Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1.[CH:23]([CH:25]=[CH2:26])=O.C([N:29](CC)CC)C.O>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23](/[CH:25]=[CH:26]/[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:4]([CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[C:5]2[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=2)=[CH:15][CH:16]=1)#[N:29]
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Reactant: C=CC=O
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(/C=C/C#N)cc1)c1ccnc(C#N)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 638.2 %

Procedure:
4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile (0.1 g, 0.2 mmoles), acrolein (0.02 ml, 0.3 mmoles), and triethylamine (0.04 ml, 0.3 mmoles) are dissolved in 5 ml of acetonitrile and Pd(OAc)2 (2.6 mg, 0.012 mmoles) is added at rt. The mixture is stirred at 100° C. for overnight. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 423 mg of desired 4-[[4-((E)-2-cyano-vinyl)-benzyl]-(2,2-dimethyl-propyl)-amino]-pyrimidine-2-carbonitrile in 45% yield.
Reaction SMILES: [C:1]([C@H:4]([C@@H:14]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]([NH:17][N:18]1[C:22](=[O:23])[CH2:21][N:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:19]1=[O:29])=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(O)=[O:2].[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.C(OCC)(=O)C.Cl.C(N=C=NCCCN(C)C)C>[CH2:34]([O:41][NH:42][C:1]([C@H:4]([C@@H:14]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]([NH:17][N:18]1[C:22](=[O:23])[CH2:21][N:20]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:19]1=[O:29])=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:2])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(CCN(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(CCN(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
A solution of 0.151 g of 2(R)-[1(S)-(carboxy)-4-phenylbutyl]-N-[3-[2-(dimethylamino)ethyl]-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide and 0.157 g of O-benzylhydroxylamine in 0.25 ml of dimethylformamide was treated with 0.054 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give a residue which was purified by flash column chromatography on silica gel, using methanol/dichloromethane (5:95) for the elution, to give 0.061 g of 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-N-[3-[2-(dimethylamino)ethyl]-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide in the form of a white foam.
Reaction SMILES: [F:1][CH:2]([F:11])[C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C1COCC1.CO.O>[F:1][CH:2]([F:11])[C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)[C@@H]1CC[C@H]1C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CC[C@H]1C(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.6 %

Procedure:
To a solution of Intermediate 238B (200 mg, 1.218 mmol) in THF (1 mL), MeOH (0.3 mL) and water (1 mL) was added NaOH (97 mg, 2.437 mmol) and the resulting solution was stirred at RT for 12 h. The volatiles were removed under reduced pressure and the residue was added water and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 4 using an aqueous solution of 1.5 N HCl and the compounds were extracted with EtOAc (3×10 mL). The combined organic layer was dried on Na2SO4, filtered and filtrate evaporated under reduced pressure to afford Intermediate 238C as a viscous liquid (120 mg, 65.6% yield). The crude product was taken further without any purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.24 (bs, 1H), 5.87-6.21 (m, 1H), 3.03 (q, J=8.85 Hz, 1H), 2.89 (dd, J=8.82, 4.05 Hz, 1H) 1.94-2.14 (m, 2H) 1.79-1.94 (m, 2H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 22 mg, 0.55 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (135 mg, 0.56 mmol) in THF (1.0 mL) at 0° C. After 1 h at 0° C., [(Z)-4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester (150 mg, 0.56 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 16.5 h at rt, the reaction was quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30%→60% EtOAc/CH2Cl2, gradient) afforded 91 mg (42%) of the title compound.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si](C)(C)C.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Mg].Br>O1CCCC1.C1(C)C=CC=CC=1>[Br-:20].[C:1]1([S+:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1
Agent: Br
Agent: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: [Br-]
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Yield: 67.9 %

