Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: c1c[nH]cn1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)n1ccnc1
Yield: 91.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 1.4 g of imidazole were used as the starting materials. 6.5 g (91%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][Si](C)(C)C)[N:4]=1.C1C=CC(O[C:22](Cl)=[S:23])=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]=[C:22]=[S:23])[N:4]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COc1nc(C)nc(N[Si](C)(C)C)n1
Solvent: Cc1ccccc1C
Product: COc1nc(C)nc(N=C=S)n1
Temperature: 140 °C
Reaction time: 6.5 h
Yield: 23.3 %

Procedure:
To 50 ml of xylene are added 15.0 g of 4-methoxy-6- methyl-2-trimethylsilylamino-1,3,5-triazine and 12.2 g of phenyl chlorothionocarbonate. The mixture is stirred at about 140° C. for 6.5 hours. After cooling the reaction mixture to room temperature, insoluble matters are filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, ethyl acetate:toluene=1:3) to yield 3.0 g of the title compound as an oil.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[F:9][Si:10](F)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[CH2:5]([Si:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[F:9])[CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCBr
Reactant: F[Si](F)(c1ccccc1)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: C=CCC[Si](F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
In a two-neck flask equipped with a condenser was placed magnesium (3.46 g, 142 mmol) and a crystal of iodine. The flask was warmed with heat gun until iodine had sublimed. A solution of 4-bromo-1-butene (9.62 g, 71.3 mmol) in ether (100 mL) was added dropwise in 30 min and the resulting mixture refluxed for 2 h. This Grignard solution was cooled to rt and added over 30 min via cannula to a second flask containing 24 (15.7 g, 71.3 mmol) in ether (100 mL) at rt. After stirring overnight at rt under argon, the reaction mixture was quenched with water (20 mL) and the organic layer isolated. The aqueous layer was extracted twice with 50-mL portions of ether. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Distillation (134° C., 1.5 mm Hg) provided pure 31 as a colorless oil (15.2 g, 83%): 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=7.8 Hz, 4H), 7.50–7.39 (m, 6H), 5.97–5.83 (m, 1H), 5.02 (dd, J=17.1, 1.7 Hz, 1H), 4.94 (dd, J=10.2, 1.7 Hz, 1H), 2.28–2.20 (m, 2H), 1.38–1.30 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 140.9, 135.9, 134.1, 129.7, 127.8, 113.1, 26.9, 14.0.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[O:23]1[CH2:24][CH2:25][N:20]([CH2:1][C@@H:3]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][N:4]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CN1CCOCC1
Yield: 89.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Aubry, S. et al., Tetrahedron Lett., 47:1319-1323 (2006)) (71 mg, 0.27 mmol) and morpholine (28 μL, 0.33 mmol) were converted to the title compound (80 mg, 89%). 1H NMR (CDCl3, mixture of rotamers) δ 7.24-7.20 (m, 4H), 4.85-4.66 (m, 1H), 4.54-4.42 (m, 1H), 4.30-4.17 (m, 1H), 3.67 (br s, 4H), 3.13-2.96 (m, 1H), 2.93-2.69 (m, 1H), 2.62-2.29 (m, 5H), 2.18-2.01 (m, 1H), 1.51 (s, 9H); MS(ESI+) m/z 333.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH:7]=O.[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>Cl.C(O)C>[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:15]=[CH:7][CH:6]=[CH:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1C=CC=O
Reactant: CN(N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccccc1C=CC=NN(C)c1ccccc1

Procedure:
3.2 g of 2-methoxycinnamaldehyde and 2.4 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suctional funnel. The thus obtained crude 2-methoxycinnamaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 2.6 g (49.1%) of light yellow scalelike crystals which melt at 100.5°-101.5° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([Br:18])[O:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([Br:18])[O:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCC(Br)c1nc2oc(Br)cc2c(=O)n1Cc1ccccc1
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2oc(Br)cc2c(=O)n1Cc1ccccc1

