Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[NH:4][C:5](=[O:19])[C@H:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](F)[N:9]=1)#[N:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C.CCCC(C)C>O1CCCC1>[C:1]([CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[NH:4][C:5](=[O:19])[C@H:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:9]=1)#[N:2]
Reactant: COc1ccccc1C(C#N)NC(=O)[C@H](CC(C)C)Nc1ccnc(F)n1
Reactant: C1COCCN1
Solvent: CCCC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccccc1C(C#N)NC(=O)[C@H](CC(C)C)Nc1ccnc(N2CCOCC2)n1

Procedure:
The product from step (iii) (0.5 g), morpholine (0.12 ml) and N,N-diisopropylethylamine (0.24 ml) in tetrahydrofuran (20 ml) was stirred at room temperature overnight. The solvent was removed under vacuum to yield a crude oil which was subjected to column chromatography on silica eluting with ethyl acetate/isohexane 3:1 to give a white solid (0.4 g).
Reaction SMILES: [C:1]([O:13]C)(=O)[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.O.[NH2:40][NH2:41]>C1COCC1.O>[C:6]1([C:4]2[NH:3][CH2:2][C:1](=[O:13])[NH:41][N:40]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CNC(=O)c1ccccc1
Reactant: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=C1CNC(c2ccccc2)=NN1
Temperature: 50 °C

Procedure:
To 5.8 g. of methyl hippurate dissolved in 35 ml THF was added 3.9 g. of triphenylphosphine and 10.0 g. of carbon tetrachloride in 15 ml THF. The mixture was heated to about 50° C. for 6 hours and 3.0 g. of hydrazine hydrate was added. The mixture was refluxed for about 18 hours, cooled and poured into water. The solution was extracted with ethyl acetate, and the organic phase was then extracted with 1 N HCl. The acidic extract was neutralized with 6 N sodium hydroxide and the product was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under vacuum. The solid was recrystallized from methanol to yield about 0.200 g. of solid. Yield 4%. M.P.=212°-216° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH2:23][CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH2:23][CH3:24])=[C:14]([Cl:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reactant: O=C1CCC(=O)N1Cl
Product: CCOc1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 5, intermediate) (4R,9aR)-6-ethoxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-chlorosuccinimide.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH2:18]([C:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[CH:23][N:22]=1)[CH2:19][CH3:20]>ClCCCl>[CH2:18]([C:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[C:23]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])[N:22]=1)[CH2:19][CH3:20]
Reactant: CCCc1ncc2ccccn12
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1nc(C(=O)c2cccc3ccccc23)c2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
To a solution of 1-naphthoyl chloride (409 ml, 2.70 mmol, 2 eq) in 1,2-dichloroethane (10 ml) was added aluminum trichloride (415 mg, 3.11 mmol, 2.3 eq). The reaction mixture was stirred at room temperature for 10 min., then a solution of 3-propyl-imidazo[1,5-a]pyridine (216 mg, 1.35 mmol) in 1,2-dichloroethane (5 ml) was added. The reaction mixture was stirred at room temperature for 1 h. Then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (119 mg, 28%). 1H NMR (DMSO-d6) δ 8.59 (1H), 8.28 (1H), 8.10-8.01 (3H), 7.80 (1H), 7.61 (1H), 7.57 (1H), 7.43 (1H), 7.41 (1H), 7.12 (1H), 2.92 (2H), 1.67 (2H), 0.09 (3H); m/z (M+H)=315.17.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:23]=[C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:15]=3)[CH:11]=[N:12][CH:13]=2)[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[C:32]1([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[N:23][C:14]([C:10]2[CH:9]=[C:8]([CH:5]([CH2:4][OH:3])[CH2:6][OH:7])[CH:13]=[N:12][CH:11]=2)=[N:15]3)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1(C)OCC(c2cncc(-c3nc(NCc4ccccn4)c4c(-c5ccccc5)cccc4n3)c2)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: OCC(CO)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Reaction time: 2 h
Yield: 4.7 %

