Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][C@@H:12]2[C:15]3[C:16]([O:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:21][C@@H:11]2[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[CH3:23][O:22][C:16]1[C:15]2[C@@H:12]3[C@@H:11]([CH2:10][NH:9][CH2:14][CH2:13]3)[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2c1[C@H]1CCN(Cc3ccccc3)C[C@H]1C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc2c1[C@H]1CCNC[C@H]1C2
Yield: 82.6 %

Procedure:
The product from Example 41 (1.80 g) was combined with 0.90 g 20% Pd/C. in 100 ml methanol and hydrogenated at 4 atm for 4 h. The reaction was filtered and evaporated to yield 1.08 g of the desired product as a white solid, mp: 140-3° C. NMR (d6DMSO) δ 1.70 (m, 1H), 2.02 (m, 1H), 2.60 (m, 1H), 2.78-3.30 (m, 7H), 3.77 (s, 3H), 6.80 (d, 1H), 6.84 (d, 1H), 7.15 (t, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2COCC[Si](C)(C)C)=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:1][N:2]([CH3:25])[C:3]1[NH:4][C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[C:6]2[C:10]([N:11]=1)=[N:9][CH:8]=[N:7]2
Reactant: CN(C)c1nc(-c2ccco2)c2ncn(COCC[Si](C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1nc2ncnc-2c(-c2ccco2)[nH]1
Yield: 76.3 %

Procedure:
A solution of N,N-dimethyl-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine-2-amine (200 mg, 0.56 mmol) in THF (5 mL) was treated with tetra-n butylammonium fluoride (1-M in THF, 0.67 mL, 0.67 mmol), refluxed for 4 h, cooled, poured into water and extracted with EtOAc. The combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2; EtOAc) to give the title compound (98 mg, 76%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3]/[N:4]=[C:5](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][Cl:17])[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].ClC1C=CC=C(C(OO)=[O:69])C=1>C1C=CC=CC=1>[CH2:1]([O:3]/[N:4]=[C:5](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:39][CH:40]=1)\[C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:13]([CH2:16][Cl:17])[CH2:14][S:15](=[O:69])[C@H:10]12)=[O:7])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: c1ccccc1
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.9 %