Procedure:
In 600 ml of tetrahydrofuran were dissolved, 21.1 g (0.1 mol) of diphenylsulfoxide under nitrogen atmosphere, then 27.2 g (0.25 mol) of chlorotrimetylsilane was poured into them. A Grignard reagent prepared from 39.3 g (0.25 mol) of bromobenzene and 6.1 g of magnesium metal in accordance with the conventional manner was added dropwise thereto under ice-cooling, followed by allowing to react at the same temperature for 3 hours. After completion of the reaction, 500 ml of 24% aqueous solution of hydrobromic acid was added dropwise to the reaction solution at 0 to 5° C., and then 600 ml of toluene was poured into them, followed by stirring and separation, the organic layer was extracted twice with 120 ml of 12% aqueous solution of hydrobromic acid, and the resulting aqueous layers were combined and extracted 3 times with 480 ml of methylene chloride. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 23.3 g (yield: 68%) of triphenylsulfonium bromide as a white crystal.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45])#[N:40]>C(Cl)Cl>[C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:45])#[N:40]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)N2CCN(c3ccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (0.318 g) in CH2Cl2 (15 mL) containing Et3N (79 mg) was added dropwise 3-cyano-benzoyl chloride (0.129 g) and the mixture was stirred at room temperature for 1 hour. The solution was then washed with water, with brine, dried over Na2SO4, filtered and evaporated. The residue was then purified by flash chromatography eluting with CH2Cl2/AcOEt (80/20) and the solid obtained was recrystallized from AcOEt to give the title compound (0.29 g) as white crystals.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][CH:26]=[O:27])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:25][CH:26]([OH:27])[CH3:32])[CH2:28][CH3:29])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC=O)C1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(C)O)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal (540 mg, 1.18 mmol; Example 130, Step A) in THF (12 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (2.52 mL, 3.53 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 3 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the crude title compound as a mixture of diastereomers.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH2:15]O>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH2:15][Br:2]
Reactant: COc1cc(CO)c(Br)cc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1cc(CBr)c(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
Phosphorus tribromide (11.56 mL, 122.5 mmol) was added to a solution of (2-bromo-4-fluoro-5-methoxy-phenyl)-methanol (Preparation 33, 14.4 g, 61.26 mmol) in DCM (235 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred at that temperature for 18 hours. The reaction mixture was cooled to 0° C. and quenched by slow addition of saturated sodium hydrogen carbonate aqueous solution until effervescence had ceased. The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (17.48 g) in a 96% yield.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-:16].[K+].[K+]>CN(C)C=O>[Br:11][CH2:12][CH2:13][O:16][C:6]1[CH:5]=[CH:4][C:3]([C:8](=[O:10])[CH3:9])=[CH:2][CH:7]=1
Reactant: BrCCBr
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccccc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCBr)cc1
Temperature: 50 °C
Yield: 39.3 %

Procedure:
A mixture of 1-(hydroxyphenyl)ethanone (2.72 g, 20.0 mmol), 1,2-dibromoethane (7.676 g, 40.0 mmol), and potassium carbonate (5.52 g, 40 mmol) in dried dimethylformamide (40 mL) was heated at 50° C. overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (SiO2, 20-70% ethyl acetate/hexane) to provide the title compound (1.91 g, 39% yield): 1H NMR (CDCl3) 7.95 (t, 2H), 6.95 (t, 2H), 4.36 (t, 2H), 3.67 (t, 2H), 2.57 (s, 3H); ES-MS (m/z) 243 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccccc3Cl)cc21

Procedure:
6-(2-Chloro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 4 from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 2-chlorophenyl boronic acid, as a white solid: mp 181-182° C.; MS (ESI) m/z 288 ([M+H]+, 70%); Anal. Calcd. For C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87. Found: C, 66.78; H, 4.82; N, 4.55.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=4)=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:32][C:28]1[CH:27]=[C:26]([NH:25][C:23]2[O:24][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)=[CH:15][CH:16]=3)=[CH:21][N:22]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Clc1cccc(Nc2ncc(-c3ccc(C4=CCNCC4)cc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[2-(3-chlorophenylamino)-oxazol-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.5 g, 5.5 mmol) in MeOH (1 mL) is added 4M HCl in dioxane (3 mL) and the mixture is stirred at RT for 2 h. It is concentrated and used in the next step as the bis HCl salt: (M+H)+352.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][C:10]1=[O:21])[CH:6]=O.[NH2:22][CH:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=3[CH:38]=2)[C:25](=[O:39])[CH2:24]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][CH:5]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][C:10]1=[O:21])[CH2:6][NH:22][CH:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=3[CH:38]=2)[C:25](=[O:39])[CH2:24]1
Reactant: COCOC(C=O)Cn1c(=O)cnc2ccc(OC)cc21
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCOC(CNC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1)Cn1c(=O)cnc2ccc(OC)cc21
Temperature: 25 °C
Yield: 64.6 %

