Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[C:5](=[N:18][NH2:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]2[CH2:32][O:31][C:30](=[O:33])[CH2:29]2)[CH:25]=[CH:26][CH:27]=1.[OH-].[Na+]>ClCCl>[C:5](=[N:18][NH:19][C:30](=[O:33])[CH2:29][CH:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=1)[CH2:32][OH:31])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C2COC(=O)C2)c1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cccc(C(CO)CC(=O)NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trimethylaluminum (12 mL, 2 M in hexane, 24 mmol) is added dropwise to a solution of benzophenone hydrazone (1.57 g, 8 mmol) in dichloromethane (20 mL) at room temperature and under nitrogen. After the mixture is stirred for 30 min, 4-(3-methoxy-phenyl)-dihydro-furan-2-one, (1.54 g, 8 mmol) in dichloromethane (5 mL) is added. The mixture is refluxed for 5 h cooled to room temperature and diluted with dichloromethane (30 mL). The mixture is treated with 4 N sodium hydroxide (30 mL) and stirred one hour. The organic layer is separated, washed with brine and, dried over magnesium sulfate. The mixture is filtered, concentrated in vacuo and chromatographed on SiO2 (2% methanol/dichloromethane) to yield the title compound, 2.25 g (73%) as a pale yellow oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][F:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCCOCCF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCF)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
2-(2-Fluoroethoxy)ethanol (0.11 g, 1.0 mmol), p-toluenesulfonyl chloride (0.19 g, 1.0 mmol), and DMAP (0.12 g, 1.0 mmol) were dissolved in dichloromethane (2 ml) at 0° C. The resulting mixture was stirred for 2 h at 0° C., after which it was subjected directly to silica gel chromatography using dichloromethane as the eluent to give the title compound (70 mg, 27%) as a clear oil. It was observed that the size of the column affects reaction yield, with a smaller column giving a better yield. 1H NMR (CDCl3, 300 MHz): δ 7.79 (d, 2H, J=11.6 Hz), 7.33 (d, 2H, J=11.6 Hz), 4.48 (dt, 2H, J1=64.0 Hz, J2=5.6 Hz), 4.17 (t, 2H, J=6.4 Hz), 3.71 (t, 2H, J=6.4 Hz), 3.66 (dt, 2H, J1=5.6 Hz, J2=39.2 Hz), 2.44 (br S, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=O)[CH3:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:18])[NH2:17].C(O)(=O)C>C(O)C>[CH3:15][N:16]([CH3:18])[N:17]=[C:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)[CH3:13]
Reactant: CN(C)N
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NN(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]-ethanone (40 g), N,N-dimethylhydrazine (50 ml), glacial acetic acid (2 ml) and ethanol (35 ml) was heated under reflux for 78 hours. Removal of the solvent gave a residue which was distilled (104°-106°/0.1 mm Hg) to give 1-[1-(4-chlorophenyl)cyclobutyl]ethanone N,N-dimethylhydrazone.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30](Br)[C:29]2=[O:35])=[N:25][C:24]=1[CH3:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30]([NH:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=3)[C:29]2=[O:35])=[N:25][C:24]=1[CH3:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(N2CCCC(Br)C2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(NCc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 5, making variation as required to use (4-(trifluoromethyl)phenyl)methanamine in place of 2-cyclopropylethanamine to react with N-benzyl-2-(3-bromo-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide in place of 2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 20% yield: mp 39-40° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.39-7.21 (m, 5H), 6.03 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 4.32-4.21 (m, 1H), 4.06-3.96 (m, 1H), 3.93 (s, 2H), 3.50-3.39 (m, 1H), 2.62 (s, 3H), 2.30-2.05 (m, 2H), 1.99-1.83 (m, 2H), 1.81-1.66 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.4, 162.5, 156.6, 152.0, 143.8, 137.9, 129.4, 128.8, 128.3, 127.9, 127.7, 125.5, 125.4, 119.7, 57.9, 50.9, 47.5, 44.1, 26.5, 20.4, 17.4; MS (ES+) m/z 503.3 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@H:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[C:45](=[O:47])[CH3:46].