Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:16]([NH2:17])=[C:15]([C:18](=O)[CH2:19]C)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.Cl.C([OH:25])C>[Pd]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:16]3[NH:17][C:19]([OH:25])=[CH:18][C:15]=3[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CCC(=O)c1ncnc(N2CCc3ccc(Cl)cc32)c1N
Agent: [Pd]
Agent: Cl
Product: Oc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2[nH]1

Procedure:
To a solution of 4(6Chloro-2,3-dihydro-indol-1-yl)-5-amino-6-methylacetyl-pyrimidine (541 mg, 1.55 mmol) in 40 mL of ethanol was added 25 mol % of 10% palladium on carbon (125 mg) and 0.11 mL of 1N HCl (1.55 mmol). The mixture was hydrogenated for 3 hours at 3.4 atm (50 psi)(H2). The reaction is filtered through Celite® and concentrated in vacuo. The brown residue was slurried in methanol and the white solid was filtered off (279 mg, 63%): LC-MS: 287 (M+); anal. RP18-HPLC RT: 5.61 minutes; MP: 250° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[S:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:22]=1[C:23]([NH:1][C:2]1[S:13][C:5]2[C:6]([CH3:11])([CH3:12])[O:7][C:8]([CH3:9])([CH3:10])[C:4]=2[C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])=[O:24]
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Reactant: CCCOC(=O)c1c(N)sc2c1C(C)(C)OC2(C)C
Product: CCCOC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 62A and commercially available 2-fluoro-6-(trifluoromethyl)benzoyl chloride using the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 0.90 (t, J=7.5 Hz, 3H), 1.49 (s, 6H), 1.54 (s, 6H), 1.62-1.74 (m, 2H), 4.20 (t, J=6.7 Hz, 2H), 7.74-7.88 (m, 3H), 11.61 (br s, 1H). MS (ESI+) m/z 474 (M+H)+. Anal. calcd. for C22H23F4NO4S: C, 55.81; H, 4.90; N, 2.96. Found: C, 56.11; H, 5.04; N, 3.01.
Reaction SMILES: OS(O)(=O)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.CC(C)=O>[O:19]=[C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(NC1CCCCC1O)OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC1CCCCC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
CrO3 (0.70 g) and concentrated H2SO4 (0.61 mL) was diluted with H2O to the volume of 6 mL to make Jones Reagent at a concentration of 1.17 M. To a solution of benzyl 2-hydroxycyclohexylcarbamate (1.60 g, 6.43 mmol) in acetone (5.4 mL), cooled in a water bath, was added Jones Reagent (5.51 mL, 1.17 M, 6.43 mmol) dropwise over 5 min. The reaction mixture was stirred at room temperature for 1.5 hr, quenched with 20% aq. K2CO3 to pH=8. The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-30% over 8 min, 30-45% over 10 min) to give benzyl 2-oxocyclohexylcarbamate as a colorless oil at a retention time of 8.5-11 min (1.26 g, 79% yield) HPLC: RT=2.69 min, Purity 99% (HPLC Method 1) NMR: 400 MHz 1H (CDCl3) 7.33 ppm, 5 H, m; 5.76 ppm, 1 H, s; 5.11 ppm, 2 H, m; 4.27 ppm, 1 H, m; 2.65 ppm, 1 H, dd, J=6.60, 2.75 Hz; 2.52 ppm, 1 H, m; 2.38 ppm, 1 H, m; 2.13 ppm, 1 H, m; 1.89 ppm, 1 H, m; 1.77 ppm, 1 H, m; 1.64 ppm, 1 H, m; 1.42 ppm, 1 H, m.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C:9]([CH:11]=[O:12])=[CH:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].[BH4-].[Na+].CO>C(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C:9]([CH2:11][OH:12])=[CH:8][N:7]1[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[O:5]
Reactant: CCOC(=O)[C@@H]1CC(C=O)=CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(CO)=CN1C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
