Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[C@@H:28]1[C:32]([F:34])([CH3:33])[C@@:31]([O:36][C:37](=[O:39])[CH3:38])([CH3:35])[CH:30]([CH2:40][O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:29]1)(=O)C.Cl[Sn](Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(#N)C>[C:42]([O:41][CH2:40][C@@H:30]1[C:31]([O:36][C:37](=[O:39])[CH3:38])([CH3:35])[C@:32]([F:34])([CH3:33])[CH:28]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][C:9]([NH2:11])=[N:10][C:2]=3[Cl:1])[O:29]1)(=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(=O)O[C@H]1OC(COC(=O)c2ccccc2)[C@@](C)(OC(C)=O)C1(C)F
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)nc(N)nc32)[C@]1(C)F
Yield: 310 %

Procedure:
To a stirred solution of 6-chloro-9H-purin-2-amine (about 0.18 g, 1.08 mmol) in acetonitrile (about 6 ml) was added N,O-Bis(trimethylsilyl)acetamide (about 1.59 ml, 6.5 mmol) at room temperature and refluxed for about 2 hours. To this added (2R,4R)-5-(benzoyloxymethyl)-3-fluoro-3,4-dimethyltetrahydrofuran-2,4-diyl diacetate (about 0.20 g, 0.54 mmol) in acetonitrile (about 6 ml) drop wise at about 0° C., and added SnCl4 (about 0.09 ml, 0.81 mmol) then refluxed for about 2 hours. Completion of the reaction monitored by thin-layer chromatography and neutralized the reaction mixture with saturated sodium bicarbonate solution. Aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 2% methanol in dichloromethane as eluent furnished title compound (0.8 g) as a colorless solid. Yield: 33%; 1H NMR (300 MHz, CDCl3): δ 8.29 (d, 1H, J=4.2 Hz), 8.06-8.03 (m, 2H), 7.59-7.56 (m, 1H), 7.49-7.44 (m, 2H), 6.80 (d, 1H, J=21.6 Hz), 5.09 (s, 2H), 4.83-4.78 (m, 2H), 4.51-4.44 (m, 1H), 2.17 (s, 3H), 1.89 (d, 3H, J=2.4 Hz), 1.48 (d, 3H, J=23.1 Hz); ES Mass: [M+1] 478 (30%), [M+Na] 500 (30%); HPLC:. 93.1%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:20](N1C=CN=C1)(N1C=CN=C1)=O.CO.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:12][CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: O=C1CCC(Oc2cc(F)c(C(=O)O)cc2Cl)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Cl)c(OC2CCC(=O)CC2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
To a solution of 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoic acid (1.14 g, 3.98 mmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1′-carbonyldiimidazole (1.71 g, 10.50 mmol). The solution was heated to reflux under a nitrogen atmosphere for 1 hours and cooled to ambient temperature. To the solution was added anhydrous methanol (0.49 mL, 12.00 mmol) and 1,8-diazabicycloundec-7-ene (1.8 mL, 12.00 mmol). The solution was stirred at ambient temperature for 4 h, then diluted with ethyl acetate (150 mL) and washed with 1 M hydrochloric acid (2×150 mL), brine (150 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford the title compound as an off-white solid (1.05 g, 87%): 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J=7.6 Hz, 1H), 6.74 (d, J=12.0 Hz, 1H), 4.79 (br s, 1H), 3.89 (s, 3H), 2.79-2.68 (m, 2H), 2.39-2.31 (m, 4H), 2.13-2.02 (m, 2H); MS (ES+) m/z 300.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21]>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: COc1cccc(CNC(=O)c2c(Cl)ncnc2Cl)c1
Solvent: C1COCCO1
Product: COc1cccc(CNC(=O)c2c(N)ncnc2Cl)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 86.2 %

Procedure:
4,6-Dichloro-N-(3-methoxybenzyl)pyrimidine-5-carboxamide (523 mg, 1.68 mmol) was dissolved in dioxane (8 ml) and cooled in an ice bath. Ammonia solution (1.2 ml, 8.40 mmol, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h. After evaporation of the solvent under reduced pressure, the residue was suspended in ethyl acetate and filtered, washing several times with ethyl acetate. The organics were evaporated under reduced pressure to yield the final compound as a solid (424 mg, 97% purity, 84% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [OH:1][CH:2]([C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:29][CH:30]=1)[CH:3]([NH:18]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:18][CH:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:14])[F:15])[CH:6]=1)[CH:2]([C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:29][CH:30]=1)[OH:1]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl (1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate (1.67 g, 3.17 mmol) in chloroform (20 ml) was added trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was basified with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol (1.17 g, 87%) as colorless crystals.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32]([N:37]4[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)[C:33]([F:36])([F:35])[F:34])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O.F[C:69](F)(F)[S:70](O)(=[O:72])=[O:71]>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:17][C:18]([CH:32]([N:37]3[CH2:38][CH2:39][N:40]([S:70]([CH3:69])(=[O:72])=[O:71])[CH2:41][CH2:42]3)[C:33]([F:34])([F:35])[F:36])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(N4CCN(C(=O)OC(C)(C)C)CC4)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(N3CCN(S(C)(=O)=O)CC3)C(F)(F)F)cc2-c2nc(C)nc(N)n2)cc1F

Procedure:
The title compound was prepared from tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethyl)piperazine-1-carboxylate via the similar deprotection step as previously described in Example 178, Step 4 using trifluoroacetic acid and trifluoromethanesulfonic acid and isolated (quantitative) as a yellow solid. m/z (ESI, +ve ion) 572 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.96 (s, 1H) 8.84 (d, J=2.15 Hz, 1H) 8.40 (d, J=2.35 Hz, 1H) 8.29-8.39 (m, 2H) 8.03 (br. s., 1H) 7.88 (br. s., 1H) 4.86 (q, J=9.45 Hz, 1H) 3.95 (s, 3H) 3.13 (t, J=4.60 Hz, 4H) 2.86 (s, 3H) 2.69-2.78 (m, 2H) 2.58-2.69 (m, 2H) 2.45 (s, 3H).
Reaction SMILES: C1COCC1.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[Mg]Br.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCCC.C(OCC)(=O)C>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:18]1[CH:17]=[CH:16][N:15]=[CH:14][CH:19]=1
Reactant: Brc1ccccn1
Reactant: Br[Mg]c1cccs1
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1csc(-c2ccncc2)c1
Reaction time: 24 h
Yield: 94 %

Procedure:
Using a THF solution of 2-thienylmagnesium bromide (3.00 mL, 1.00 M, 3.0 mmol) and 2-bromopyridine (316.0 mg, 2.0 mmol), CoF2.4H2O (20.3 mg, 0.12 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (102.3 mg, 0.24 mmol) as starting materials, the reaction was performed at a scale of 2.0 mmol at 80° C. for 24 hours in the same manner as in Example 23. After performing silica gel column chromatography (ethyl acetate=5% in hexane), the above compound was obtained as a yellow solid (0.303 g, yield=94%, purity=>98% (GC analysis)).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanonephase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 153.6° C.