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:45]([C:31]1[CH:32]=[CH:33][C:34]([C:2]2[N:7]=[C:6]([C@H:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:16]([CH3:27])[CH:15]=3)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=2)=[CH:35][C:30]=1[O:29][CH3:28])(=[O:47])[CH3:46]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(C)=O
Reactant: CCCC[C@@H](Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCC[C@@H](Oc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(C)=O)c(OC)c2)n1
Temperature: 80 °C
Yield: 74.2 %

Procedure:
Ethyl [(4-{[(1R)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (50 mg, 0.11 mmol) was dissolved in DME (0.76 mL) and then treated with 1-[2-(methyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (41 mg, 0.15 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and then a solution of Na2CO3 (49 mg, 0.46 mmol) in water (0.42 mL). The resulting mixture was then placed under nitrogen and heated at 80° C. for 18 h. The solvents were the removed under vacuum (Genevac) and the residue purified by mass directed autoprep HPLC) to give the title compound as an oil (39 mg).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[O:34][CH3:33])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: COc1ccccc1CN
Solvent: O
Solvent: CCO
Product: COc1ccccc1CNc1ncnc2c1ncn2C1O[C@H](COC(=O)c2ccccc2)C(C)(OC(C)=O)[C@@]1(C)F
Yield: 33 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (5 ml) was added 2-methoxybenzylamine (about 0.67 ml, 5.19 mmol) and refluxed for about 20 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.08 g) as a colorless gummy mass. Yield: 35%; 1H NMR (300 MHz, CDCl3): δ 8.51 (s, 1H), 8.06-7.96 (m, 3H), 7.58-7.33 (m, 5H), 6.94-6.88 (m, 2H), 6.54 (d, 1H, J=23.1 Hz), 6.27 (bs, 1H), 4.85-4.78 (m, 2H), 4.48-4.44 (m, 1H), 3.88 (s, 3H), 2.16 (s, 3H), 1.88 (d, 3H, J=2.4 Hz), 1.44 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 564 (100%), [M+Na]+ 586 (60%); IR cm−: 3429, 2929, 2863, 2177, 1733, 1466, 1240, 1033, 713; HPLC: 93.1%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(Br)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
To a solution of methyl (6-bromopyridin-2-yl)acetate (Example 350, Step 1) (6.00 g, 26.1 mmol) in CCl4 (100 mL) were added NBS (4.87 g, 27.4 mmol) and benzoyl peroxide (474 mg, 1.96 mmol). The reaction was heated at reflux overnight. The solution was then cooled to room temperature, filtered, and evaporated. Silica gel chromatography (0-40% EtOAc/hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18]([NH2:32])=[N:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:33]([O-:35])=[O:34])[CH:3]=1.[CH2:36]([N-:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[C:37]#[CH:38].CCN(CC)CC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:7]1[C:2]([C:38]#[C:37][CH2:36][NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[CH:3][C:4]([N+:33]([O-:35])=[O:34])=[C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18]([NH2:32])=[N:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:13])([CH3:14])[CH3:12])[CH:6]=1
Reactant: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c([N+](=O)[O-])cc1I
Reactant: C#CC[N-]C(=O)C(F)(F)F
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c([N+](=O)[O-])cc1C#CCNC(=O)C(F)(F)F
Yield: 91.6 %

Procedure:
