Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=NC([N:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:11]3[N:10](CCOC)[C:9]2=[O:20])=NC=1.[C:21]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])#[CH:22]>>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[C:21]1[C:12]([C:11]#[CH:15])=[N:8][C:9]([CH:14]2[CH2:15][CH:11]3[NH:10][C:9](=[O:20])[NH:8][CH:12]3[CH2:13]2)=[N:10][CH:22]=1
Reactant: COCCN1C(=O)N(c2ncc(Br)cn2)C2CCCC21
Reactant: C#Cc1cc(F)ccc1F
Product: C#Cc1nc(C2CC3NC(=O)NC3C2)ncc1-c1cc(F)ccc1F

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 5 starting from (rac)-1-(5-bromopyrimidin-2-yl)-3-(2-methoxy-ethyl)-hexahydro-cyclopenta[d]imidazol-2(1H)-one (Example 5, step 3) and 1-ethynyl-2,5-difluorobenzene to yield racemic material ((+/−)-(3aRS,6aSR)-1-(2-methoxy-ethyl)-3-(5-(2,5-difluoro-phenyl-ethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as a light brown solid; MS: m/e=399.2 (M+H+). Separation using chiral HPLC and similar separation conditions as described in example 1 yielded the enantiomerically pure enantiomers (−)-(3aR,6aS)-1-(2-methoxy-ethyl)-3-(5-(2,5-difluoro-phenylethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as an off-white solid; MS: m/e=399.2 (M+H+) and (+)-(3aS,6aR)-1-(2-methoxy-ethyl)-3-(5-(2,5-difluoro-phenylethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as a light yellow oil which solidified on standing; MS: m/e=399.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:17]1([CH3:29])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.Cl>[CH3:29][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:14][CH:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([F:1])([F:15])[F:16])(=[O:26])=[O:27]
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3ccccc23)C(F)(F)F)c(C)c1
Temperature: 45 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A mixture of 42 mg (0.18 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 45 mg, 0.21 mmol) of mesitylenesulfonyl chloride in 0.5 mL of pyridine was warmed to 45° C. The reaction was monitored by thin layer chromatography (ethyl acetate-hexanes (3:7)) indicating a new less polar product compared to the amine. After 6 hours, the mixture was cooled and diluted with 7 mL of 1 N aqueous HCl and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 5 mL portions of 1 N aqueous HCl, 5 mL of brine, and three 5 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 62 mg (82.1%) of crude solid. The crude material was adsorbed onto silica gel and chromatographed on silica gel using dichloromethane-hexanes (gradient: 50%-100%). The material from the column was crystallized from ether-hexanes to afford 52 mg (67%) of the title compounds as a white solid, m.p. 189° C.-191° C.; MS: m/z 409.15 (M−).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.N#N.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:13]([OH:18])[OH:14])[CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCCCc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
This compound was prepared according to the procedure described by Watson, I.D.G.; Ritter, S.; Toste, F.D. J. Am.Chem.Soc. 2009, 131, 2056-2057. 1-Bromo-2-(pent-4-en-1-yl)benzene (480 mg, 2.132 mmol) was dissolved in a mixture of toluene (8 mL) and THF (2 mL). Then triisopropyl borate (0.490 mL, 2.132 mmol) was added. While under N2 atmosphere, the reaction mixture was cooled to −78° C. Using a manual syringe, n-butyllithium (0.853 mL, 2.132 mmol)(2.5 M in hexanes) was added dropwise over the course of 30 min. The resulting nearly colorless solution was stirred at −78° C. for 60 min and then at −20° C. for 15 min. The reaction was quenched with 10 mL of 2 N HCl and allowed to stir to warm to rt. The aqueous layer was extracted with ether. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. Biotage purification eluting with 5-50% EtOAc/hexanes gave the desired product (65 mg, 0.342 mmol, 16.04% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.27-8.18 (m, 1H), 7.51 (td, J=7.5, 1.4 Hz, 1H), 7.36-7.31 (m, 2H), 5.90-5.80 (m, 1H), 5.04-4.91 (m, 2H), 3.26-3.18 (m, 2H), 2.18 (q, J=6.9 Hz, 2H), 1.83 (dt, J=15.3, 7.7 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[N:19]2)=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:25]([O:24][C:22]([C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([NH:11][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])[CH:21]=2)=[O:23])[CH3:26]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3Br)ccc2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 2-Bromobenzoyl chloride (5.38 g, 24.5 mmol) in 100 ml chloroform was added dropwise at room temperature to a solution of ethyl 7-aminoquinoline-3-carboxylate (2.65 g, 12.25 mmol), 4-N,N-dimethylaminopyridine (150 mg, 1.23 mmol) and pyridine (3.96 ml, 49 mmol) in 100 ml chloroform. The resulting solution was heated under reflux for 4 hr, then cooled to room temperature. The chloroform solution was then washed sequentially with dilute aqueous hydrochloric acid solution, water and brine, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was chromatographed on silica gel, eluting with 60:40 hexane/ethyl acetate to yield the title product as a solid foam (2.45 g 50% yield).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:22])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:22]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCN=[N+]=[N-])O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCN)O2)c(=O)[nH]c1=O

