(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: COc1ccc(OC)c(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2,5-dimethoxybenzene-1-sulfonylchloride.