Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[CH3:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]1=[O:17].[Cl-].[NH4+]>CCOCC>[CH3:4][C:11]1([OH:17])[C:12]([CH3:16])([CH3:15])[CH2:13][CH2:14][C:10]1([CH3:18])[CH3:9]
Reactant: CCOCC
Reactant: CC1(C)CCC(C)(C)C1=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(C)CCC(C)(C)C1(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 ml of a 3M methylmagnesium bromide/ether solution was added to a solution of 30 g of 2,2,5,5-tetramethylcyclopentanone in 50 ml of ether under a nitrogen gas atmosphere, and the mixture was stirred at room temperature overnight. Then, 65 ml of aqueous saturated ammonium chloride solution was added dropwise thereto and the mixture was stirred for 10 minutes. The ether layer was subjected to decantation and the residue was extracted with ether. The ether layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure, whereby 30 g of 1,2,2,5,5-pentamethylcyclopentanol was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:5][CH:6]=C.[O:23]=[O+][O-].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:23]
Reactant: O=[O+][O-]
Reactant: C=CCC(C(=O)OC)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(CC=O)c1ccc(OCc2ccccc2)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, 2-(4-benzyloxy-phenyl)-pent-4-enoic acid methyl ester (750 g; 2.53 mol) is dissolved in ethyl acetate (7.5 L), and the resulting mixture cooled to −70° C. Ozone is introduced subsurface into the reaction for 3 h causing the reaction mixture to turn blue. The reaction mass is purged subsurface with nitrogen for 0.5 h to displace any residual ozone. At this point HPLC analysis indicates complete consumption of the starting material. The reaction mixture is warmed to −30° C. and held. In a separate vessel, zinc (450 g; 6.88 mol) and aqueous acetic acid (500 mL in 500 mL water) are combined and cooled to 0° C. The contents of the ozonolysis reactor are added to the aqueous acidic zinc mixture at such a rate as to maintain a reaction temperature of ≦0° C. After the addition is complete and the mixture has been held for 2 h, HPLC indicates conversion of intermediates to the desired aldehyde. The reaction mixture is filtered through Celite®, washed with water (2×4.5 L), and water (4.5 L) is added to the organic phase. Sodium bicarbonate (150 g; 1.79 mol) is added to the mixture, and stirring for 0.25 h gives a pH of >7. The aqueous layer is removed, and the volume is reduced to 2.25 L by reduced pressure distillation. The mixture is held at 50° C., and heptane (3L) is added to slowly provide a precipitate. The resulting slurry is cooled to 20° C. over 2 h, the solids are filtered, washed with heptane (3 L), and dried to constant weight at 45° C. and ˜25″ Hg. The title aldehyde, compound A (513 g; 68% isolated yield) is afforded as a tan solid.
Reaction SMILES: P(Cl)(Cl)[Cl:2].[C:5]1([O:11][P:12](OC2C=CC=CC=2)[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)P(=O)(N(C)C)N(C)C>[C:5]1([O:11][P:12]([Cl:2])[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClP(Cl)Cl
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: ClP(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Yield: 181.4 %