Procedure:
2-(Methoxymethoxy)-3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (0.340 mmol) and 6-(4-amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 84 mg, 0.340 mmol) were dissolved in a mixed solvent of dichloromethane/N,N-dimethylformamide (10:1,11 ml). Acetic acid (0.039 ml, 0.680 mmol) and anhydrous sodium sulfate (200 mg) were added to this solution, and the mixture was stirred at room temperature for two and a half hours. Sodium triacetoxyborohydride (144 mg, 0.680 mmol) was added thereto, the mixture was stirred for 14 hours and then the solvent was removed under reduced pressure. Chloroform was added to the residue, the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 115 mg (65%) of the title compound in the form of a colorless clear oily product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[N:6]=C(C)[O:8][C:4]=2[CH:3]=1.[CH2:13]([N:31]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39]([Cl:42])(=[O:41])=[O:40])[CH:34]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>N1C=CC=CC=1.ClCCl>[ClH:42].[NH2:6][C:5]1[C:4]([OH:8])=[CH:3][C:2]([NH:1][S:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([C:32](=[O:43])[N:31]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:34]=2)(=[O:41])=[O:40])=[C:11]([CH3:12])[CH:10]=1
Reactant: Cc1nc2cc(C)c(N)cc2o1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cc(O)c(N)cc2C)c1
Product: Cl
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a stirred solution of 6-amino-2,5-dimethylbenzoxazole (14.8 g, 0.1 mol) in 100 ml of pyridine and 500 ml of dichloromethane was added N,N-dioctadecyl-3-chlorosulfonylbenzamide (72.4 g, 0.1 mol). The mixture was stirred overnight and then washed with water, 10 percent aqueous hydrochloric acid and again with water. To the organic layer was added 10 ml of hydrochloric acid, 300 ml of water and 1000 ml of THF. The mixture was stirred overnight and the precipitate collected, washed with acetonitrile and nearly dried. The damp filter cake was placed in 2 liters of THF and 50 ml of concentrated hydrochloric acid and refluxed 2 hours. The mixture was concentrated to an oil and triturated with one liter of acetonitrile to yield 77.5 g (90 percent) of the product.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28])[CH:17]=1.C(N(CC)CC)C.CN(C=O)C>O>[C:32]([O:31][C:30]([NH:29][C@@H:27]([CH3:28])[CH2:26][O:25][C:18]1[CH:17]=[C:16]([S:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(=O)OC(C)(C)C)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A mixture of 2-ethylhexyl 3-sulfanylpropanoate (2.17 g), tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (3.00 g), triethylamine (1.39 mL) and DMF (30 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.50 g). MS (ESI+): [M+H]+ 514.3.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#N)=[CH:5][CH:4]=1.[H-].[Na+].CI.[CH2:18](OC(=O)C)C.C[N:25]([CH:27]=O)C>CCCCCC.O>[CH3:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)([CH3:18])[C:27]#[N:25]
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Solvent: O
Product: CC(C)(C#N)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
(4-Trifluoromethyl-phenyl)-acetonitrile (1 g, 5.4010 mmol) in DMF (8.1 mL) was added to a stirred mixture of NaH (518.49 mg, 21.604 mmol) in DMF (8.1 mL) at 0° C. This was followed by the addition of methyl iodide (3.3 mL, 54.0102 mmol) and the resulting mixture was heated to 80° C. for 3 hours. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was diluted with cold water and extracted with diethyl ether. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 1.2 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[C:27](OC(=O)C)(=O)[CH3:28]>CN(C=O)C.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[CH:10]([OH:20])[C:3]3[C:2](=[C:7]([CH3:8])[C:6]([OH:9])=[CH:5][CH:4]=3)[O:1][C:27]=2[CH3:28])=[CH:13][CH:14]=1
Reactant: COc1ccc(CC(=O)c2ccc(O)c(C)c2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(C)Oc3c(ccc(O)c3C)C2O)cc1
Reaction time: 5 h

