Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[NH:10][C:9]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:22]([O:26][C:27](=[O:36])[CH:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]([CH:28]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:36])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To a chilled solution of 5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (808 mg, 3.1 mmol) in dry DMF (15 mL) was added NaH (60% dispersion mineral oil, 131 mg, 3.3 mmol) under N2 atmosphere. The reaction was stirred at room temperature for 15 min. Then at 0° C., a solution of bromo-phenylacetic acid tert-butyl ester (887 mg, 3.3 mmol) in DMF (5 mL) was added. The reaction was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with water, with a saturated NH4Cl aqueous solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using 15% ethyl acetate in n-heptane as eluent to afford 3-(tert-butoxycarbonyl-phenyl methyl)-5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (VIIc) (1.1 g, 78%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:22])=[C:12]3[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:32][C:33]([NH2:35])=[O:34].O>CN(C=O)C>[NH2:35][C:33](=[O:34])[CH2:32][N:14]1[CH:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=2)=[O:9])[C:11](=[O:22])[C:12]2[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]1=2
Reactant: Cc1c(CO)sc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(CC(N)=O)c12
Temperature: 50 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-7-hydroxy-2-(hydroxymethyl)-3-methylthieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.276 mmol), potassium carbonate (57 mg, 0.41 mmol) and iodoacetamide (255 mg, 1.38 mmol) in DMF (1.5 mL) was stirred at 50° C. for 18 hrs. Additional iodoacetamide (255 mg) and potassium carbonate (57 mg) were added, and the reaction was stirred at the same temperature for another 12 hrs. After cooling, cold water was added, and the resulting ppt was collected by filtration after chilling in an ice bath. The collected crude solid was recrystallized from aq. ethanol to give the title compound (65 mg) as a lt. brown solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[C:6]3[CH:12]=[N:11][NH:10][C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[K+].[I:28]I>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[C:6]3[C:12]([I:28])=[N:11][NH:10][C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C3CC3)cnc3[nH]ncc23)CC1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C3CC3)cnc3[nH]nc(I)c23)CC1
Temperature: 60 °C
Yield: 102.1 %

Procedure:
A mixture of tert-butyl 4-(5-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.44 g, 4.19 mmol) and powdered potassium hydroxide (0.692 g, 10.5 mmol) in DMF (20 mL) was treated with iodine (2.13 g, 8.39 mmol), and the mixture was heated at 60° C. for 5 hours. The mixture was diluted with EtOAc (200 mL) and successively washed with saturated Na2S2O3 solution (2×20 mL) and water (2×50 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo to provide the crude tert-butyl 4-(5-cyclopropyl-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (2.01 g, 4.28 mmol, 