Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[S:7].Cl[CH2:15][S:16][C:17]#[N:18]>>[S:16]([CH2:15][O:8][C:6](=[S:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=1)[C:17]#[N:18]
Reactant: N#CSCCl
Reactant: OC(=S)c1cccc(C(F)(F)F)c1
Product: N#CSCOC(=S)c1cccc(C(F)(F)F)c1
Yield: 69 %

Procedure:
23 g (0.1 mol) of the K salt of 3-trifluoromethyl thiobenzoic acid and 14.3 g (0.13 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 19 g of a yellowish oil having a density of 1.4 (this corresponds to a yield of 69% of the theoretical conversion).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([O-])=O)=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH:20]([CH3:22])[CH3:21].[C:23](N1C=CN=C1)(=O)C.[C:31]([O-:34])([O-])=[O:32].[Na+].[Na+]>CC#N.O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:19]=[CH:18][C:14]([CH2:15][C:31]([O:34][CH3:23])=[O:32])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)c1cc(C#Cc2ccc(C(=O)[O-])cc2)ccc1CBr
Reactant: CC(=O)n1ccnc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1ccc(C#Cc2ccc(CBr)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of ethyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl]-benzoate (Intermediate 155, 120.0 mg, 0.31 mmol) and 1-acetylimidazole (36.0 mg, 0.33 mmol) in 5 mL CH3CN was heated at 65° C. for 4 hours and then at 55° C. for 16 hours. The solution was cooled to room temperature, diluted with H2O and made basic by addition of Na2CO3, and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure. Column chromatography (1% Et3N in 5% MeOH-EtOAc) afforded 75.0 mg (65%) of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.IC.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][S:24][C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:25])[F:26])[CH:5]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(S)o4)cc23)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CSc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A suspension of the obtained 5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol, iodomethane (2.17 mL, 34.8 mmol) and potassium carbonate (3.61 g, 26.1 mmol) in N,N-dimethylformamide (70 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=4/1) and recrystallized from hexane/ethyl acetate to give the title compound (1.01 g, yield 15%) as colorless crystals.
Reaction SMILES: OO.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[C:10]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14])([O-:5])=[O:4].FC(F)(F)C(O)=[O:30]>O>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N+:17]=2[O-:30])[C:10]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14])([O-:5])=[O:4]
Reactant: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: O
Product: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c[n+]1[O-]
Reaction time: 0.08 h
Yield: 85 %

Procedure:
2.8 g (0.0413 mol) of 50% strength hydrogen peroxide were added to a mixture of 10 g (0.0275 mol) of 4-nitro-5-propionamido-1-(3-chloro-5-trifluoromethyl-2-pyridyl)pyrazole and 100 ml of trifluoroacetic acid at 20° C. with stirring in the course of 5 minutes and it was stirred at 25° C. for 14 hours. The reaction mixture was poured onto 500 ml of water and extracted 3× with methylene chloride. The organic phase was washed with water, sodium hydrogencarbonate and saturated sodium chloride solution in succession and dried over magnesium sulfate. After concentrating under reduced pressure, stirring with ether/pentane, filtering off with suction and drying, 9.0 g (85% of theory) of 4-nitro-5-propionamido-1-(3-chloro-5-trifluoromethyl-(N-oxido)-2-pyridyl)pyrazole of m.p. 143-146° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:17][C@@H:18]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:19](=[O:31])[NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[NH:30])[CH3:29])[CH2:24][CH2:23]1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:17][C@@H:18]([CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[C:19]([NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[NH:30])[CH3:29])[CH2:24][CH2:23]1)=[O:31]
Reactant: CC(=N)N1CCC(CNC(=O)[C@@H](NC(=O)OCc2ccccc2)C2CCCCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=N)N1CCC(CNC(=O)[C@@H](N)C2CCCCC2)CC1
Yield: 113.3 %

Procedure:
(S)-(Cyclohexyl-{[1-(1-imino-ethyl)-piperidin-4-ylmethyl]-carbamoyl}-methyl)-carbamic acid benzyl ester trifluoroacetic acid salt (340 mg, 0.62 mmol) was hydrogenated in methanol (50 ml) and acetic acid (3 ml) using palladium/charcoal (10%) as a catalyst. The solvent was evaporated and the residue solved in water and lyophilized to give 287 mg of the desired product (88%). MS m/z: 295.4 (M+H)+.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]4[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=4)=[CH:18][C:12]=3[N:11]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:18][C:12]=2[N:11]=1
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCCN3C(=O)c4ccccc4C3=O)nc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCCN)nc2c1
Temperature: 25 °C
Yield: 3.3 %

