Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].[Cl:8][C:9](=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH3:11].[CH2:23]([N:25]1[C:29]([NH2:30])=CC=[N:26]1)[CH3:24]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([CH2:1][CH3:2])[N:30]=[C:29]2[N:25]([CH2:23][CH3:24])[N:26]=[CH:11][C:10]=12
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(C(=O)OCC)=C(Cl)CC
Reactant: CCn1nccc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Temperature: 25 °C

Procedure:
Triethylamine (230 ml) was added dropwise to a mixture of diethyl (1-chloropropylidene)propanedioate (208 g, e.g. which can optionally be as prepared in Intermediate 2) and 1-ethyl-1H-pyrazol-5-amine (101 g, e.g. which can optionally be as prepared in Intermediate 1) in toluene (2.65 L). The mixture was heated under reflux for 16 hours. The reaction mixture was then cooled to room temperature, and filtered through a sintered glass funnel to remove the solid present. The filtrate was evaporated under reduced pressure. The residue was then treated with phosphorus oxychloride (POCl3, 2.65 L) and the mixture was heated under reflux for 16 hours. Excess phosphorus oxychloride was removed by distillation (e.g. under reduced pressure). The reaction mixture was then cooled and poured onto a mixture of saturated aqueous sodium hydrogen carbonate solution (4 L) and ethyl acetate (1.5 L), maintaining the temperature at 5° C. The organic layer was separated and the aqueous layer further extracted with ethyl acetate (2×1 L). The combined organic extracts were washed with aqueous sodium hydrogen carbonate solution (1×2 L, e.g. optionally a saturated solution thereof) and were dried (Na2SO4). Evaporation of solvent under reduced pressure afforded the crude product (202 g). The crude product was purified by chromatography (silica gel 60-120 mesh, 3.5 kg) eluting with 3% ethyl acetate in hexane. Fractions containing the product were pooled and evaporated to give the title compound (133 g) (which in one embodiment can be e.g. a pale yellow thick liquid or oil which may solidify on standing). 1H NMR (200 MHz, chloroform-d) δ (delta) ppm 1.37 (3H, t, J=7.1 Hz), 1.45 (3H, t, J=7.1 Hz), 1.57 (3H, t, J=7.2 Hz), 2.91 (2H, q, J=7.1 Hz), 4.48 (2H, q, J=7.2 Hz), 4.57 (2H, q, J=7.1 Hz) 8.05 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1.I[CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44]>CN(P(N(C)C)(N(C)C)=O)C.CN(C=O)C>[CH3:42][C:43]([CH3:46])([CH3:45])[CH2:44][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:5][C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Reactant: CC(C)(C)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(CC(C)(C)C)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
To a cooled (−15° C.) solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.200 g; 0.589 mmol) in a mixture of dry DMF (1.2 mL) and HMPA (0.3 mL) was wadded a 1N solution of KHMDS in THF (0.825 mL; 0.825 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of 1-iodo-2,2-dimethylpropane (0.313 mL; 2.357 mmol). After stirring for 1 h at (−15° C.) the mixture was allowed to warm up to room temperature and stirring was carried on 4 h. The reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.024 g (9%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[F:31])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>C(Cl)Cl>[F:31][C:22]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][NH:18][C:12]1[N:13]=[C:14]([O:16][CH3:17])[N:15]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:42](=[O:43])[CH2:41][O:40][CH3:39])[CH:9]=[CH:8][CH:7]=2)[CH:11]=1
Reactant: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CCN)c2)n1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)NCCc1cccc(-c2cc(NCCc3ccc(C(F)(F)F)cc3F)nc(OC)n2)c1
Reaction time: 0.17 h