A solution of compound 66 (245 mg, 0.4 mmol), N-propargyltrifluoroacetylamide (603 mg, 4.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (92 mg, 0.8 mmol), CuI (30 mg, 0.16 mmol), and Et3N (240 μL, 1.7 mmol) in anhydrous DMF (5.0 mL) was stirred at 50° C. for 12 hours. The mixture was concentrated in vacuo and purified by silica gel column chromatography to yield 5-{(S)-1-[5-methoxy-4-(3-trifluoroacetamido-1-propynyl)-2-nitrophenyl]-2,2-dimethyl-propyloxy}methyl-2′-deoxycytidine 67 (230 mg, 91%). 1H NMR (400 MHz, MeOD-d4): δ 7.98 (s, 1H, Ph-H), 7.92 (s, 1H, H-6), 7.19 (s, 1H, Ph-H), 6.15 (t, 1H, J=6.4 Hz, H-1′), 5.21 (s, 1H, Ph-CH), 4.41 (d, 1H, J=13.2 Hz, 5-CH2a), 4.33 (m, 3H, H-3′ and CH2), 4.27 (d, 1H, J=13.2 Hz, 5-CH2b), 3.96 (s, 3 H, OCH3), 3.88 (m, 1H, H-4′), 3.72 (m, 2H, H-5′), 2.30 (m, 1H, H-2′a), 2.12 (m, 1H, H-2′b), 0.84 (s, 9H, C(CH3)3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:34][CH3:35])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([OH:33])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:14])([F:15])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:34][CH3:35])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([O:33][CH2:43][C:44]([F:47])([F:46])[F:45])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(O)cnc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OCC(F)(F)F)cnc12
Temperature: 40 °C
Yield: 36.1 %

Procedure:
tert-Butyl[(1R,2R)-2-({[5-ethyl-4-(6-hydroxypyrazolo[1,5-a]pyrimidin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (81.0 mg, 0.155 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (40.3 mg, 0.173 mmol), and potassium carbonate (27.9 mg, 0.202 mmol) were placed in a sealed tube and heated to 40° C. for 6 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with 1N NaOH (aq) once and 1N HCl (aq) twice. Water was added and the product extracted 3× with dichloromethane. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via column chromatography (0-100% EtOAc/Hex) to give the title compound (34.0 mg, 0.056 mmol). LRMS (APCI) calc'd for (C26H30F5N5O4S) [M+H]+, 604.2; found 604.0.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9]C1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[CH3:17][Si:2]([CH3:1])([CH3:16])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: C[Si](C)(C)C#CCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C[Si](C)(C)C#CCCCCO
Yield: 73.6 %

Procedure:
1-Trimethylsilyl[6-(oxacyclohex-2-yloxy)]hex-1-yne (76 g, 300 mmol) and pyridinium p-toluenesulfonate (0.05 g) were heated at reflux in methanol (200 mL). After cooling the solvent was removed under reduced pressure, the residue was dissolved in methylene chloride and washed with water, brine and dried (MgSO4). Evaporation of the solvent under reduced pressure afforded a residue which was distilled (b.p. 96° C., 3 mm Hg) to give 37.6 g (64%) of the product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.[CH:22]1([C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[N:30]=[C:29]([C:31]3[NH:1][C:2]4=[N:7][C:6]([N:8]5[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:9]5)=[CH:5][CH:4]=[C:3]4[N:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1
Reactant: CN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Reactant: O=Cc1cccc(C2CC2)n1
Product: CN(C)C(=O)[C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1

Procedure:
The title compound was prepared using a method analogous to the one used for Example 112 but using (R)-1-(6-amino-5-nitropyridin-2-yl)-N,N-dimethylpiperidine-3-carboxamide and 6-cyclopropylpicolinaldehyde as starting materials. 1H NMR (300 MHz, CDCl3) δ 1.01-1.18 (m, 4H), 1.63-1.74 (m, 1H), 1.84 (m, 1H), 1.93 (m, 2H), 2.10 (br s, 1H), 2.85 (br s, 1H), 2.96-3.03 (m, 3H), 3.08 (m, 1H), 3.15 (s, 3H), 3.50 (s, 1H), 4.35 (d, 1H), 4.50 (d, 1H), 6.73 (d, 1H), 7.20 (d, 1H), 7.68 (d, 1H), 7.89 (d, 1H), 8.10 (br s, 1H), 10.14 (br. s, 1H); MS (ES+APCI) (M+H) 391.2; LCMS retention time 1.831 min (Method W).
