Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:10][C:11]1[C:12]([Br:19])=[CH:13][C:14]([F:18])=[C:15]([CH:17]=1)[NH2:16])[CH:8]=[CH2:9].N1C=CC=CC=1>C(Cl)Cl>[CH2:7]([O:10][C:11]1[C:12]([Br:19])=[CH:13][C:14]([F:18])=[C:15]([NH:16][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH:17]=1)[CH:8]=[CH2:9]
Reactant: C=CCOc1cc(N)c(F)cc1Br
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOc1cc(NC(=O)OCC)c(F)cc1Br
Temperature: 10 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
Ethyl chloroformate (5.97 g) was added dropwise to a solution of 5-allyloxy-4-bromo-2-fluoroaniline (12.3 g) and pyridine (7.90 g) in methylene chloride (100 ml) at 0° C., and the mixture was stirred at 10° C. for 3 hours. After the reaction, this was extracted with methylene chloride, then washed with diluted hydrochloric acid and an aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off to obtain to the objective ethyl N-(5-allyloxy-4-bromo-2-fluorophenyl)carbamate (15.67 g).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:43]([O:46]CC)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([OH:46])(=[O:45])/[CH:44]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCC/C=C/C=O
Reactant: CCOC(C)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To trans-2-undecenal (5.0 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenylphosphorane (9.9 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-tridecadienoic acid (5.2 g). Potassium hydroxide (6.5 g) was dissolved in a mixed solvent of ethanol-water (1:1) (100 ml). The methyl ester of trans,trans-2,4-tridecadienoic acid (5.2 g) was added to the mixture, and the resulting mixture was stirred at 60° C. for 40 minutes. After the reaction mixture was cooled, it was adjusted to the weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-tridecadienoic acid (4.4 g). To trans,trans-2,4-tridecadienoic acid dissolved in N,N-dimethylformamide (DMF, 50 ml) were added para-nitrophenol (3.0 g) and N,N'-dicyclohexylcarbodiimide (4.4 g), and the mixture was stirred for 12 hours. After precipitates obtained were removed by filtration and the solvent (DMF) was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-tridecadienoic acid (2.4 g). To the active ester (880 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycylspicaminyl-amino)purine hydrochloride (800 mg) and triethylamine (2.0 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK281 in the yield of 380 mg.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12].C(NCC)C.Cl>[Pd].CN(C)C=O.C(OCC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([OH:14])=[O:13])=[CH:3][CH:4]=1
Reactant: C=CC(=O)O
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCNCC
Product: COc1ccc(C=CC(=O)O)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of 2.34 g (10 mmol) of p-iodoanisole, 0.756 g (10.5 mmol) of acrylic acid, 0.803 g (11 mmol) of diethylamine and 16 mg of palladium on charcoal in 4 ml of dimethylformamide is stirred at 140° C. for 4 hours. Subsequently, the mixture is worked up by adding diethyl ether and 2N hydrochloric acid, washing the separated organic phase with water and subsequently drying over anhydrous sodium sulphate, concentrating the organic phase under reduced pressure and recrystallizing the solid residue from ethanol. In this manner there is obtained p-methoxycinnamic acid in 65% yield. M.p. 170° C. (no depression upon mixing with a pure sample of this acid); 1H-NMR (CDCl3, 200 MHz): 3.85 ppm (s, 3H), 6.33 ppm (d, 15.5 Hz, 1H), 6.68-6.97 ppm (duplettoid, m 1H), 7.47-7.56 ppm (dupletteid m, 1H), 7.75 ppm (d, 15.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:3][CH:4]1[CH:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C-:34]#[N:35].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCC>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([O:24][C:7]([CH:6]2[CH:4]([CH:3]=[C:2]([Cl:1])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2([CH3:11])[CH3:10])=[O:8])[C:34]#[N:35])=[CH:21][C:20]=1[O:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [C-]#N
Reactant: CC1(C)C(C=C(Cl)c2ccccc2)C1C(=O)Cl
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C(C=C(Cl)c2ccccc2)C1C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Yield: 75.6 %

Procedure:
