Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[O-]CC.[Na+].[Na].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CS(C)=O.C(O)C>[I:1][C:2]1[C:7]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(I)c(O)c1
Reactant: ClCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cnc(I)c(OCc2ccccc2)c1
Yield: 94 %

Procedure:
2-Iodo-3-hydroxy-5-methylpyridine (13.5 g, 57.4 m.mole) was added to a solution of sodium ethoxide (57.4 m.mole, prepared freshly from sodium and dry ethanol (100 ml)). Dry dimethyl sulfoxide (250 ml) was added, and the ethanol was removed by distillation under reduced pressure. Benzyl chloride (7.27 g, 57.4 mole) was added portionwise with cooling and then the mixture was heated at 90°14 100° for 15 hours. The dimethyl sulfoxide was boiled off under reduced pressure, water was added (100 ml) and the product was extracted from this with chloroform. After drying with magnesium sulfate and evaporation under reduced pressure, a crude product was obtained (17.62 g, 94% yield) a tiny portion of which, after heating in water and then recrystallising from methanol-water, gave 2-iodo-3-benzyloxy-5-methylpyridine which was pure by N.M.R. (mp 83°-5°).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[NH:8][C:7]1=[S:16])[CH2:4][CH3:5].[CH3:17]I>O1CCCC1>[CH3:17][S:16][C:7]1[N:6]([CH2:3][CH2:4][CH3:5])[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[N:8]=1
Reactant: CCCn1c(=S)[nH]c2ccsc2c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(SC)nc2ccsc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a sulfonation flask, 0.84 g (0.021 mol) of a ˜60% sodium hydride dispersion is added to 20 ml of absolute tetrahydrofuran, and then 4.8 g (0.021 mol) of 3-propyl-2-thioxo-2,3-dihydro-1H-thieno-[3.2-d]pyrimidin-4-one, dissolved in 80 ml of tetrahydrofuran, are added dropwise such that the internal temperature remains constant at about 25° C. The mixture is stirred for 1 hour at room temperature and then 4.3 g (0.03 mol) of methyl iodide are added all at once. The mixture is refluxed for 4 hours and then the tetrahydrofuran is removed in a water-jet vacuum. The residue is taken up in ethyl acetate and the organic phase is extracted three times with water. The organic phase is dried over sodium sulfate and the solvent is removed in the water-jet vacuum, giving the crude product which is purified by column chromatography over silica gel (eluant: ethyl acetate/hexane 1:3). 2-Methylsulfanyl-3-propyl-3H-thieno[3.2-d]pyrimidin-4-one is obtained in virtually quantitative yield and having a melting point of 142-144° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>C1COCC1>[C:12]1([C:11]2[O:5][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[N:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino benzoic acid (10 mmol) in THF was added benzoyl chloride (2.8 g, 20 mmol) followed by pyridine (1.58 g, 20 mmol). The mixture was stirred for 1 h at room temperature. The 2-phenyl-benzo[d][1,3]oxazin-4-one formed was filtered and the residue was washed with water and dried in vacuum desiccator.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH2:3][CH3:4].[NH2-].[Na+].[C:8]1([CH2:14][O:15][CH2:16][C:17]([O:19]C)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[C:8]1([CH2:14][O:15][CH2:16][C:17](=[O:19])[CH2:1][C:2](=[O:5])[CH2:3][CH3:4])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)COCc1ccccc1
Reactant: CCC(C)=O
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: CCC(=O)CC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Butanone (47.65 ml) was added dropwise over 10 min to a mechanically stirred suspension of sodium amide (95%; 20.78 g) dry ether (600 ml) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 15 min. A solution of methyl phenylmethoxyacetate (48.0 g) in dry ether (50 ml) was added dropwise over 13 min at room temperature under nitrogen, and the reaction progressed according to the method of Intermediate 16, to give the title compound as a yellow oil (23.35 g)
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]([NH2:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:24]([O:26][CH3:27])=[O:25])#[C:19][C:20]([O:22][CH3:23])=[O:21].C([O-])(=O)C.[Na+].Cl.C(=O)(O)[O-].[Na+]>O.CO>[C:2]1([C:8]2[C:18]([C:24]([O:26][CH3:27])=[O:25])=[C:19]([C:20]([O:22][CH3:23])=[O:21])[NH:17][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: NC(C(=O)c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: COC(=O)c1[nH]c(-c2ccccc2)c(-c2ccccc2)c1C(=O)OC
Reaction time: 2 h
Yield: 63 %

