Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=2)=[CH:4][C:5]([C@H:10]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:13]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:12]([CH2:40][O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:11]2)=[C:6]([CH2:8][OH:9])[CH:7]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC.[C:89]([CH2:93]O)([F:92])([F:91])[F:90]>C1(C)C=CC=CC=1>[CH2:33]([O:32][C@H:13]1[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:10]([C:5]2[CH:4]=[C:3]([CH2:49][C:50]3[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=3)[C:2]([Cl:1])=[CH:7][C:6]=2[CH2:8][O:9][CH2:93][C:89]([F:92])([F:91])[F:90])[O:11][C@@H:12]1[CH2:40][O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OCC(F)(F)F
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CO)cc2Cl)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(COCC(F)(F)F)cc2Cl)cc1
Reaction time: 0.17 h

Procedure:
To a solution of (5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)methanol (0.783 g, 1 mmol) (V-1) in toluene (2 mL) was added ADDP (2 mmol) at room temperature. The mixture was stirred for 10 min and then Bu3P (2 mmol) was added. After stirring for 1 h, CF3CH2OH (1.0 g, 10 mmol) was added. The mixture was stirred overnight. After removal of volatiles under reduced pressure, the residue was purified by preparative LC-MS to obtain (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-5-(4-ethylbenzyl)-2-((2,2,2-trifluoroethoxy)methyl)phenyl)tetrahydro-2H-pyran (intermediate V-2).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[H-].[Na+].[CH3:26]I>CN(C=O)C>[CH3:23][O:22][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([N:14]([CH3:26])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: CI
Reactant: COC(OC)c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(OC)c1cc(N(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To tert-butyl 3-(dimethoxymethyl)-5-(trifluoromethyl)phenylcarbamate (125 mg, 0.37 mmol) in DMF (5 ml) at 0° C., sodium hydride (22 mg, 0.56 mmol) was added. After stirring at rt for 0.5 h, methyl iodide (263 mg, 1.85 mmol) was added and stirred overnight at rt. Reaction mixture was then cooled, quenched with methanol, extracted with ether. Organic layer was dried and evaporated and the crude residue was column purified (10% ethylacetate/90% hexanes) to yield 110 mg of tert-butyl 3-(dimethoxymethyl)-5-(trifluoromethyl)phenyl(methyl)carbamate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:17](Cl)(Cl)=[O:18].ClC(OC(Cl)(Cl)Cl)=O>O1CCCC1>[O:18]=[C:17]1[O:1][CH2:2][C:3]2[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=2[NH:5]1
Reactant: Nc1ccccc1CO
Reactant: O=C(Cl)Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2CO1

Procedure:
To a mixture of 2-hydroxymethylaniline (25 g), triethylamine (32 ml) and tetrahydrofuran (250 ml) was introduced phosgene generated from trichloromethyl chloroformate (12.2 ml) and active carbon at room temperature with stirring. After stirring for 1 hour at room temperature, the reaction mixture was filtered off and the filtrate was concentrated. The resulting residue was recrystallized from diethyl ether-n-hexane to give 4H-1,2-dihydro-2-oxo-[3,1]benzoxazine (22.3 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25].[O-]S([O-])(=O)=O.[Mg+2]>CC#N>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[N:15]/[C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][O:19][C:20]3=[O:25])=[CH:9][CH:8]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: CN1CCCC1c1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CN1CCCC1c1ccc(/C=N/c2cccc3c2COC3=O)cc1
Temperature: 120 °C
Yield: 41 %