8.1 g (0.03 mole) of 3-(2-chloro-2-phenyl-vinyl)-2,2-dimethyl-cyclopropane-carboxylic acid chloride and 6.5 g (0.03 mole) of 4-fluoro-3-phenoxy-benzaldehyde are added dropwise to a mixture of 2.25 g of sodium cyanide, 3.5 ml of water, 150 ml of n-hexane and 0.75 g of tetrabutylammonium bromide at 20° to 25° C., whilst stirring. The reaction mixture is then stirred at 20° to 25° C. for 4 hours and is subsequently diluted with 300 ml of toluene and washed twice with 300 ml of water each time. The organic phase is dried over magnesium sulphate and the solvent is distilled off under a waterpump vacuum. Last residues of solvent are removed by brief incipient distillation at 60° C./1 mbar. 10.8 g (76% of theory) of 3-(2-chloro-2-phenyl-vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid 4-fluoro-3-phenoxy-α-cyano-benzyl ester are obtained as a viscous oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:35]=[CH:34][C:30](C(O)=O)=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][S:24][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CNC[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.[CH3:68][N:69]([CH3:72])[CH:70]=[O:71]>C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:70]([N:69]([CH3:72])[CH2:68][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:71])=[CH:34][CH:35]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH2:23][S:24][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CSC)C2CCCCC2)cc1
Yield: 100 %

Procedure:
A solution of 4-[(cyclohexyl{2-[(methylsulfanyl)methyl]-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methyl)amino]benzoic acid (1.0 g), ethyl 3-(methylamino)propanoate (0.3 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.5 g), hydroxybenzotriazole monohydrate (0.4 g) and triethylamine (0.3 mL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 40% ethyl acetate/hexane) to give the title compound (1.2 g, 100%) as an amorphous compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:10]([F:15])[F:14])[CH:7]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: FC(F)Oc1cncc(Br)c1

Procedure:
A mixture of 3-bromo-5-hydroxypyridine (Aldrich, Buchs, Switzerland, 1.394 mmol), sodium chlorodifluoroacetate (Aldrich, Buchs, Switzerland, 1.672 mmol) and potassium carbonate (2.79 mmol) in acetonitrile (10 ml) was refluxed for 4 h 45 min. The reaction was cooled and diluted with dichloromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated to give the title compound as a brown oil. (HPLC: tR 2.91 min (Method A); M+H=224, 226 MS-ES).
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24].C(N(CC)CC)C>ClCCl>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([NH:24][C:8](=[N:9][C:10]#[N:11])[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of diphenylcyanocarbonimidate (2 mmol, 476 mg), 3,5-bis(trifluoromethyl)aniline (2 mmol, 458 mg) and triethylamine (2 mmol, 202 mg) in dichloromethane (15 ml) was stirred under nitrogen for 12 h. After concentration the residue was stirred with toluene (5 ml) for 2 h and the solid was collected by filtration giving 550 mg of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (73.6%);
Reaction SMILES: [H-].C[O:3]CCO[Al+]OCCOC.[Na+].[H-].[F:15][C:16]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]2)[C:21]([O:30][CH3:31])=[CH:20][C:17]=1[C:18]#N.O.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:15][C:16]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]2)[C:21]([O:30][CH3:31])=[CH:20][C:17]=1[CH:18]=[O:3]
Reactant: COc1cc(C#N)c(F)cc1-n1cnc(C)c1
Reactant: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(F)cc1-n1cnc(C)c1
Reaction time: 1 h

Procedure:
Sodium bis(2-methoxyethoxy)aluminum hydride (65% solution in toluene, 11.4 mL) was added dropwise to a suspension of 2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzonitrile (8.85 g) in THF (180 mL) in a nitrogen atmosphere at −15° C., and the reaction solution was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Then, a 5 N aqueous solution of sodium hydroxide and ethyl acetate were added to the mixture and the organic layer was partitioned. The resulting organic layer was made acidic with 5 N aqueous hydrochloric acid, and the mixture was stirred. Then, the mixture was neutralized with 5 N aqueous sodium hydroxide and the organic layer was partitioned. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 3.32 g of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])=[O:12])[C:4](=[O:21])[CH:3]=[CH:2]1.[NH2:23][C@H:24]([C:26]([OH:28])=O)[CH3:25].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH2:55][C@H:56]3[CH:62]=[N:61][C:60]4[CH:63]=[C:64]([O:69][CH2:70][CH2:71][CH2:72][O:73][C:74]5[C:75]([O:96][CH3:97])=[CH:76][C:77]6[C:83](=[O:84])[N:82]7[CH:85]=[C:86]([C:88]8[CH:93]=[CH:92][C:91]([OH:94])=[CH:90][CH:89]=8)[CH2:87][C@H:81]7[CH:80]=[N:79][C:78]=6[CH:95]=5)[C:65]([O:67][CH3:68])=[CH:66][C:59]=4[C:58](=[O:98])[N:57]3[CH:99]=2)=[CH:50][CH:49]=1>CO.ClCCl>[O:22]=[C:1]1[CH:2]=[CH:3][C:4](=[O:21])[N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][C@@H:14]([CH:15]([CH3:16])[CH3:17])[C:18]([NH:23][C@@H:24]([CH3:25])[C:26]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH2:55][C@H:56]3[CH:62]=[N:61][C:60]4[CH:63]=[C:64]([O:69][CH2:70][CH2:71][CH2:72][O:73][C:74]5[C:75]([O:96][CH3:97])=[CH:76][C:77]6[C:83](=[O:84])[N:82]7[CH:85]=[C:86]([C:88]8[CH:89]=[CH:90][C:91]([OH:94])=[CH:92][CH:93]=8)[CH2:87][C@H:81]7[CH:80]=[N:79][C:78]=6[CH:95]=5)[C:65]([O:67][CH3:68])=[CH:66][C:59]=4[C:58](=[O:98])[N:57]3[CH:99]=2)=[CH:50][CH:49]=1)=[O:28])=[O:20])=[O:12]