Procedure:
In a 2 l RB 3-neck flask with mechanical stirrer and condenser was placed 76.7 g (0.31 mole) of desyl amine hydrochloride [Pschorr et al., Chem. Ber., 35, 2740 (1902)], 750 ml methanol, 88 g (0.62 mole) dimethyl acetylenedicarboxylate (freshyl distilled) and 61 g (0.75 mole) anhydrous sodium acetate. The mixture was then heated at reflux for two hours. Then another 44 g (0.31 mole) of dimethyl acetylenedicarboxylate was added, and heating continued another two hours. While the reaction mixture was still at reflux, concentrated hydrochloric acid (~60 ml, to pH ~2) was added dropwise. The mixture was heated at reflux another hours, then poured into 2 l water containing 200 ml 10% sodium bicarbonate solution, With stirring, more sodium bicarbonate was added until the solution was neutral. The gummy solid which precipitated was collected and washed with water. Trituration of this gummy material with ~500 ml of 50% aqueous ethanol gave a tan powdery solid, which was recrystallized from ~85% aqueous ethanol to give 65.5 g (63%) of white crystals, m.p. 191°-2° [Lit. m.p. 185°-7°; J. B. Hendrickson et al., J. Am. Chem. Soc., 86, 107 (1964)].
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:14](=[O:19])[NH:15]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 4-pentynoic acid methyl ester (75.7 mg, 0.68 mmol) (see Example 8, supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene)]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (31.2 mg) and CuI (5.0 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 7 h to yield (Z)-5-[2,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 86 mg, 90%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([N:36]([CH3:37])[C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CNC1CCN(CCSc2cnc3ccc(OC)cc3n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCN3CCC(N(C)C(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (26 mg, 0.11 mmol, 1.0 eq) is added at room temperature to a stirred solution of {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine (40 mg, 0.11 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (45 mg, 0.11 mmol, 1.0 eq), and triethylamine (16 μL, 0.11 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amide as a yellow solid (22 mg, 35% yield).
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30])=O)C1C=CC=CC=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(OCC)C>[NH2:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30]
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOCC
Product: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (3.0 g) and hydrobromic add (45% in acetic add, 6.2 ml) was stirred for 1 h at room temperature under an atmosphere of nitrogen. The mixture was then diluted with cold anhydrous diethyl ether (40 ml) and stirred at 0° C. for 45 min. The white precipitate was collected by filtration, washed with cold diethyl ether (4×30 ml) and then dissolved in a mixture of water (30 ml) and aq. sodium hydroxide (2M, 15 ml). The basic aqueous phase was extracted with ethyl acetate (3×70 ml) and the combined organic layers were washed with brine (30 ml), dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel, using 94:6, dichloromethane:methanol as the eluant, to afford the title compound (1.6 g) as a pale pink solid. Mp 133°-136° C. 1H NMR (360 MHz, CDCl3) δ 1.02-1.40 (4H, m), 1.47-1.56 (1H, m), 1.61-1.74 (3H, m), 1.84-1.91 (1H, m), 1.96-2.06 (1H, m), 2.17 (2H, brs), 2.70-2.80 (1H, m), 3.39 (3H, s), 4.29 (1H, s), 7.20-7.27 (2H, m), 7.44-7.54 (2H, m).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Temperature: 45 °C
Reaction time: 48 h
Yield: 45.5 %

Procedure:
A mixture of 7-allyl-3,7-dihydro-1H-purine-2,6-dione (10.0 g, 0.052 mol), sodium carbonate (8.3 g, 0.078 mol), and 1-iodopentane (12 g, 0.062 mol) in DMF (100 mL) was stirred at 45° C. for 2 days. The reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was treated with ether and the solid formed was filtered to provide the desired product as white solid (6.2 g, 45.4%). LCMS calculated for C13H19N4O2 (M+H): 263.2. found: 263.2.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[C:24]1([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[NH2:40][C@H:41]([C:45]([O:47]CC=C)=[O:46])[CH:42]([CH3:44])[CH3:43].N1CCOCC1>C1COCC1.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>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[C:24]1([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[NH2:40][C@H:41]([C:45]([OH:47])=[O:46])[CH:42]([CH3:44])[CH3:43]
Reactant: C=CCOC(=O)[C@@H](N)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: N[C@@H](Cc1cccc2ccccc12)C(=O)O
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC(C)[C@H](N)C(=O)O
Reaction time: 0.5 h