Procedure:
A solution of {6-[3-(2-amino-ethyl)-phenyl]-2-methoxy-pyrimidin-4-yl}-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine (150 mg, 0.35 mmol) and triethylamine (0.24 mL, 1.73 mmol) in DCM (5 mL) is treated with methoxyacetyl chloride (75 mg, 0.69 mmol) at 10° C. After 10 minutes at 10° C., the mixture is quenched with aqueous NaHCO3 solution (8 mL), and filtered through Chem-Elut with CH2Cl2 washing (10 mL). The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 80% EtOAc in heptane to 5% MeOH in CH2Cl2 to give N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-2-methoxy-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-2-methoxy-acetamide hydrochloride [76 mg, Example 64]. LCMS: RT=2.24 minutes, MS: 507 (M+H). 1H NMR (300 MHz, CDCl3) □9.35 (1H, s), 7.9 (1H, brs), 7.6-7.4 (7H, m), 6.65 (1H, s), 4 (3H, s), 3.76 (3H, s), 3.8-3.7 (2H, m), 3.4 (2H, q, J=6.9 Hz), 3.25 (2H, s), 3.06 (2H, t, J=6.6 Hz), 2.82 (2H, t, J=7.5 Hz). IC50=56 nM
Reaction SMILES: [BrH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:16])[C:11](=[O:15])[NH:12]2)=[C:7]([CH2:17][NH:18][CH:19](C2C=CC=CC=2)CC(O)=O)[CH:6]=1)([O-:4])=[O:3].CO.[C:32]([OH:35])(=O)[CH3:33]>>[BrH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:16])[C:11](=[O:15])[NH:12]2)=[C:7]([CH2:17][N:18]([CH3:19])[CH2:33][CH2:32][OH:35])[CH:6]=1)([O-:4])=[O:3]
Reactant: CC(=O)O
Reactant: O=C(O)CC(NCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)c1ccccc1
Agent: Br
Solvent: CO
Product: CN(CCO)Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
3-[N-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)amino]-3-phenyl-propionic acid hydrobromide, ESCl+ -MS: (M+H)+ =385; TLC: methanol/acetic acid (9:1) Rf =0.34;
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1)=[O:4].[F:15][C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)(=[O:24])=[O:23])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1n[nH]c2ccc(N)cc12
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: CNC(=O)c1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 27.9 %

Procedure:
N-Methyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide can be obtained as described in Example 2 from 40 mg of N-methyl-5-amino-1H-indazole-3-carboxamide, 1.2 ml of pyridine and 40 mg of 3-fluorobenzenesulfonyl chloride. 20 mg of N-methyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide are thus obtained in the form of an off-white solid melting above 260° C. (Analysis C15H13N4O3S.0.74H2O % calculated C, 51.72; H, 3.76; F, 5.45; N, 16.08; O, 13.78; S, 9.20. % found C, 51.74; H, 3.31; N, 15.71; S, 8.36).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:14]([CH3:31])=[C:13]([CH3:32])[N:12]=1>COCCOCCOC.C(OCC)(=O)C>[CH3:32][C:13]1[C:14]([CH3:31])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCc2ccncc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCc2ccncc2)c1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
Under a nitrogen atmosphere, diglyme (25 mL) was added to sodium hydride (1.81 g, 45.2 mmol), which is available as a 60% dispersion in mineral oil, and the mixture was cooled to 5° C. A solution of phenol (4.54 g, 48.2 mmol) in diglyme (50 mL) was added dropwise over a period of 15 minutes. The reaction became homogeneous after 15 minutes. A solution of (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-[2-(pyridin-4-ylmethoxy)ethyl]amine (10.15 g, 30.14 mmol) was added, and the reaction was heated at 160° C. for 13 hours. An analysis by HPLC indicated the presence of starting material. Additional phenol (3.12 g, 33.2 mmol) was added to 60% sodium hydride (1.24 g, 31.1 mmol) in diglyme, and the mixture was stirred until it became homogeneous. This solution was added to the cooled reaction flask, and the reaction was heated at 160° C. for 9.5 hours. The reaction was allowed to cool to room temperature, and the volatiles were removed under reduced pressure to provide a black oil. The oil was dissolved in ethyl acetate, and the solution was washed with 1 N potassium hydroxide (3×) and brine (3×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 80:20 ethyl acetate:hexane) to provide 2.47 g of (2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)-[2-(pyridin-4-ylmethoxy)ethyl]amine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12](O)[C:11]=1[I:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([Cl:20])[C:11]=1[I:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc(COCc2ccccc2)c1I
Product: Clc1ncnc(COCc2ccccc2)c1I
Yield: 97 %