100%) yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:20][CH2:21][N:22]2[CH2:25][CH:24]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)[CH2:23]2)[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[Cl:8].FC1C=CC(C(CCN2CC(N3CCSCC3)C2)CN(C)C(=O)OC(C)(C)C)=CC=1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:10][NH:11][CH3:12])[CH2:20][CH2:21][N:22]2[CH2:25][CH:24]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)[CH2:23]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C[C@@H](CCN1CC(N2CCC(O)CC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: CN(CC(CCN1CC(N2CCSCC2)C1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Product: CNC[C@@H](CCN1CC(N2CCC(O)CC2)C1)c1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
The compound was synthesized in an analogous way to that of Method 3e but using tert-butyl {(2S)-2-(3,4-dichlorophenyl)-4-[3-(4-hydroxypiperidin-1-yl)azetidin-1-yl]butyl}methylcarbamate rather than tert-butyl [2-(4-fluorophenyl)-4-(3-thiomorpholin-4-ylazetidin-1-yl)butyl]methylcarbamate (yield, 100%). 1H NMR (500 MHz, CD3OD): 1.8-2.2 (m, 6H), 2.7 (s, 3H), 3.2-4.8 (cm, 17H), 7.4 (dd, 1H), 7.6-7.7 (m, 2H), LCMS: m/z 387 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[N:13]([O-])=O.[Na+]>O>[Cl-:2].[Cl:2][C:3]1[CH:9]=[CH:8][C:6]([N+:7]#[N:13])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(Cl)cc1[N+](=O)[O-]
Product: [Cl-]
Temperature: 65 °C

Procedure:
To a 500 mL three-necked flask fitted with a mechanical stirrer are added 134.2 g of concentrated hydrochloric acid and 60 g of 4-chloro-2-nitroaniline. After heating to 65° C., 106.6 g of water is added at which time the temperature is reduced to 0° C. Sodium nitrite (63.4 g, 40 wt %) is slowly added to the slurry while maintaining the solution at 0° C. The diazonium salt solution (281 g) is then filtered and stored at −15° C. until later use.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=C)[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1.ClCCl.C[OH:17]>>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:17])[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1
Reactant: CO
Reactant: C=Cc1nc(Cl)nc(Cl)c1OC
Solvent: ClCCl
Product: COc1c(Cl)nc(Cl)nc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of 2,6-dichloro-5-methoxy-4-vinyl pyrimidine (50 g, 0.24 mol) in dichloromethane:methanol (4:1, 2 L) was cooled to −78° C. Ozone gas was bubbled therethrough for 5 h. The reaction was quenched with dimethyl sulfide (50 mL). The mixture was slowly warmed to room temperature and concentrated under reduced pressure at 40° C. to provide the title compound (50.5 g, 100%); high-performance liquid chromatography (HPLC) (85% acetonitrile buffered with 0.1% volume per volume (v/v) acetic acid).
Reaction SMILES: C(OC(C1C=C2C(=CC=1)NC(=O)C2)=O)C(C)C.CN(C=C1C2C(=CC(CO[Si](C(C)(C)C)(C)C)=CC=2)NC1=O)C.[CH2:41]([O:45][C:46]([C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52](=[O:57])[C:51]2=[CH:58][N:59]([CH3:61])C)=[O:47])[CH:42]([CH3:44])[CH3:43].Cl.NC1[CH:69]=[CH:68][C:67]([S:70]([NH2:73])(=[O:72])=[O:71])=[CH:66][CH:65]=1>>[CH2:41]([O:45][C:46]([C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52](=[O:57])[C:51]2=[CH:58][NH:59][C:61]1[CH:69]=[CH:68][C:67]([S:70](=[O:72])(=[O:71])[NH2:73])=[CH:66][CH:65]=1)=[O:47])[CH:42]([CH3:43])[CH3:44]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)COC(=O)c1ccc2c(c1)C(=CN(C)C)C(=O)N2
Agent: CC(C)COC(=O)c1ccc2c(c1)CC(=O)N2
Agent: CN(C)C=C1C(=O)Nc2cc(CO[Si](C)(C)C(C)(C)C)ccc21
Agent: Cl
Product: CC(C)COC(=O)c1ccc2c(c1)C(=CNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 66 %