A solution of (S)-4-formyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (3.32 g, 12.3 mmol) in CH2Cl2 (51.4 mL) was cooled at −78° C. under nitrogen atmosphere, solid NaBH4 (1 g, 24.7 mmol) was added portionwise maintaining the temperature at −78° C. MeOH (25.7 mL) was added dropwise and the reaction mixture was allowed to reach 0° C. and was stirred 1 h30 at 0° C. The reaction was quenched with an aqueous saturated solution of NH4Cl and extracted with CH2Cl2 (×3). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1 to EtOAc) to give the desired material as a yellow oil. Rf, TLC (c-hexane/EtOAc 1:1)=0.30; MS (UPLC-MS): 272.2 [M+H]+, 316 [M+HCOO]−; tR (HPLC conditions f): 1.74 min.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13](OC)=[O:14])[C@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.C(O)(C)C>[CH2:20]([N:10]1[C@@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=C1OC[C@@H]2[C@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A solution of (4R,5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =+27.7° at c=1.0 in DMF, 368 mg) in toluene (2 ml) and isopropanol (3 ml) was added dropwise to a suspension of sodium borohydride (100 mg) in toluene at 5°-10° C. The obtained mixture was allowed to warm up to room temperature and to react at the same temperature for 18 hours. Then, 1N hydrochloric acid (10 ml) was added dropwise to the mixture. The mixture was stirred at 55°-60° C. for 30 minutes. Aqueous layer was separated from organic layer and extracted once with toluene (15 ml). The organic layers were combined, washed successively with water, 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated to give (3aR,6aS)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (301 mg). M.P., 116°-118° C. [α]D25 =-61.8° (c=1, CHCl3).
Reaction SMILES: BrC1C=C[C:5]([N:8]2[CH2:13][C@H:12](C)[NH:11][C@H:10]([CH3:15])[CH2:9]2)=CC=1.I[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1.CN(C)[C@H]1CCNC1>>[I:23][C:20]1[CH:21]=[CH:22][C:17]([N:11]2[CH2:10][CH2:15][C@H:13]([N:8]([CH3:5])[CH3:9])[CH2:12]2)=[CH:18][CH:19]=1
Reactant: Ic1ccc(I)cc1
Reactant: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)N1
Agent: CN(C)[C@H]1CCNC1
Product: CN(C)[C@H]1CCN(c2ccc(I)cc2)C1

Procedure:
The title compound was synthesized according to the synthesis of 1-(4-bromophenyl)-cis-3,5-dimethylpiperazine, except reacting 1,4-diiodobenzene (2.41 g, 7.30 mmol) with (S)—N,N-dimethylpyrrolidin-3-amine (1.0 g, 8.8 mmol). The title compound was purified by silica gel chromatography (MeOH/CH2Cl2, 2:98 to 1:9) as a yellow solid (1.27 g, 55%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.7 Hz, 2H), 6.33 (d, J=8.0 Hz, 2H), 3.47-3.38 (m, 2H), 3.32-3.26 (m, 1H), 3.16-3.12 (m, 1H), 2.89-2.83 (m, 1H), 2.33 (s, 6H), 2.26-2.21 (m, 1H), 1.99-1.89 (m, 1H); MS ESI 317.0 [M+H]+, calcd for [C12H17N2+H]+ 317.04.
Reaction SMILES: [N:1]12CCCCC1C=N[CH2:4][CH2:3][CH2:2]2.Cl.[Cl:13][CH2:14][C:15]([NH2:17])=[NH:16].O.C(OCC)(=O)C>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][N:17]=[C:15]([CH2:14][Cl:13])[N:16]=1
Reactant: C1=NCCCN2CCCCC12
Reactant: N=C(N)CCl
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccnc(CCl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
Solutions of 2-chloroacryloitrile (15.7 g.) in acetronitrile (20 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (27 g.) in acetonitrile (20 ml.) were added simultaneously over 30 minutes to a stirred, ice-cooled solution of 2-chloroacetamidine hydrochloride (19.2 g.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (22.5 g.) in acetonitrile (200 ml.), keeping the temperature below 30° and the mixture stirred a further 4 hours at room temperature after the addition was complete. The resulting mixture was stirred with a mixture of water (100 ml.) and ethyl acetate (200 ml.) and then filtered through a pad of diatomaceous earth and the ethyl acetate phase separated. The aqueous phase was further extracted with ethyl acetate (2×100 ml.) and the combined ethyl acetate extracts dried and evaporated to dryness to give 4-amino-2-chloromethylpyrimidine (14.5 g.) which was used without further purification.