Procedure:
Cbz-Asp(O-tBu)-3-(1-naphtyl)-L-alanine-Val-OAllyl (1 g; 1.51 mmol) was co-evaporated with THF to dryness (2*10 ml), then dissolved under argon in dry THF (18 ml, inhibitor free). The solvent was degassed three times under argon (3 min+2+2) before dropwise addition of morpholine (0.658 ml, 5 eq) followed with addition of Tetrakis in one shot (174 mg, 0.1 eq). The mixture was purged under argon for 3 min. the reaction was carried out in the absence of light and at room temperature for 30 minutes. It was then diluted with ether (18 ml) followed with citric acid 0.5M (18 ml). The mixture was stirred for 3 minutes, then extracted. The aqueous layer was washed with ether (3*18 ml) then combined, dried with MgSO4. The solvent was evaporated to dryness. The crude was purified on C-18 column 50 g (pH: 3.5; gradient: 10 to 100° A) MeOH/Water; 4 ml methanol injection volume) to get 0.75 g of the desired product (second pic). NMR 1H (CD3OD, 500 MHz) δ 8.20 (d, 1H, J=8.5 Hz); 7.85 (d, 1H, J=8.1 Hz); 7.75-7.72 (m, 1H); 7.56-7.46 (m, 2H); 7.37-7.27 (m, 7H); 5.09 (q, 2H, J=12.35 Hz); 4.85 (m, 1H); 4.47-4.44 (m, 1H); 4.30 (d, 1H, J=5.8 Hz); 3.68 (dd, 1H, J=14.10; 5.80 Hz); 3.43-3.37 (m, 1H); 2.66 (dd, 1H, J=16.30; 5.9 Hz); 2.46 (dd, 1H, J=16.20; 8.1 Hz); 2.19-2.12 (m. 1H); 1.41 (s, 9H); 0.96 (d, 6H, J=6.80 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[OH:13][CH2:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 66.4 %

Procedure:
To a solution of 1-Boc-azetidine-3-carboxylic acid (Astatech, 1.0 g, 4.97 mmol) in tetrahydrofuran (10 mL) at −10° C. was added 4-methylmorpholine (0.55 mL, 5.0 mmol). This mixture was stirred for 1 minute and then ethyl chloroformate (0.47 mL, 4.97 mmol) was added dropwise. The mixture was stirred at −10° C. for 15 min then was filtered through Celite and the filtrate was added dropwise via syringe to a mixture of NaBH4 (0.42 g, 11.2 mmol) in H2O (5 mL) at 5° C. The mixture was allowed to warm to ambient temperature and was stirred vigorously for 3 h. The reaction mixture was quenched with 5 mL saturated, aqueous NH4Cl, the layers were separated and the aqueous layer was extracted with 3×5 mL ethyl acetate. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO2, 30% hexanes in ethyl acetate) to give the title compound (0.62 g, 3.3 mmol, 66% yield). MS (DCI/NH3) m/z 188 (M+H)+.
Reaction SMILES: S(C)C.[C:4]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15](O)=[O:16])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>>[C:4]([O:8][C:9]([N:11]1[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CC(CO)C1

Procedure:
Using a procedure analogous to Example 40-B (using Me2S.BH3), 1-t-butoxycarbonylazetidine-3-carboxylic acid gave the title compound (3.0 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:13](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 900.2 %