Reaction SMILES: [CH2:1]1[O:7][P:5]([OH:8])(=[O:6])[CH2:4][O:3][C@H:2]1[CH2:9][N:10]1[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[CH:12]=[CH:11]1.C1(NC(N2CCOCC2)=NC2CCCCC2)CCCCC1.Br[CH2:40][CH2:41][CH2:42][O:43][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][CH3:59]>>[CH3:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][CH2:40][O:6][P:5]1([O:7][CH2:1][C@H:2]([CH2:9][N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[CH:12]=[CH:11]2)[O:3][CH2:4]1)=[O:8]
Reactant: Nc1ccn(C[C@H]2COP(=O)(O)CO2)c(=O)n1
Reactant: CCCCCCCCCCCCCCCCOCCCBr
Agent: C1CCC(N=C(NC2CCCCC2)N2CCOCC2)CC1
Product: CCCCCCCCCCCCCCCCOCCCOP1(=O)CO[C@@H](Cn2ccc(N)nc2=O)CO1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a heterogeneous solution of cyclic cidofovir (39 g, 0.131 mol., 1 equiv, purchased from Gilead Sciences) in N,N-DMF (2.0 L) under a nitrogen atmosphere was added N,N′-dicyclohexyl-4-morpholinecarboxamidine (DCMC) (0.131 mol, 38.51 g, 1 equiv.). This was stirred overnight. This dissolved most of the solid in the reaction mixture. To this solution was added 1-bromo-3-hexadecyloxypropane (238.45 g, 0.656 mol, 5 equiv.). The reaction mixture was heated to 80° C. and stirred for 6 hours. The crude reaction mixture was concentrated in vacuo at 80° C. The crude reaction mixture was absorbed on silica gel (300 g) and purified via column chromatography (800 g SiO2). The column was eluted with dichloromethane (6 L) to remove the excess 1-bromo-3-hexadecyloxypropane. The solvent phase was then switched to 9:1 CH2Cl2:EtOH(32 L). The product came off with this solvent system. Fractions 30-39 were combined to give hexadecyloxypropyl-cyclic cidofovir (17.8 g) in a 25% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[C:8](C)[CH:9]=1)(=[O:3])[NH2:2].NC1C=C(C=C([F:36])C=1)C(N)=O.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[C:8]([F:36])[CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(C(Nc2cc(C)cc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: NC(=O)c1cc(N)cc(F)c1
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2cc(F)cc(C(N)=O)c2)C(=O)O)cc1OC

Procedure:
Using a procedure analogous to that described for the preparation of 89D, 91A was reacted with 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate to give 91B. 1H NMR (400 MHz, CD3OD) δ ppm 3.81 (s, 3H) 3.82 (s, 3H) 5.06 (s, 1H) 6.49 (d, J=11.43 Hz, 1H) 6.79 (d, J=9.23 Hz, 1H) 6.93 (d, J=8.35 Hz, 1H) 6.97 (s, 1H) 7.04-7.10 (m, 1H) 7.12 (s, 1H); LC/MS 349 (M+H).