Reaction SMILES: [CH2:1]([NH:8]/[CH:9]=[CH:10]/[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1(C)C=CC=CC=1>[CH2:1]([N:8](/[CH:9]=[CH:10]/[CH2:11][CH3:12])[C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC/C=C/NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC/C=C/N(Cc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 62a (3.22 g, 20 mmol) in 10 mL of toluene, was added triethylamine (2.79 mL, 20 mmol). The mixture was cooled to 0° C. and acetic anhydride (1.89 mL, 20 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. It was then concentrated on high vacuum to give crude 62b.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[CH:37]=[CH:36][C:21]([C:22]([NH:24][CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][C@H:29]2[C:33]([OH:35])=O)=[O:27])=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:33]([C@@H:29]2[CH2:30][CH2:31][CH2:32][N:28]2[C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[C:21]2[CH:36]=[CH:37][C:18]([S:15](=[O:17])(=[O:16])[NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:19][CH:20]=2)=[O:35])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(NCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@@H]2CCCN2C(=O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccccc3Oc3ccccc3)cc2)CC1

Procedure:
The title compound was prepared from (S)-1-{2-[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-pyrrolidine-2-carboxylic acid and piperazine-1-carboxylic acid tert-butyl ester according to the method described in Example 1.1/d. MS (EI) 714.3 (M+Na+).
Reaction SMILES: [ClH:1].Cl.Cl[N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[OH-].[Na+].[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O>[Cl:1][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][N:4]([C:25](=[O:26])[CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:5][CH2:6]2)=[CH:11][CH:12]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: ClN1CCN(c2ccccc2)CC1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Cc1ccccc1)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
To a cold solution of 8.09 g. of p-chlorophenyl piperazine dihydrochloride and 40 ml. of 10% sodium hydroxide in 60 ml. of water was added dropwise with stirring, 4.64 g. of phenylacetyl chloride. The mixture was stirred for one hour, then neutralized with 2 N hydrochloric acid. The solid was collected and recrystallized from ethanol-water, giving 4.2 g. of the desired product, m.p. 93°-94° C.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[C:5]([Mg]Cl)([CH3:8])([CH3:7])[CH3:6].[CH2:11]([Mg]Cl)[CH2:12][CH2:13][CH3:14]>C(OCC)C>[CH2:11]([P:1]([C:5]([CH3:8])([CH3:7])[CH3:6])[Cl:4])[CH2:12][CH2:13][CH3:14]
Reactant: CC(C)(C)[Mg]Cl
Reactant: ClP(Cl)Cl
Reactant: CCCC[Mg]Cl
Solvent: CCOCC
Product: CCCCP(Cl)C(C)(C)C
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phosphorus trichloride (55 g) in dry diethyl ether (200 cm3) stirred and maintained at between -25° C. and -30° C. in an atmosphere of dry nitrogen a 2 molar solution of tert-butyl magnesium chloride in diethyl ether (200 cm3, solution supplied by Aldrich Chemical Co.) was added during 45 min. After a further 30 min., a 2 molar solution of n-butyl magnesium chloride (200 cm3, solution supplied by Aldrich Chemical Co.) was added in the same way. The suspension was stirred at -25° C. for a further 45 min., then allowed to reach ambient temperature, and finally boiled under reflux for 30 min., cooled, filtered to remove magnesium chloride, and distilled, yielding n-butyl tert-butyl chlorophosphine (30.8 g), b.p. 76°-78° C. under a pressure of 15 mm of mercury.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:35]=[CH:34][C:6]2[N:7]([CH2:10][C:11]3[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([C:20]([N:22]([CH3:33])[CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)=[O:21])[N:12]=3)[N:8]=[N:9][C:5]=2[C:4]=1[O:36][C:37]1[CH:42]=[C:41]([C:43]#[N:44])[CH:40]=[C:39]([Cl:45])[CH:38]=1>O1CCOCC1>[Cl-:2].[Cl:2][C:3]1[CH:35]=[CH:34][C:6]2[N:7]([CH2:10][C:11]3[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([C:20]([N:22]([CH3:33])[CH2:23][CH2:24][NH3+:25])=[O:21])[N:12]=3)[N:8]=[N:9][C:5]=2[C:4]=1[O:36][C:37]1[CH:42]=[C:41]([C:43]#[N:44])[CH:40]=[C:39]([Cl:45])[CH:38]=1