Procedure:
A solution of 3-benzyl-6-bromo-2-(1-bromopropyl)furo[2,3-d]pyrimidin-4(3H)-one (1-4, 1 equiv) and N,N-dimethylethylenediamine (3 equiv) in ethanol is heated at reflux for 18 h. The reaction mixture is concentrated, and the residue is partitioned between EtOAc and brine. The organic layer is dried (MgSO4) and concentrated to provide 3-benzyl-6-bromo-2-(1-{[2-(dimethylamino)-ethyl]amino}propyl)furo[2,3-d]pyrimidin-4(3H)-one (1-5)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:11]=1[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOCC.[Pd]>[NH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1cccc(N)c1C(=O)O
Yield: 65.1 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid (2.19 g, 75 mmol) in methanol (530 mL) and palladium/carbon (0.2 g) was hydrogenated with a Parr-shaker overnight at 51 psi. The black mixture was filtered through a pad of Celite, and the filtrate was evaporated to give a foamy brown oil, which was stirred in ether (300 mL) overnight. The suspension was filtered to give 2-amino-6-(tert-butoxycarbonylamino-methyl)-benzoic acid as a yellow solid (13.0 g, 65% yield). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(N(CC)CC)C>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:14][C:3]1[CH:2]=[N:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2ccccc2)cn1
Reaction time: 6 h
Yield: 75 %

Procedure:
To a stirred solution of 3-bromo-5-phenyl-2-amino pyrazine (80 mg; 0.32 mmol), in ethyl acetate (1 mL) was added triethylamine (139 μL; 1.0 mmol) and Pd(OH)2 (10 mg; 20% wt on carbon). The reaction was placed under a hydrogen atmosphere at 45 psi and shook for 6 hours. The reaction was filtered and concentrated under reduced pressure. The product was purified using a biotage 12L eluting with ethyl acetate to yield an off white solid (75% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)=[C:4]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)=[O:22])[CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][C:4]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(NC(=O)Nc2cc(Cl)ccc2OCCCN)cn1
Yield: 6 %

Procedure:
A solution of Example 38A in trifluoroacetic acid (0.1 mL) and dichloromethane (0.9 mL) was stirred at room temperature for 3 hours and concentrated. The concentrate was purified by HPLC with acetonitrile/water containing 0.1% TFA to provide 2.8 mg (6%) of the desired product. MS (ESI(−)) m/z 347 (M−H)−; 1H NMR (500 MHz, DMSO-d6) δ 10.93 (br s, 1H), 10.09 (br s, 1H), 8.91 (s, 1H), 8.85 (s, 1H), 8.26 (d, J=2.5 Hz, 1H), 7.71 (br s, 2H), 7.12 (dd, J=8.7, 2.2 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.03 (br s, 2H), 2.10 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH2:17]>ClCCl>[C:1]([CH2:3][C:4]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:14]([CH3:13])[CH:15]=1)=[O:6])#[N:2]
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(NC(=O)CC#N)ccc1[N+](=O)[O-]
Yield: 60.3 %

Procedure:
Cyanoacetic acid (1.5 g; 17.6 mmol) and phosphorus pentachloride (4.1 g; 19.4 mmol) are heated under reflux in dichloromethane (40 ml) for 1 hour. 3-Methyl-4-nitroaniline (1.6 g; 10.6 mmol) is added and the mixture is heated for a further hour under reflux conditions. After cooling, the solid is filtered and stirred with water for a further hour, the mixture is filtered and the filtrate is brought to dryness under reduced pressure. 2-Cyano-N-(3-methyl-4-nitrophenyl)acetamide (1.4 g; 64%) is thus obtained.
Reaction SMILES: C(N1C(=O)C(=C2N(C)C3C(O[CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=CC=CC=3S2)SC1=NC1C=C(C=CC=1NCC)C#N)C1C=CC=CC=1.[CH2:45]([N:52]1[C:56](=[O:57])[C:55](=[C:58]2[N:62]([CH3:63])[C:61]3[CH:64]=[CH:65][C:66]([O:68]CCO)=[CH:67][C:60]=3[S:59]2)[S:54][C:53]1=[N:72][C:73]1[CH:74]=[C:75]([CH:78]=[CH:79][C:80]=1[NH:81][CH2:82][CH3:83])[C:76]#[N:77])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([N:52]1[C:56](=[O:57])[C:55](=[C:58]2[N:62]([CH3:63])[C:61]3[CH:64]=[CH:65][C:66]([O:68][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:67][C:60]=3[S:59]2)[S:54][C:53]1=[N:72][C:73]1[CH:74]=[C:75]([CH:78]=[CH:79][C:80]=1[NH:81][CH2:82][CH3:83])[C:76]#[N:77])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cccc(OCCN4CCOCC4)c3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(OCCO)ccc3N2C)C(=O)N1Cc1ccccc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(OCCN4CCOCC4)ccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 60 by replacing the product of Example 60 with the product of Example 261. MS(ESI): 627 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([S:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:14](=[O:21])[C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17]Cl>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:22][C:13]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:14]2[C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][O:21]2)=[CH:24][CH:25]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(CCCl)C(=O)C(Br)Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)CCOC1=C(Sc1ccc(Cl)cc1)n1ccnc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 40.7 %