Procedure:
4.0 g (4.7 mmol) of benzhydryl 7-[(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate was dissolved in 40 ml of benzene, and 1.0 g (5.8 mmol) of m-chloroperbenzoic acid was added under cooling with ice. The mixture was stirred at room temperature for 40 minutes. The reaction solution was poured into ice water, and extracted with ethyl acetate. The extract solution was washed with a 5% acid sodium bisulfite aqueous solution and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was solidified by an addition of n-hexane, collected by filtration and dried to obtain 3.8 g (yield: 93%) of a powder of the above identified compound.
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10](Cl)[C:11](=[O:17])[NH:12]3)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.C(N(CC)CC)C>[Pd].CN(C)C=O>[C:4]1(=[O:19])[N:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[C:1](=[O:24])[C:2]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:3]12
Reactant: O=C1Nc2cccc(CCN3C(=O)c4ccccc4C3=O)c2C1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Cc2c(CCN3C(=O)c4ccccc4C3=O)cccc2N1
Temperature: 30 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A 10 L pressure reactor was charged with dry Pd/C (30 gm), 4-(2′-phthalimidoethyl)-3-chloro-1,3-dihydro-2H-indol-2-one (300 gm, 0.882 mol), triethylamine (133 gm, 0.952 mol) and dimethylformamide (6 L). The reaction mixture was hydrogenated at 30-50° C. and 70-75 psi for 2 hours. The catalyst was filtered at 50° C. and filtrate was concentrated in vacuum. Water (1.5 L) was added to residue and slurry was stirred for 30 minutes at 30° C. The solids were filtered at suction and washed with water, and dried in oven at 60-70° C. to give title compound as yellow solid (225 gm, 83.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17](OB(O)O)=[CH:16][CH:15]=1)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>COCCOC>[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:16][CH:15]=1)[CH3:12]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Under an argon atmosphere, tetrakistriphenylphosphine palladium (69 mg) was added to 5 ml of 1,2-dimethoxyethane. A mixture resulting from dissolving 5-bromo-2-fluorobenzaldehyde (406 mg) in 5 ml of 1,2-dimethoxyethane was added. A mixture resulting from dissolving 4-ethoxyphenylboric acid (398 mg) in 1.5 ml of 1,2-dimethoxyethane was added. Two milliliter of 2M sodium carbonate solution was added. Stirring was conducted for one hour and ten minutes under reflux. After cooling to room temperature, 20 ml of toluene was added and was washed with 10 ml of water twice, 10 ml of a 2N sodium hydroxide solution twice and 10 ml of water twice. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was purified by silica gel chromatography (hexane/ethyl acetate=4/1). The resulting effective fractions were concentrated to yield 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde (369 mg, Yield 76%).
Reaction SMILES: [CH3:1][C:2]1([CH:5]([OH:9])[CH2:6][CH:7]=[CH2:8])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>O1CCCC1>[CH2:16]([O:15][CH:14]([O:18][CH2:19][CH3:20])[CH2:13][O:9][CH:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)[CH2:6][CH:7]=[CH2:8])[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: C=CCC(O)C1(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(OCC(OCC)OCC)C1(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(1-methylcyclopropyl)but-3-en-1-ol (C52) (6.0 g, 47.6 mmol) in tetrahydrofuran (50 mL) was added to a 0° C. suspension of sodium hydride (60% in mineral oil, 7.7 g, 190.5 mmol) in tetrahydrofuran (200 mL). After stirring at room temperature for 10 minutes, 2-bromo-1,1-diethoxyethane (97%, 37.5 g, 190.5 mmol) was added drop-wise at room temperature. The reaction mixture was heated to 75° C. for 24 hours. It was then cooled to 0° C., slowly quenched with water (200 mL) and extracted with dichloromethane (3×500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1.II.[I:14](O)(=O)(=O)=O.C(O)(=O)C.O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:6]=[C:5]([I:14])[S:4][C:3]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1
Reactant: Brc1ccsc1-c1nnc[nH]1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc(I)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a mixture of 3-(3-bromo-2-thienyl)-4H-1,2,4-triazole (1.12 g, 4.87 mmol), iodine (1.12 g, 4.41 mmol) and periodic acid (4.80 g, 24.8 mmol) in acetic acid (11.0 mL, 200 mmol) were added water (8.0 mL, 400 mmol) and sulfuric acid (2.0 mL, 40 mmol) and the reaction mixture was stirred at rt for two days. The resulting white precipitate was collected by filtration. The solid cake was washed with water and dried under high vacuum at 40° C. to yield product as a white solid (1.74 g, 100% yield, as a white solid). LCMS: (FA) ES+, 357.7. 1H NMR (400 MHz, d6-DMSO) δ: 8.63 (s, 1H), 7.43 (s, 1H)
Reaction SMILES: [C:1]1([C:7]#[C:8]/[CH:9]=[CH:10]/[CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:26]([O:28][C:29](=[O:42])[C@@H:30]([O:39][CH2:40][CH3:41])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH3:27].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:42])[C@@H:30]([O:39][CH2:40][CH3:41])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:12][CH2:11]/[CH:10]=[CH:9]/[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:34][CH:33]=1)[CH3:27]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C/C#Cc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccccc2)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
(E)-5-Phenyl-pent-2-en-4-yn-1-ol (328 mg, 2.07 mmol), tributylphosphine (606 mg, 3.0 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (Tetrahedron Letters, Vol. 35, No. 19, 3139–3142, 1994) (495 mg, 2.07 mmol) were successively dissolved in dry benzene (30 mL) under a nitrogen atmosphere and the solution cooled to 0° C. Solid 1,1′-(azodicarbonyl) dipiperidine (756 mg, 3.0 mmol) was added, the mixture stirred for 10 min., then warmed to room temperature and stirred for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The product was purified by flash column chromatography eluting with toluene graduated to toluene/ethyl acetate (19:1) to give 450 mg (57%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=1[NH2:17]>>[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][C:16]=1[NH:17][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:13]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc([N+](=O)[O-])ccc1O
Yield: 31.1 %

Procedure:
Using 5-nitrosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:9][NH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:6][CH2:7][CH3:8])[CH3:2].C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:9][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[NH:17][C:24]1=[O:25])[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCC(CNc1ncccc1N)C(=O)OCC
Solvent: C1CCOC1
Product: CCCC(Cn1c(=O)[nH]c2cccnc21)C(=O)OCC
Temperature: 25 °C
Reaction time: 120 h
Yield: 64.4 %