Procedure:
A mixture of 4-(1-methylpyrrolidin-2-yl)benzaldehyde (1.89 g, 10 mmol), 4-aminoisobenzofuran-1(3H)-one (1.49 g, 10 mmol) and MgSO4(12 g, 100 mmol) in CH3CN (60 mL) was refluxed at 120° C. for 4 days. After a hot filtration, CH3CN was partially removed under reduced pressure and a white precipitate was appeared, the title compound was obtained by a direct filtration (1.3 g, yield 41%) as a white solid. LC-MS (ESI) m/z: 440 (M+1)+.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[Si:60]([O:67][CH2:68][C:69](OCC#N)=[O:70])([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>O.O1CCCC1>[Si:60]([O:67][CH2:68][C:69]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:70])([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (144 mg, 0.227 mmol) in water (1 ml) and a solution of cyanomethyl 2-(tert-butyldimethylsilyloxy)acetate (Compound 21) (104 mg, 0.453 mmol) in tetrahydrofuran (1 ml) were added to buffer A (30 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (2R,3S,4R,5R)-2-((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(phosphonooxymethyl)tetrahydrofuran-3-yloxy)(hydroxy)phosphoryloxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-(tert-butyldimethylsilyloxy)acetate (Compound 22) (104.5 mg, 57%).
Reaction SMILES: CO[C:3](=[O:26])[C:4]([OH:25])=[CH:5][C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:35][N:36](C)[C:37](C1CN(C)C(=O)C=1O)=O>>[Cl:23][C:18]1[CH:17]=[C:16]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]([C:5]2[CH2:35][N:36]([CH3:37])[C:3](=[O:26])[C:4]=2[OH:25])=[O:24])[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CN1CC(C(=O)N(Cc2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 68 %

Procedure:
3-[(3,4-Dichlorophenyl)-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 78-B) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (68% yield); mp 195° C., dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.9 (3H, s, NCH3), 3.03 (2H, s, NCH2), 4.90 (2H, s, NCH2), 6.87 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.02 (2H, m, aromatics), 7.2 (2H, m, aromatics), 7.22 (1H, d, J=2.5 Hz, aromatic), 7.49 (1H, d, J=8.6 Hz, aromatic), 11.9 (1H, broad, OH). Anal. calcd for C19H15Cl2FN2O3: C, 55.76; H, 3.69; N, 6.84. Found: C, 55.53; H, 3.61; N, 6.75.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].C(=O)([O-])[O-].[Ca+2].[CH3:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[CH3:26][CH:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)=[O:5])[CH2:29][CH2:28]1
Reactant: CC1CCNCC1
Reactant: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2N2CCC(C)CC2)cc1
Yield: 54.2 %

Procedure:
Proceeding as indicated in example 2, with 0.0635 mole (18.5 g) of 2-chloro-4'-methoxy-5-nitro-benzophenone, 0.076 mole (10.5 g) of calcium carbonate and 0.127 mole (12.57 g) of 4-methyl piperidine in 50 cm3 of ethanol, 12.2 g (Yield: 53%) of the expected product are obtained. M.P. 119° C.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:10]([C:14]1[N:15]([CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]#[N:40])[C:16]([C:20]([OH:22])=[O:21])=[C:17]([Cl:19])[N:18]=1)[CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([C:14]1[N:15]([CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]#[N:40])[C:16]([C:20]([O:22][CH2:1][CH3:2])=[O:21])=[C:17]([Cl:19])[N:18]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Reaction time: 1.5 h

Procedure:
Ethyl iodide (561.5 mg, 3.60 mmol) and cesium carbonate (1.5g, 4.5 mmol) were added to a solution of 2-butyl-4-chloro-1-[[1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5carboxylic acid (779.2 mg, 1.80 mmol, prepared as described in part C of Example 9) in dimethylformamide (3.72 ml). After 1.5 hours at room temperature, the reaction was diluted with ethyl acetate and filtered to remove the cesium carbonate. The ethyl acetate was washed with pH=4 buffer (2×20 ml), pH=7 buffer (2×25 ml), saturated sodium chloride (20 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated to a yellow oil (890 mg). Purification by flash chromatography (83 g Merck silica gel, 8:2 hexane/ethyl acetate) gave 662 mg of the title A compound.
Reaction SMILES: [N:1]1[C:2](=[O:10])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:15][CH:14]=1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Reactant: O=C1C=c2ccccc2=N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc(C=C2C(=O)Nc3ccccc32)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 1.33 g of indole-2-one (10 mmol), 1.99 g of 4-dimethylamino-1-naphthaldehyde (10 mmol) and 3 drops of piperidine are refluxed in 40 ml of ethanol for 5 hours. The desired product precipitates as an orange solid during the reaction. After cooling to room temperature, the product is filtered off, washed with ethanol and dried in vacuo. Yield 2.67 g (85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C@@H:10]([CH3:13])[CH2:11]O)[CH3:9])[NH:5][C:4](=[O:14])[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH3:9])[C@@H:10]([CH3:13])[CH2:11][N:5]2[C:4](=[O:14])[N:3]=1
Reactant: C[C@@H](CO)N(C)c1cc(Cl)nc(=O)[nH]1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one (700 mg, 3.22 mmol) and triethylamine (1.35 mL, 9.65 mmol) in tetrahydrofuran (THF) (20 mL) was added methanesulfonyl chloride (0.508 mL, 6.43 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h and concentrated. Purification via Prep-HPLC (column: YMC-Actus Triart C18 150×30 mm; 2 M NH3 in methanol) afforded the title product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([CH2:15][NH:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[C:26]([O:30][C:31](N1CCC(N)CC1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][CH2:15][C:14]2[C:9]3[N:8]([CH2:24][CH3:25])[C:7]([C:3]4[C:2]([NH2:1])=[N:6][O:5][N:4]=4)=[N:23][C:10]=3[CH:11]=[N:12][CH:13]=2)[CH2:18][CH2:19]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNC3CCNCC3)c21
Product: CCn1c(-c2nonc2N)nc2cncc(CNC3CCN(C(=O)OC(C)(C)C)CC3)c21

