Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][O:27][C:28]1[CH:48]=[CH:47][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[N:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=3)[CH2:35][CH2:34]2)=[CH:30][CH:29]=1>C(Cl)Cl.CO>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[N:45]=[CH:44][C:43]([NH:46][C:23]([C:20]4[CH:21]=[CH:22][C:13]([C:3]5[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=5[Cl:1])=[C:14]5[C:19]=4[N:18]=[CH:17][CH:16]=[CH:15]5)=[O:24])=[CH:42][CH:41]=3)[CH2:35][CH2:34]2)=[CH:47][CH:48]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: COc1ccc(CN2CCN(Cc3ccc(N)cn3)CC2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 6-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-3-ylamine (Step 111.1) and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 672.1 [M+H]+; TLC: Rf=0.45 (DCM/MeOH, 9:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[NH:11][C:10]=1C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[NH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 120 °C
Yield: 77.1 %

Procedure:
A suspension of 3-Benzyloxy-6-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (3.2 g, 0.02 mol) in DMF (30 ml) was heated in an oil bath at 120° C. for 8 hrs. The mixture was cooled to room temperature and the insoluble solid was filtered. The solid was washed with hexane and dried under vacuum for 16 hrs to give 5-benzyloxy-2-methyl-1H-pyridin-4-one (3.32 g, 77% yield).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[O:27][CH3:28])[N:9]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:6][O:7][C:8]1[C:13]([NH:14][C:1](=[O:4])[CH2:2][CH3:3])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:18][C:17]=2[O:27][CH3:28])[N:9]=1
Reactant: CCC(=O)Cl
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c(N)cc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Reaction time: 3 h

Procedure:
Propionyl chloride (0.058 ml, 0.67 mmol) is added to a solution of 2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-ylamine (0.2 g, 0.61 mmol) and diisopropylethylamine (0.13 ml, 0.73 mmol) in CH2Cl2 (1.5 ml) at room temperature. The mixture is kept at room temperature for 3 hours, and is then diluted with EtOAc The mixture is washed with 1N NaOH and brine. After drying over Na2SO4, the solvent is removed under reduced pressure and the residue is purified by flash column chromatography (hexane/EtOAc=4:1) to give the N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propionamide. Rf (hexane/EtOAc=4:1)=0.2.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]2[CH:17]=[C:16]([C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[S:15][C:14]=12)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>C1COCC1>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([C:16]3[S:15][C:14]4=[C:10]([CH2:9][OH:8])[N:11]=[CH:12][N:13]4[CH:17]=3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(CO[Si](C)(C)C(C)(C)C)c4s3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(CO)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.2 %

Procedure:
To a solution of 334.6 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 10 ml of THF were added 0.28 ml of acetic acid and 1.64 ml of a 1 M solution of tetra-n-butylammonium fluoride in THF, and the mixture was stirred at room temperature for 2.5 hours. After the reaction mixture was adjusted to pH 8.2 with a saturated aqueous sodium hydrogen carbonate solution, it was extracted twice with ethyl acetate, and semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give 183 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxylmethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][N:3]1[CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][N:3]1[CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(OCCN2COc3ccccc3C2=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(OCCN3COc4ccccc4C3=O)cc2)S1
Yield: 87 %