Procedure:
To a stirred solution of 2-[(3-amino-pyridin-2-ylamino)-methyl]-pentanoic acid ethyl ester (70 mg, 0.28 mmol) in THF (10 ml) was added CDI (135 mg, 0.84 mmol). The resulting solution was stirred at room temperature for 5 days after which time the reaction appeared to be complete. Silica gel was added and the mixture was concentrated. The remaining solid was purified via silica gel flash column chromatography (Companion, 12 g silica gel, 30-100% EtOAc/hexanes) to give 50 mg (65%) of the title compound as oil which solidified on standing.
Reaction SMILES: [C:1]([C:5]1([CH2:11][CH2:12][CH3:13])[CH:9]=[CH:8][CH:7]([CH3:10])[O:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CCOCC>[C:1]([C:5]1([CH2:11][CH2:12][CH3:13])[CH2:9][CH2:8][CH:7]([CH3:10])[O:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCCC1(C(C)(C)C)C=CC(C)O1
Agent: [Pd]
Solvent: CCOCC
Product: CCCC1(C(C)(C)C)CCC(C)O1
Yield: 126.8 %

Procedure:
At ambient temp., a suspension of 2.91 g (10.4 mmol) of 2-tert-butyl-5-methyl-2-propyl-2,5-dihydrofuran and 1.06 g (1.00 mmol) of 10% palladium on activated charcoal in 60 mL of dry ether was hydrogenated for 4 h in a Parr apparatus at 2.5 bar hydrogen pressure. The catalyst was filtered off over a pad of Celite, and the solvent evaporated. The resulting residue was distilled in a Kugelrohr apparatus to provide at 75-85° C./20 mbar 2.43 g (80%) of the title compound as a colorless odoriferous liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Temperature: -10 °C
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl(2-hydroxyethyl)carbamate (0.960 mL, 6.08 mmol) in pyridine (25 ml) was added 4-methylbenzene-1-sulfonyl chloride (2.341 g, 12.16 mmol) at −10° C. The solution was stirred at −10° C. for 40 min. The reaction mixture was stored in a fridge at 4° C. for 4 days. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed aqueous citric acid (10%), dried using MgSO4, filtered and evaporated to give the title compound as a yellow oil. (UPLC-MS 3) ESI-MS 316.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 7.79 (d, 2H), 7.36 (d, 2H), 4.84 (s, 1H), 4.06 (t, 2H), 3.41-3.35 (m, 2H), 2.45 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].[Cl:15]SCl>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:15])=[O:10]
Reactant: ClSCl
Reactant: O=C(O)CCCOc1cccc(F)c1
Product: O=C(Cl)CCCOc1cccc(F)c1
Temperature: 25 °C

Procedure:
A solution of 4-(3-fluorophenoxy)butanoic acid (3.00 g, 15.1 mmol) in dichlorosulfane (15 mL) under N2 was refluxed for 3 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:17]C)[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]CCC3CCCCN3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(CC2c3ccc(O)cc3CN2c2ccc(F)cc2)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 2-(4-fluorophenyl)-5-methoxy-1-{4-[(2-piperidyl)ethoxy]benzyl}isoindoline (0.14 g, 0.3 mmol) in CH2Cl2 (8 mL) under nitrogen at −10° C. was added a 1.0 M solution of boron tribromide in CH2Cl2 (0.6 mL, 0.6 mmol) dropwise. After stirring at −10° C. for 1 hour, the reaction was quenched with ice and saturated sodium bicarbonate, then extracted with methylene choride. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was then purified by HPLC (C-18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid) to provide the title compound (0.084 g, 84% yield): 1H NMR (DMSO-d6) 7.04 (t, 2H), 6.88 (d, 1H), 6.69 (dd, 1H), 6.61-6.65 (m, 5H), 6.56 (d, 1H), 5.21 (m, 1H), 4.67 (s, 1H), 4.51 (s, 1H), 4.29 (d 1H), 4.10 (dd, 1H), 3.00-3.14 (m, 2H); ES-MS (m/z) 336 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7]>CO.[Pd]>[OH:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCC[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.03 h
Yield: 98.8 %

Procedure:
Tert-butyl (2S,3S,E)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (0.51 g, 1.4 mmol) was taken up in 10 mL of MeOH. 0.10 g of 10% Pd on carbon was added, and hydrogen was bubbled through the mixture. After 2 minutes, the bubbling was ceased and the reaction was kept under a balloon of hydrogen. After 2 hours, the mixture was filtered through Celite and concentrated under reduced pressure, affording tert-butyl (2S,3S)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hexan-2-ylcarbamate (0.50 g, 97% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:12][C:2]([F:11])([F:1])[S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][Br:13])=[CH:8][CH:9]=1
Reactant: Cc1ccc(SC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Sc1ccc(CBr)cc1
Reaction time: 4 h

