Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[C:5]([F:11])[CH:4]=1.Br[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cl-].[Zn+2].[Cl-]>[F:11][C:5]1[CH:4]=[C:3]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:8]=[C:7]([F:9])[C:6]=1[F:10]
Reactant: Brc1ccsc1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Product: Fc1cc(-c2ccsc2)cc(F)c1F
Temperature: 40 °C

Procedure:
In a first three-necked round-bottom flask (100 ml), metallic magnesium (52 mmol) (product #25411-8, manufactured by Aldrich Chemical) was flame dried in an argon atmosphere for 3 to 4 minutes. Upon cooling under the argon atmosphere, 50 ml of freshly dried tetrahydrofuran (product #T 397-4, manufactured by Fisher Scientific) was previously distilled from a sodium/bentophenone mixture and directly drawn into the flask from the distillation head. Into this mixture of magnesium and tetrahydrofuran was added 1-bromo-3,4,5-trifluorobenzene (26 mmol) (product #33084-1, manufactured by Aldrich Chemical), which remained in an argon atmosphere and was stirred. After the mixture was warmed to about 40° C. (after about 3 to 4 minutes), the flask was cooled (e.g., via an ice bath) and continuously stirred for 2 hours to form a magnesium complex. Anhydrous zinc chloride (ZnCl2) (31 mmol) (product #20808-6, manufactured by Aldrich Chemical) previously dried at 160° C. and weighed under vacuum conditions was added to the magnesium complex at room temperature. After stirring for 30 minutes, the zinc complex suspension was transferred (e.g., via Teflon tubing) under argon pressure to a second three-necked round-bottomed flask (250 mL) containing a solution of 3-bromothiophene (21 mmol) (product #10622-4, manufactured by Aldrich Chemical) and Pd(dppf)Cl2 catalyst (product #37967-0, manufactured by Aldrich Chemical). This coupling reaction mixture was then heated (e.g., via an oil bath) for 0.5 hour with continuous stirring at 60° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[C:15]([OH:17])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>>[CH2:18]([N:20]([CH2:21][CH3:22])[C:15]([C:11]1[CH:12]=[N:13][O:14][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:17])[CH3:19]
Reactant: CCNCC
Reactant: O=C(O)c1cnoc1-c1ccc([N+](=O)[O-])cc1
Product: CCN(CC)C(=O)c1cnoc1-c1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 5-(4-nitrophenyl)isoxazole-4-carboxylic acid (11.7 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified, first by preparative HPLC method A and then by method B, to give a solid (4.3 mg). MS (pos) m/z 290.2 (M+1).
Reaction SMILES: [NH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[NH2:2].[C:14](N1C2N(C(=O)C)C(=O)N(C(=O)C)C2N(C(=O)C)C1=O)(=[O:16])[CH3:15].C(O)(=O)C>C(#N)C.C(O)C>[C:14]([NH:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1C(=O)N(C(C)=O)C2C1N(C(C)=O)C(=O)N2C(C)=O
Reactant: NNc1ccc(OCC(=O)O)cc1
Solvent: CCO
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)NNc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Yield: 122.4 %

Procedure:
4-Hydrazinophenoxyacetic acid 0.1H2O (10.0 g) and 1,3,4,6-tetraacetyltetrahydroimidazo[4,5-d]imidazole-2,5-(1H,3H)-dione (7.8 g) were suspended in dry acetonitrile (200 ml) containing acetic acid (1 ml). The mixture was heated under reflux for 3 hours, cooled to room temperature, and filtered. The precipitate was washed well with acetonitrile; the washings were combined with the filtrate, and this solution was evaporated to give a dark oil. The residue was taken up in hot ethanol (25 ml) and the brownn powder which precipitated on chilling was filtered off and dried. Recrystallization from acetonitrile gave the product as chunky, tan crystals (6.9 g).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17][CH2:18][CH2:19][NH2:20]>>[CH3:16][S:17][CH2:18][CH2:19][NH:20][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: CSCCN
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Product: CSCCNCc1ccc(Oc2ccccc2)cc1
Yield: 92.5 %

Procedure:
Following the procedure described in Example 68A, 4-phenoxybenzaldehyde (1.98 g, 10 mmol) and 2-methylthioethylamine (0.912 g, 10 mmol) were combined to give the title compound (2.53 g, 93%) 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 4 H), 7.09. (t, 1 H), 6.97 (m, 4 H), 3.80 (s, 2 H), 2.84 9t, 2 H), 2.68 (t, 2 H), 2.10 (s, 3 H).
Reaction SMILES: [C:1]([CH:4]1[O:8][C:7]2[C:9](=[O:19])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH2:5]1)=[C:14]([OH:18])[CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:4]1[O:8][C:7]2[C:9](=[O:19])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[C:14]([OH:18])[CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)C1CC2=C(O1)C(=O)c1cccc(O)c1C2=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc2c(o1)C(=O)c1cccc(O)c1C2=O
Temperature: 25 °C
Yield: 29.8 %

