Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]([F:22])([F:23])[C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A solution of (E)-4-(4,4,4-trifluoro-3-oxo-1-butenyl)phenoxyacetic acid, 1,1-dimethylethyl ester (1.578 g, 4.77 mmol) in dichloromethane (90 ml) was treated with trifluoroacetic acid (10 ml) and stirred at 22° C. for 4 h. The solvent and excess reagent were evaporated under reduced pressure and the last traces of trifluoroacetic acid were co-evaporated with toluene. Crystallization of the residue from ethyl acetate-hexane gave 1.29 g (98%) of the title material as white cubes: mp 156-156.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C@H:8]3[CH2:13][NH:14][CH2:15][CH2:16][N:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:17]=O>>[CH3:17][N:14]1[CH2:15][CH2:16][N:7]2[C@@H:8]([CH2:9][CH2:10][O:11][C:12]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=32)[CH2:13]1
Reactant: Cc1cccc2c1OCC[C@H]1CNCCN21
Reactant: C=O
Product: Cc1cccc2c1OCC[C@H]1CN(C)CCN21

Procedure:
To a solution of Example 226 (50 mg, 0.229 mmol) in a pH 4 buffer solution (10 mL, made from 48 g acetic acid and 30.5 g sodium acetate in 1 L methanol) was added formaldehyde (36% solution, 13.8 mg, 0.46 mmol) and macroporous-cyanoborohydride resin (0.32 g, 0.69 mmol). The reaction was allowed to stir for 2 hours before the macroporous-cyanoborohydride resin was removed by filtration, and the solution concentrated. The concentrate was basified to pH=10 with NaOH (1 M aqueous), and the product was extracted with ethyl acetate. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.69-6.86 (m, 3H), 4.24-4.37 (m, 1H), 4.06-4.16 (m, 1H), 2.99-3.18 (m, 3H), 2.56-2.68 (m, 1H), 2.46-2.55 (m, 1H), 2.18-2.29 (m, 1H), 2.21 (s, 3H), 2.02-2.16 (m, 1H), 2.09 (s, 3H), 1.79-1.99 (m, 2H); MS (DCI+) m/z 233 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(C(F)(F)F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-trifluoromethylphenol: SMS m/e: 559.1 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[C:4]#[N:5])=[O:2]>C(O)C>[NH2:5][CH:4]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[CH:1]=[O:2]
Reactant: N#CC(C=O)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: NC=C(C=O)c1cccc(C(F)(F)F)c1

Procedure:
portions of α-formyl-3-(trifluoromethyl)benzeneacetonitrile each in 250 ml. of ethanol are hydrogenated in the presence of 40 g. of Raney Nickel (number 28) at 20 psi pressure until no more hydrogen is absorbed. The resulting mixtures are filtered and the filtrates are combined and passed through 150 g. of alumina (Woelm, activity II) with 1:1 methylene chloride-ethyl acetate. The resulting eluate is concentrated at reduced pressure and the residue triturated with hexane to give 39.4 g. of the product of the Example as a yellow solid, m.p. 63°-70° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1 H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 62-64° C.; 1H NMR (300 MHz, CDCl3): δ 6.92 (s, 1 H), 6.67 (s, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 5.02-4.92 (m, 1 H), 4.38 (t, J=7.7 Hz, 2 H), 3.79 (s, 3 H), 3.66 (dd, J=10.3, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.6 Hz, 1 H), 3.36 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.90-1.70 (m, 2 H), 0.94 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C19H25N3O3Cl (M+H)+: 378.1584; Found m/z 378.1604.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1oc(=O)oc1C
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1oc(=O)oc1CBr

Procedure:
To a stirred solution of 3.0 g of 4,5-dimethyl-2-oxo-1,3-dioxole in 100 ml of carbon tetrachloride was added 4.63 g of N-bromosuccinimide. The resulting solution was heated under reflux and irradiated for 15 minutes. The reaction mixture was cooled to 0°-5° C., filtered and evaporated to give the title product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][C:13]([OH:15])=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C.C(Cl)Cl>[F:7][C:8]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:9]=1[O:10][CH2:11][CH2:12][C:13]2=[O:15]