Procedure:
To a solution of 2-chloro-5-fluoronicotinic acid 6 (50 g, 285 mmol) and DMF (2 mL, 28 mmol) in DCM (400 mL) at 0° C. was added oxalyl chloride (64 mL, 741 mmol) dropwise. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The resulting yellow liquid was dissolved in 1,4-dioxane (600 mL), cooled at 0° C. and NH3(g) was bubbled through the solution for 30 minutes. The mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filtrate was concentrated to give compound 3 (44 g, 89%) as a beige solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.84 (s, 1H), 7.96 (dd, 1H), 8.09 (s, 1H), 8.49 (d, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]2=[O:31])=[C:4]([OH:33])[CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]2=[O:31])=[C:4]([OH:33])[CH:3]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(F)c(F)cc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc(F)c(F)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a solution of 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (11.72 g, 26.4 mmol) in trifluoroacetic acid (60 mL) under nitrogen was added triethylsilane (10.55 mL, 66.0 mmol), and the reaction mixture was stirred for 16 h. Following concentration in vacuo, the residue was purified by column chromatography (30% ethyl acetate in hexanes). Precipitation from diethyl ether/hexanes followed by filtration yielded 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (6.29 g, 56%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.27 (brs, 1H), 7.37-7.12 (m, 12H), 6.94 (s, 1H), 6.87 (dd, J=11.3, 7.1 Hz, 1H), 6.76 (dd, J=11.2, 8.9 Hz, 1H), 6.58-6.56 (m, 1H), 5.12 (s, 1H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [Si](O[C@@H]1[C@@](COS(C)(=O)=O)(CO)O[C@@H]([N:22]2[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]2=[O:24])C1)(C(C)(C)C)(C)C.[Na+].[I-].[Si](O[C@@H]1[C@@](CI)(CO)O[C@@H](N2C=C(C)C(=O)NC2=O)C1)(C(C)(C)C)(C)C>CC(=O)CCC(=O)C>[NH:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@](CO)(COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: CC(=O)CCC(C)=O
Agent: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@](CO)(CI)O2)c(=O)[nH]c1=O
Agent: [I-]
Product: Cc1c[nH]c(=O)[nH]c1=O
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A solution of the 4'-α and 4'-β isomers of 3'-O-t-butyldimethylsilyl-4'-methanesulfonyloxymethylthymidine (88 mg, 0.18 mM) prepared, e.g., as described in Preparation 5, with NaI (270 mg, 1.8 mM) in 2,5-hexanedione (3 ml) was stirred at 130° C. for 2 hours, at 95° C. for 60 hours and at 130° C. for 24 hours. Solid material was filtered off and the solvent was removed by evaporation under reduced pressure. The residue was purified (twice) by flash chromatography on silica gel. The column was eluted with CH2Cl2 +4% CH3OH+0.05% acetic acid followed by CH2Cl2 +4% CH3OH. The two fractions with identical TLCs and were combined yielding a mixture of the 4'-α and 4'-β isomers of 3'-O--t-butyldimethylsilyl-4'-iodomethylthymidine (70 mg, 0.14 mM), as a light brownish material. MS(CI) 514(M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C1C(=O)N([Br:20])C(=O)C1.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Br)c(C)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Br)c(CBr)c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 4-bromo-3-methylbenzoate (50 g; 218 mmol) in CHCl3 (1 L) were added NBS (46.6 g; 262 mmol) in one portion and α,α′-azoisobutyronitrile (0.72 g; 4.37 mmol). The reaction mixture was stirred at 70° C. for 2 days. It was cooled down to RT and water was added. The organic layer was washed with aq. NaHCO3, then brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with n-pentane to afford the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 8.24 (d, J=1.9 Hz, 1H), 7.88-7.82 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). HPLC (Method A): Rt 4.44 min (purity 97.9%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>C(O)C>[N+:8]([C:7]1[C:2]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCc1ccccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1NCc1ccccn1
Yield: 95.1 %

Procedure:
To a stirred solution of 2-chloro-3-nitropyridine (26.56 g, 0.168 mol) in absolute ethanol (250 mL) was added 2-(aminomethyl)pyridine (20.0 g, 0.185 mol) and triethylamine (16.99 g, 0.168 mol). The solution was heated at reflux for 2 hr and evaporated under reduced pressure. The residue was triturated in ethyl acetate several times and filtered. The filtrate was washed 3 times with a saturated sodium chloride solution, dried (sodium sulfate), filtered and evaporated under reduced pressure to give 36.8 g of N-(3-nitro-2-pyridinyl)-2-pyridinemethanamine (95% yield). A 1.0 g portion of the solid was recrystallized from isopropyl ether and dried under high vacuum to give 0.57 g of N-(3-nitro-2-pyridinyl)-2-pyridinemethanamine, mp 112°-115° C.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:22]([C:11]([OH:13])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[N:21]2)=[CH:23][CH:24]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cccc(N)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 3-methoxy-aniline were reacted and treated with phenyl oxide to obtain ethyl 7-methoxy-4-hydroxy-3-quinoline-carboxylate melting at >260° C.