Procedure:
5.0 g (17 mM) of 4-[2-(4-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)ethoxy]benzaldehyde (Compound 4A) and 2.1 (18 mM) of 2,4-thiazolidinedione were dissolved in 150 ml of toluene. After the addition of a catalytic amount of acetic acid and piperidine, the mixture was reacted for two hours with heating while refluxing in a Dean Stark apparatus. After confirming completion of the reaction by TLC, the reaction mixture was gradually returned to room temperature. The resulting crystals were collected by filtration and washed with a small amount of toluene and then with hexane, and dried under vacuum at 50° C, to obtain 5.8 g (yield 87%) of the title compound as pale yellow crystals.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:22][CH2:21][C:17]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]([NH2:20])=[O:19])[CH2:16][CH2:15]1.[BH4-].[Na+]>CO.O>[OH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:15][CH2:16][C:17]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]([NH2:20])=[O:19])[CH2:21][CH2:22]1
Reactant: NC(=O)C1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Finely-ground 1-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)-methyl]-4-anilino isonipecotamide, hydrochloride (1:1) (5.0 g) is slurried in methanol (100 ml) and cooled in ice. To this mixture is added an aqueous solution of sodium borohydride (3.0 g) in water (25 ml). The resulting mixture is stirred for 15 hours at room temperature under nitrogen. Dilution of the reaction mixture with water (200 ml), extraction with methylene chloride, and concentration of the dried organic solution give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@H:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@H:30]([OH:31])[CH2:32][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CCc1ccc(OC[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CCc1ccc(OC[C@H](O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 228 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined in procedure Z. M.p.=145-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, J=7.6 Hz, 1H), 7.81-7.76 (m, 2H), 7.59-7.54 (m, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.87-6.82 (m, 2H), 4.85 (d, J=4.8 Hz, 1H), 3.99-3.92 (m, 2H), 3.86-3.81 (m, 1H), 3.07 (s, 2H), 2.85-2.75 (m, 2H), 2.55-2.41 (m, 6H), 1.98 (d, J=14.4 Hz, 2H), 1.85-1.77 (m, 2H), 1.14 (t, J=8.0 Hz, 3H); LCMS: 480 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](Br)[CH:8]=1)[NH2:5].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[NH:24]1[CH:28]=[CH:27][CH:26]=[N:25]1>CS(C)=O.[Cu]I.O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[C:7]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[CH:8]=1
Reactant: Nc1cc(Br)cc(Br)c1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Br)cc(-n2cccn2)c1
Temperature: 110 °C
Yield: 42 %

Procedure:
To a solution of 3,5-dibromoaniline (0.50 g, 1.99 mmol) in DMSO (2.0 mL) was added sequentially L-Proline (0.041 g, 0.36 mmol), Cs2CO3 (1.16 g, 3.58 mmol), CuI (0.038 g, 0.20 mmol) and pyrazole (0.12 g, 1.80 mmol). The reaction mixture was degassed for 10 min and then heated to 110° C. for 48 h. After the completion of reaction (TLC monitoring), the reaction mixture was cooled to room temperature, added water and extracted with ethyl acetate (×3). The combined organics was washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (230-400 M, 15% EtOAc-Hexane) to get the desired compound (0.18 g, 37%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Si:13]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH2:1][CH3:2])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1cc(C(C)=O)ccc1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a stirred solution of 1-(3-ethyl-4-hydroxyphenyl)-1-ethanone (9.24 g, 56.27 mmol) in DMF (60 ml) was added tert-butyldimethylsilyl chloride (9.33 g, 61.9 mmol), imidazole (4.6 g, 67.52 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was fractionally distilled under reduced pressure (180° C., 0.5 mmHg) to give title compound (12.3 g, 78% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=1.[C:24](Cl)(=[O:26])[CH3:25]>C(OCC)(=O)C>[C:24]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methoxycarbonylbenzoyl)indole (Example 133) and acetyl chloride. m.p.: 190-193° C. (ethyl acetate)
Reaction SMILES: [Cl:1]/[C:2](/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[CH:3]\[CH2:4]O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6](/[C:2](/[Cl:1])=[CH:3]/[CH2:4][Cl:15])=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OC/C=C(\Cl)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: ClC/C=C(\Cl)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (Z)-3-chloro-3-(4-chloro-phenyl)-prop-2-en-1-ol (101 mg) in toluene (3 ml) was added thionyl chloride (0.11 ml) and one drop of dimethylformamide. After 1 h, the solution was concentrated in vacuo to afford 120 mg of the desired allylic chloride (100%) as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:23][C:22]=2[N+:34]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.O.C1CCCCC=1>O1CCCC1.[Pd]>[NH2:34][C:22]1[CH:23]=[C:24]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)[NH:15][N:14]=1)=[O:37]
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(N)c2)CC1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
N-(5-benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide (1.71 g, 3.29 mmol) was suspended in a mixture of tetrahydrofuran (17 mL), ethanol (33 mL), water (25 mL) and cyclohexene (17 mL), treated with 10% palladium on carbon and stirred under reflux. After two hours the reaction was cooled to room temperature and filtered over celite washing thoroughly with tetrahydrofuran. Evaporation of the filtrate and purification of the crude product by flash chromatography over silica gel (eluent: dichloromethane/methanol/33% NH4OH in 95:5:1 ratio) afforded 1.39 g of title compound as a yellow powder (86% yield).
Reaction SMILES: O[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:12]C.COC1C=CC(C=O)=CC=1O>>[OH:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:2]=1)[C:8](=[O:11])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1O)C(=O)CC2
Agent: COc1ccc(C=O)cc1O
Product: O=C1CCc2cc(O)ccc21