Procedure:
The title compound was prepared from the product of Step 1 and 4-Amino-piperidine-1-carboxylic acid tert-butyl ester according to the general method of Example 149; MS (ES+) m/e 443 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br.O1CCOCC1>O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1)C(=O)O
Temperature: 95 °C

Procedure:
A mixture of methyl 2-[4-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]phenoxy]isobutyrate (50 mg), 48% w/v hydrobromic acid (0.74 ml), dioxane (1 ml) and water (3 ml) was heated at 95° C. for 4 hours. The solution was cooled, diluted with water and freeze-dried to give the title compound, 40 mg, as a pale yellow solid: m.p. 163°-167° C.; NMR (D2O) δ8.40 (2H, d), 8.16 (2H, d), 7.40 (2H, d), 7.21 (2H, d), 5.21 (2H, s), 4 32 (4H, b), 3 89 (4H, bt), 1.86 (6H s); m/e 384 (M+H)+ ; calculated for C21H25N3.2HBr.2H2O: C, 43.3; H, 5.3; N, 7.2. found: C, 43.6; H, 5.3; N, 7.3%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH2:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH:19][S:30]([CH3:29])(=[O:32])=[O:31])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NS(C)(=O)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 575.9 %

Procedure:
A solution of 39 (0.10 g, 0.26 mmol), methanesulfonyl chloride (0.08 mL, 1.03 mmol), NEt3 (0.04 mL, 0.28 mmol) and a catalytic amount of DMAP in CH2Cl2 (50 mL) was stirred at room temperature for 2 h. The mixture was washed with 2N HCl (30 mL), 2N NaOH (30 mL), and H2O (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude solid. The crude solid was purified by column chromatography (eluent: 2% MeOH/CH2Cl2) to afford 0.7 g (56%) of 42 as a white crystalline solid, mp 262-265° C. (EtOAc/n-hexanes); 1H NMR (CDCl3); δ 1.09 (3H, s); 1.46 (3H, s); 1.60 (3H, m); 1.79 (1H, dd, J=2.7, 9.6); 2.07 (2H, m); 2.18 (1H, m); 2.21 (1H, s); 2.50 (2H, m); 2.75 (1H, dd, J=3.6, 13.2); 2.99 (3H, s); 3.72 (3H, s); 4.15 (1H, m); 5.34 (1H, d, J=5.4); 5.55 (1H, dd, J=5.1, 11.4); 6.38 (1H, dd, J=0.9, 1.2); 7.41 (1H, dd, J=1.5, 1.8); 7.43 (1H, dd, J=0.9, 1.5).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[CH:28][C:23]=1[CH:24]=[CH:25][CH2:26]Br>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:26][CH:25]=[CH:24][C:23]3[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([O:32][CH3:33])[C:22]=3[O:21][CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: COc1ccc(C=CCBr)c(OC)c1OC
Product: COc1ccc(C=CCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and (2,3,4-trimethoxy)cinnamyl bromide to produce the above.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](F)[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:10]=1[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][NH2:37]>CS(C)=O.O>[CH2:29]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[C:10]([F:28])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:37][CH3:36])[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CN
Reactant: Fc1cc(-c2c[nH]nc2-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)ccn1
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)ccn1