Procedure:
To a solution 2-(5-(2,2-dimethyl-1,3-dioxan-5-yl)pyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (45 mg, 0.83 mmol) in methanol (5 mL) was added pTSA (30 mg, 0.17 mmol) and the mixture was stirred for 2 h. The reaction was quenched by the addition of sat. Na2CO3 solution and the volatile solvents removed under reduced pressure. The residue was dissolved in ethyl acetate then washed with water and brine. The organic layer was dried, concentrated and purified by filter column 80% EtOAc in Hexanes to provide 2-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)propane-1,3-diol (18 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.74 (s, 1H), 9.60 (d, 1H, J=2 Hz), 9.56 (d, 1H, J=2 Hz), 8.26 (d, 1H, J=4.8 Hz), 7.90 (dd, 1H, J=1.2, 9.2 Hz), 7.83 (t, 1H, J=7.2 Hz), 7.72 (dd, 1H, J=1.8, 7.6 Hz), 7.61-7.50 (m, 5H), 7.38-7.30 (m, 2H), 7.26 (dt, 1H, J=1.2, 8 Hz), 6.80 (br s, 1H), 4.74 (d, 1H, J=4.4 Hz), 4.70 (t, 1H, J=5.2 Hz), 3.85-3.77 (m, 2H), 3.76-3.68 (m, 2H), 3.30-2.95 (m, 1H). LCMS Method T: retention time 1.40 min; [M+1]=464.2; HPLC Method A4: purity 99.4%, retention time=5.48 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:18][CH2:19][N:20]2[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:36])[O:31]C(C)(C)C)[CH2:25][CH2:24][N:23]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[CH2:22][CH2:21]2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:4][CH:3]=1.Cl.O1CCOCC1>C(OCC)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][N:23]([CH2:37][C:38]([OH:40])=[O:39])[CH2:24][CH2:25][N:26]([CH2:29][C:30]([OH:36])=[O:31])[CH2:27][CH2:28]2)[CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(CCN(CC(=O)OC(C)(C)C)Cc2ccc(N)cc2)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1ccc(CN(CCN2CCN(CC(=O)O)CCN(CC(=O)O)CC2)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.7 %

Procedure:
To Compound 9 (39 mg, 62.9 μmol) with an ice cooling bath around was added 6 mL of 4 M HCl/dioxane dropwise. After the addition was complete, the reaction mixture was gradually warmed to room temperature and allowed to stir overnight at room temperature. After completion 50 mL of ethyl ether was added to the reaction mixture with vigorous stirring and the resulting slurry was kept in the freezer for 2 h. The precipitate was collected and washed with ethyl ether, then immediately lyophilized with water and evaporated to provide pure salt as light yellow solid Compound 10 (34 mg, 85%). NMR (D2O, 300 MHz) δ 2.97 (m, 4H), 3.21 (m, 6H), 3.33 (s, 4H), 3.48 (t, J=5.4 Hz, 2H), 3.93 (s, 4H), 3.99 (s, 2H), 4.46 (s, 2H), 7.40 (d, J=6.4 Hz, 2H), 7.59 (d, J=6.4 Hz, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].S(O[CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])(=O)(=O)C>CN(C)C=O>[CH:34]([O:33][CH2:32][CH2:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: CC(C)OCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (2.76 g, 8.72 mmol), and sodium hydride (0.38 g, 9.5 mmol) in dimethylformamide (30 mL). After 30 minutes, add 2-(isopropoxy)ethyl mesylate (0.51 g, 5.5 mmol). Heat to 80° C. After 2.5 hours, cool the reaction mixture to ambient temperature and partition between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with water and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give (1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine: Rf=0.73 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide, 90/10/0.1).
Reaction SMILES: C(OC(=O)[C:5]([C:14](=[O:33])[C:15]1[CH:20]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])[C:18]([O:30][CH3:31])=[CH:17][C:16]=1F)=[CH:6][NH:7][C@H:8]([CH2:12][OH:13])[CH:9]([CH3:11])[CH3:10])C.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][C:19]1[CH:20]=[C:15]2[C:16](=[CH:17][C:18]=1[O:30][CH3:31])[N:7]([C@H:8]([CH2:12][OH:13])[CH:9]([CH3:10])[CH3:11])[CH:6]=[CH:5][C:14]2=[O:33]
Reactant: CCOC(=O)C(=CN[C@H](CO)C(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1Cc1cccc(Cl)c1F)c(=O)ccn2[C@H](CO)C(C)C
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylic acid ethyl ester prepared in Step IX in N,N-dimethylformamide was added anhydrous potassium carbonate (4.86 g) with stirring at room temperature. After stirring at 95-105° C. for 6 hr, N,N-dimethylformamide (10 ml) and water (50 ml) were successively added dropwise at 65-75° C. to allow crystallization. After stirring for 1 hr, the mixture was cooled to room temperature, and further stirred for 1 hr. Water (20 ml) was further added and, after stirring for 1 hr, and the mixture was filtrated, and the residue was successively washed with 50% aqueous N,N-dimethylformamide solution (20 ml) and water (20 ml), and vacuum dried to give 6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylic acid ethyl ester (13.5 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1COCC1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2ccccc2)CCCN(Cc2ccccc2)C1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a solution of 1-benzyl-3-piperidinone (0.193 g, 1.02 mmol) in toluene dry (10 mL) cooled at 0° C. was added a solution of phenyl magnesium bromide 3.1M in THF (0.48 mL, 1.4 mmol). The resulting solution was maintained at 0° C. for 2 h, then was allowed to warm at 25° C. for 1 h. Water (50 mL) was added and the mixture was extracted with EtOAc (2×50 mL). The collected organic phase was dried and concentrated under reduced pressure. The crude compound was purified by flash chromatography on silica gel using EtOAc/cyclohexane as eluant to afford the title compound as a white solid (0.235 g, 80%). 1H NMR (CDCl3): 1.65-1.85 (m, 3H), 1.9-2.15 (m, 1H), 2.067 (bd, J=8.1 Hz, 1H), 2.34 (d, J=11.1 Hz, 1H), 2.77 (d, J=11.1 Hz, 1H), 2.95 (bd, J=8.1 Hz, 1H), 3.60 (s, 2H), 4.005 (bs, 1H), 7.2-7.4 (m, 8H), 7.50 (s, 1H), 7.525 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:14]([O:16][CH3:17])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:65][C:66]1[CH:71]=[CH:70][C:69]([CH:72]([CH3:76])[C:73](O)=[O:74])=[CH:68][CH:67]=1>>[Si:20]([O:19][CH2:18][C@@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:73](=[O:74])[CH:72]([C:69]2[CH:70]=[CH:71][C:66]([Cl:65])=[CH:67][CH:68]=2)[CH3:76])[C:7]1=[O:12])[C:14]([O:16][CH3:17])=[O:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)cc3)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-(tert-butyldimethylsilyloxy)propanoate (500 mg, 0.001 mol), N,N-dimethylformamide (2 mL, 0.03 mol), N,N-diisopropylethylamine (0.5 mL, 0.003 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1 g, 0.003 mol) and 2-(4-chlorophenyl)propanoic acid (340 mg, 0.0018 mol) and the reaction stirred at room temperature overnight then for another 12 h. The solvent was removed and the residue purified by flash chromatography to yield the product as a white solid. MS m/z=545.4 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C@@H:11]([NH2:23])[CH2:12][CH2:13][C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:23][C@@H:11]([CH2:12][CH2:13][C:14]([CH3:22])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:10][OH:9]
Reactant: CCOC(=O)[C@@H](N)CCC(C)(C)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(CC[C@H](N)CO)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of lithium aluminum hydride (68 mg) in tetrahydrofuran (3 ml) was added a solution of (S)-2-amino-5-methyl-5-phenyl-hexanoic acid ethyl ester (280 mg) in tetrahydrofuran (1 ml) and the mixture was stirred for 3 hours at room temperature. Sodium sulphate solution (1N) was added until gas evolution ceased and the suspension was filtered through Celite. The solvent was evaporated and the residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: dichloromethane/MeOH=90:10) to yield a light yellow oil, (122 mg, 52%); MS (ISP): 208.2 ((M+H)+).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7](S(NCC2C=CC=C(OC(=O)C)C=2)(=O)=O)=[CH:6][C:5]=1Cl.[OH-].[Li+]>CO.O1CCCC1>[C:3]([OH:26])(=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2cccc(OC(C)=O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1