Procedure:
The indanone building blocks (18) were prepared as described in Scheme 11. The commercially available vanillin (33a) was reacted with Wittig reagent (34) in toluene at reflux temperature to give the corresponding unsaturated ester (35a) as cis and trans mixture. The ester (35a) was subjected to hydrogenation using palladium-carbon catalyst in methanol to give the saturated ester (36a). The ester (36a) was hydrolyzed using aqueous potassium hydroxide in THF to give carboxylic acid which after cyclization in the presence of concentrated sulfuric acid gave the target 6-hydroxyindan-1-one (18a) in overall good yield. Similarly, 5-hydroxyindan-1-one (18b) was prepared from the commercially available starting building block isovanilin (33b) in overall good yields.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH3:12].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[N:30]=1.O>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][CH:23]=2)[N:18]([CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=2)[CH:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Reactant: BrCc1cccc(Br)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.3 %

Procedure:
25.6 mL of potassium hexamethyldisilazane (12.91 mmol, 0.5 M in tolene) was added to 2.5 g (10.76 mmol) of 7-Methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester dissolved in 22 mL of tetrahydrofuran and was stirred at room temperature for 15 minutes. 3.24 g (12.91 mmol) of 2-Bromo-6-bromomethyl-pyridine was added and stirred at room temperature for 2.5 h. Water and ethyl acetate were added and the layers separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and dried in vacuo. The crude product was purified on silica gel eluting with 50/50 ethyl acetate/hexane to yield 0.620 g of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:26])[NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])C.[OH-].[Na+].Cl>CO>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:17]([NH:16][C:15]([C:8]2[N:9]3[C:10]([CH2:11][O:12][CH2:13][CH2:14]3)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)=[O:26])[CH3:18])=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)n2c1COCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](NC(=O)c1cc(C(=O)O)c2n1CCOC2)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 6-[(R)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (9.0 g, 25 mmol) in methanol (38 ml) was added 2 N aqueous sodium hydroxide (38 ml, 76 mmol). The mixture was stirred for 1 h at 60° C., then cooled down to 25° C. acidified with excess 10 M aqueous hydrochloric acid. After extraction (3 times with dichloromethane), the combined organic layers were dried over sodium sulfate and the solvents evaporated to give 7.2 g (85%) 6-[(R)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid as a white solid. LC/MS (method 4): Rt=1.11 min; m/z=333.06 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[CH:16]=[C:15]([CH3:17])[C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C(O[CH:34](N(C)C)[N:35]([CH3:37])[CH3:36])(C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:9]2[CH:16]=[C:15](/[CH:17]=[CH:34]/[N:35]([CH3:37])[CH3:36])[C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:27][CH:28]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(C)c(C#N)cn2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(/C=C/N(C)C)c(C#N)cn2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 113.7 %