Reactant: O=C(O)CCOc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCOc2c(F)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0° C. for 2 hours, then aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hex) to give of the title compound (8.20 g, 98%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.CI.[C:16](=O)([O-])O.[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH3:16])[C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)N(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium hydride (101.5 mg, 2.33 mmol) (55% in paraffin liquid) was added to a solution of 249 mg (1.16 mmol) of the title compound produced in step (i) of Reference Example 7 in N,N-dimethylformamide (2.5 ml), and the mixture was stirred at room temperature for 30 min. Thereafter, methyl iodide was added, and the mixture was stirred at room temperature for 1 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 239 mg (yield 90%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10]C(C)(C)C)=O)[CH2:4][CH:3]1[C:15]1[N:16]=[N:17][N:18]2[C:23]=1[C:22]1[CH:24]=[CH:25][NH:26][C:21]=1[N:20]=[CH:19]2.[C:27]([CH2:29]C(O)=O)#[N:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>O1CCOCC1.Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH2:29][C:27]#[N:28])[CH2:4][CH:3]1[C:15]1[N:16]=[N:17][N:18]2[C:23]=1[C:22]1[CH:24]=[CH:25][NH:26][C:21]=1[N:20]=[CH:19]2
Reactant: N#CCC(=O)O
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1c1nnn2cnc3[nH]ccc3c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CC1CCN(C(=O)CC#N)CC1c1nnn2cnc3[nH]ccc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
tert-Butyl 4-methyl-3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate (5.6 mg, 0.016 mmol) in 4 M hydrogen chloride-1,4-dioxane solution (1.0 mL) was stirred under cooling with ice for 1 hour and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL) and mixed with 2-cyanoacetic acid (2.7 mg, 0.0314 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (11.9 mg, 0.0314 mmol) and then with N,N-diisopylethylamine (0.0082 mL, 0.0471 mmol) and stirred at room temperature for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (NH-PLC05 plate manufactured by Fuji Silysia Chemical Ltd.: chloroform/methanol=15/1 (v/v)) and further purified by silica gel thin layer chromatography (ethyl acetate) to give the title compound as a pale yellow solid (0.62 mg, yield 12%).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](Br)=[CH:24][C:16]([C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([Li])(C)(C)C.[CH:33](=[O:35])[CH3:34]>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[CH:25]=[CH:24][C:16]([C:17]([NH:19][S:20]([CH2:23][CH:33]([OH:35])[CH3:34])(=[O:22])=[O:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Br)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: CC=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(O)CS(=O)(=O)NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
To a solution of 4-(adamantan-1-ylmethoxy)-5-bromo-2-fluoro-N-(methylsulfonyl)benzamide (0.340 g, 0.74 mmol) in anhydrous tetrahydrofuran (5 mL) was added tert-butyllithium (1.7 M solution in pentane, 1.31 mL, 2.22 mmol) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C. followed by addition of acetaldehyde (0.21 mL, 3.70 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. After quenched with 1 N hydrochloric acid (5 mL), the mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate gave a residue which was purified by reverse-phase preparative HPLC to afford the title compound as an off-white solid (0.075 g, 24%): 1H NMR (300 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.60 (t, J=8.7 Hz, 1H), 6.93 (dd, J=13.0, 2.2 Hz, 1H), 6.86 (dd, J=8.7, 2.3 Hz, 1H), 5.04 (br s, 1H), 4.17-4.07 (m, 1H), 3.65-3.56 (m, 1H), 3.63 (s, 2H), 3.45 (dd, J=14.3, 5.1 Hz, 1H), 2.02-1.94 (m, 3H), 1.76-1.57 (m, 12H), 1.20 (d, J=6.3 Hz, 3H); MS (ES−) m/z 424.2 (M−1).