Procedure:
A solution of 6-benzyloxymethyl-4-hydroxy-5-iodo-pyrimidine (6.56 g, 1.9 mmol) dissolved in phosphorus oxychloride (200 ml) was stirred at reflux for 20 min. The POCl3 was removed under reduced pressure and the residue evaporated from toluene. The reddish residue was partitioned between ice-water and t-butyl methyl ether, then treated with NaHCO3, and the layers separated, and the aqueous layer was further extracted (×2). The combined organic extracts were washed twice with 5% sodium bicarbonate solution and once with brine, and then dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product as a brown oil (6.64 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][C:5]([CH2:8][S:9]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:33])=[N:6][CH:7]=1
Reactant: Cc1cnc(CSc2cc3ccccc3[nH]2)cc1N1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cnc(CS(=O)c2cc3ccccc3[nH]2)cc1N1CCCCC1
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of 2-[(5-methyl-4-piperidino-2-pyridyl)methylthio]indole (80 mg, 0.24 mmol) in chloroform (2.4 ml) was added m-chloroperbenzoic acid (60 mg, 0.35 mmol) under ice-cooling, and the mixture was stirred at that temperature for further 30 minutes. The reaction solution was diluted with chloroform (10 ml) and then washed with a 1% aqueous sodium hydrogen carbonate solution (2.5 ml) and then with a saturated aqueous sodium chloride solution (1 ml). The resulting chloroform layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. Ethylether (20 ml) was added to the resulting concentration residue to precipitate crystals. After filtration, the titled compound (68 mg) was obtained. Yield: 81%, m.p.: 178° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.Cl.[NH2:24][C:25]1[CH:34]=[CH:33][C:32]([N:35]([CH3:37])[CH3:36])=[CH:31][C:26]=1[C:27](OC)=[O:28].[C:38](N1C=CN=C1)(N1C=CN=C1)=[O:39].C(#N)C>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:27](=[O:28])[C:26]3[C:25](=[CH:34][CH:33]=[C:32]([N:35]([CH3:36])[CH3:37])[CH:31]=3)[NH:24][C:38]2=[O:39])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(N(C)C)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(-n2c(=O)[nH]c3ccc(N(C)C)cc3c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
3 g of N-(t-butoxycarbonyl)-4-amino-L-phenylalanine methylester, 2.73 g of methyl 2-amino-5-(dimethylamino)benzoate dihydrochloride, 1.65 g of CDI (carbonyldiimidazole) and 50 mL of acetonitrile were stirred at room temperature. Then, 2.8 mL of triethylamine was added thereto and stirred at 60° C. overnight. After removing the solvent, the obtained residue was extracted with ethyl acetate, washed with water and saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removing the solvent, the obtained residue was purified with silica gel column chromatography to obtain 2 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)Cl
Temperature: 25 °C
Yield: 119.8 %

Procedure:
2-Amino-4-nitrobenzoic acid (15 g, 82 mmol) was refluxed with sulfurous dichloride (40 mL, 82 mmol) for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated to give Intermediate 69A (19.7 g, 119%) as a brown oil. HPLC: Rt=2.323 (as methyl ester) min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm.). MS (ES): m/z=197 (as methyl ester) [M+H]+.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:25]([CH3:27])[CH3:26])[C:11]([N:13]([CH2:21][C:22](O)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:58])[CH:34](N)[C@H:35](C(OCC=C)=O)[CH:36]([C:38]1[O:39][CH:40]=[C:41]([C:43]2[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=2[Cl:50])[N:42]=1)[OH:37])([CH3:31])([CH3:30])[CH3:29].C([SnH](CCCC)CCCC)CCC.C1C=CC2N(O)N=[N:78]C=2C=1.C(Cl)CCl>[Pd](Cl)Cl.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.CN(C=O)C.C(Cl)Cl>[C:28]([O:32][C:33](=[O:58])[CH2:34][C@H:35]([NH:78][C:22](=[O:23])[CH2:21][N:13]([C:11](=[O:12])[C@@H:10]([NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:25]([CH3:27])[CH3:26])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:36]([C:38]1[O:39][CH:40]=[C:41]([C:43]2[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=2[Cl:50])[N:42]=1)[OH:37])([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Reactant: On1nnc2ccccc21
Agent: Cl[Pd]Cl
Agent: CCCC[SnH](CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a suspension of compound 704 (318 mg, 0.86 mmol) and compound 707 (370 mg, 0.78 mmol) in 1:1 CH2Cl2 :DMF (8.0 mL) was added bis(triphenylphosphine) palladium dichloride (10 mg), followed by the dropwise addition of tri-n-butyl tin hydride (320 μL, 1.19 mmol). After the addition was complete, HOBT (212 mg, 1.57 mmol) was added and the reaction was cooled to 0° C. added EDC (180 mg, 0.94 mmol) was added and the reaction allowed to warm to rt and stir overnight. The reaction was concentrated in vacuo and the residue taken up into EtOAc and sat. aq. KHSO4. The layers were separated and the organic phase was washed with sat. aq. K2CO3, brine, dried over MgSO4, filtered and concentrated in vacuo. Chromatography on silica gel (elution with 2% MeOH:CH2Cl2) provided 150 mg of compound 708. ##STR87##
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].FC(F)(F)C(O)=O.S(Cl)(Cl)=O>>[C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[CH:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(OCCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: CC(=O)CC(=O)C=Cc1ccc(OCCc2ccccc2)cc1

