Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1>C(O)C.[Pt](=O)=O>[F:22][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C=CC1(c2cccc(C(F)(F)F)c2)CCOCC1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)CCC1(c2cccc(C(F)(F)F)c2)CCOCC1
Yield: 97.3 %

Procedure:
A solution of ethyl 3-(4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)acrylate (101 mg, 308 μmol) and platinum(IV) oxide (10.3 mg, 46 μmol) in ethanol (2 mL) was hydrogenated at 1 atmosphere for 4.25 h. The catalyst was removed by filtration through a Whatman Autovial filter and the filtrate was concentrated under vacuum to afford ethyl 3-(4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)propanoate (99 mg, 97% yield) as a viscous colorless oil. 1H NMR (400 MHz, CDCl3): δ ppm 7.34-7.60 (m, 4H), 4.02 (q, 2H), 3.81 (ddd, 2H), 3.43-3.63 (m, 2H), 2.07-2.23 (m, 2H), 1.97-2.04 (m, 2H), 1.84-1.96 (m, 4H), 1.19 (t, 3H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[C:19](OC(=O)C)(=[O:21])C.S(=O)(=O)(O)O>>[CH3:19][O:21][C:7]1[CH:8]=[CH:3][C:4]2[S:9][C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=[O:14])[C:5]=2[CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1Sc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 80 °C

Procedure:
Finally, 2-methoxythioxanthen-9-one (S-17) was prepared. To a mixture of 2-(2-methoxyphenylthio)benzoic acid (11.0 g, 42 mmol) and 43.1 g (423 mmol) of acetic anhydride was added dropwise 4.14 g (42 mmol) of concentrated sulfuric acid. The mixture was heated at 80° C. for 4 h, cooled to ambient, and poured very slowly onto 500 g of ice. The precipitate was extracted with dichloromethane, and the extract was washed with 10% aqueous NaHCO3 and then with brine. The solution was dried (MgSO4), passed through a short column of silica gel, and concentrated to deposit an orange solid. The product was purified by successive recrystallizations from isopropanol and from toluene/heptane. 1H NMR (CDCl3): δ 3.95 (s, 3H), 7.27 (dd, 1H), 7.5 (m, 2H), 7.6 (m, 2H), 8.09 (d, 1H), 8.64 (d 1H).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:29][CH2:28]2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[O:4]>[OH-].[Na+].CO>[C:3]([CH2:5][CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:31][CH2:32]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])([OH:4])=[O:2]
Reactant: COC(=O)CCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 0.08 g (0.142 mmol) of 9-[4-(4-quinolin-2-yl-piperazin-1-yl)-butyl]-9H-fluorene-9-carboxylic acid-(2-methoxycarbonyl-ethyl)-amide in 2 ml of 2N sodium hydroxide solution and 35 ml of methanol is stirred for 14 hours at ambient temperature. Then the mixture is concentrated by evaporation, diluted with water and adjusted to a pH of 5 with 1N hydrochloric acid. The precipitate formed is filtered off.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[O:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[BH4-].[Na+].Cl>CCO.O1CCOCC1>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CO)cnc32)cc1
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (37.6 g, 125 mmol) in EtOH (500 mL) and 1,4-dioxane (500 mL) was added NaBH4 (4.72 g, 125 mmol) in one portion. After about 3 h, aqueous HCl (1N, 400 mL) was slowly added to the reaction mixture. The mixture was concentrated to one-half the original volume under reduced pressure and EtOAc (1000 mL) and water (500 mL) were added to the mixture. The layers were separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (35.9 g, 95% yield) as a tan solid: LC/MS (Table 2, Method a) Rt=1.97 min; MS m/z: 304 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][C:21]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=4[N:28]=3)[C:14]2=[O:29])[CH2:9][CH2:8]1)=[O:4].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][C:21]4[CH2:27][CH2:26][N:25]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:24][CH2:23][C:22]=4[N:28]=3)[C:14]2=[O:29])[CH2:11][CH2:12]1)=[O:4]
Reactant: ClCc1ccccc1
Reactant: COC(=O)CC[C@H]1CC[C@H](N2CCN(c3cnc4c(n3)CCNCC4)C2=O)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC[C@H]1CC[C@H](N2CCN(c3cnc4c(n3)CCN(Cc3ccccc3)CC4)C2=O)CC1