Procedure:
3-Methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester was prepared in 59% yield from isobutyl 4-aminobenzoate according to Procedure D: 1H NMR (DMSO-d6): δ 0.93 (d, J=6.6 Hz, 6H), 1.93 (s, 3H), 1.98 (septet, J=6.6 Hz, 1H), 4.02 (m, 2H), 4.62 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 7.79 (s, J=1H), 7.86 (d, J=8.2 Hz, 1H), 10.91 (s, 1H); ESI−MS m/z 302 (M+23)−. Zinc reduction of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester according to Procedure δ provided 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester in 99% yield: 1H NMR (DMSO-d6): δ 0.93 (d, J=6.6 Hz, 6H), 1.97 (septet, J=6.6 Hz, 1H), 3.53 (s, 2H), 3.99 (d, J=6.6 Hz, 2H), 6.88 (d, J×8.2 Hz, 1H), 7.75 (s, J=1H), 7.82 (d, J=8.2 Hz, 1H), 10.72 (s, 1H); ESI−MS m/z 256 (M+23)+. Conversion of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester to 3-[(dimethylamino)methylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester (mixture of E and Z isomers) was accomplished in 75% yield according to Procedure G: 1H NMR (DMSO-d6): δ 0.94 Z (d, J=8.8 Hz, 6H), 0.94 E (d, J=8.8 Hz, 6H), 1.94-2.01 Z and E (m, 2H), 3.30 Z (s, 6H), 3.32 E (s, 6H), 3.97-3.99 Z and E (m, 4H), 6.75 Z (d, J=8.2 Hz, 1H), 6.83 E (d, J=8.2 Hz, 1H), 7.47 E (s, 1H), 7.53 Z (d, J=.8.2 Hz, 1H), 7.59 E (d, J=8.2 Hz, 1H), 7.73 Z (s, 1H), 7.88 Z (s, 1H), 7.98 E (s, 1H), 10.34 Z (bs, 1H), 10.44 E (bs, 1H); ESI−MS m/z 289 (M+1)+. The title compound was prepared in 66% yield from 3-[(1(dimethylamino)methylene]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid isobutyl ester and 4-aminobenzenesulfonamide hydrochloride according to Procedure J: 1H NMR (DMSO-d6): δ 0.96 (d, J=6.6 Hz, 6H), 2.01 (septet, J=6.6 Hz, 1H), 4.04 (d, J=6.6 Hz, 2H), 6.93 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.71 (dd, J=1.6, 8.2 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 8.27 (s, 1H), 8.86 (d, J=12.5 Hz, 1H), 10.83 (d, J=12.5 Hz, 1H), 10.95 (s, 1H); APCI−MS m/z 414 (M−H)−. Anal. Calcd for C20H21N3O5S: C, 57.82, H, 5.09; N, 10.11; S, 7.72. Found C, 57.91, H, 5.16; N, 10.02; S. 7.65.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[CH3:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]([CH3:18])=[CH:13][S:12]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH3:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]([CH3:18])=[C:13]([CH:22]2[CH:23]=[CH:24][N:19]([C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[CH:20]=[CH:21]2)[S:12]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: c1ccncc1
Reactant: CC1=CSC(C)C(=O)N1
Solvent: CC#N
Product: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SC(C)C(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
2,2,2-Trichloroethylchloroformate (1.68 ml) was added dropwise to a solution of 2,5-dimethyl-2H-1,4-thiazin-3(4H)-one (1.43 g) and pyridine (1.6 ml) in acetonitrile (50 ml) under ice-cooling, and the solution was stirred for 30 minutes at 0° C. The mixture was further stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The residue was extracted with chloroform, was washed with 2N hydrochloric acid and successively with water and was dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel (Wakogel C-200) column, using ethyl acetate-n-hexane (=1:1) as an eluant. The eluate was washed with ether to give the titled compound (1.68 g, yield 42%) as pale yellow crystals.