Reaction SMILES: [CH2:1]([N:5]([CH3:23])[C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])=[O:7])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>O1CCCC1.CO.O.C(Cl)(Cl)Cl>[CH2:1]([N:5]([CH3:23])[C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:17]=1)[C:11]([OH:13])=[O:12])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 3-{[butyl(methyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoate (660 mg, 2.1 mmol) in tetrahydrofuran/methanol/water (1:1:1, 9 mL) is added lithium hydroxide monohydrate (175 mg, 4.2 mmol), and the reaction is stirred at room temperature 16 h. The solution is diluted in chloroform and washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give the title compound. ESI MS m/z 301.1 [M−H]−.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[C:7]([CH3:9])[N:8]=1.F[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>CN(C)C=O>[CH3:3][C:4]1[N:5]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: Cc1c[nH]c(C)n1
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2ccccc2C#N)c(C)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Sodium hydride (8.65 grams 60%, 0.216 mol) was stirred in 75 mL of anhydrous dimethylformamide. To this was added dropwise a solution of 2,4-dimethylimidazole (20.75 grams, 0.216 mol) in 100 mL of DMF. After stirring at ambient temperature for 1 hour a solution of 2-fluorobenzonitrile (23.0 mL, 0.216 mol) in 75 mL of DMF was added dropwise. This was stirred at 50° C. for 2 hours and then at ambient temperature for 16 hours. The mixture was then poured into water and the product extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The crude product was chromatographed (silica gel) and eluted with 19:1 dichloromethane-methanol then 9:1 dichloromethane-methanol to afford the product as a solid. LCMS data confirmed structure.
Reaction SMILES: [F:1][C:2]1[C:26]([F:27])=[C:25]([F:28])[C:24](F)=[C:23](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][C@@H:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15]O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+].[OH2:33]>C1COCC1>[F:1][C:2]1[C:3]2[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]3[C@@H:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:15][O:33][C:24]([C:23]=23)=[C:25]([F:28])[C:26]=1[F:27]
Reactant: O
Reactant: CCOC(=O)C(=CN[C@H](CO)c1ccccc1)C(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)OC[C@@H]2c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of ethyl (S)-2-(2,3,4,5,6-pentafluorobenzoyl)-3-[(2-hydroxy-1-phenylethyl)amino]acrylate (2.15 g, 5.00 mmol) in THF (20 mL) was added NaH (440 mg, 11.0 mmol, 60% in oil) at 0° C. and the mixture was stirred at 0° C. for 0.5 h, at room temperature for 1 h, and then refluxed for 2 h. The mixture was treated portionwise at 0° C. with water. A precipitate formed and was collected by filtration, washed successively with EtOAc and then dried to give ethyl (S)-8,9,10-trifluoro-2,3-dihydro-7-oxo-3-phenyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (465 mg, 24%) as a pale yellow solid.
Reaction SMILES: N1C=CC=C[CH:2]=1.[F:7][C:8]([F:19])([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=[O:10]>CO>[F:7][C:8]([F:19])([C:12]([F:17])([F:18])[C:13]([F:14])([F:15])[F:16])[C:9]([O:11][CH3:2])=[O:10]
Reactant: c1ccncc1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CO