Procedure:
0.54 g (1 26 mmol) of 6-[2-(4-phthalimidobutyl)-1H-benzimidazol -5 yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 0 3 ml (6.3 mmol) of hydrazine hydrate are boiled in 20 ml of ethanol for 2 hours. After cooling to room temperature, the solution is filtered, the filtrate is concentrated by evaporation under vacuum and the residue is taken up with 10 ml of 2N hydrochloric acid. The resulting solution is again filtered and is then adjusted to pH 11 with 3N sodium hydroxide solution and concentrated by evaporation to half its original volume. On cooling in an ice bath, a colorless solid crystallizes, which is recrystallized from ethanol. 0.26 g (69%) of crystals are obtained which melt at 185° to 187° C. and resolidify but thereafter do not melt until heated to 280° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:26][C:27](Br)=[O:28].[NH2:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1>>[CH3:24][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:26][C:27]([NH:30][CH:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32]2)=[O:28])=[CH:22][CH:23]=1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)NCC2
Reactant: NC1CCc2ccccc21
Product: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:19][C:20](=[O:34])[CH2:21][O:22][C:23]1[CH:32]=[CH:31][C:30]([SH:33])=[C:29]2[C:24]=1[CH2:25][CH2:26][CH2:27][O:28]2>>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:33][C:30]3[CH:31]=[CH:32][C:23]([O:22][CH2:21][C:20]([OH:34])=[O:19])=[C:24]4[C:29]=3[O:28][CH2:27][CH2:26][CH2:25]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCCO2
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(C(F)(F)F)cc3)on2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 42C and (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester. mp 112-113° C.; MS m/z 480 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:33](O)=[O:34])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]([CH:39]=O)[CH3:38]>C1COCC1>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:24]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:33]([NH:8][C:14]2[CH:15]=[CH:16][C:17]([CH2:39][N:37]([CH3:36])[CH:38]3[CH2:27][CH2:26][O:25][CH2:22][CH2:21]3)=[CH:18][CH:13]=2)=[O:34])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In THF (5 ml) was dissolved 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3 g). Under ice-cooling, to the solution were added oxalyl (0.11 ml) and DMF (catalytic amount). The mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure. In THF (25 ml) was dissolved the residue, the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.15 g) and triethylamine (0.44 ml) in THF (10 ml), under ice-cooling. The mixture was stirred at room temperature under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 33) (0.26 g) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([S:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C)C(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([S:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)(=[O:25])=[O:26])=[CH:23][C:17]=1[O:16][CH3:15])=[O:5]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1cc(S(=O)(=O)c2ccncc2)ccc1N
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1cc(S(=O)(=O)c2ccncc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.35 g) in N,N-dimethylacetamide (20 mL) was rapidly added thionyl chloride (1.01 g) and the mixture (a precipitate formed after a few minutes) was stirred at -15 to -5° C. for 1 hour. 2-Methoxy-4-(4-pyridylsulfonyl)aniline (1.50 g) was then added in one portion and the mixture allowed to stir at room tmmperature overnight. The solution was poured into ice water (200 mL) and the resulting tan solid was collected and recrystallized from absolute ethanol to yield the title compound as a white solid (1.58 g); mp 220-222° C.; MS: 405(M+1); NMR (250 MHz): 1.53 (s,3,), 4.02 (s,3), 7.62 (d,1, J=1.9), 7.68 (dd,1, J=1.9, J=8.5), 7.92-7.95 (m,2,), 8.02 (s,1,), 8.46 (d,1, J=10) 8.80-8.89 (m,2,), 9.90 (s,1). Analysis for C16H15F3N2O5S: Calculated: C, 47.53; H, 3.74; N, 6.93; Found: C, 47.56; H, 3.77; N, 6.76.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:30][C@H:31]1[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[NH:33][C:32]1=[O:39]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:30][C@H:31]1[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[NH:33][C:32]1=[O:39])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1N
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -2.5 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-alanine (1.604 g, 7.188 mmole) and triethylamine (799 mg, 7.91 mmole) in dichloromethane (30 ml), ethyl chloroformate (738 mg, 6.83 mmole) was added at -15° C. The reaction mixture was stirred at -10 to 5° C. for 1.5 hrs. Then a precooled (ca. -15° C.) solution of (3S,4S)-3-amino-4-acetoxy-azetidin-2-one in ethyl acetate (see above) was added at -15° C. and the resulting mixture was stirred at 0° C. to room temperature for 2 hrs. After removal of solvent, the residue was dissolved in ethyl acetate, washed with cold saturated NaHCO3 solution, water, brine and dried over sodium sulfate. After removal of solvent, the residue was recrystallized from dichloromethane and (3S,4S)-3-(N-benzyloxycarbonyl-L-alanyl) amino-4-acetoxy-azetidin-2-one was obtained (1.36 g, 54% yield).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:6]([NH:13][C:14](=[O:16])[CH3:15])=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=1)#[N:4].Br[CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CS(C)=O>[NH2:4][C:3]1[C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24])[C:14](=[O:16])[CH:15]=1.[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][CH2:18][N:13]([C:6]1[C:5]([C:3]#[N:4])=[CH:10][N:9]=[C:8]([S:11][CH3:12])[N:7]=1)[C:14](=[O:16])[CH3:15])([CH3:28])([CH3:27])[CH3:26]
Reactant: CSc1ncc(C#N)c(NC(C)=O)n1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ncc(C#N)c(N(CCCO[Si](C)(C)C(C)(C)C)C(C)=O)n1
Product: CSc1ncc2c(N)cc(=O)n(CCCO[Si](C)(C)C(C)(C)C)c2n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 468 mg) was added portionwise, at RT, under argon atmosphere, to a solution of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide (2.03 g, 9.75 mmol) in anhydrous DMSO (20 mL) and the resulting mixture was stirred at RT for 40 min. (3-Bromopropoxy)-tert-butyldimethylsilane (3.39 mL, 14.63 mmol) was then added dropwise over a period of 2 min at RT and the reaction mixture was stirred for 2 h. The resulting mixture was then heated at 85° C. for 2 h; a second portion of NaH (60% suspension in mineral oil, 78 mg) was then added and was followed after 30 min by (3-bromopropoxy)-tert-butyldimethylsilane (0.45 mL). The resulting mixture was heated at 85° C. for 1 h, cooled and quenched with water. The resulting mixture was extracted with EtOAc (3×50 mL); the combined organic layers were washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography to afford 800 mg (22% yield) of 5-amino-8-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one and 600 mg of uncyclized N-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide which was converted in the title compound by treatment with lithium bis(trimethylsilyl)amide as described in Preparation 2 Step C.
Reaction SMILES: [CH2:1]([N:12]1[CH:19]=[C:18]([CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[N:25][CH:26]=2)[C:16](=[O:17])[NH:15][C:13]1=[S:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(C(C)C)CC)(C)C.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([N:12]1[CH:19]=[C:18]([CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[N:25][CH:26]=2)[C:16](=[O:17])[N:15]=[C:13]1[S:14][CH2:44][C:43]1[CH:46]=[CH:47][C:40]([F:39])=[CH:41][CH:42]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCCCCCCCCCn1cc(Cc2cnc(OCC)nc2)c(=O)[nH]c1=S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCn1cc(Cc2cnc(OCC)nc2)c(=O)nc1SCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 1-undecyl-5-(2-ethoxypyrimidin-5-ylmethyl)-2-thiouracil (5.0 g) and diisopropylethylamine (2.1 ml) in dry methylene chloride (200 ml) was added 4-fluorobenzyl bromide (1.5 ml) and the mixture stirred under argon at room temperature for 20 h. The solution was washed with 5% aqueous sodium bicarbonate and the organic layer was added directly to a silica gel column (200 g). Elution with ethyl acetate to 5% methanol in ethyl acetate gave the desired product (2.7 g). 1H-NMR (CDCl3) δ0.8-0.95 (3H,m), 1.15-1.4 (16H,m), 1.43 (3H,t), 1.55-1.8 (2H,m), 3.68 (2H,s), 3.71 (2H,t), 4.41 (2H,q), 4.47 (2H,s), 6.86 (1H,s), 6.9-7.1 (2H,m), 7.3-7.45 (2H,m), 8.45 (2H,d); MS (APCI+) found (M+1)=527; C29H39FN4O2S requires 526.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([O:27][CH2:28][C:29]([O:31]C)=[O:30])[CH:21]=[CH:20]3)=[CH:15][N:16]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([O:27][CH2:28][C:29]([OH:31])=[O:30])[CH:21]=[CH:20]3)=[CH:15][N:16]=1
Reactant: COC(=O)COc1ccc2cc(-c3cnc(Cc4ccc5ccccc5c4)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2cc(-c3cnc(Cc4ccc5ccccc5c4)o3)ccc2c1
Yield: 98.7 %