Procedure:
The procedure described in example 8 was repeated by using 5.9 g of 4-(2-phenylethoxy)benzaldehyde, 3.9 ml of 2,4-pentanedione, 26 ml of trifluoroacetic acid and 2.1 ml of thionyl chloride. Yield 4.7 91 an viscous oil.
Reaction SMILES: [F:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].CS([O-])(=O)=O.[CH2:24](O)[CH2:25][CH2:26][OH:27]>>[F:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:24][CH2:25][CH2:26][OH:27]
Reactant: OCCCO
Reactant: CC(F)CCCCCCCCCCCCCCO
Agent: CS(=O)(=O)[O-]
Product: CC(F)CCCCCCCCCCCCCCOCCCO

Procedure:
A general procedure for the preparation of penultimate fluorinated alkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated in Scheme 6, below. Fluoroalkoxyalkyl esters of acyclic nucleoside phosphonates such as 3-(15-fluorohexadecyloxy)propyl cidofovir 42 (15-F-HDP-CDV) and 3-(15-fluorohexadecyloxy)propyl (S)-HPMPA 43 (15-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, with reference to Scheme 6, commercially available 2-bromopropanoic acid 35 is reduced to the alcohol with borane:THF complex solution to provide 2-bromo-1-propanol 36. Fluorination of 36 is achieved with 1,1,2-trifluoro-2-chloroethyldiethylamine, a mild and safe reagent to convert 1-hydroxy-2-halogenoalkanes into the corresponding rearranged fluoride 37. Conversion of 37 into a Grignard reagent followed by reaction with 13-bromo-tridecanol in the presence of the catalyst provides 15-fluorohexadecanol 38. Conversion of alcohol 38 into the methanesulfonate derivative, followed by reaction with 1,3-propanediol provides 3-(15-fluorohexadecyloxy)propan-1-ol 39. Reaction of 39 with cyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2 (step a), provides the cyclic esters (40 and 41, respectively) which can then be converted to the desired compounds (42 and 43, respectively) using the general method set forth in Example 2 (step b).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[N:15]=[CH:14][C:13]([NH:16]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)=[C:6]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[O:33])=[CH:27][C:26]=2[F:45])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:54]>>[ClH:54].[ClH:54].[NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][N:15]=2)=[C:6]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[O:33])=[CH:27][C:26]=2[F:45])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2c(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccnc2N)nc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Nc1ccc(C#Cc2c(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccnc2N)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 6-(2-(2-amino-4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)ethynyl)pyridin-3-ylcarbamate (23 mg, 0.037 mmol) in CH2Cl2 (2 mL) and treated with TFA (0.5 mL) and stirred at RT for 1 h. The mixture was concentrated in vacuo and the crude product purified by preparative HPLC (Column B) and converted to its hydrochloride salt (11 mg, 52%) in the same manner as Step E of Example 36. 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 10.62 (s, 1H), 8.05 (s, 1H), 7.97 (d, 1H, J=2.7 Hz), 7.94 (d, 1H, J=7.1 Hz), 7.82 (d, 1H, J=12.1 Hz), 7.66 (d, 1H, J=8.8 Hz), 7.45-7.45 (m, 2H), 7.35 (dd, 2H, J=8.2, 5.5 Hz), 7.20 (d, 1H, J=6.6 Hz), 7.16 (t, 2H, J=8.8 Hz), 6.24 (d, 1H, J=6.6 Hz), 3.74 (s, 2H); MS(ESI+): m/z 515.19 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4](C(OCC)=O)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37].CO>CN(C=O)C>[CH3:39][N:38]([CH3:40])[C:36](=[O:37])[CH2:35][O:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: CCOC(=O)n1[nH]c(=O)c2cnc(NC(=O)N[C@H](C)c3ccccc3)cc21
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(OCC(=O)N(C)C)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-Ethyl 3-oxo-6-(3-(1-phenylethyl)ureido)-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (29 mg, 0.079 mmol), potassium carbonate (32.6 mg, 0.236 mmol), and 2-chloro-N,N-dimethylacetamide (8.8 μL, 0.087 mmol) were stirred in DMF (1 mL) at room temperature for 24 h. MeOH (0.5 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The insoluble inorganics were removed by filtration and the reaction mixture was purified via mass triggered, reverse phase prep-HPLC. Fractions containing pure product were concentrated in vacuo and the residue dissolved in MeOH. The MeOH solution was passed through a PS—HCO3 cartridge and the filtrate concentrated in vacuo to give (R)—N,N-dimethyl-2-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yloxy)acetamide. MS ESI calc'd. For C19H22N6O3 [M+1]+ 383. found 383. 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.94 (s, 1H), 8.58 (s, 1H), 7.77 (br s, 1H), 7.49 (s, 1H), 7.34-7.31 (m, 4H), 7.25-7.20 (m, 1H), 5.04 (s, 2H), 4.89-4.83 (m, 1H), 2.98 (s, 3H), 2.82 (s, 3H), 1.39 (d, J=7.0 Hz, 3H).