Procedure:
1.5 g of 1-[trans-4-[2-(methoxycarbonyl)ethyl]cyclohexyl]-3-(6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)imidazolidin-2-one, 480 mg of benzyl chloride, 520 mg of N-ethyldiisopropylamine and 100 mg of sodium iodide are heated under reflux in 20 ml of acetonitrile for 1 hour. The mixture is cooled, and the solid is filtered off with suction and purified by chromatography on an alumina column with methylene chloride/methanol (99:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([Cl:10])=[CH:4][N:3]=1.COP(C)(=O)O>[Zn]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: Clc1cnc(Cl)c(Cl)c1Cl
Agent: COP(C)(=O)O
Agent: [Zn]
Product: Clc1cnc(Cl)c(Cl)c1
Yield: 76.7 %

Procedure:
By the method described in Example 1, 11.0 g (0.05 mol) of 2,3,4,5-tetrachloropyridine, 4.4 g (0.065 gram atom) of zinc dust (96%) and 9.5 g (0.075 mol) of the ammonium salt of methanephosphonic acid monomethyl ester are reacted to obtain 7.0 g (76% of theory) of 2,3,5-trichloropyridine, m.p. 37°-40° C., which contains, according to gas-chromatographical analysis, 78.8% of 2,3,5-trichloropyridine, 2.5% of 2,3,4,5-tetrachloropyridine and 0.61% of unknown products.
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[NH2:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8]>O.CO>[CH2:5]([NH2:4])[CH2:6][S:7]([O-:10])(=[O:9])=[O:8].[CH2:5]([NH2:4])[CH2:6][S:7]([O-:10])(=[O:9])=[O:8].[Mg+2:2]
Reactant: NCCS(=O)(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NCCS(=O)(=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of magnesium hydroxide (433 mg, 7.46 mmol; Aldrich) and taurine (1.87 g, 14.9 mmol) in 20 ml water was heated under reflux for seven hours. The resulting milky mixture was allowed to cool, diluted with 40 ml methanol and allowed to stand overnight at room temperature. A white powder, consisting mostly of magnesium taurate complex, was removed by filtration. The clear filtrate was concentrated under vacuum to a pasty slurry, then diluted slowly with 10 ml methanol. After 2 hours, crystalline magnesium taurate salt was obtained by filtration. The yield was 940 mg (41%). The melting point (decomposition) was about 300° C. This salt was identical to that obtained in Example 2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6](=[NH:9])OC.[NH3:15]>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([NH2:15])=[NH:9]
Reactant: N
Reactant: COC(=N)c1ccc(OC)c(Cl)c1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=N)N)cc1Cl
Temperature: -78 °C
Reaction time: 20 h
Yield: 191.7 %

Procedure:
Methyl 3-chloro-4-methoxybenzimidate hydrochloride, (19.9 g, 0.084 mole) was added to a solution of ammonia (12 g) in CH3OH (100 ml) cooled to -78° C. The stirred mixture was allowed to warm to room temperature. After 20 hours, the solution was evaporated to dryness under reduced pressure. The solid residue was triturated with Et2O and collected to yield 17.8 g (96%) of 27, m.p. dec. 243°-245° C. A sample triturated with acetone melted at 241°-243° C. dec.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[NH:35]1[C:43]2[C:38](=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1.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.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:39]4[CH:40]=[CH:41][CH:42]=[C:43]5[C:38]=4[CH:37]=[CH:36][NH:35]5)=[CH:32][C:17]=3[C:18]=2[C:28]([NH:29][CH3:30])=[O:31])=[CH:26][CH:25]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc4[nH]ccc34)cc12
Temperature: 90 °C
Yield: 47.8 %