Procedure:
A mixture of methyl ({6-[2-(2-naphthylmethyl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (184 mg, 0.433 mmol), prepared in the previous step, and 1N NaOH (650 μL, 0.65 mmol) in 10 mL of THF, 10 mL of methanol and 5 mL of H2O was refluxed for 2 h. The reaction was acidified by the addition of 700 μL of 1N HCl and then concentrated under reduced pressure to remove the THF and methanol. The white solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (175 mg, 99%) as a white solid, mp 258-260° C. Elemental Analysis for C26H19NO4+0.20 H2O Calc'd: C, 75.61; H, 4.73; N, 3.39. Found: C, 75.41; H, 4.91; N, 3.22
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>C(Cl)Cl.[OH-].[Na+]>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10])(=[O:11])=[O:10]
Reactant: NCCCCN
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)NCCCCNS(=O)(=O)c2c(C)cc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
2-Mesitylenesulfonyl chloride (54.40 g, 0.249 mol) in CH2Cl2 (300 ml) was added to 1,4-diaminobutane (11.34 g, 0.129 mol) in 1 N NaOH (300 ml) at 0° C., and the biphasic mixture was stirred for 24 hours at room temperature. Organic solvent was evaporated and 2.4 N HCl (250 ml) was added to the combined portions. Solid was filtered, washed with water (250 ml) and recrystallized from aqueous ethanol to give 50.46 g (90%) of (1) as needles: mp 156.5-157.5° C.; NMR (CDCl3/TMS) δ1.36-1.60 (m, 4H), 2.27 (s, 6H), 2.57 (s, 12H), 2.69-2.96 (m, 4H), 4.65 (t, 2H, J=6), 6.89 (s, 4H). Anal. calcd. for C22H32N2O4S2: C—58.38, H—7.13, N—6.19. Found: C—58.31, H—7.19, N—6.14.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]#[C:24][C:25](O)=[O:26].ClCCl.C(O)C.N>>[ClH:15].[CH2:13]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:25](=[O:26])[C:24]#[C:23][C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])=[CH:10][CH:11]=1)[CH3:14]
Reactant: O=C(O)C#Cc1ccc(Cl)cc1Cl
Reactant: CCN(CC)CCc1ccc(N)cc1
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: CCN(CC)CCc1ccc(NC(=O)C#Cc2ccc(Cl)cc2Cl)cc1
Product: Cl