Procedure:
32.5 g (0.24 mole) of phosphorus trichloride is added dropwise, with stirring, to a mixture, cooled to 0° to 5° C, of 155.2 g (0.5 mole) of triphenylphosphite and 10.0 g of hexamethylphosphoric acid triamide. The reaction mixture is subsequently heated to room temperature and stirred at this temperature for a further 4 hours. On vacuum distillation of the reaction mixture there is obtained 110 g (61.1% of theory relative to phosphorus trichloride) of diphenylchlorophosphite, b.p. 170°-172° C/11 Torr.
Reaction SMILES: ClC1C(C(C2[CH:11]=[N:12][N:13](C)C=2C2C=CC(C)=CC=2)=O)=C(Cl)N=CN=1.C(N(CC)C(C)C)(C)C.N1CC[C@H](N2CCCCC2)C1.Cl[C:45]1[C:50]([C:51]([C:53]2[CH:54]=[N:55][N:56]([CH3:65])[C:57]=2[C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)=O)=[C:49]([N:66]2[CH2:70][CH2:69][C@H:68]([N:71]3[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]3)[CH2:67]2)[N:48]=[CH:47][N:46]=1.CNN>C(#N)C>[CH3:11][N:12]1[C:45]2=[N:46][CH:47]=[N:48][C:49]([N:66]3[CH2:70][CH2:69][C@H:68]([N:71]4[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76]4)[CH2:67]3)=[C:50]2[C:51]([C:53]2[CH:54]=[N:55][N:56]([CH3:65])[C:57]=2[C:58]2[CH:59]=[CH:60][C:61]([CH3:64])=[CH:62][CH:63]=2)=[N:13]1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3N3CC[C@H](N4CCCCC4)C3)cnn2C)cc1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Agent: C1CCN([C@H]2CCNC2)CC1
Agent: CNN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(-c2c(-c3nn(C)c4ncnc(N5CC[C@H](N6CCCCC6)C5)c34)cnn2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a mixture of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C5) (7.3 g, 21 mmol) and N,N-diisopropylethylamine (13.56 g, 104.9 mmol) in acetonitrile (100 mL) was added 1-[(3S)-pyrrolidin-3-yl]piperidine (4.8 g, 31 mmol), and the resulting reaction mixture was stirred at room temperature for 3 hours. To this solution of {4-chloro-6-[(3S)-3-(piperidin-1-yl)pyrrolidin-1-yl]pyrimidin-5-yl}[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C7) was added drop-wise a solution of methylhydrazine (12.1 g, 262 mol) in acetonitrile (20 mL). After being stirred overnight at room temperature, the reaction mixture was concentrated in vacuo and partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated; purification via silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 8.64 g, 18.9 mmol, 90% yield. LCMS m/z 457.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.39-1.49 (br m, 2H), 1.53-1.73 and 2.00-2.25 (br multiplets, presumed 8H), 2.31 (s, 3H), 2.32-2.45 (br m, 2H), 2.56-2.68 (br m, 1H), 2.90-3.16 (v br m, 1H), 3.26-3.78 (br m, 3H), 3.87 (s, 3H), 4.00 (s, 3H), 7.16 (br AB quartet, JAB=8 Hz, ΔνAB=26 Hz, 4H), 7.66 (s, 1H), 8.29 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]([CH3:11])[CH2:7][C@H:8]([OH:10])[CH3:9])[CH:4]=[CH2:5].F[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[C:26]([CH3:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2>C1COCC1>[CH2:3]([N:6]([CH3:11])[CH2:7][C@@H:8]([CH3:9])[O:10][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[C:26]([CH3:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2)[CH:4]=[CH2:5]
Reactant: C=CCN(C)C[C@@H](C)O
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Temperature: 65 °C
Yield: 51.1 %

Procedure:
Sodium hydride (960 mg, 60% dispersion in oil, 20 mmol) was added portion wise to an ice-cooled solution of (2R)-1-[allyl(methyl)amino]propan-2-ol (3.87 g, 30 mmol, obtained as described in Example 2.3, preparation of starting materials) and 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (3.6 g, 10 mmol) in THF (25 ml). The mixture was heated at 65° C. for 24 hours. After cooling, the solvents were evaporated under vacuum. The mixture was diluted with DCM, and washed with water and brine. The organic layer was dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol in DCM) to give 5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (2.4 g, 51%) as a brown oil; Mass spectrum: MH+ 470.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][CH:11]=[C:12]([CH3:16])[C:13]([OH:15])=[O:14].[CH2:20](Br)[C:21]#[CH:22]>>[CH2:22]([O:14][C:13](=[O:15])[C:12]([CH3:16])=[CH:11][CH:10]=[CH:9][CH2:8][CH:7]([CH3:17])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:18])[CH3:19])[C:21]#[CH:20]
Reactant: C#CCBr
Reactant: COC(C)(C)CCCC(C)CC=CC=C(C)C(=O)O
Product: C#CCOC(=O)C(C)=CC=CCC(C)CCCC(C)(C)OC