Reaction SMILES: I[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]([CH3:17])[CH3:16])[C:4]=2[S:5][C:6]=1[CH3:7].IC1C2C=CC(OC)=CC=2SC=1C>>[CH:15]([O:14][C:8]1[C:4]2[S:5][C:6]([CH3:7])=[CH:2][C:3]=2[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])([CH3:17])[CH3:16]
Reactant: COc1ccc2c(I)c(C)sc2c1OC(C)C
Agent: COc1ccc2c(I)c(C)sc2c1
Product: COc1ccc2cc(C)sc2c1OC(C)C
Yield: 67 %

Procedure:
When 3-iodo-7-isopropoxy-6-methoxy-2-methylbenzo[b]thiophene was substituted for 3-iodo-6-methoxy -2-methylbenzo[b]thiophene in Step C of Comparator D, the identical process provided the title compound in 67% yield, as a heavy colourless syrup. 1H-NMR (CDCl3) 1.33 (d, 6H, J=6.14 Hz); 2.51 (s, 3H); 3.88 (s, 3H); 4.69 (m, 1H, J=6.14 Hz); 6.84(1H); 6.96 (d, 1H, J=8.51 Hz); 7.27 (d, 1H, J=8.51 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[C:12]=2[O:15][CH3:16])[CH:7]1O)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:7][C:8]2[C:13](=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[C:9]=2[O:21][CH3:22])[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCCCCC1(C(=O)OCC)Cc2c(OC)c(OC)c(OC)c(OC)c2C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCCCCC1(C(=O)OCC)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
To ethyl 8-(2-ethoxycarbonyl-1-hydroxy-4,5,6,7-tetramethoxyindan-2-yl)octanoate (3.77 g, 7.59 mmols), added was trifluoroacetic acid (40 ml) at room temperature, and then triethylsilane (4.85 ml, 30.4 mmols) was added thereto, and stirred for 15 minutes. The reaction mixture was concentrated in vacuo, a saturated aqueous sodium bicarbonate solution was added thereto, and extracted with ethyl acetate, and the resulting organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 10:1) to obtain the entitled compound (1.31 g) as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7][S:8][C:9]2[CH2:10][S:11][C@@H:12]3[C@H:32]([NH:33][C:34](=[O:82])/[C:35](/[C:57]4[N:58]=[C:59]([NH:62]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:60][CH:61]=4)=[N:36]\[O:37]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:31](=[O:83])[N:13]3[C:14]=2[C:15]([O:17]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:16])=[CH:5][CH2:4][O:3]1.Cl>C(O)=O>[NH2:62][C:59]1[S:60][CH:61]=[C:57](/[C:35](=[N:36]/[OH:37])/[C:34]([NH:33][C@@H:32]2[C:31](=[O:83])[N:13]3[C:14]([C:15]([OH:17])=[O:16])=[C:9]([S:8][CH2:7][C:6]4[C:2](=[O:1])[O:3][CH2:4][CH:5]=4)[CH2:10][S:11][C@H:12]23)=[O:82])[N:58]=1
Reactant: O=C1OCC=C1CSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: Cl
Solvent: O=CO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCC4=CCOC4=O)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.6 %

Procedure:
Diphenylmethyl 3-(2,5-dihydro-2-oxofuran-3-ylmethylthio)-7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetamido]ceph-3-em-4-carboxylate (422 mg) was completely dissolved in 98-100% formic acid (3.7 ml) and then treated with 1.0M hydrochloric acid (370 μl). After stirring at room temperature for 45 mins. a drop of concentrated hydrochloric acid was added and stirring continued for 1 hour. The solvent was removed and then toluene was twice evaporated from the residue. The residue was triturated with ether and the resulting solid collected and washed with ether. Suspension of the solid in water was followed by adjustment of the pH to 2.6 with 0.1M sodium hydroxide. Care was taken to allow time for pH equilibration between additions of alkali. The solid was filtered, washed with cold water and dried in vacuo to give the title compound as an amorphous solid (87 mg). υmax (KBr disc) 1775 and 1750cm-1 ; δH [(CD3)2SO] 3.57-3.84 (4H, m), 4.85 (2H, s), 5.16 (1H, d, J 4.7Hz), 5.73 (1H, dd, J 8.3Hz, 4.7Hz), 6.67 (1H, s), 7.16 (2H, bs), 7.57 (1H, s), 9.48 (1H, d, J 8.3Hz), 11.30 (1 H, bs). [mass spectrum: +ve ion (thioglycerol) MH+ 498].
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.Br[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1.C(N(CC)CC)C>CC#N>[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][C:32]4[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=4)[CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1
Reactant: O=Cc1ccc(OCCCBr)cc1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4ccc(C=O)cc4)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.244 g), 4-(3-bromopropoxy)benzaldehyde (example 8, step a) (0.15 g) and triethylamine (0.344 mL) in MeCN (2 mL) was heated at 60° C. After 16 h, the reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate:triethylamine, 10:1 to give the subtitled compound as an oil. Yield 0.24 g.