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][O:6][CH2:7][C:8]([NH2:10])=[NH:9].[CH2:11]([O:13][CH2:14][C:15](=O)[CH2:16][C:17](OCC)=[O:18])[CH3:12]>CO>[CH2:11]([O:13][CH2:14][C:15]1[N:10]=[C:8]([CH2:7][O:6][CH3:5])[N:9]=[C:17]([OH:18])[CH:16]=1)[CH3:12]
Reactant: COCC(=N)N
Reactant: CCOCC(=O)CC(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOCc1cc(O)nc(COC)n1
Reaction time: 4 h
Yield: 85.8 %

Procedure:
Sodium methylate (6.5 g, 0.12 mole) was added to a solution of methoxyacetamidine hydrochloride (6.23 g, 0.05 mole) and ethyl ethoxyacetoacetate (8.72 g. 0.05 mole) in methanol (50 ml) at room temperature, and the resulting white suspension liquor was stirred at 45° to 50° C. for 4 hours. The reaction mixture was treated in the same manner as in Example 5. Recrystallization from ether gave 8.5 g of 6-(ethoxymethyl)-4-hydroxy-2-(methoxymethyl)pyrimidine as white needle-like crystals (m.p. 96.5°-98° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]=12)#[N:2].[OH-].[Na+].OO.S([O-])([O-])(=[O:25])=S.[Na+].[Na+]>CO.O>[C:1]([C:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]=12)(=[O:25])[NH2:2]
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCn2ccc(C#N)c2C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2ccc(C(N)=O)c2C1
Temperature: 55 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
To a solution of 26.7 g (108 mmol) of tert-butyl 8-cyano-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 490 ml of methanol are added 80 ml (864 mmol) of concentrated aqueous 32% sodium hydroxide and 4.0 g (41 mmol) of aqueous 35% hydrogen peroxide solution. The reaction medium is heated at 55° C. for 2 hours. 4 times 4.0 g (41 mmol) of aqueous 35% hydrogen peroxide solution are then added every 2 hours and heating is then continued at 55° C. for 18 hours. The medium is then treated with an aqueous solution of 30 g (190 mmol) of sodium thiosulfate in 250 ml of water and the reaction mixture is stirred for 1 hour and then partially concentrated under reduced pressure. The product is extracted with 350 ml and then twice 100 ml of dichloromethane, and the organic phases are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in a mixture of dichloromethane and ethyl acetate and then precipitated by slow concentration to give 21.1 g of tert-butyl 8-carbamoyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after drying in an oven at 60° C. under reduced pressure.
Reaction SMILES: Br[CH:2]([C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1)[C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:13])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=O.CON(C)C(C1C=CC2[N:38](C3C=CC=CC=3)[C:39](=O)[NH:40]C=2C=1)=O.O.C(N)=O>[OH-].[NH4+]>[CH3:12][N:11]1[C:7]2[CH:6]=[C:5]([C:3]3[N:38]=[CH:39][NH:40][C:2]=3[C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[CH:21]=[CH:20][C:8]=2[N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:13]
Reactant: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)n(C)c(=O)n3-c2ccccc2)c1
Reactant: CON(C)C(=O)c1ccc2c(c1)[nH]c(=O)n2-c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: NC=O
Product: Cc1cccc(-c2[nH]cnc2-c2ccc3c(c2)n(C)c(=O)n3-c2ccccc2)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
5-(Bromo-m-tolyl-acetyl)-3-methyl-1-phenyl-1,3-dihydro-benzoimidazol-2-one (prepared from 2-oxo-1-phenyl-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide as described in the general procedure, 0.26 gm, 0.60 mmol) was added to 5 mL of 8% water/formamide and the mixture was heated to 140° C. for 14 hours. The reaction mixture was then cooled to room temperature and diluted with 20 mL of ammonium hydroxide with rapid stirring. After stirring for ½ hour, the solid precipitate was filtered and purified by column chromatography (0.5% methanol in ethyl acetate) to afford 75 mg of the title compound. MS (M+1)=381.2
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[C:28]2[CH2:27][CH2:26][C@H:25]3[C@@H:20]([CH2:21][CH2:22][CH2:23][NH:24]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@H:20]([C:19]5[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[C:28]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1cccc2c1CC[C@@H]1NCCC[C@@H]21
Product: COc1cccc2c1CC[C@H]1[C@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 49 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-7-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 49% of theory; LC (method 1): tR=2.68 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: NCCCCCCSc1ccc(Cl)cc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCCCCCCSc2ccc(Cl)cc2)c(Nc2ccncc2)c1=O
Yield: 62 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 6-(4-chloro-phenylsulfanyl)-hexylamine