Procedure:
Cesium carbonate (176 mg, 0.539 mmol) was added to Pd(Ph3P)4 (20.77 mg, 0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (150 mg, 0.359 mmol), 1H-indol-4-ylboronic acid (87 mg, 0.539 mmol). Dioxane (3 mL) and water (600 μL) was added at rt. The reaction was degassed 3× and then heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (BIOTAGE®, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (66 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.28 (1H, br. s.), 8.48-8.57 (1H, m), 7.98-8.07 (2H, m), 7.86 (1H, br. s.), 7.79 (1H, d, J=8.24 Hz), 7.69 (1H, d, J=7.93 Hz), 7.37-7.47 (4H, m), 7.21 (1H, t, J=7.63 Hz), 7.14 (1H, d, J=7.02 Hz), 6.60 (1H, br. s.), 2.84 (3H, d, J=4.27 Hz). LC-MS retention time: 1.53 min; m/z (MH+): 385. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=13.46 min, purity=99%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=12.27 min, purity=97%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4].[CH3:35][NH:36][CH3:37].C(=O)([O-])O.[Na+]>C(#N)C>[CH3:35][N:36]([CH3:37])[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4]
Reactant: O=C(CCl)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (120 mg, 0.244 mmol), aqueous dimethylamine (3 mL) solution and acetonitrile (3 mL) was heated to 80° C. and stirred for 3 hr. After the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol to give the title compound (85 mg, 70%) as a pale-yellow powder.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][N:29]([CH3:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[CH:32][CH:31]=1>>[CH3:28][N:29]([CH3:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:13]2[CH:12]=[C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]4[N:19]=[CH:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)[O:10]3)=[CH:15][CH:14]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1ccc(N(C)C)cc1
Product: CN(C)c1ccc(C#Cc2ccc3c(=NO)cc(-c4cc5ccccc5cn4)oc3c2)cc1

Procedure:
7-(4-dimethylaminophenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 8% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 4-dimethylaminophenylacetylene. The title compound was isolated as an orange solid and as a 95/5 mixture of Z/E oxime isomers.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27](O)=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:21][C:22]1[C:27]([O:19][C:18](=[O:20])[CH2:17][NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
1.9 g. (6.2 mmole) of tert.-butyloxycarbonyl-L-methionyl-glycine [M.A. Ondetti, I. Phuscec, E.F. Sabo, J.T. Sheehan, N-Williams; J. Am. Chem. Soc. 92, 195 (1970)] and 1.92 g. (7.2 mmole) of pentachlorophenol are dissolved in 31 ml. of dimethyl formamide. The solution is cooled to 0° C., the solution of 1.41 g. (6.85 mmole) of dicyclohexyl carbodiimide in 6.2 ml. of dimethyl formamide is added dropwise under stirring and the mixture is stirred for a further hour at the same temperature. The mixture is allowed to stand over night; on the following day the precipitated dicyclohexyl urea is filtered off and the filtrate is evaporated to dryness under reduced pressure. The evaporation residue is triturated with ether, the product filtered, washed with a minor amount of ether and recrystallized from a 15-fold amount of ether. 2.19 g. of tert.-butyloxycarbonyl-L-methionyl-glycine pentachlorophenyl ester (63.6% of the theoretical yield) are obtained; m.p. 169°-171° C.; Rf (in the 8:2 mixture of chloroform and ethanol) = 0.8.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C>[CH2:10]([NH:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: NC1CCC(=O)NC1=O
Solvent: CCN(CC)CC
Product: O=C1CCC(NCc2ccccc2)C(=O)N1

Procedure:
A solution of 0.50 g 3-aminopiperidine-2,6-dione (K. Fickentscher, Arch. Pharm. 1974, 307, 840-844), 1.5 ml triethylamine and 0.4 ml benzyl bromide was stirred for 20 h at 20° C. It was then evaporated, the residue taken up in 50 ml aqueous potassium carbonate solution (10% K2CO3) and the solution extracted twice with 40 ml ethyl acetate each. The organic phases were washed with 50 ml each of distilled water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel with a mixture of ethyl acetate/cyclohexane (2/1) containing 1% triethylamine as eluent, whereby 0.21 g (26% of theoretical) of the title compound was obtained as viscous oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:38])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:25]([Cl:37])[CH:24]=1)=[O:4].[C:39](Cl)(=[O:42])[CH:40]=[CH2:41].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:37][C:25]1[CH:24]=[C:23]([NH:22][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[C:6]([NH:5][C:3]([C@@H:2]([NH:1][C:39](=[O:42])[CH:40]=[CH2:41])[CH3:38])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: C=CC(=O)Cl
Reactant: COCCCOc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)[C@H](C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCCOC
Yield: 25 %