Procedure:
A stirred solution of 4-[(3-acetoxybenzylamino)sulfonyl]-2-chlorobenzoic acid methyl ester (163 mg; 0.41 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated at room temperature with an aqueous 1 N lithium hydroxide solution (1.65 mL). After 2 hr the volatiles were removed under reduced pressure and the residual material was dissolved in water (15 mL) and the solution filtered through Celite. The filtrate was acidified with 1 N HCl (2 mL) and extracted with ethyl acetate (3×10 mL). After the extracts were backwashed in turn with brine, they were combined, dried (Na2SO4) and evaporated in vacuo to furnish 140 mg of 2-chloro-4-[(3)-hydroxybenzylamino)sulfonyl]benzoic acid. A small sample of the product was crystallized from ethyl acetate-hexane to give a colorless solid, mp 167-169° C. FAB LRMS: (C14H12ClNO5S) Obs. Mass 342 Calcd. Mass 342 (M+H).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:13][CH2:14][N:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]1[CH3:23].[NH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[NH:26][C:25]1=[O:35].[OH-].[K+]>CN(C)C=O.CO.C1(C)C=CC=CC=1>[CH3:23][C:16]1[N:15]([CH2:14][CH2:13][N:26]2[C:27](=[O:34])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:24][C:25]2=[O:35])[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ncc([N+](=O)[O-])n1CCn1c(=O)[nH]c2ccccc2c1=O

