Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Cl)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[C:18]([O:22][C:23](=[O:26])[NH:24][NH2:25])([CH3:21])([CH3:20])[CH3:19]>C(O)CCC>[C:18]([O:22][C:23](=[O:26])[NH:24][NH:25][C:4]1[N:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[C:2]([CH3:1])[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc(Cl)nnc1-c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCCCO
Product: Cc1cc(NNC(=O)OC(C)(C)C)nnc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 5.49 g. of 5-methyl-6-(m-nitrophenyl)-3-chloropyridazine and 8.71 g. of t-butylcarbazate in 100 ml. of butanol is heated at reflux for 3 hours and then allowed to cool to room temperature overnight. The butanol is removed on a rotating evaporator leaving a heavy liquid residue. The final product is obtained after crystallization from a minimum amount of methanol on standing, washing with methanol, water and drying, m.p. 160°-162° C.
Reaction SMILES: [N:1]1C=CC=CC=1N1CCNCC1.[CH3:13][CH:14]([NH:28][C:29]([C:31]1[O:35][C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[N:33][C:32]=1[CH2:43][CH2:44][CH3:45])=[O:30])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1>>[NH2:1][C:24]1[N:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:14]([NH:28][C:29]([C:31]3[O:35][C:34]([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)=[N:33][C:32]=3[CH2:43][CH2:44][CH3:45])=[O:30])[CH3:13])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCCc1nc(-c2ccc(F)cc2)oc1C(=O)NC(C)CN1CCN(c2ccccn2)CC1
Product: CCCc1nc(-c2ccc(F)cc2)oc1C(=O)NC(C)CN1CCN(c2cccc(N)n2)CC1

Procedure:
Similarly, following the procedure set forth in Example 1(B-G) substituting 1-pyridin-2-yl-piperazine for (intermediate “Ia”), 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid [1-methyl-2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-amide (compound 24) was prepared.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11]([CH3:15])[CH2:12][CH2:13]O>>[CH2:13]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:13][CH2:12][CH:11]([CH3:15])[CH3:10])=[O:6])[OH:3])[CH2:12][CH:11]([CH3:15])[CH3:10]
Reactant: CC(C)CCO
Reactant: O=C(O)CC(O)C(=O)O
Product: CC(C)CCOC(=O)CC(O)C(=O)OCCC(C)C
Temperature: 110 °C

Procedure:
Diisoamyl-DL-malate was prepared using a procedure similar to that in Example 4. To the reaction flask, DL-malic acid (87.54 g), 3-methyl-1-butanol (285 mL) and Amberlyst® 15 ion exchange resin (11.9) were added. The mixture was placed under nitrogen and heated to reflux. At 109° C., two phases started to collect in the Dean-Stark trap. The reaction was maintained at 110° C. for 8 hr, during this time water was continuously removed. The product was dissolved in diethyl ether and separated from the catalyst via filtration over a bed of silica. The organic layer was washed with saturated sodium bicarbonate a number of times, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Diisoamyl-DL-malate was obtained as a low viscosity, clear colorless liquid with a slight odor (130 g, 72% yield) after pumping on the sample in vacuo to remove residual 3-methyl-1-butanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:61]1[CH:62]=[N:63][CH:64]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:66]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][C:61]2[CH:62]=[N:63][CH:64]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:66]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: Cc1cc(NC(=O)c2nc(C)sc2N)ccn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2nc(C)sc2Nc2cncc(C(F)(F)F)c2)ccn1
Yield: 46.4 %

Procedure:
A microwave vial was charged with 5-amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide (0.200 g, 0.806 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.159 g, 0.275 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.086 g, 0.083 mmol). Degassed dioxane (10 ml) was added, followed by 3-bromo-5-(trifluoromethyl)pyridine (0.223 g, 0.991 mmol) and cesium carbonate (0.527 g, 1.62 mmol) The vial was then irradiated in a microwave oven at 150° C. for 90 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography on silica gel with dichloromethane/methanol 100:0→90:10 gradient to yield the title compound (0.147 g, 46%) as an off-white solid, MS (ISP): m/e=394.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=O)[CH2:8][CH:7]1[CH3:21])=[O:5])[CH3:2].Cl.[NH2:23][OH:24].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=[N:23][OH:24])[CH2:8][CH:7]1[CH3:21])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=NO)CC1C
Reaction time: 0.17 h
Yield: 116.8 %