Procedure:
To a solution of 1-(2,4-dihydroxy-3-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone (1 eq) in anhydrous DMF was added K2CO3 (3 eq). Acetic anhydride (3 eq) was added dropwise to the solution, which was then refluxed, under nitrogen whilst stirring for 5 h. The solution was taken up in water and extracted using ethyl acetate, dried over MgSO4 and concentrated in vacuo to give 3-(4-methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol as a yellow solid.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].[OH:11]C1C=C(C=CC=1)C#N.P(S)(OCC)(OCC)=S>O>[OH:11][C:7]1[CH:2]=[C:3]([C:8](=[S:10])[NH2:9])[CH:4]=[CH:5][CH:6]=1
Reactant: NC(=S)c1ccccc1O
Reactant: N#Cc1cccc(O)c1
Agent: CCOP(=S)(S)OCC
Solvent: O
Product: NC(=S)c1cccc(O)c1
Yield: 57 %

Procedure:
The procedure used for the preparation of 3a was repeated with 3-hydroxybenzonitrile (5.48 g, 46.1 mmol), (EtO)2P(S)SH (7.72 mL, 46.1 mmol) and water (9.2 mL) at 80° C. for 36 hr to give 3d (4.04 g, 57%) as a yellow solid after chromatographic purification on silica gel (gradient EtOAc/CH2Cl2 : 6-12%) and crystallization from EtOAc/hexane. mp 139.0°-140.0° C.; IR (KBr) 3340, 3280, 3165, 1629, 1590, 1462 cm-1 ; 1H NMR (DMSO-d6) δ6.83 (1H, br d, J=7.0 Hz, Ar), 7.10-7.25 (2H, m, Ar), 7.27 (1H, s, Ar), 9.33 (1H, br s, NH), 9.58 (1H, s, OH), 9.72 (1H, br s, NH); FDMS m/z 153 (M+); Anal. Calcd for C7H7NOS: C, 54.88; H, 4.60; N, 9.14. Found: C, 55.01; H, 4.53; N, 9.02.
Reaction SMILES: I[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[C@H:5]([F:16])[C@@H:4]1[OH:17].[OH-].[NH4+].[H][H]>C(O)C.[Pd]>[F:16][C@@H:5]1[C@H:4]([OH:17])[C@@H:3]([CH3:2])[O:7][C@H:6]1[N:8]1[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]
Reactant: O=c1ccn([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](F)[C@@H]1O
Reaction time: 5 h

Procedure:
2′,5′-Dideoxy-5′-iodo-2′-fluorouridine (2.9, 8.1 mmoles) was dissolved in 95% ethanol (25 mL). Ammonium hydroxide (1.1 mL, 16.2 mmoles, 2 eq.) was added followed by 10% Pd/C (Aldrich, 0.1 g). Reaction under 50 psi hydrogen was carried out for 5 hours. The mixture was filtered and the pH adjusted to 7 with 1N HCl. The solvents were removed in vacuo and the residue dissolved in water. The product was extracted with ethyl acetate (3×). The ethyl acetate solution was dried with MgSO4, filtered, and the solvent removed in vacuo. The residue was purified by chromatography on 100 g of silica gel eluted with ethyl acetate. The product containing fractions were combined and the solvents removed in vacuo. The yield was 1.1 g, 58%. MS (APCl(−)): m/z (rel. intensity) 229 (100%, M−); 1H NMR (DMSO-d6) δ7.54 (d, 1H, H6, J=8 Hz), 5.76 (d, 1H, H-1′, J=22 Hz), 5.59 (d,1H, H5, J=8 Hz), 5.55 (d, 1H, OH, J=6 Hz), 5.05 (d, 1H, H-2′, J=53 Hz), 3.8 (m, 2H), 1.27 (d, 3H, H-5′, J=6 Hz).