Procedure:
To a solution of dibenzyl-{2,4-difluoro-3-[4-(2-fluoro-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-amine (400 mg, 0.849 mmol) in DMSO (4.24 mL), a 40% methyl amine solution in water (3.5 mL) was added. The mixture was irradiated in the microwave oven at 120° C. for one hour and then poured into water and extracted with ethyl acetate. The organic layer was washed three times with saturated aqueous NaHCO3 and once with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduce pressure and the crude product was used in the following step without further purification.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N1CCNCC1)CC1C=CC=CC=1.[CH:41]1([CH2:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][CH2:47][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:51][CH2:52]2)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cc(Br)ccc1OCc1ccccc1
Reactant: C1CCC(CCCN2CCNCC2)CC1
Agent: COc1ccc(Br)cc1C
Agent: c1ccc(CCN2CCNCC2)cc1
Product: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Yield: 100.4 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene was replaced with 1-benzyloxy-4-bromo-2-chlorobenzene (861 mg), and l-phenethylpiperazine was replaced with 1-(3-cyclohexylpropyl)piperazine (730 mg). Whereby obtained crude product was purified on silica gel column chromatography (eluent, chloroform: methanol=10:1) to provide 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine (1.24 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 14.5 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 110 ml DMF were added 4.5 ml benzyl bromoacetate and 17.8 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 400 ml ethyl acetate and extracted with aqueous LiCl (4% w/w). The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with a gradient of n-heptane/ethyl acetate.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N(C2C=CC=CC=2)[C:20]([NH:22][CH2:23][CH:24]2[CH2:29][CH:28]3[CH2:30][CH:25]2[CH:26]=[CH:27]3)=[O:21])C=CC=CC=1.CN(C)C=O.[H-].[Na+]>CCOCC>[CH:28]12[CH2:30][CH:25]([CH:24]([CH2:23][NH:22][C:20]([NH:12][S:9]([CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:11])=[O:21])[CH2:29]1)[CH:26]=[CH:27]2
Reactant: O=C(NCC1CC2C=CC1C2)N(c1ccccc1)c1ccccc1
Reactant: NS(=O)(=O)C=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(NCC1CC2C=CC1C2)NS(=O)(=O)C=Cc1ccccc1

Procedure:
To a solution of 1.8 g. of 2-phenylethenesulfonamide and 4.8 g. of 1,1-diphenyl-3-(bicyclo[2.2.1]hept-2-en-5-ylmethyl)urea in 20 ml. of N,N-dimethylformamide, is added, with stirring 0.64 g. of a 56.6% dispersion of sodium hydride in mineral oil. The mixture is stirred at ambient temperature overnight, during which time a heavy precipitate forms. To the reaction mixture is then added 200 ml. of ether. After stirring for 15 minutes, the precipitate is filtered off. It is dissolved in 50 ml. of water, and then the crude product is precipitated by acidification usng concentrated hydrochloric acid. It is filtered off and recrystallized from aqueous acetone. The yield is 1.9 g. (56%) of a solid, m.p. 161°-163.5° C.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[Cl:9][C:10]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:11]=1[CH:12]=O>CO>[NH2:1][C:2]([C:7]#[N:8])=[C:3]([N:6]=[CH:12][C:11]1[C:14]([Cl:22])=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:10]=1[Cl:9])[C:4]#[N:5]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CO
Product: N#CC(N)=C(C#N)N=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 77.3 %

Procedure:
Diaminomaleonitrile (4.4 g, 0.04 mol) was dissolved in methanol (100 ml) and 2,6-dichloro-4-trifluoromethylbenzaldehyde (9.6 g, 0.04 mol) was added with stirring at ambient temperature. The reaction mixture was stirred for 30 minutes and heated at reflux for 1 hour. After cooling to 10° C. a solid which had separated was filtered off co give 1-amino-2-(2,6-dichloro-4-trifluoromethylbenzylideneamino)-1,2-dicyanoethylene (10.3 g) as a yellow crystalline solid, m.p. 218°-219° C.