Reactant: CN(CCNC(=O)OC(C)(C)C)C(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)c2cccnc21
Agent: Cl
Solvent: C1COCCO1
Product: CN(CC[NH3+])C(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)c2cccnc21
Product: [Cl-]
Reaction time: 2 h

Procedure:
Hydrochloric acid in dioxane (4 M, 5 mL) was added to tert-butyl {2-[[(3-{[5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridin-1-yl)carbonyl](methyl)amino]ethyl}carbamate (620 mg, 974 mmol) at 0° C. After 2 hours, the reaction mixture was concentrated under reduced pressure and the residue crystallized from ethanol. 1H NMR (DMSO-d6) δ 8.68 (d, J=4.5 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.90 (s, 1H), 7.82 (m, 1H), 7.55 (m, 1H), 7.43 (m, 1H), 6.50 (s, 2H), 3.65 (m, 2H), 3.1 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[CH:11][N:12](C)C)[C:7](=O)[C:6]=2[CH:16]=1.O.[NH2:18]N.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8]3[CH:11]=[N:12][NH:18][C:7]=3[C:6]=2[CH:16]=1
Reactant: CN(C)C=C1CSc2ccc(Cl)cc2C1=O
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)-c1[nH]ncc1CS2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6-chloro-2,3-dihydro-3-dimethylaminomethylene-4H-1-benzothiopyran-4-one (7 g), hydrazine hydrate (2.01 ml), and acetic acid (2.37 ml) in methanol (140 ml) was stirred at room temperature for 5 hours and then evaporated in vacuo. To the residue was added aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue solid was recrystallized from ethyl acetate to give 8-chloro-1,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole (2.85 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12](OC(C)C)[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.Cl[CH:22]1N([N+]([O-])=O)C=CC(Cl)=N1.CC1NN=C(N)C=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:22])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])N1C=CC(Cl)=NC1Cl
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Agent: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 30 using 2,6-dichloro-3-nitropyrimidine and 5-methyl-1H-pyrazol-3-amine as the starting materials. LCMS: 255 [M+1].
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH:12][C:13]1[C:14]([CH3:24])=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O-:27])=[O:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.CC#N>[CH2:5]([N:12]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=1)[C:13]1[C:14]([CH3:24])=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1c(NCc2ccccc2)cccc1NS(C)(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CC(Cl)Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
Glacial acetic acid (0.37 mL, 6.4 mmoles) was added to a solution of Example 8A (0.46 g, 1.6 mmoles) and 4-nitrobenzaldehyde (0.48 g, 3.2 mmoles) in dichloroethane (3.2 mL) and CH3CN (4.0 mL). The reaction was stirred for 4 hours at room temperature and was treated with sodium triacetoxyborohydride (0.68 g, 3.2 mmoles). The reaction mixture was stirred overnight at room temperature. The mixture was poured into saturated aqueous NaHCO3 (150 mL) and extracted with diethyl ether (150 mL). The organic phase was washed with brine (150 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (5:2→1:1 hexanes:ethyl acetate) to provide the title compound as a brown solid (0.034 g, 5% yield). 1H NMR (300 MHz, CDCl3) δ8.12 (d, J=8.9 Hz, 2H), 7.37 (d, J=8.9 Hz, 2H), 7.27 (m, 6H), 7.12 (t, J=7.8 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.14 (s, 1H), 4.18 (s, 2H), 4.06 (s, 2H), 2.99 (s, 3H), 2.38 (s, 3H); MS (APCI+) m/z 426 (M+H)+.