Procedure:
64.9 g (0.94 mole) of imidazole and 129.7 g (0.94 mole) of potassium carbonate are dissolved in 1,300 ml of toluene. 173.9 g (0.47 mole) of 1-bromo-1-(4-chlorophenylthio)-5-chloro-3,3-dimethyl-2-pentanone in 360 ml of toluene are added dropwise to this mixture at 80° C. The reaction mixture is subsequently stirred at 90° C. for 15 hours and is cooled, and the inorganic residue is filtered off with suction. The filtrate is washed with water, dried over sodium sulphate and concentrated. The residue is recrystallized from diethyl ether. 61.4 g (40.8% of theory) of 4-chlorophenylthio-(imidazol-1-yl)-(3,3-dimethyl-tetrahydrofuran-2-ylidene)-methane of melting point 134° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1N
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
A mixture of 0.5 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.36 g of o-toluidine in 60 ml of N,N-dimethylformamide is refluxed for 16 hours. The mixture is poured into 200 ml of ice-water and extracted with three 100 ml portions of chloroform. The extract is washed with water, dried (Na2SO4) and the solvent removed. The residue is purified by chromatography on silica gel prep-plates with hexane-ethyl acetate (5:1) as solvent to give 0.56 g of yellow solid: mass spectrum (CI) 395.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)Cl

Procedure:
2-Methyl-4-bromobenzoic acid (26.8 g) was treated with oxalyl chloride (16.3 ml) in dry dichloromethane (250 ml) and the product was isolated by the method described in Example 1 (i) to give 2-methyl-4-bromobenzoyl chloride as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[N:6][C:7]=1Cl.[CH3:13][C@@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[N:6][C:7]=1[N:18]1[CH2:17][CH2:16][NH:15][C@H:14]([CH3:13])[CH2:19]1
Reactant: C[C@@H]1CNCCN1
Reactant: CC(C)(O)c1cnc(Cl)c(Cl)c1
Product: C[C@@H]1CN(c2ncc(C(C)(C)O)cc2Cl)CCN1

Procedure:
A mixture of 2-(5,6-dichloro-pyridin-3-yl)-propan-2-ol from step (b) above (140 mg, 0.68 mmol) and (R)-(−)-2-methyl-piperazine (75 mg, 0.75 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound. MS (ESI, pos. ion) m/z: 270 (M+1).
Reaction SMILES: COC(=O)[C@H:4]([N:7]([C:17](=[O:28])[C@@H:18]([NH:20][C:21](OC(C)(C)C)=[O:22])[CH3:19])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:5][CH3:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:5]([C@H:4]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:17](=[O:28])[C@H:18]([CH3:19])[NH:20][C:21]1=[O:22])[CH3:6]
Reactant: CC[C@H](C(=O)OC)N(Cc1ccc(OC)cc1)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N[C@@H](C)C(=O)N1Cc1ccc(OC)cc1
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a solution of 7.60 g of (R)-2-[((S)-2-tert-butoxycarbonylamino-propionyl)-(4-methoxy-benzyl)-amino]-butyric acid methyl ester in 116 ml DCM were added 116 ml of TFA at 0° C. during 1 h. After 2 h at 0° C. the reaction mixture was allowed to come to r.t. and stirred for another 1.5 h. The reaction mixture was then concentrated in vacuo, dissolved in EtOAc, and 120 ml of 1M aqueous NaHCO3-solution were added. After stirring for 1 h, the layers were separated. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 5.34 g (100%) of the title compound, which was used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.[Pd]>[CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1C
Product: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1