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Cationic fluorochemical surfactants useful as antistatic agents and lubricants for polymeric shapes are prepared from 2,2,3,4,4,4-hexafluorobutanol or perfluorobutyric acid. Hexafluorobutanol is reacted with bromoundecanoic acid to obtain a bromoester which is then reacted with pyridine to obtain a cationic surfactant. Perfluorobutyric acid is esterified with methanol to obtain methyl perfluorobutyrate which is then reacted with dimethylaminopropylamine to obtain an amino-amide which is then reacted with hydrogen peroxide to obtain the N-oxide derivative which is neutralized with glycolic acid to obtain a cationic surfactant, a salt of the N-oxide derivative.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][N:4]([C:11]([C:13]1[CH:17]=[C:16]([Cl:18])[S:15][C:14]=1[Cl:19])=O)[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.B(F)(F)F.CCOCC.S(C)C.CN(CCN(C)C)C>O1CCCC1>[CH3:1][CH:2]([CH3:20])[CH2:3][N:4]([CH2:11][C:13]1[CH:17]=[C:16]([Cl:18])[S:15][C:14]=1[Cl:19])[CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)CN(C(=O)c1cc(Cl)sc1Cl)C1CCNCC1
Agent: CN(C)CCN(C)C
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CSC
Solvent: CCOCC
Product: CC(C)CN(Cc1cc(Cl)sc1Cl)C1CCNCC1
Yield: 27.6 %

Procedure:
To a solution of N-(2-methylpropyl)-N-[(2,5-dichlorothiophen-3-yl)-carbonyl]piperidin-4-amine (0.72 g, 2.14 mmol) in anhydrous tetrahydrofuran (5 ml) is added BF3.Et2O (0.73 g, 5.14 mmol) and the reaction mixture is heated to reflux. While refluxing, BH3.Me2S (1.6 ml, 3.2 mmol) is added and the reaction vented to remove Me2S for 10 minutes. After an additional 2 hrs at reflux, TMEDA (0.75 g, 6.42 mmol) is added and the reaction mixture heated at reflux for 1 hr. The reaction mixture is cooled, and the precipitate is filtered and washed with dichloromethane. The filtrate is concentrated in vacuo. Aliquots of methanol (5 ml) are added to the residue and concentrated. This process is repeated until no more gas evolution is observed. The resulting residue is purified on silica gel (0-100%) 5% 2N NH3 in methanol in dichloromethane to give N-(2-methylpropyl)-N-[(2,5-dichlorothien-3-yl)methyl]piperidin-4-amine (0.19 g, 28%). m/z=321 (M+1); 1H NMR (CD3OD): δ=6.87 (1H, s), 3.65 (2H, s), 3.34-3.30 (2H, m), 2.86-2.78 (2H, m), 2.74-2.63 (1H, m), 2.26 (2H, d), 1.95-1.89 (2H, m), 1.72-1.58 (4H, m), 0.86 (6H, d).
Reaction SMILES: [CH2:1]([C@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]1[C@H:42]2[C@H:38]([O:39][CH2:40][CH2:41]2)[O:37][CH2:36]1)[C@H:9]([OH:31])[CH2:10][N:11]([O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>[Pd].C(OCC)(=O)C>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:10][C@@H:9]([OH:31])[C@@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)OC2CCCCC2)cc1
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (115 mg, 0.186 mmol) in a 1:1 mixture of ethanol : ethyl acetate (6 mL) was added Palladium on charcoal (10 wt %, 30 mg). The starting material was reduced under an atmosphere of Hydrogen gas over 16 hrs. The reaction mixture was filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 uM) eluting with 3:1 ethyl acetate : hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate(89 mg, 81%). H1-NMR (chloroform-D3): 1.26 (m, 6H), 1.58 (m, 5H), 2.05 (m, 2H), 2.90 (m, 4H), 3.09 (b, 2H), 3.68 (m, 2H), 3.88 (m, 4H), 4.16 (m, 1H), 4.24 (b, 1H), 4.81 (d, 1H), 5.00 (m, 1H), 5.63 (d, 1H), 6.66 (d, 2H), 7.23 (m, 5H), 7.56 (d, 2H). MS(ESI): 612(M+Na).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].CO[C:12](OC)(OC)[CH2:13][CH2:14][CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>COCCO>[CH2:13]([C:12]1[NH:9][C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[Cl:1])[N:8]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Nc1ncnc(Cl)c1N
Reactant: CCCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCCc1nc2ncnc(Cl)c2[nH]1
Yield: 26.8 %

Procedure:
A mixture of 6-Chloro-4,5-diaminopyrimidine (0.289 g, 2 mmol) (from Step 1 of Example 12), trimethylorthovalerate (0.52 ml, 3 mmol) and p-TsOH (0.04 g) in 2-methoxyethanol (10 ml) was refluxed for 24 hours. The product was isolated and purified as described in Step 2 of Example 12 to give the crystalline titled compound (0.113 g, 23%). NMR (CDCl3): δ 0.997 (t, J=9 Hz, 3H), 1.484 (m, 2H), 1.925 (m, 2H), 3.075 (m, 2H), 7.27 (s, 1H) and 8.723 (s, 1H). FAB-MS: m/e 211 and 213 (M+H). Analysis calculated for C9H11N4Cl: C, 51.31; H, 5.26; N, 26.60. Found: C, 51.34; H, 5.30, N, 26.46.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[CH3:22][O:23][C:24]1([O:31][CH3:32])[CH2:29][CH2:28][O:27][CH2:26][C:25]1=[O:30]>C1COCC1>[CH3:22][O:23][C:24]1([O:31][CH3:32])[CH2:29][CH2:28][O:27][CH2:26][C@H:25]1[OH:30]