Procedure:
A solution of 0.28 of 5'-(2-azidoethyl)-2',5'-dideoxy-5-ethyluridine in 50 ml of ethanol was hydrogenated over 50 mg of 10% palladium-on-carbon catalyst for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness to give 0.23 g of 5'-(2-aminoethyl)-2',5'-dideoxy-5-ethyluridine in the form of a colorless oil which crystallized upon standing.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([O:35][CH2:36][CH3:37])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][N:16]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:17](=[O:18])[N:16]([CH2:15][C:12]1([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH:4]([O:35][CH2:36][CH3:37])[C:3]([OH:38])=[O:2])=[CH:11][CH:10]=2)[CH2:13][CH2:14]1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1)C(=O)Nc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)O)cc2)CC1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
A solution of 3-(4-{1-[3-(2,4-difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid methyl ester (50 mg, 0.094 mmol) and 1 M LiOH (0.283 mmol, 0.283 mL) in tetrahydrofuran (1 mL) was allowed to stir at room temperature for 18 hours. 2 N HCL was then added until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-{1-[3-(2,4-difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid as a clear oil (29.6 mg, 61%).
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][N:15]([CH2:17][CH2:18][C@@H:19]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:20][N:21]([CH3:35])[C:22](=[O:34])[C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Br:33])[CH:24]=4)[CH2:14]3)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.N1CC(N2CCC([C:53](N3CCOCC3)=[O:54])CC2)C1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[Br:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=1)[C:22]([N:21]([CH2:20][C@H:19]([C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)[CH2:18][CH2:17][N:15]1[CH2:14][CH:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:5]([N:1]3[CH2:4][CH2:3][O:54][CH2:53][CH2:2]3)=[O:6])[CH2:12][CH2:11]2)[CH2:16]1)[CH3:35])=[O:34]
Reactant: O=C(C1CCN(C2CNC2)CC1)N1CCOCC1
Reactant: CN(C[C@@H](CCN1CC(N2CCC(C(=O)N3CCC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C[C@@H](CCN1CC(N2CCC(C(=O)N3CCOCC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1; 0.14 g, 0.31 mmol) and 4-[(1-azetidin-3-ylpiperidin-4-yl)carbonyl]morpholine (see method 5; 0.11 g, 0.42 mmol) were dissolved in methylene chloride (10 mL) together dry methanol (0.2 mL). To the resultant solution were added DIPEA (0.12 g, 0.94 mmol) and sodium triacetoxyborohydride (0.13 g, 0.63 mmol). The mixture was stirred under nitrogen for 4 h at RT. The mixture was diluted with methylene chloride and washed twice with saturated aqueous NaHCO3 and then with brine. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-methylene chloride, 10:1). There was obtained 0.11 g (53%) of the title compound as a white foam. 1H NMR (500 MHz, CDCl3): δ 1.4-3.8 (cm, 32H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 684 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[N:4]([CH2:12][C:13]([CH3:15])=O)[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[Cl-].[OH:22][NH3+:23].C(N(CC)CC)C>C(O)C.C(Cl)Cl>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[N:4]([C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6])[CH2:12][C:13](=[N:23][OH:22])[CH3:15]
Reactant: CC(=O)CN(C(=O)c1ccco1)c1c(C)cccc1C
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CC(CN(C(=O)c1ccco1)c1c(C)cccc1C)=NO
Yield: 85.2 %