Procedure:
To a 500 ml, 3-necked round bottom flask were added 92 g (500 mmole) p-aminodiphenylamine, 61 ml (600 mmole) cyclohexanone, 82 ml (800 mmole) nitrobenzene, 120 ml xylene solvent and 1.0 g of 5% palladium on carbon catalyst (0.05 g Pd). Using essentially the procedure of Example 1 the reaction was (A) carried out without acid and then again (B) in the presence of 3 millimoles of sulfuric acid. Reaction (B) provided about 40% (mole) more yield of DPPD over reaction (A) after 7 hours at reflux.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[C:22]([O:24][SiH:25]([CH3:27])[CH3:26])[C:8]2[N:9]=[C:10]([C:12]3[S:13][C:14]([CH3:21])([CH3:20])[CH:15]([C:17](O)=[O:18])[N:16]=3)[S:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:31])=O.CN(C)C=O>C(Cl)Cl>[C:1]([C:5]1[CH:23]=[C:22]([O:24][SiH:25]([CH3:27])[CH3:26])[C:8]2[N:9]=[C:10]([C:12]3[S:13][C:14]([CH3:21])([CH3:20])[CH:15]([C:17]([Cl:31])=[O:18])[N:16]=3)[S:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[SiH](C)Oc1cc(C(C)(C)C)cc2sc(C3=NC(C(=O)O)C(C)(C)S3)nc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[SiH](C)Oc1cc(C(C)(C)C)cc2sc(C3=NC(C(=O)Cl)C(C)(C)S3)nc12
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
2-(6-tert.-butyldimethylsilyloxybenzothiazole-2-yl)-4,5-dihydro-5,5-dimethyl-4-thiazole carboxylic acid is dissolved under argon atmosphere in 8 ml dry methylene chloride, the clear solution is cooled to −15° C. and a mixture of 0.162 ml (1,875 mmol) oxalyl chloride and 500 μl of freshly distilled dimethyl formamide are added dropwise to the reaction under vigorous stirring. Slight gas emission can be observed during this step. The reaction mixture is stirred for additional 30 minutes at −15° C. and subsequently diluted with freshly destilled methylene chloride to a final volume of 30 ml.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][C:9](=[O:12])[NH:10][CH2:11][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][C:9](=[O:12])[NH:10][CH2:11][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CNC(=O)CCN2C(=O)C(F)(F)F
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(=O)C(F)(F)F)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-1-(2,2,2-trifluoro-acetyl)-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide in an analogous manner to Example 1221d. Title compound isolated as a yellow solid (66 mg, 23%). mp 181-183° C.; LCMS: m/z=583.83 (M+H+), HPLC (90% purity); 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.77 (s, 1H), 7.57 (m, 2H), 7.42 (m, 2H), 7.29 (m, 2H), 7.10 (m, 1H), 6.87 (m, 1H), 6.72 (m, 1H), 4.67 (m, 1H), 4.06 (m, 2H), 3.48 (m, 1H), 3.02 (s, 3H), 2.92 (m, 1H), 2.75 (m, 1H), 2.55 (m, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=3)=[O:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCCO2
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCCO3)cc1

Procedure:
Prepared from 2-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-nicotinic acid and 2-(4-Aminomethyl-phenyl)-propan-2-ol. MS: m/e 421 (M++1), 1HNMR (CDCl3) δ1.51 (6H, s), 4.24 (4H, s), 4.66(2H, d), 6.57 (1H, dd), 6.85 (1h, d), 7.11(1H, dd), 7.28(2H, d), 7.41(2H, d), 8.19(2H, m), 8.61(1H, d).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.50 g), ethyl 3-(4-hydroxyphenyl)propionate (0.31 g), anhydrous potassium carbonate (0.22 g) and N,N-dimethylformamide (15 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.38 g, 51%) of ethyl 3-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 105-106° C.