Procedure:
400 mg of (2S)-2-amino-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(3-methoxypropoxy)-quinazolin-6-yl}-propionamide as a starting material was dissolved in 10 ml of THF and 3 ml of water, and reacted with 0.07 ml of acryloylchloride at room temperature for 1.5 hours after adding 188 mg of sodium bicarbonate. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=15:1) to obtain the title compound (110 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3([O:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:31](O)=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:25]12[CH2:24][CH:23]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[S:12][C:11]([C:13]5([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:15][CH2:14]5)=[N:10][CH:9]=4)=[CH:4][CH:3]=3)=[O:32])[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: COC(=O)COC1(c2ncc(-c3ccc(N)cc3)s2)CCC1
Reactant: O=C(O)C1Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COC1(c2ncc(-c3ccc(NC(=O)C4Cc5ccccc54)cc3)s2)CCC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of Example 24B (0.150 g, 0.470 mmol), 1,2-dihydrocyclobutabenzene-1-carboxylic acid (0.070 g, 0.470 mmol), N-methylmorpholine (0.103 mL, 0.940 mmol), and 1-hydroxybenzotriazole hydrate (0.080 g, 0.940 mmol) in N,N-dimethylformamide (2 mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.115 g, 0.589 mmol). The solution was heated to 50° C. for 3 h, cooled to room temperature, and partitioned between H2O (2 mL) and ethyl acetate (2 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×2 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (5 mL) and 2 N NaOH (0.50 mL) was added. After 5 h, the methanol was removed under reduced pressure. The aqueous was acidified with 10% HCl to pH 1. The solid was filtered and air-dried. Purification of the residue by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) provided the title compound as a white-solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67-1.94 (m, 2H), 2.39-2.47 (m, 4H), 3.31-3.40 (m, 2H), 3.93 (s, 2H), 4.44 (dd, J=4.9 and 2.9 Hz, 1H), 7.09-7.31 (m, 4H), 7.56-7.68 (m, 2H), 7.67-7.78 (m, 2H), 8.07 (s, 1H), 10.37 (s, 1H); MS (ESI) m/z 435 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:36]>CO>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([NH2:36])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N
Reactant: CCOC(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Solvent: CO
Product: NC(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 70 °C
Yield: 39.8 %

Procedure:
A solution of ethyl 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinate (230 mg, 0.288 mmol) in MeOH (5 mL) was purged with ammonia gas for 5 minutes at −10° C. The reaction mixture was heated in a sealed tube at 70° C. for 12 h. The volatile components were removed under reduced pressure and the resulting residue was purified by HPLC (Condition 20 as described in general methods) to afford 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinamide (50.0 mg, 39.8%) as a yellow solid. LCMS (Condition 2): retention time 1.90 min, [M+1]=433.0. HPLC (Condition 25): retention time=5.20 min, purity 98.63%. 1H NMR (400 MHz, DMSO-d6) δ 4.66 (d, J=4.0 Hz, 2 H), 6.32 (dd, J=4.0 Hz, J=4.4 Hz, 1 H), 7.22-7.24 (m, 1 H), 7.28 (d, J=7.6 Hz, 1 H), 7.51-7.60 (m, 5 H), 7.68-7.73 (m, 3 H), 7.84 (dd, J=1.2 Hz, J=8.4 Hz, 1 H), 7.93 (dd, J=7.2 Hz, J=8.4 Hz, 1 H), 8.22-8.24 (m, 1 H), 8.28 (br s, 1 H), 8.51 (t, J=2.0 Hz, 1 H), 8.99 (d, J=2.0 Hz, 1H), 9.18 (d, J=2.0 Hz, 1 H).