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)O
Reactant: C[C@H](N)C(=O)O
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(O)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCCCCN5C(=O)C=CC5=O)C(C)C)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(O)cc3)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A flame-dried flask was charged with maleimidocaproyl-valine-alanine linker (Compound 36 of Example 13 in WO 2011/130613 A1) (11 mg, 29 μmol, 1.5 eq) dissolved in 0.8 mL of 5% methanol in anhydrous dichloromethane. The acid was pre-activated by addition of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (9 mg, 34 μmol, 1.8 eq), followed by stirring at room temperature under nitrogen for 15 minutes. The activated acid was then added to a flame-dried flask containing PBD dimer 14 (13 mg, 19 μmol, 1 eq). The reaction was stirred for 4 hours at room temperature under nitrogen, at which time LC-MS revealed conversion to product. The material was diluted in dichloromethane and purified by radial chromatography on a 1 mm chromatotron plate eluted with CH2Cl2/MeOH mixtures (100:0 to 80:20) to provide 15 (7.7 mg, 38%). LC-MS: m/z (ES+) found 1075.5 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH2:13]([O:20][C:21]1[C:30]([CH3:31])=[CH:29][C:24]([C:25]([NH:27][NH2:28])=O)=[CH:23][C:22]=1[CH3:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO.C1COCC1.[Pd]>[CH2:13]([O:20][C:21]1[C:22]([CH3:32])=[CH:23][C:24]([C:25]2[O:12][C:10]([C:8]3[S:9][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[N:28][N:27]=2)=[CH:29][C:30]=1[CH3:31])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH2:1]([C:5]1[S:9][C:8]([C:10]2[O:12][C:25]([C:24]3[CH:29]=[C:30]([CH3:31])[C:21]([OH:20])=[C:22]([CH3:32])[CH:23]=3)=[N:27][N:28]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(=O)O)s1
Reactant: Cc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1O
Product: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(4-Benzyloxy-3,5-dimethyl-phenyl)-5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazole is prepared in analogy to Example 21 step a) and b) by coupling and cyclising 5-isobutyl-thiophene-2-carboxylic acid with 4-benzyloxy-3,5-dimethyl-benzoic acid hydrazide, LC-MS: tR=1.06 min, [M+1]+=437.17. To a solution of this compound (2.83 g, 6.75 mmol) in EtOH (50 mL) and THF (50 mL) is added Pd/C (10% Pd, 400 mg) and the slurry is stirred at rt for 48 h under 5 bar of H2. The mixture is filtered, the filtrate is concentrated and the crude product is purified by CC on silica gel eluting with heptane:EA 8:25 to give 4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenol (943 mg) as a white powder; LC-MS: tR=1.09 min, [M+1]+=329.36.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:2].[CH:22]1([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:44])=[C:32](OS(C(F)(F)F)(=O)=O)[C:33]=3[F:35])[C:28](=[O:45])[C:27]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:26]2)[CH2:24][CH2:23]1.O>C(N(CC)CC)C.CN(C)C=O>[CH:22]1([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:44])=[C:32]([C:2]#[C:1][C:3]4[CH:4]=[C:5]([CH2:6][C:7]5[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=5)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=4[O:18][CH3:19])[C:33]=3[F:35])[C:28](=[O:45])[C:27]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:26]2)[CH2:23][CH2:24]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(OS(=O)(=O)C(F)(F)F)c(F)cc2c1=O
Reactant: C#Cc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 200 mg of 5-[3-ethynyl-4,5-dimethoxy-benzyl]-pyrimidine-2,4-diamine (Example 11b)), 207 mg of ethyl 1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-7-[[(trifluoromethyl)sulphonyl]oxy]-quinoline-3-carboxylate (J. Heterocyclic Chem., 28, 1581 (1991)) and 10 mg of bis-triphenylphosphinepalladium dichloride in 1.5 ml of triethylamine and 7.5 ml of dimethylformamide is stirred at 900 for one hr. The reaction mixture is cooled to room temperature, poured into 50 ml of water and extracted four times with 50 ml of methylene chloride each time. The combined organic phases are washed with 100 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is chromatographed on silica gel with methylene chloride/methanol 9:1. 108 mg (39%) of ethyl 1-cyclopropyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are isolated as a colourless solid. M.p.>230°. Mass spectrum: peaks: inter alia at 575 (M+, 36%), 503 (18%), 481 (20%), 123 (42%), 32(100%).