Procedure:
Utilizing the procedure of Example 15, 11-methoxy-2,7,11-trimethyl-2,4-dodecadienoic acid and propargyl bromide are reacted. After chromatography on Kieselgel, using diethyl ether/petroleum ether (1:3 parts by volume) as the eluant, there is obtained 11-methoxy-2,7,11-trimethyl-2,4-dodecadienoic acid propargyl ester in pure form; boiling point 110°C/0.002 mmHg.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH2:31])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(=O)([O-])[O-].[K+].[K+].C1C(=O)N([O:45][C:46]([CH2:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=2)=O)C(=O)C1>O.CS(C)=O>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH:31][C:46](=[O:45])[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](N)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](NC(=O)CCc2ccc(O)cc2)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
3'-Amino-3'-deoxyadenosine 5'-triphosphate (6 mg, 11 mmol) and potassium carbonate (7.2 mg, 55 mmol.) were dissolved in 0.8 ml of water. 3-(4-Hydroxyphenyl) propionic acid N-hydroxysuccinimide ester (27 mg, 0.1 mmol) in 0.4 ml of DMSO was added at room temperature, and the mixture was stirred for 24 hours at room temperature. The product was purified by the procedure described for 3'-acetylamino-3'-deoxyadenosine 5'-triphosphate (above); t=14 min (4.3 mg obtained, 41% yield). UV: lmax =259 nm. High resolution MS for C19H24N6O14P3 : calcd. 653.0563, found 653.0596 (MH3-).
Reaction SMILES: C(NC1C=C(C=C(C2OC=CN=2)C=1)[C:13]([NH:15][C@@H:16]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:17]([C@H:26]1[CH2:30][C@@H:29]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH2:28][N:27]1C(OC(C)(C)C)=O)[O:18][Si](C(C)(C)C)(C)C)=[O:14])(=O)C1C=CC=CC=1.[CH2:59]([N:62]([CH2:79][CH2:80][CH3:81])[C:63]([C:65]1[CH:66]=[C:67]([CH:71]=[C:72]([C:74]2[O:75][CH:76]=[CH:77][N:78]=2)[CH:73]=1)C(O)=O)=[O:64])[CH2:60][CH3:61].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Si](O[C@H]([C@H]1CC(O)(C2C=CC=CC=2)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C>C(Cl)Cl>[OH:18][C@H:17]([C@H:26]1[CH2:30][C@@H:29]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH2:28][NH:27]1)[C@@H:16]([NH:15][C:13](=[O:14])[C:67]1[CH:71]=[C:72]([C:74]2[O:75][CH:76]=[CH:77][N:78]=2)[CH:73]=[C:65]([C:63]([N:62]([CH2:59][CH2:60][CH3:61])[CH2:79][CH2:80][CH3:81])=[O:64])[CH:66]=1)[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCCS(=O)(=O)[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cc(F)cc(F)c1)NC(=O)c1cccc(C(N)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)[C@H]2C[C@@H](S(=O)(=O)CCC)CN2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
Step 17 (F): (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-(oxazol-2-yl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-phenylpropyl)-4-(propylsulfonyl)pyrrolidine-1-carboxylate. To a solution of 3-(dipropylcarbamoyl)-5-(oxazol-2-yl)benzoic acid (prepared as reported in WO 2002/02512, 20 mg, 0.062 mmol) in DCM is added HATU (28 mg, 0.073 mmol) and DIEA (33 mg, 0.26 mmol). After the solution is stirred at rt for 5 min, a 28 mg portion of the compounds of step 17 (E) (0.052 mmol) is added. The reaction solution was stirred 16 h at rt, and then the reaction solution was partitioned between ethyl acetate and water, the organic layer was concentrated, and the crude product was purified by chromatography eluting with a step gradient of 20% to 50% to 70% ethyl acetate in hexanes to provide 40 mg (98%) of the desired amide. MS (ESI) (M+H−Boc)+=739.34
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)=[O:13])[N:10]=[C:6]2[C:5]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]3)=[N:42][CH:43]=2)O1.C([O-])([O-])=O.[K+].[K+]>>[O:27]1[CH2:28][CH2:29][N:24]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([NH:11][C:12]([C:14]4[CH:23]=[CH:22][C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]=4)=[O:13])[N:10]=3)[C:2]([C:38]3[CH:39]=[CH:40][C:41]([N:44]4[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]4)=[N:42][CH:43]=3)=[CH:3][N:4]=2)[CH2:25][CH2:26]1
Reactant: O=C(Nc1cn2c(Br)cnc(N3CCOCC3)c2n1)c1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(NC(=O)c5ccc6ccccc6n5)cn34)cn2)CC1