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].Cl[C:6]1[N:7]=[C:8]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[N:22]=1.O.C1C[O:33][CH2:32][CH2:31]1>>[CH2:2]([O:4][C:6]1[N:7]=[C:8]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:9]2[N:14]=[C:13]([O:33][CH2:32][CH3:31])[N:12]=[C:11]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[N:22]=1)[CH3:3]
Reactant: CCO
Reactant: Clc1nc(N2CCCCC2)c2nc(Cl)nc(N3CCCCC3)c2n1
Reactant: C1CCOC1
Agent: [Na]
Solvent: O
Product: CCOc1nc(N2CCCCC2)c2nc(OCC)nc(N3CCCCC3)c2n1
Yield: 84 %

Procedure:
Sodium metal (0.115 g, 5 mmol) was added to ethanol (0.23 g, 5 mmol) in dry THF (5 ml) and stirred until all had dissolved. Then, 2,6-dichloro-4,8-dipiperidinopyrimidopyrimidine (0.184 g, 0.5 mmol) dissolved in dry THF (10 ml) was added to the alkoxide and the mixture was heated under reflux for 18 hours. After cooling to room temperature water (20 ml) was added and the product extracted into ethyl acetate (4×20 ml). The organic layers were combined, dried (MgSO4), filtered and the solvent removed in vacuo. Recrystallisation from methanol/water yielded the title compound as an orange crystalline solid (0.167 g, 84%), m.p. 142-143° C. Found: C, 62.11; H, 7.81; N, 21.34. C20H30N6O2 requires C, 62.15; H, 7.82; N, 21.74%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from 2-(t-butoxycarbonylamino)-2-methylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.42 (s,12H), 1.46 (s,3H), 1.90 (m,1H), 2.5-3.0 (m,3H), 4.48 (m,1H), 5.01 (br s,1H), 6.97 (d,8Hz,1H), 7.1-7.3 (m,3H), 7.9 (br s,1H). FAB=MS: calculated for C19H27N3O4 361; found 362 (M+H,30%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:40]/[C:41](/[CH3:50])=[CH:42]\[C:43]([O:45][CH2:46][CH2:47][O:48][CH3:49])=[O:44]>C(O)(C)C>[CH3:16][C:14]1[NH:40][C:41]([CH3:50])=[C:42]([C:43]([O:45][CH2:46][CH2:47][O:48][CH3:49])=[O:44])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]=1[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:26]1)=[O:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COCCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 19.5 %

Procedure:
A mixture of m-nitrobenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and 2-methoxyethyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzhydryl-1-piperazinyl)ethyl 2-methoxyethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 62°-66° C. (sintering). Yield 19.5%. IR(Nujol)cm-1 : 3300, 1685, 1675. NMR(CDCl3) δ: 2.33(6H,s, ##STR39## 2.5(2H,t,J=6,--CH2CH2N>), 3.29(3H, s,OCH3), 3.49(2H,t,J=4.5,--CH2CH2O--), 5.08(1H,s,C(4) --H), 5.77(1H,broad s, NH).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][O:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1.C(N(CC)CC)C>CN(C=O)C>[CH3:33][O:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
To a solution of 3,3 Diphenylpropionic acid (2.00 g, 8.85 mmol) in DMF (20 mL) was added EDC (2.04 g, 10.62 mmol), HOBT (1.44 g, 10.62 mmol) and L-proline methyl ester hydrochloride (1.76 g, 10.62 mmol) with stirring at ambient temperature. Triethylamine (2.96 mL, 21.24 mmol) was added to adjust the pH of the mixture to 8.5. After 24 hrs the DMF was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL)- H2O (50 mL). The aqueous layer was washed with EtOAc (2×50 mL), organics combined, washed with 10% citric acid soln, aq satd NaHCO3 soln, brine and dried (Na2SO4). Filtration and concentration to dryness gave 3.50 g of crude product which was chromatographed (SiO2)eluting with 99 CH2Cl2 :1 MeOH to 98 CH2Cl2 :2 MeOH to give 2.48 g (83%) of N-(3,3-diphenylpropionyl)-L-proline methylester.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:52])([CH3:51])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:51])([CH3:52])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (459 mg), sodium hydrogen carbonate (739 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (237 mg) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (86 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (81 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (102 mg, 39%).