Reactant: COC1(OC)CCOCC1=O
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: COC1(OC)CCOC[C@H]1O
Temperature: 40 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A 12-L 4-neck round bottom flask equipped with a overhead air stirrer, addition funnel with nitrogen inlet adapter, condenser, and thermocouple was charged with S-(−)-2-methyl-CBS-oxazaborolidine (40 g, 0.12 mol) and THF (2.2 L). The mixture was warmed under nitrogen to 40° C. then Me2S—BH3 (108 mL, 1.15 mol) was added to the THF-catalyst mixture via syringe. An addition funnel charged with 4,4-dimethoxydihydro-2H-pyran-3(4H)-one (as prepared in the previous step, 165 g, 0.59 mol) in THF (2.1 L) was added drop wise over a 7 h period. After the addition was complete, the reaction was allowed to stir for 18 h at 40° C. The reaction was chilled to 10° C. in an ice-acetone bath and quenched by slow addition of MeOH (1.1 L) over 1 h period. The cooling bath was removed and the mixture allowed to warm to room temperature for 3 h. After the gas evolution ceased, the mixture was concentrated on a rotary evaporator to give 188 g. Purification on silica gel using a mixture of EtOAc and heptanes afforded the title compound (166 g, 99%, chiral GC 93% ee) as a yellow oil.
Reaction SMILES: C[Si](C)(C)[Si](C)(C)C.Cl[Si](C)(C)C.[OH:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1.ClCCl.CO>[OH:18][CH2:17][C:16]1[C:15](=[O:14])[NH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cccnc1O
Agent: CC(C)C[Al+]CC(C)C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[Si](C)(C)C
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]cccc1CO
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
At RT, 23.2 g (144 mmol) of hexamethyldisilane and 0.781 g (7.19 mmol) of chlorotrimethylsilane are added to a suspension of 10.0 g (71.9 mmol) of 2-hydroxynicotinic acid in 100 ml of toluene, and the mixture is stirred with a KPG stirrer at 110° C. for 30 min. The mixture is then cooled to −40° C., and 22.5 g (158 mmol) of a 1 molar solution of diisobutylaluminium hydride in dichloromethane are added dropwise to the solution. The mixture is thawed to RT, stirred at RT for 18 h and finally, at −10° C., adjusted to pH=4 with dilute hydrochloric acid, and 500 ml of methanol are added such that the temperature does not exceed −10° C. The precipitate formed is filtered off, 100 ml of water are added to the filtrate, the mixture is stirred at 50° C. for 1 h and the precipitate is filtered off. Concentration of the filtrate gives 8.55 g (95% of theory) of the desired compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:5]([CH2:12][C:13]([OH:24])([CH3:23])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1>O1CCOCC1>[CH3:23][C:13]1([CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[O:24][C:4]2=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]2[CH2:12]1
Reactant: CC(O)(CCC(=O)OC(C)(C)C)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCC1(C)Cn2cc([N+](=O)[O-])nc2O1
Yield: 42.2 %

Procedure:
Sodium hydride (0.12 g, 3.07 mmol) was added to a solution of tert-butyl 5-(2-chloro-4-nitroimidazol-1-yl)-4-hydroxy-4-methylpentanoate prepared in Example 43 (0.93 g, 2.79 mmol) in 1,4-dioxane (10 ml) with cooling on ice-bath followed by stirring under reflux for 7.5 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the solution, and the resulting mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was treated with diethyl ether to afford tert-butyl 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propionate (0.35 g, 42%) as a white solid.