Procedure:
Compound 21d was prepared from compound 21c and tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate using the reaction conditions described in Example 1, Step G, and substituting K2CO3 as the base. Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H37N9O4: 636.3 (M+H). Found 636.4.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH2:36]OS(C)(=O)=O)[CH:33]=[C:32]([O:42][CH2:43][CH3:44])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16]>C1COCC1>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH2:36][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:33]=[C:32]([O:42][CH2:43][CH3:44])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(COS(C)(=O)=O)cc(OCC)c1
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CN2CCCC2)cc(OCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
N-Ethyldiisopropylamine (132 mg, 1.02 mmol) and pyrrolidine (145 mg, 2.04 mmol) were added to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-methane-sulphonyloxymethyl-phenyl)-acetate (221 mg, 0.511 mmol) obtained in Example 234.3 in THF (2 ml) and the mixture was stirred for 1 h. at room temperature. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2/MeOH 99:1). There were obtained 153 mg (73%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-pyrrolidin-1-ylmethyl-phenyl)-acetate as a yellowish foam; MS: 408 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br-:8].[Br:9][CH2:10][CH2:11][CH2:12][N+:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15]>CN(C=O)C>[Br-:9].[Br-:8].[CH2:14]([N+:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:12][CH2:11][CH2:10][N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:15]
Reactant: Cc1ccncc1
Reactant: CC[N+](CC)(CC)CCCBr
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC[N+](CC)(CC)CCC[n+]1ccc(C)cc1
Yield: 57.4 %

Procedure:
4-Methylpyridine (307 mg, 3.3 mmol), (3-bromopropyl)triethylammonium bromide (1.0 g, 3.3 mmol), and 4 mL DMF were stirred at 100° C. in a pressure vessel for 41 h. Precipitates formed during the reaction. After cooling down, the precipitates were filtered out and washed with CH2Cl2 to give 1-(3-triethylammoniopropyl)-4-methylpyridinium dibromide as a light pink solid (750 mg, 57%), which was used in the next aldol condensation without further purification. 1H NMR (400 MHz, CD3OD): δ 1.34 (t, J=7.0 Hz, 9 H), 2.50 (m, 2 H), 2.70 (s, 3 H), 3.35-3.47 (m, 8 H), 4.73 (t, J=7.8 Hz, 2 H), 7.99 (d, J=6.4 Hz, 2 H), 8.98 (d, J=6.4 Hz, 2 H); 13C NMR (100 MHz, CD3OD): δ 8.0, 22.1, 25.2, 54.4, 54.5, 58.3, 130.1, 145.2, 161.9; HRMS (FAB+): m/z=315.1428 [M-Br]+ (calcd for C15H28BrN2: 315.1430).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C(OC1N=NC(C(C2C=CC=CC=2)=C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C([O:54][C:55]1[N:56]=[N:57][C:58]([C:69]([C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)=[CH2:70])=[CH:59][C:60]=1[O:61]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[F:77][C:74]1[CH:75]=[CH:76][C:71]([CH:69]([C:58]2[CH:59]=[C:60]([OH:61])[C:55](=[O:54])[NH:56][N:57]=2)[CH3:70])=[CH:72][CH:73]=1
Reactant: C=C(c1ccc(F)cc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1ccc(F)cc1)c1cc(O)c(=O)[nH]n1