Reaction SMILES: [F:1][C:2]1([F:39])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]4[CH:17]=[C:18]([CH2:20][CH2:21][C:22]5[CH:31]=[CH:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[N:19]=[C:15]4[C:14]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[N:13][CH:12]=3)[CH:9]=2)[NH:4][C:3]1=[O:38].O(C)[K:41]>CO>[F:39][C:2]1([F:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]4[CH:17]=[C:18]([CH2:20][CH2:21][C:22]5[CH:31]=[CH:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[N:19]=[C:15]4[C:14]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[N:13][CH:12]=3)[CH:9]=2)[N-:4][C:3]1=[O:38].[K+:41]
Reactant: O=C1Nc2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2C1(F)F
Reactant: CO[K]
Solvent: CO
Product: O=C1[N-]c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2C1(F)F
Product: [K+]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Compound 37c (65.3 mg, 0.124 mmol) was added to a MeOH solution of KOMe (8.69 mg, 0.124 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 15 min, allowed to warm to rt, and stirred for another 30 min. The resulting mixture was concentrated and the resulting residue was dried under reduced pressure to obtain the title compound 59. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.25 (d, J=8.6 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.45-7.59 (m, 4H), 7.40 (br. s., 1H), 7.26 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 4.06 (m, 4H), 3.68 (m, 4H) 3.27-3.35 (m, 2H), 3.19-3.27 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H24F2N6O2: 527.2 (M+H). Found 527.5.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:14]=[C:15]([C:20]2[N:24]([CH3:25])[C:23]([S:26][CH3:27])=[N:22][N:21]=2)[CH:16]=[C:17]([F:19])[CH:18]=1.[OH-:28].[Na+]>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([C:20]2[N:24]([CH3:25])[C:23]([S:26]([CH3:27])(=[O:9])=[O:28])=[N:22][N:21]=2)[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Reactant: CSc1nnc(-c2cc(F)cc(F)c2)n1C
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(-c2cc(F)cc(F)c2)nnc1S(C)(=O)=O
Yield: 98 %

Procedure:
m-CPBA (10 g, 33-50 mmol, 57-86% pure) was added to a solution of 3-(3,5-difluorophenyl)-4-methyl-5-(methylthio)-4H-1,2,4-triazole (4.9 g, 20.3 mmol) in DCM (60 mL) and the reaction was stirred o.n. 2M NaOH (50 mL) was added and the mixture was extracted. The water phase was re-extracted with EtOAc (2×) and the combined organic phases were dried (MgSO4) and evaporated to give 5.4 g (98%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([C@H:14]([OH:23])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([C@H:14]([OH:23])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](C/C=C/c1ccccc1)[C@H](O)C(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Yield: 93 %

Procedure:
A solution of (E)-(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pent-4-enoic acid methyl ester (1.55 g, 4.65 mmol) in methanol (15 ml) was hydrogenated at 50 psi over Pd/C for 4 hrs. The catalyst was removed by filtration through celite and the filtrate concentrated under reduced pressure to give (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester as yellow solid (1.45 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:17]2[N:16]=[C:15]3[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=4)=[N:14]3)=[CH:19][CH:18]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccc2ccc(Oc3ccc(F)cc3)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccc(F)cc4)nc3n2)cc1
Temperature: 4 °C
Yield: 73.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (14.3 g), N,N'-carbonyldiimidazole (15.2 g) and 2-amino-7-(4-fluorophenoxy)-1,8-naphthyridine (15.2 g). The product produced by precipitation in water (22.6 g; m.p. approximately 70° C.) is dissolved in boiling ethanol (130 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×15 cc) and dried at 25° C. under reduced pressure (0.067 kPa). N-[7-(4-fluorophenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (17 g) is produced, m.p. 100° C.