Reaction SMILES: C[O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18](OCOC)=[CH:17][CH:16]=3)C3CC(O)CC3[C:7]=2[CH:6]=1.C([Mg]Cl)C=C.CC[O:36]CC.C([O-])(O)=O.[Na+].[CH2:44]([CH:46]1[CH2:72][CH:49]2[CH:50](C3C=CC(OCOC)=CC=3)[O:51][C:52]3[CH:53]=CC(OCOC)=CC=3C2C1)[CH3:45]>C1COCC1>[CH2:52]([O:51][C:50]([CH:49]1[CH:72]([CH2:46][CH:44]=[CH2:45])[C:6]2[C:5](=[CH:14][CH:13]=[C:12]([O:11][CH2:10][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=2)[O:4][C:3]1=[O:2])=[O:36])[CH3:53]
Reactant: CCC1CC2c3cc(OCOC)ccc3OC(c3ccc(OCOC)cc3)C2C1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Reactant: CCOCC
Agent: C=CC[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1c2cc(OCc3ccccc3)ccc2OC(=O)C1C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a 0 C. solution of Preparation 27 (10.0 g, 30.8 mmol) in THF (125 mL) add a solution of allyl magnesium chloride in Et2O (46 mL, 1.0 M, 46 mmol). Maintain the reaction at 0 C. for 30 min, then pour the reaction contents into a solution of ½ satd. NaHCO3 (250 mL). Extract the solution with Et2O (2×150 mL) and EtOAc (150 mL). Wash the combined organic extracts with H2O (150 mL) and brine (150 mL), dry the organics over Na2SO4, and concentrate to afford a brown oil. Purify the product by MPLC (0% to 15% to 25% EtOAc/hexanes) to afford Preparation 38 (7.72 g, 68%) as a light yellow solid. 1H NMR (CDCl3) δ 7.31-7.43 (m, 5H), 7.01 (d, J=8.8. Hz, 1H), 6.87 (dd, J=8.8, 3.0 Hz, 1H), 6.79 (d, J=3.0 Hz, 1H), 5.71 (m, 1H), 5.15 (dd, J=0.8, 9.8 Hz, 1H), 5.10 (dd, J=0.8, 17.6 Hz, 1H), 5.04 (A of AB, JAB=14.2 Hz, 1H), 5.03 (B of AB, JAB=14.2 Hz, 1H), 4.08 (m, 2H), 3.80 (d, J=2.4 Hz, 1H), 3.41 (m, 1H), 2.35 (m, 2H), 1.08 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:3].C[Si](C)(C)[N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>C1C=CC=CC=1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[O:3])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Reactant: C[Si](C)(C)N1CCCC1=O
Solvent: c1ccccc1
Product: O=C1CCCN1C(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a solution of 4-bromophenyl chloroformate (4.19 g, 20.0 mmol) in anhydrous benzene (20 ml) was added a solution of 1-trimethylsilyl-2-pyrrolidinone (3.46 g, 22.0 mmol) in anhydrous benzene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. Recrystallization from 2-propanol afforded 3.00 g of colorless prisms. Yield 53%
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:30][C@H:31]([C:35]([O:37][CH2:38][CH:39]([O:43][C:44](=[O:62])[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:40](O)=[O:41])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:40](=[O:41])[CH:39]([O:43][C:44](=[O:62])[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])[CH2:38][O:37][C:35](=[O:36])[C@H:31]([CH:32]([CH3:33])[CH3:34])[NH:30][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (404 mg, 1.5 mmole), 3-(N-CBZ-L-valyloxy)-2-stearoyloxy-propanoic acid (1.06 g, 1.75 mmole), DMAP (24 mg, 0.2 mmole) and HOBT (264 mg, 1.82 mmole) was coevaporated two times with DMF and reduced to about 30 ml. DCC (372 mg, 1.8 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (50 ml) was added and the organic phase was washed twice with 5% acetic acid, with 5% sodium hydrogen carbonate and with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.73 g
Reaction SMILES: Cl.[C:2](=[NH:7])(OC)[CH2:3][CH3:4].[C:8](O)(=O)C(O)=O.[NH2:14][CH:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(=O)C.[Na+]>C(O)C>[NH2:22][C:21]1[N:7]=[C:2]([CH2:3][CH2:4][CH3:8])[NH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(N)C#N
Reactant: CCC(=N)OC
Reactant: O=C(O)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(N)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
A mixture of methyl propionimidate hydrochloride (4.8 g), ethyl 2-amino-2-cyanoacetate oxalate (4.0 g), anhydrous sodium acetate (9.1 g), and absolute ethanol (75 mL) was stirred at room temperature for 18 hours. Solids were removed by filtration and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated NaCl, dried over MgSo4, and evaporated. Flash chromatography on silica gel, eluting with a gradient of dichloromethane-ethyl acetate (75:25) to ethyl acetate gives the title compound (2.7 g) as a pale yellow solid, mp 111°-114° C.; MS (DEI) 211 (m).