Reaction SMILES: CC(CC(O)=O)CC(O)=O.Br[CH2:12][CH:13]([CH3:19])[CH2:14][C:15]([O:17][CH3:18])=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-].BrCC(C)CC=O.[Cl:41][C:42]1[CH:51]=[C:46]([C:47]([NH:49][OH:50])=[O:48])C(O)=[CH:44][CH:43]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOCC>[Cl:41][C:42]1[CH:43]=[CH:44][C:18]2[O:17][CH:15]3[CH2:14][CH:13]([CH3:19])[CH2:12][O:50][N:49]3[C:47](=[O:48])[C:46]=2[CH:51]=1
Reactant: O=C(NO)c1cc(Cl)ccc1O
Reactant: COC(=O)CC(C)CBr
Agent: CC(CBr)CC=O
Agent: CC(CC(=O)O)CC(=O)O
Agent: COCCO[Al+]OCCOC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1CON2C(=O)c3cc(Cl)ccc3OC2C1

Procedure:
80 g. of the methyl half ester of 3-methylglutaric acid (Linstead, lunt and Weedon, J. Chem. Soc. 1950, 3331) was converted to methyl 4-bromo-3-methylbutyrate as described by Marks and Polgar, J. Chem. Soc. 1955, 3854. The bromoester (51 g.) was reduced with sodium bis (2-methoxyethoxy)aluminum hydride in a mixture of toluene and ether yielding 43 g. of 4-bromo-3-methylbutyraldehyde. The aldehyde and 49 g. of 5-chlorosalicylhydroxamic acid were condensed by the method described in Example 1 and the product was ring-closed with 10 percent aqueous sodium hydroxide to give 8-chloro-3-methyl-2,3,4,4a-tetrahydro-10H-1,2-oxazino(3,2-b) (1,3)benzoxazin-10-one which melted at 121- 140° C. after recrystallization from ethanol.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]1([C:16]2[O:21][C:20](=[O:22])[CH2:19][CH2:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.Cl>[CH2:3]([N:2]([CH3:1])[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC=C(c2ccccc2)O1
Reactant: CNCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(Cc1ccccc1)C(=O)CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 5-oxo-5-phenylpentanoic acid benzyl-methyl amide was prepared by refluxing N-methylbenzylamine (10.5 mmol) and 6-phenyl-3,4-dihydro-pyran-2-one (10.5 mmol) in toluene for one hour. The reaction was allowed to stir overnight at room temperature. It was poured into 100 mL of ethyl acetate and 100 mL of IN HCl. The organic extracts were washed with 100 mL of 1N NaOH, 100 mL of water and dried over MgSO4. The crude product was flash chromatographed (CH2Cl2 /MeOH 98/2) to afford a liquid. 1H NMR (CDCl3) δ 2.0-2.2 (m, 2 H), 2.5 (t, 2 H), 2.93/2.96 (s/s, 3 H), 3.0-3.2 (m, 2 H), 4.5/4.6 (s/s, 2 H),7.1-7.6 (m, 8 H), 7.8-8.0 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:9]=2[N:10]=1.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:19]([N:3]1[C:4](=[O:18])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH:13]([CH2:16][O:17][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:14][OH:15])[C:9]=2[N:10]=[C:2]1[NH2:1])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Nc1nc(O)c2ncn(COC(CO)CO)c2n1
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2COC(CO)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
2-(2-Amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol (ganciclovir) was bis-tritylated at the N and O functionalities as follows: to a slurry of 4.1 kg ganciclovir, 9.5 g DMAP, and 8.65 kg TEA in dimethylformamide (38.3 kg ) at 50° C. was added a solution of 11.9 kg trityl-chloride in 38.2 kg dimethylformamide over 25 minutes. The reaction mixture was heated and stirred at 50° C. overnight. The following morning the reaction was complete by HPLC. This yields a mixture of N-trityl-ganciclovir, O-trityl-ganciclovir, N,O-bis-trityl-ganciclovir, and tris-trityl-ganciclovir in a approximate ratio of mono to bis to tri-substituted ganciclovir of 1:2:1. The tris-trityl-ganciclovir which is dimethylformamide insoluble is then filtered from the dimethylformamide mixture by cooling the reaction mixture to 10° C. and filtering out the tris-trityl-ganciclovir. The tris-tritylated-ganciclovir was washed with 10 kg dimethylformamide, and the transfer lines were washed with 2.3 kg dimethylformamide. The mono- and bis-tritylated-ganciclovir were then precipitated from this dimethylformamide solution by warming the bistrityl-ganciclovir/monotrityl-ganciclovir/dimethylformamide solution to 20° C. and adding 90 kg water over 1 hour. An additional 60 kg water was then added. Some purification of the bistrityl-ganciclovir from the monotrityl-ganciclovir occurs at this point. The temperature of the above mixture rose to 32° C. The mixture was seeded with 0.5 g of N,O-bistrityl-ganciclovir and allowed to age overnight at room temperature. The following morning crystals had formed. The solid was filtered out. Further purification of the bis-trityl-ganciclovir was achieved by washing the solid with 50 kg of water and then with 21 kg of ethyl acetate. The solid was dried under a stream of nitrogen overnight and then in a vacuum oven (~50° C., ~650 millitorr, nitrogen sweep) for 4 days. Yield: 63.2%. Weight: 7.51 kg. HPLC: greater than 90% N,O-bistrityl-ganciclovir, impurities 1.8%.