Procedure:
A mixture of 4-3 (7.20 g, 19.3 mmol), tert-butoxy bis(dimethylamino)methane (16.0 mL, 77.5 mmol), and N,N-dimethylformamide (5.40 mL) was stirred at 70° C. for 16 hours under an atmosphere of nitrogen gas. The reaction mixture was concentrated under reduced pressure to give 9.40 g of 4-4 as a brown oil. The crude product was used for next step without further purification.
Reaction SMILES: O.[OH:2][CH2:3][CH:4]([O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2)[CH2:5][OH:6].[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CCOCC>CN(C)C=O.N1C=CC=CC=1>[OH:2][CH2:3][CH:4]([O:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2)[CH2:5][O:6][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Reactant: CCCCCCCC(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCC(=O)OCC(CO)OCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C

Procedure:
A suspension of 410 mg (1.5 mmole) of 9-(1,3-dihydroxy-2-propoxymethyl)guanine monohydrate in 6 ml of dry dimethylformamide and 1.5 ml of dry pyridine was stirred under a drying tube with cooling in an ice bath as a solution of 489 mg (3.0 mmole) of octanoyl chloride in 1.5 ml of dimethylformamide was added dropwise by syringe over approximately 5 minutes. The mixture was allowed to warm gradually to room temperature, and after 24 hours it was concentrated under high vacuum. The residual oil was purified by preparative TLC on nine 1000-μ silica gel plates (developed in 5:1 CHCl3 --MeOH). The product bands were isolated, combined, and extracted with dimethylformamide. Concentration of the extracts under high vacuum gave a gummy residue. Crystallization from isopropanol gave a material which again turned gummy on the filter. However, thorough trituration with ether yielded 105 mg (18%) of very pale yellow crystals, m.p. 201.5°-203.5°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:24])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (0.940 g, 3.41 mmol), (3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylate (1.017 g, 4.09 mmol) and Hunig's Base (1.788 ml, 10.24 mmol) in DMF (3.0 ml) in a reaction vial was stirred at 90° C. for 2 h. The reaction solution was added slowly to a stirred ice-water resulting in a light tan precipitate. The suspension was stirred for 30 min at 0° C. After filtration, (3S,4S)-benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-ethylpyrrolidine-1-carboxylate was collected as a light tan solid (1.716 g, 3.52 mmol, 100% yield). ESI-MS (analytical LCMS Method A): m/z 489.1, 487.1 ([M+H]+).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[Br:17]Br>C(O)(=O)C>[Br:17][C:15]1[C:13](=[O:14])[NH:12][C:10](=[O:11])[N:9]([C@@H:4]2[O:5][C@H:6]([CH2:7][OH:8])[C@@H:2]([F:1])[CH2:3]2)[CH:16]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](F)[C@@H](CO)O2)cc1Br
Reaction time: 18 h
Yield: 64 %

Procedure:
The 5'-O-toluoyl derivative of 1-(2,3-dideoxy-3-fluoro-β-D-erythropentofuranosyl)uracil, prepared as described in Example 1, (200 mg, 0.574 mmol), glacial acetic acid (5 ml) and bromine (0.08 ml of an 8M solution in glacial acetic acid, 0.64 mequiv.) were stirred at 25° for 18 hours. The solution was evaporated to a glass which was treated with sodium methoxide and methanol as described in Example 1. Product was eluted from a silica gel column with 5% MeOH-CH2Cl2 as white crystals (135 mg). Recrystallization from EtOH gave title compound as white crystals (115 mg, 64% overall yield); m.p. 193.5°-194° dec.; Anal Calcd for C9H10BrFN2O4 : C, 34.97; H, 3.26; N, 9.06; Br, 25.85; F, 6.15. Found: C, 35.07; H, 3.31; N, 9.00; Br, 25.78; F, 6.04; UV λ max (H2O): 277 nM; structure further confirmed by 'H-NMR and mass spectrum.