Procedure:
A stirred solution of 6,7-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (10.0 g, 34.1 mmol), hydroxylamine hydrochloride (7.1 g, 102 mmol), and sodium acetate (7.0 g, 85 mmol) in ethanol (50 mL) was heated at reflux for 2 h. Water (50 mL) was added, and the volatiles were removed in vacuo. Ethyl acetate (175 mL) was added, and the mixture was stirred vigorously for 10 min. The aqueous phase was separated and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white foam (12.28 g, ca. 100%). 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.32 (t, 3H), 2.77 (dd, 1H), 3.07 (dd, 1H), 3.89 (s, 6H), 4.2-4.4 (m, 2H), 5.0 (m, 1H), 7.18 (s, 1H), 7.26 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([Cl:18])=[C:7]([CH:14]=[C:15]([Br:17])[CH:16]=1)[C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])C=C.BrC1C(OC)=C(OC)C(Cl)=C(C=1)[C:25](O)=[O:26]>>[Br:17][C:15]1[C:16]([O:26][CH3:25])=[C:5]([O:4][CH3:1])[C:6]([Cl:18])=[C:7]([CH:14]=1)[C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9]
Reactant: COc1c(Br)cc(C(=O)O)c(Cl)c1OC
Reactant: C=CCOc1cc(Br)cc(C(=O)N(C)OC)c1Cl
Product: COc1c(Br)cc(C(=O)N(C)OC)c(Cl)c1OC

Procedure:
Similar procedure with preparation of 182 proceeded except for using compound 158 to obtain the compound 195.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:5]([CH2:11][CH:12]1[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]1)=[N:6]2.[O-2].[Ca+2].[H][H]>[Pd].CO>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:4]2[C:3]3[C:7](=[N:8][CH:9]=[N:10][CH:2]=3)[N:6]=[C:5]2[CH2:11][CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ncnc(Cl)c32)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: Fc1ccc(Cn2c(CC3CCNCC3)nc3ncncc32)cc1
Yield: 54 %

Procedure:
A mixture of 15 parts of 6-chloro-7-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-7H-purine. 5 parts of calcium oxide and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia. (95:5→85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 5.8 parts (54%) of 7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purine as a residue (compound 55).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[NH:14][C:15](=[O:22])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=3[CH:11]=[C:10]([C:23](O)=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][C:28]1[N:32]=[C:31]([C@H:33]([NH2:35])[CH3:34])[O:30][N:29]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[NH:14][C:15](=[O:22])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=3[CH:11]=[C:10]([C:23]([NH:35][C@@H:33]([C:31]3[O:30][N:29]=[C:28]([CH3:27])[N:32]=3)[CH3:34])=[O:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(O)Cn1c(=O)[nH]c2c(-c3ccc(F)cc3)cc(C(=O)O)cc21
Reactant: Cc1noc([C@@H](C)N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c3[nH]c(=O)n(CC(C)(C)O)c3c2)n1
Temperature: 50 °C
Yield: 39.9 %