Procedure:
A mixture of 4-trifluoromethylthiotoluene (1.5 g.), N-bromosuccinimide (1.53 g.) and benzoyl peroxide (0.05 g.) in dry carbon tetrachloride (30 ml.) was refluxed, with stirring for 4 hours. The mixture was cooled and filtered. The filtrates were evaporated in vacuo and 4-trifluoromethylthiobenzyl bromide was obtained as a crystalline solid (2.5 g.).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=O.O.[NH2:22][NH2:23]>CCO>[CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:3]=1[C:4]1[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[NH:23][N:22]=1
Reactant: NN
Reactant: Cc1cc(C)c(C(=O)c2ccccc2C(=O)O)c(C)c1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(-c2n[nH]c(=O)c3ccccc23)c(C)c1
Reaction time: 0.17 h

Procedure:
A mixture of 2-(2,4,6-trimethylbenzoyl-benzoic acid (5.0 g, 18.7 mmol) and hydrazine hydrate (2 mL) in 15 mL of EtOH was stirred at reflux for 8. hours. The solvent was then removed from the mixture. The residue was heated to melt for about 10 minutes and then solidified by cooling. The resulting yellow solids were triturated with ether and filtered. The solid was washed with 1 N NaOH and water, and dried to give 1.8 g of titled compound as yellow solids, m.p. 259-62° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31][CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31][CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCSc1ccccc1Br
Product: C[Si](C)(C)CCOCSc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-pyrazin-2-amine and (2-(((2-bromophenyl)thio)methoxy)ethyl)trimethylsilane. MS (ESI): mass calcd. for C22H26FN3OSSi, 427.16; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.43-8.36 (m, 1H), 8.07 (d, J=1.5, 1H), 7.89 (m, 1H), 7.73 (dd, J=6.7, 1.4, 1H), 7.40-7.17 (m, 5H), 4.90 (s, 2H), 3.64-3.50 (m, 2H), 0.91-0.78 (m, 2H), 0.04 (s, 9H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([NH:14]C(=O)C(C)C)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]2)[CH2:3][CH2:2]1.[OH-].[Na+].C1(C)C=CC=CC=1.[OH:36][S:37]([OH:40])(=[O:39])=[O:38]>C(O)(C)C>[CH2:2]1[CH:1]([NH:4][C:5]2[C:6]3[N:7]=[CH:8][N:9]([C@H:20]4[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]4)[C:10]=3[N:11]=[C:12]([NH2:14])[N:13]=2)[CH2:3]1.[CH2:2]1[CH:1]([NH:4][C:5]2[C:6]3[N:7]=[CH:8][N:9]([C@H:20]4[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]4)[C:10]=3[N:11]=[C:12]([NH2:14])[N:13]=2)[CH2:3]1.[OH:39][S:37]([OH:40])(=[O:38])=[O:36]
Reactant: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 22.5 °C
Yield: 87.8 %

Procedure:
N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide (6.56 g, 18.40 mmol) was slurried in a mixture of isopropanol (32.8 ml) and 10% solution of NaOH (36.1 ml, 92.0 mmol). The mixture was refluxed for 1 h. The resulting solution was cooled to 20-25° C. and toluene (32.8 ml) was added. The layers were separated and H2SO4 96% (0.61 ml, 11.03 mmol) was added dropwise to the organic layer. This mixture was cooled to 0-5° C. and the resulting slurry filtered off. The solid was dried under vacuum at 40° C. Abacavir hemisulfate (5.42 g, 88%) was obtained as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][N:9]=1>ClCCl>[Cl:7][C:8]1[N:9]=[CH:10][C:11]([C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:13])=[CH:15][CH:16]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1CCOCC1
Reaction time: 2 h

Procedure:
Morpholine (0.2 ml, 2.2 mmol) was added to stirred solution of 6-chloronicotinoyl chloride (250 mg, 1.4 mmol) in dichloromethane (10 ml). After 2 hours the reaction was allowed to cool and the crude mixture was applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol. The methanolic fractions were concentrated in vacuo to afford the title compound (D5).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]1([SH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:15][C:16]1[N:24]=[C:23](Cl)[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Cl-].[Na+].O>[NH2:15][C:16]1[N:24]=[C:23]([S:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: SC1CCCCC1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SC2CCCCC2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (256 mg, 6.4 mmol, 60% in mineral oil) were added cyclohexanethiol (2 ml, 16 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was heated at 100° C. for 3.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (112 mg, yield 86%).