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 41) except that the solvent mixture used for the hydrogenation consisted of ethyl acetate and tetrahydrofuran and the product was recrystallised from a mixture of heptane and MTBE.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[NH:7][CH:6]=1)=[O:4].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[N:31]=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>[CH3:28][C:2]([CH3:1])([CH3:27])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:31]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Reactant: Brc1cccc(N2CCCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCCC4)n3)nc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 1.9 %

Procedure:
A mixture of 2,2-dimethyl-1-(2-tributylstannanyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-propan-1-one (115 mg, 0.23 mmol), 2-bromo-6-pyrrolidin-1-yl-pyridine (53 mg, 0.23 mmol), and Pd(PPh3)4 (27 mg, 0.023 mmol) in dioxane (1 mL) was stirred at 140° C. in a microwave for 1 h. The resulting mixture was treated with additional Pd(PPh3)4 (27 mg, 0.023 mmol), stirred at 150° C. in a microwave for 30 min, and concentrated. The crude product was purified by flash chromatography using 4 g of silica gel and EtOAc in hexanes as eluant, 3 consecutive purifications by preparative thin layer chromatography using 2:1 hexanes:EtOAc as eluant, and a recrystallization from CH2Cl2 and ethyl ether to provide 1.5 mg of 2,2-dimethyl-1-[2-(6-pyrrolidin-1-yl-pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a yellow powder. M+H 350.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:22][CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: C1CNCCNCCNCCNCNC1
Temperature: 100 °C
Yield: 39 %

Procedure:
A mixture of 1,4,7,10,14-penta(p-toluenesulfonyl)-1,4,7,10,14-pentaazacyclopentadecane prepared as in Example 12 A (28.5 g, 0.0279 mole) and concentrated H2SO4 (100 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 H. To the resulting brown solution, ethanol (100 ml) was added dropwise with stirring at 0° C. followed by ethyl ether (1 l). The tan solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution filtered and washed with ethyl ether. The pH of the solution was adjusted to 11 with 10N NaOH and the solvent was removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and the THF extracts were filtered. The filtrates were combined and the solvent was removed in vacuo. The oily residue was dissolved in hot hexane and the insoluble impurities were removed by filtration. The solvent was removed in vacuo and the residual oil was purified by vacuum distillation to give 2.68 g (39% yield) of the product as a light yellow oil: bp 140-5° C. (0.10 mm Hg); 1H NMR (CDCl3) δ 1.51 (br s, 5 H), 1.68 (quint, J=6.1 Hz, 4 H), 2.73 (m, 20 H); Exact mass (M+H)+ : calcd., 244.2501; Found: 244.2555 (C12H30N5).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16].O.Cl.[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C1C=CC2N(O)N=NC=2C=1>ClCCl>[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 56.6 %

Procedure:
9.10 Milliliters of WSC was gradually added to 100 ml of a solution of 12.47 g of Boc-Leu-OH.H2O, 6.98 g of HCl.H-Gly-OEt and 6.76 g of HOBT dissolved in dichloromethane, with ice-cooling. The mixture was stirred for 42 hours at room temperature. The reaction mixture was mixed with 100 ml of 1N hydrochloric acid, and the resulting precipitate was removed by filtration. The filtrate was washed with 100 ml of 1N hydrochloric acid, two 100-ml portions of a saturated aqueous sodium bicarbonate solution and 100 ml of a saturated aqueous sodium chloride solution in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added petroleum ether to crystallize the residue. The resulting crystal was recrystallized from ethyl acetate-petroleum ether to obtain 8.68 g (yield: 56.6%) of the above objective compound. Melting point: 79.5°-82.5° C.