Procedure:
27.1 g (0.1 mol) of 2,6-dimethyl-N-acetonyl-N-(2-furoyl)-aniline, 14 g (0.2 mol) of hydroxyammonium chloride and 15 ml of triethylamine in 150 ml of ethanol were heated under reflux for 3 hours. The reaction mixture was then largely freed from solvent in vacuo, the residue was taken up in methylene chloride and the methylene chloride mixture was washed with water, dried over sodium sulphate and concentrated. The crystalline residue was triturated with ether and the solid was filtered off. 24.4 g (85% of theory) of 2,6-dimethyl-N-(2-furoyl)-N-(2-hydroxyimino-prop-1-yl)-aniline of melting point 155°-156° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[C:12]([C:14]#[N:15])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1Br.[F:18][C:19]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[NH2:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([NH:29][C:20]2[CH:21]=[CH:22][C:23]([Si:25]([CH3:27])([CH3:26])[CH3:28])=[CH:24][C:19]=2[F:18])[C:4]([C:3]([O:2][CH3:1])=[O:17])=[CH:13][C:12]=1[C:14]#[N:15]
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Reactant: COC(=O)c1cc(C#N)c(C(=O)OC)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(Nc2ccc([Si](C)(C)C)cc2F)c(C(=O)OC)cc1C#N
Yield: 59.5 %

Procedure:
2-Bromo-5-cyano-terephthalic acid dimethyl ester (620 mg, 2.1 mmol), 2-fluoro-4-trimethylsilanyl-phenylamine (419 mg, 2.3 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (62 mg, 0.10 mmol), potassium phosphate (486 mg, 2.30 mmol) and tris(dibenzylideneacetone)dipalladium (0) (29 mg, 0.05 mmol) were suspended in dioxane (20 ml) and the resultant mixture purged with argon. The reaction mixture was heated at reflux for 16 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (20 ml) and the resultant mixture extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-40% ethyl acetate in cyclohexane) to yield the title compound as a brown solid (0.5 g, 60%). LCMS (Method B): RT=4.74 min, M+H+=401.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)=[O:10])([O-:5])=[O:4].I[CH3:24].Cl>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([N:11]([CH3:24])[C:12]1[CH:13]=[C:14]([Cl:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1)=[O:10])([O-:5])=[O:4]
Reactant: CI
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cccc([N+](=O)[O-])c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% in oil, 1.1 g) in N,N-dimethylformamide (20 ml) was added dropwise a solution of 3-nitro-N-(3,5-dichlorophenyl)benzamide (5.89 g) in N,N-dimethylformamide (40 ml). The mixture was stirred at room temperature for 1 hour, then iodomethane (3 ml) was added thereto. After stirring at room temperature for 1 hour, dilute hydrochloric acid was added to the mixture and extracted with ethyl acetate twice. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was solidified with isopropyl ether to give 3-nitro-N-methyl-N-(3,5-dichlorophenyl)benzamide (4.62 g).
Reaction SMILES: [CH3:1][O-:2].[K+].F[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:6]=1[C:7]([OH:9])=[O:8].O>CO>[CH3:1][O:2][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1c(F)cccc1C(F)(F)F
Reactant: C[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cccc(C(F)(F)F)c1C(=O)O
Reaction time: 40 h

Procedure:
A mixture of potassium methylate in methanol (15 ml, 15%) and 2-fluoro-6-trifluoromethylbenzoic acid (2.08 g, 0.01 mol) is heated to reflux with stirring for 40 hours. Upon cooling to room temperature water is added. The reaction mixture is filtered and the filtrate is acidified with concentrated hydrochloric acid. The solid material is collected by filtration, washed with water and dried yielding white crystals, 1.4 g (64%), mp 130-131° C.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19](=O)([O:27]C1C=CC=CC=1)[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C)C=O>[C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19](=[O:27])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:16])=[O:17]
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1-c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Sodium hydride (2.6 g) was added to dry dimethylformamide (200 ml), and at less than 10° C., a solution of 2-phenylbenzenesulfonamide (23.3 g) in dimethylformamide (50 ml) was added. The mixture was then stirred at room temperature for 1 hour, and diphenyl carbonate (21.4 g) was added at room temperature. The mixture was further stirred at room temperature for 1 hour. Then, after the whole mixture was added to ice water, the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dehydrated, and ethyl acetate was distilled off under reduced pressure to give phenyl N-(2-biphenylylsulfonyl)carbamate (35 g) as a solidified desired compound represented by the following formula. mp. 114°-117° C. ##STR11##
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].Cl.[CH3:31][N:32]([CH3:39])[C:33]([CH:35]1[CH2:38][NH:37][CH2:36]1)=[O:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH:35]([C:33]([N:32]([CH3:39])[CH3:31])=[O:34])[CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CN(C)C(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N(C)C)C3)n(C)c2n1
Reaction time: 3 h
Yield: 78.7 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidine-3-carboxylic acid dimethylamide hydrochloride salt (53 mg, 0.32 mmol) in DCE (4 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 3 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) to afford 366 as a cream solid (107 mg, 83%). LCMS (Method G): RT=5.51 min, M+H+=504. 1H NMR (CDCl3, 400 MHz) δ 8.00 (m, 1 H); 7.75 (m, 1 H); 7.28 (m, 2 H); 4.34 (m, 4 H); 3.89-3.83 (m, 6 H); 3.83 (s, 3 H); 3.70-3.62 (m, 2 H); 3.57-3.46 (m, 3 H); 3.34 (q, J=7.5 Hz, 2 H); 2.96 (s, 3 H); 2.90 (s, 3 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:25]Br>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Clc1cc(Cl)cc(CBr)c1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Cl)cc(Cl)c2)c1
Yield: 54.2 %