Procedure:
To a mixture of 7-(4-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (40 mg, 0.069 mmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (13.6 mg, 0.083 mmol), 1-hydroxy-7-azabenzotriazol (1.88 mg, 0.014 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (23.2 mg, 0.121 mmol) was added N,N-dimethylformamide (0.138 mL) followed by triethylamine (0.048 mL, 0.346 mmol). Reaction heated at 50° C. for 1.5 h. Reaction cooled and filtered. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TPA) gave the title compound (12.5 mg): LC-MS [M+1]=454.4; HRMS [M+1] found=454.1884; 1H NMR (500 MHz, CHCl3-d): δ 7.65 (1H, s), 7.51-7.47 (3H, m), 7.22-7.15 (2H, m), 6.97 (1H, d, J=7.81 Hz), 5.60-5.52 (1H, m), 3.85 (2H, s), 3.12 (1H, s), 2.35 (3H, s), 1.69 (3H, d, J=7.10 Hz), 1.29 (6H, s).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[N:23]1[CH:22]=[C:21]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([CH2:10][CH2:9][OH:8])[CH:20]=[CH:19]3)[CH:26]=[N:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc2cc(-c3cncnc3)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc2cc(-c3cncnc3)ccc2c1
Yield: 83 %

Procedure:
A solution of the product from Example 26C (56 mg, 0.154 mmol) and TBAF.H2O (48 mg, 0.184 mmol, 1.2 equiv.) in THF (3 mL) was stirred at room temperature under a dry nitrogen atmosphere for 30 min. The mixture was then partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was washed with brine then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give the title compound as an off-white solid (32 mg, 83% yield) which was used in the next step without further purification.
Reaction SMILES: F[C:2]([F:14])(F)[C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].N=C=N.Cl.[NH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].CCN(CC)CC>C(Cl)Cl>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:19][C:10]([C:8]1[S:9][C:5]([C:3](=[O:4])[CH2:2][F:14])=[CH:6][CH:7]=1)=[O:12]
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)s1
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: N=C=N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccc(C(=O)CF)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 1, A1 in DCM was added Pol-supported carbodiimide (2 eq) and the suspension was stirred at RT for 30 min. A solution of 2-aminoacetophenone HCl (1.1 eq) and Et3N (1.1 eq) in DCM was added and the resulting suspension was stirred at RT overnight. The resin was filtered, washed with DCM, and the filtrate was evaporated at reduced pressure. Purification by flash chromatography on silica gel eluting with DCM gave the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of 4-bromo-3-(trifluoromethyl)aniline (5.0 g, 20.8 mmol) and pyridine (16.9 mL, 208 mmol) in THF (60 mL) was treated slowly with methanesulfonyl chloride (2.10 mL, 27.1 mmol). The resulting yellow solution was stirred at room temperature for 2 hours, concentrated to dryness and then evaporated twice from toluene to afford syrup. The crude material was purified by silica gel chromatography eluting with 0% to 10% acetone in CH2Cl2 to afford Intermediate 52A (6.6 g, 100% yield) as a white solid. HPLC Ret timed: 3.32 min. MS: m/z=318, 320 [M+H]+; 1H NMR (500 MHz, CD3OD) δ ppm 7.80-7.75 (1 H, d), 7.63 (1 H, brs), 7.43-7.37 (1 H, d), 3.03 (3 H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][NH:19][CH2:20]2)=[O:15])([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([O:13][C:14]([N:16]1[CH:17]2[CH2:23][CH2:22][CH:21]1[CH2:20][N:19]([C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1)[CH2:18]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nn1)C2
Temperature: 130 °C
Yield: 30.1 %