Reaction SMILES: [Na].[CH3:2][Sn:3](Cl)([CH3:5])[CH3:4].Br[C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>COCCOC.C(Cl)(Cl)Cl>[CH3:2][Sn:3]([CH3:5])([CH3:4])[C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: C[Sn](C)(C)Cl
Reactant: COc1cc2ccccc2nc1Br
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: COc1cc2ccccc2nc1[Sn](C)(C)C
Temperature: -10 °C
Reaction time: 4 h

Procedure:
3.00 g (130 mmol) of sodium are introduced in a sealed Schlenck-type apparatus under argon inert gas into 3 ml of absolute DME. The sodium is cut into very small pieces and, before being added to the reaction solution, is washed with absolute DME to remove any adhering paraffin. After the sodium has been suspended in DME, the reaction solution remains clear, and only a slight evolution of gas can be observed. The reaction mixture is cooled to -10° C. using an ice/common salt mixture and 1.16 g (5.84 mmol) of trimethyltin chloride are then added in solid form. After the addition, the reaction solution still remains clear. After a reaction time of 1 h, the reaction solution has a milky cloudy color. After a reaction time of 3 hours, the reaction solution becomes milky, gray and cloudy. Shortly afterwards, the reaction solution turns deep green. The solution is stirred for a total of 4 hours. The last hour of the reaction is carried out without ice cooling. In order to remove excess sodium, the reaction solution is filtered under argon inert gas through a D-2 Schlenck-type frit. 0.70 g (2.92 mmol) of 2-bromo-3-methoxyquinoline dissolved in 3 ml of absolute DME is added dropwise to the filtered cloudy and green reaction solution. Upon dropwise addition of the educt, the reaction solution spontaneously turns blood red. During the addition of the educt, the reaction solution is cooled with ice. After a short time, the reaction solution has a dark brown color, which, after a reaction time of 1.5 hours, clears to light brown. After a reaction time of 4 hours with ice cooling, the reaction mixture is filtered through a D-4 frit to remove the solids formed. This gives a light yellow reaction solution. A gray solid remains in the frit. The solvent is washed with more [lacuna], the runoff being dark brown. After evaporation of the solvent, a dark brown oil is obtained. A thin-layer chromatogram obtained in chloroform shows that the desired product is obtained. Slight traces of the hydrolysis product 3-methoxyquinoline can be detected by 1H-NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC.[Cl-].[Li+].CN(C)C=O>O1CCOCC1.O>[CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:5]=2[C:4](=[O:20])[O:3]1
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)c2c(cccc2-c2ccccn2)O1
Reaction time: 8 h

Procedure:
6.0 g (18.4 mmol) of 2,2-dimethyl-5-trifluoromethylsulfonyloxy-4H-(1,3)benzodioxin-4-one, 7.0 g (19.0 mmol) of 2-tributylstannylpyridine, 2.3 g (55.2 mmol) of lithium chloride and 420 mg (0.36 mmol) of tetrakistriphenylphosphinepalladium0 are dissolved in 60 ml of dioxane and 90 ml of dimethylformamide and the mixture is refluxed for 1.5 h (reaction temperature about 120° C.). It is stirred into 1.4 l of water at 0° C. and extracted with methyl tert-butyl ether, and the extract is washed with water and sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is taken up in 60 ml of ethyl acetate, 8 g of potassium fluoride are added and the mixture is stirred overnight. The solid is filtered off and subsequently washed with plenty of ethyl acetate, and the filtrate is concentrated in vacuo. The crude product is purified by chromatography on silica gel 60 using hexane/ethyl acetate. Yield: 2.39 g (51%). Melting point: 142° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(C)(C)C)[CH:5]=[CH:4][C:3]=1[F:13]>ClCCCl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[F:13]
Reactant: CC(C)(C)Nc1ccc(F)c(Br)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Nc1ccc(F)c(Br)n1
Yield: 68.9 %

Procedure:
A solution of (6-bromo-5-fluoropyridin-2-yl)-tert-butylamine (46 mg, 0.19 mmol) in DCE (2 mL) and TFA (2 mL) was heated at 120° C. for 10 min in a microwave reactor, and then concentrated under reduced pressure. The residue was taken up in MeOH and loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH to give 6-Bromo-5-fluoropyridin-2-ylamine as an off-white solid (25 mg, 71%). 1H NMR (400 MHz, CHCl3-d): δ 7.21 (dd, J=8.7, 7.2 Hz, 1 H); 6.39 (dd, J=8.7, 2.7 Hz, 1 H); 4.89-3.75 (s, 2 H).