Procedure:
Prepared analogously to Example 2.3.f. from 4-(2-diethylaminoethyl)phenylamine and (2,4-dichlorophenyl)propynoic acid. Yield: 0.3 g (47% of theory); melting point: 204° C.-208° C.; C21H22Cl2N2O (M=425.78); calc.: molecular ion peak (M+H)+: 389/391/393; found: molecular ion peak (M+H)+: 389/391/393; Rf value: 0.6 (silica gel, dichloromethane/ethanol/ammonia (5:1:0.01)).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[NH2:1][C@H:2]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](O)[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
L-threonine 21.2 g (178 mmol) was dissolved in toluene (100 mL), and benzyl alcohol (100 mL, 966 mmol) and p-toluenesulfonic acid monohydrate (35.0 g, 194 mmol) were added, followed by heating to reflux for 17 hours under nitrogen atmosphere. After cooling to room temperature, water (200 mL) was added, followed by washing three times with ethyl acetate (100 mL). To the aqueous layer, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out three times with ethyl acetate (100 mL). After the organic layer was washed with saturated brine, drying was carried out over anhydrous magnesium sulfate, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-15%) to afford the desired product (10.6 g, yield 28%) as a white solid.
Reaction SMILES: [Br:1]Br.[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=1>CC(O)=O>[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([Br:1])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: N[C@H](CNc1cccc(-c2ccncc2)n1)Cc1ccccc1
Solvent: CC(=O)O
Product: N[C@H](CNc1ccc(Br)c(-c2ccncc2)n1)Cc1ccccc1
Reaction time: 1 h

Procedure:
A mixture of bromine (1.6 gm, 10 mmole) and HOAc (10 mL) was added in three portions to a stirred solution of 6-((S)-2-Amino-3-phenylpropylamino)-2-(4-pyridyl)pyridine (3.04 gm, 10 mmole) in HOAc (20 mL) at rt. After 1 hr, the mixture was concentrated and purified (SiO2, CH2Cl2/MeOH/NH4OH: 100/11/8) to give 6-((S)-2-Amino-3-phenylpropylamino)-3-bromo-2-(4-pyridyl)pyridine. MS (m/z): Calcd. C19H19N4Br (M+): 383, found : 383.1 and 385.1.