Procedure:
In a mortar and pestle 6-chloro-pyridazin-3-ylamine (100 mg, 0.772 mmol) and 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (180 mg, 0.849 mmol) were grounded together, placed in a sealed tube and heated to 130° C. for 16 h. The reaction was allowed to cool to room temperature and then the contents were dissolved in a minimal amount of dichloromethane. The crude product was purified by silica gel chromatography using a 0-50% ethyl acetate heptane gradient which gave 3-(6-amino-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70.7 mg, 0.232 mmol) in 30% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:31]1[CH2:36][CH2:35][N:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([C:37]([N:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)=[O:38])=[CH:44][CH:43]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCOCC3)cc2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C(=O)N3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 67.6 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.63 mmol) and morpholino(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (260 mg, 0.82 mmol) in dioxane (10 mL), aqueous 2M Na2CO3 solution (1.13 mL, 2.27 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (250 mg, 68%). LCMS: 587.35 (M+1)+; HPLC: 93.85% (@254 nm) (Rt; 4.535; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 1.46 (bs, 1H), 8.21 (t, 1H), 7.69-7.71 (m, 2H), 7.45-7.49 (m, 3H), 7.26 (s, 1H), 5.86 (s, 1H), 4.29 (d, 2H, J=4 Hz), 3.82-3.84 (m, 2H), 3.48-3.60 (m, 8H), 3.23-3.25 (m, 2H), 3.09-3.11 (m, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.52-1.68 (m, 4H), 0.83 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[N:4][N:3]=1.Cl.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[NH4+]>CO>[CH2:15]([O:22][N:23]=[C:10]1[CH2:11][CH2:12][N:7]([C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH2:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NOCc1ccccc1
Reactant: Cc1nnc(N2CCC(=O)CC2)o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: Cc1nnc(N2CCC(=NOCc3ccccc3)CC2)o1
Yield: 96.6 %

Procedure:
A solution of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-one (1.52 g, 8.39 mmol), O-benzylhydroxylamine hydrochloride (1.50 g, 9.23 mmol) and ammonium acetate (1.62 g, 21.0 mmol) in MeOH (34.5 mL) was heated to reflux for 2 hours under nitrogen. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient from AcOEt to AcOEt/EtOH 9:1 (v/v) as eluent to yield the title compound as a light yellow viscous oil (2.32 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:9])[CH:3]=1)[CH2:8][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(CBr)c1
Yield: 81.5 %

Procedure:
A solution of 5-chloro-m-xylene (14.06 g; 0.1 mol), NBS (17.8 g; 0.1 mol) and AIBN (1.1 g; 6.7 mmol) in CCl4 was refluxed for two hours. The resultant mixture was cooled, and the solid material formed was removed by filtration. Concentration yielded the sub-title compound (17.9 g; 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[H-].[Na+].I[CH3:33].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[N:19]([CH3:33])[C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)NC2=O)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)N(C)C2=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
5-[3-(3-Bromo-4-ethoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl-methylene]-thiazolidine-2,4-dione (Compound No. 77, 0.10 g, 0.21 mmol) was dissolved in 1.00 mL of anhydrous dimethylformamide. Sodium hydride (12.74 mg, 0.32 mmol) was added under nitrogen atmosphere and iodomethane (19.78 μL, 0.32 mmol) was added 5 minutes later. The mixture was stirred at room temperature for 2 hours. When the reaction was completed, 10 mL of water was added and the solution was extracted with dichloromethane (10 mL×2 times). The organic layer was washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The product was purified with silica gel chromatography (n-hexane/ethyl acetate=4:1) to obtain 48 mg (46.7%) of the target product in yellow solid form.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][F:6].[Mg].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[F:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: FCCCCBr
Reactant: OCCCCCCCCCCCCBr
Agent: [Mg]
Product: OCCCCCCCCCCCCCCCCF

Procedure:
A general procedure for the preparation of terminal fluorinated alkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated in Scheme 7, below. Fluoroalkoxyalkyl esters of acyclic nucleoside phosphonates such as 3-(16-fluorohexadecyloxy)propyl cidofovir (16-F-HDP-CDV) 49 and 3-(16-fluorohexadecyloxy)propyl (S)-HPMPA 50 (16-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, with reference to Scheme 7, the Grignard reagent prepared from 1-bromo-4-fluorobutane and magnesium is reacted with 12-bromododecanol 44 to obtain 16-fluorohexadecanol 45. Reaction of 45 with methanesulfonyl chloride followed by reaction with 1,3-propanediol provides 16-fluorohexadecyloxy-1-propanol 46. Coupling of 46 with cyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2 (step a), provides the cyclic esters (47 and 48, respectively) which can then be converted to the desired compounds (49 and 50, respectively) using the general method set forth in Example 2 (step b).