Procedure:
A mixture of 15.0 parts of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole tosylate and 7.5 parts of 2,4(1H,-3H)-quinazolinedione is dissolved in 190 parts of warm dimethylformamide. 2.9 Parts of potassium hydroxide is dissolved in 80 parts of methanol and diluted with about 95 parts of dimethylformamide. The methanol is removed under reduced pressure, the residual solution added to the quinazolinedione solution, and the resulting mixture heated on a steam bath for 4 hours. The crude solution is cooled, filtered, and diluted with 100 parts of water. The precipitate which forms is separated by filtration and the solvent is evaporated from the filtrate to leave a residue which is stirred with 630 parts of toluene and filtered. The solvent is evaporated from the filtrate to leave a yellow residue. This is dissolved in toluene and dimethylformamide and then concentrated. A precipitate forms and it is separated by filtration to give 3-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-2,4-(1H,3H)quinazolinedione melting at about 261°-264° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Si:11]([O:18][C@@H:19]1[C@H:23]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C@@H:22]([CH3:32])[O:21][C@H:20]1[N:33]1[CH:40]=[C:39]([F:41])[C:37]([NH2:38])=[N:36][C:34]1=[O:35])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>N1C=CC=CC=1>[Si:11]([O:18][C@@H:19]1[C@H:23]([O:24][Si:25]([C:28]([CH3:30])([CH3:31])[CH3:29])([CH3:27])[CH3:26])[C@@H:22]([CH3:32])[O:21][C@H:20]1[N:33]1[CH:40]=[C:39]([F:41])[C:37]([NH:38][CH:8]=[O:10])=[N:36][C:34]1=[O:35])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=CO
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C[C@H]1O[C@@H](n2cc(F)c(NC=O)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
To ice cooled acetic anhydride (0.57 ml) was added dropwise 99% formic acid (286 μl). The solution was stirred for 15 minutes at 0° C. and for 50 minutes at 50° C., and then cooled to 0° C. To the solution was added 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine (473 mg) obtained in Reference example (a) in dry pyridine (5 ml) at 0° C. The reaction mixture was stirred for 10 minutes at 0° C. and for 26 hours at room temperature. After removal of the solvent under reduced pressure the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane - ethyl acetate) followed by recrystallization from n-hexane - ethyl acetate to give 144 mg of 2',3'-bis-O-(tert-butyldimethylsilyl)-5 '-deoxy-5-fluoro-N4 -formylcytidine, mp 188° C. (dec.); MS 502 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCCCCCCCCCBr
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COCOCCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 486 mg (1.58 mmol) of 5-(benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 281 mg (1.05 mmol) of 1-bromo-9-(methoxymethoxy)nonane in 10 mL of anhydrous THF was added 987 μL (1.58 mmol) of a 1.6 M solution of n-BuLi in pentane. The reaction mixture was stirred under argon atmosphere at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 50 mL of water. The mixture was then extracted with two 50-mL portions of ethyl acetate. The combined organic layer was washed with 80 mL of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×3 cm). Elution with 5:1 hexanes-ethyl acetate afforded the expected product as a light yellow oil: yield 289 mg (56%); silica gel TLC Rf 0.55 (5:1 hexanes-ethyl acetate); 1H NMR (CDCl381.33 (m, 12H), 1.60 (m, 2H), 1.82 (m, 2H), 2.33 (s, 6H), 2.49 (s, 3H), 2.79 (dd, 2H, J=7.6, 7.6 Hz), 3.36 (s, 3H), 3.52 (t, 2H, J=6.4 Hz), 4.62 (s, 2H), 4.90 (s, 2H), 5.87 (s, 2H) and 7.37-7.48 (m, 5H); 13C NMR (CDCl3) δ14.4, 14.4, 19.3, 26.2, 27.7, 29.4, 29.4, 29.5, 29.5, 29.6, 29.8, 31.6, 55.1, 67.9, 75.7, 96.4, 108.0, 108.0, 128.0, 128.58, 128.62, 128.7, 129.3, 136.2, 147.4, 147.4, 152.6, 161.6, 161.6 and 165.1; mass spectrum (APCI), m/z 494.3395 (M+H)1 (C30H44N3O3 requires 494.3383).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN1CCCC1=O>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Sc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(O)CNC(=O)c1nc(Sc2ccccc2)c2ccccc2c1O
Temperature: 140 °C

Procedure:
The title compound was prepared as follows: To a solution of 250 mg of [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid, (U.S. Pat. No. 6,093,730, disclosed as N-((1-chloro-4-hydroxyisoquinoline-3-yl)carbonyl)glycine), in 1 ml 1-methyl-2-pyrrolidinone was added 1.2 ml of benzenethiol. The solution was heated at 130 to 150° C. in a sealed tube for 16 h. The solution was concentrated under vacuum. The resultant residue was crystallized from methanol to yield 91 mg of a tan solid; MS (−) m/z 353.07 (M−1)