Procedure:
5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (235 mg, yield: 54.2%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][CH:6]([CH3:14])[C:7](=O)[CH2:8][C:9](OC)=[O:10].C([O-])([O-])=O.[K+].[K+].Cl>O.CO>[CH:6]([C:7]1[N:4]=[C:2]([SH:3])[N:1]=[C:9]([OH:10])[CH:8]=1)([CH3:14])[CH3:5]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: NC(N)=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1cc(O)nc(S)n1
Temperature: 105 °C
Yield: 67.8 %

Procedure:
Thiourea (1.0 g, 13 mmol) was dissolved in 1.6 mL of water at 70° C. Methyl 4-methyl-3-oxopentanoate (2.8 g, 20 mmol) was added and followed by K2CO3 (2.7 g, 19 mmol). The reaction was heated at 105° C. open to air for 1 hour to boil off any remaining methanol. After being cooled to room temperature, water (6.6 mL) was added and followed by 6 mL of concentrated HCl. The white precipitate was collected by filtration and washed with water and 1 N HCl to afford 6-isopropyl-2-mercaptopyrimidin-4-ol as a white solid (1.5 g, yield: 46%). 1H NMR (400 MHz, DMSO-d6): δ 12.34 (s, 1H), 12.19 (s, 1H), 5.67 (s, 1H), 2.66 (m, 1H), 1.13 (d, J=6.8 Hz, 6H). LCMS (ESI) m/z: 171.0 [M+H+].
Reaction SMILES: Cl.[Cl:2][CH:3]([C:8]1[C:9](=[O:17])[C:10]([OH:16])=[C:11]([CH3:15])[N:12]([CH3:14])[CH:13]=1)[C:4]([F:7])([F:6])[F:5].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CO>[ClH:2].[OH:16][C:10]1[C:9](=[O:17])[C:8]([CH:3]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:4]([F:7])([F:6])[F:5])=[CH:13][N:12]([CH3:14])[C:11]=1[CH3:15]
Reactant: CN1CCNCC1
Reactant: Cc1c(O)c(=O)c(C(Cl)C(F)(F)F)cn1C
Agent: Cl
Solvent: CO
Product: Cc1c(O)c(=O)c(C(N2CCN(C)CC2)C(F)(F)F)cn1C
Yield: 41 %

Procedure:
3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(4-methylpiperazin-1-yl)ethyl]pyridin-4(1H)-one hydrochloride (Apo7063) was prepared from 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (550 mg, 1.9 mmol) and 1-methylpiperazine (3.0 mL, 27.0 mmol) was added. The reaction was stopped when analysis of the HPLC chromatogram (Method 1) of the reaction mixture complete conversion. The reaction mixture was concentrated to give a solid. To the solid was added methanol (2 mL), the mixture was vortexed and filtered. Thus, Apo7063 was obtained as a solid (280 mg). Yield=41%; HPLC Method 1, purity (AUC)=99.8% at 280 nm; 1H NMR (DMSO-D6+a few drops of D2O) δ (ppm): 7.69 (s, 1H), 4.93 (q, J=9.7 Hz, 1H), 3.70 (s, 3H), 2.60-3.40 (b, 8H), 2.69 (s, 3H), 2.29 (s, 3H); MS-ESI m/z 320 [M+1]+ (100%), 220.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[CH2:9][C@H:10]([OH:12])[CH3:11])[CH:2]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][C@@H:10]([CH2:9]/[CH:8]=[CH:7]/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH3:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](O)C/C=C/c1cccnc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C/C=C/c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol (6.00 g, 36.81 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride (21.05 g, 110.43 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 11.67 g (84.0%) of a dark-brown, viscous oil.