Procedure:
To a solution of 2-acetyl-2,3-dihydro-5-hydroxynaphtho[2,3-b]furan-4,9-dione (2.4 g, 9.4 mmol) in chloroform (50 mL) is added 20 g of manganese dioxide (manufactured by Aldrich Corp., 85% activated manganese dioxide, <5 micron), and the resulting suspension is heated to reflux for 1 day. The mixture is cooled to room temperature, and then filtered. The filtrate is evaporated in vacuo and the residue is purified by silica gel column chromatography (eluent: chloroform) to give 2-acetyl-5-hydroxynaphtho[2,3-b]furan-4,9-dione (0.718 g, 33%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:6]2[C:7](=[O:10])[CH2:8][CH2:9][C@@H:5]2[CH2:4][O:3]1.C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.[CH3:40][C:41]([CH3:43])=[O:42]>C1COCC1>[OH:42][C:41]([CH:8]1[C:7](=[O:10])[N:6]2[C:2]([CH3:11])([CH3:1])[O:3][CH2:4][C@H:5]2[CH2:9]1)([CH3:43])[CH3:40]
Reactant: CC(C)=O
Reactant: CC1(C)OC[C@H]2CCC(=O)N21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: CC(C)(O)C1C[C@@H]2COC(C)(C)N2C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a solution of (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (6.68 g, 43.0 mmol) in THF (100 mL) cooled to −78° C., was added lithium diisopropylamide, 2.0 M solution in THF/heptane/ethylbenzene (43.0 mL, 86 mmol) and stirred at −78° C. for 1 h. The resulting mixture was treated with acetone, 99.8%, extra dry, acroseal (6.32 mL, 86 mmol) at −78° C. and then allowed to warm up to room temperature for 16 h. The reaction was quenched with sat. NH4Cl and extracted with EtOAc (2×200 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to provide (7aR)-6-(2-hydroxypropan-2-yl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (6.088 g, 28.5 mmol, 66.3% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 4.50 (s, 1H), 4.07-4.18 (m, 1H), 3.98 (dd, J=8.0, 5.7 Hz, 1H), 3.32-3.35 (m, 1H), 2.50-2.56 (m, 1H), 2.22 (ddd, J=13.4, 7.2, 2.0 Hz, 1H), 1.83 (ddd, J=13.3, 10.4, 7.6 Hz, 1H), 1.54 (s, 3H), 1.32 (s, 3H), 1.21 (s, 3H), 1.14 (s, 3H). m/z (ESI, +ve) 214 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[CH2:17]([Li])CCC.CI>C1COCC1.CCOCC>[CH3:17][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]
Reactant: [Li]CCCC
Reactant: Nc1ccccc1-c1nc2ccccc2[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(-c2ccccc2N)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(1H-benzo[d]imidazol-2-yl)benzenamine (525 mg, 2.5 mmol) in 5 mL dry THF was cooled to −78 degrees before 1 mL n-Bu-Li (2.5 mmol, 2.5 N in hexanes) was added via a syringe. The reaction was stirred at −78 degrees for 20 min and MeI (360 mg, 2.6 mmol) was added. The reaction was warmed to r.t. gradually and kept at room temperature for another hour. The reaction crude was diluted with 25 mL ether and the resulted suspension was filtered off the solid. The crude product was isolated after the solvent was removed from the collected filtrate to product 510 mg of 2-(1-methyl-1H-benzo[d]imidazol-2-yl)benzenamine in greater than 95% purity (MS, M++H=224.1).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.[N:16]([O-])=O.[Na+]>O.Cl>[NH:4]([C:5]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[NH2:16]
Reactant: O=N[O-]
Reactant: COc1ccc(C(=O)O)c(NC(C)=O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)c(NN)c1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
A suspension of 2-acetylamino-4-methoxy-benzoic acid (15 g, 73.7 mmol) in water (75 mL) was cooled to −5° C. and conc HCl (150 mL) was added followed by cooling to −5°. To this mixture was added a solution of NaNO2 (5.43 g, 77.4 mmol) in water (50 mL) that had been cooled to −5°; this solution was added at such a rate so as to maintain the temperature of the reaction mixture between −5° and 0° C. The reaction mixture was stirred for 10 min and the clear solution was added to a solution of stannous chloride (41.9 g, 221 mmol) in conc HCl (150 mL) that had been cooled to −20° C. This addition was conducted so as to maintain a temperature of −20° to −10° C. for the reaction mixture, followed by stirring the mixture for 1.5 h at −20° C. The solid that formed was collected by filtration, washed with chilled EtOH, and dried to give an off-white solid (10.8 g): APCl/LCMS m/z 183 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH:11][CH3:12].ClC1N=C(N(C)C)C=CC=1C.ClC1N=C(N(C)C)C(C)=CC=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:11]([CH3:12])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Reactant: CNC
Agent: Cc1ccc(Cl)nc1N(C)C
Agent: Cc1ccc(N(C)C)nc1Cl
Product: Cc1cc(Cl)nc(N(C)C)c1

Procedure:
The compound was prepared from 2,6-dichloro-4-methylpyridine and dimethylamine using the method described in the preceding example 86 (6-chloro-5-methyl-pyridin-2-yl)-dimethyl-amine and (6-chloro-3-methyl-pyridin-2-yl)-dimethyl-amine).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]([O:16][C:17]2[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:26])=[C:19]([CH3:27])[CH:18]=2)=[C:11]([Br:28])[C:10]=1[C:29]([F:32])([F:31])[F:30])=[O:7])C.[Li+].[OH-].Cl>C1COCC1>[Br:28][C:11]1[C:10]([C:29]([F:32])([F:30])[F:31])=[C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:33])=[O:3])[CH:14]=[C:13]([Br:15])[C:12]=1[O:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[C:20]([OH:26])=[C:19]([CH3:27])[CH:18]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(Br)c(Oc2cc(C)c(O)c(C(C)C)c2)c(Br)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Oc2c(Br)cc(NC(=O)CC(=O)O)c(C(F)(F)F)c2Br)cc(C(C)C)c1O
Reaction time: 1 h
Yield: 42 %

Procedure:
To a stirred solution of compound N-[3,5-dibromo-4-[4-hydroxy-5-isopropyl-3-methylphenoxy]-2-trifluoromethyl-phenyl]malonamic acid ethyl ester of Part 11 G (15 mg, 0.027 mmol) in THF (0.5 mL) was added LiOH (0.25 mL, 1N). After 1 hour stirring the pH of reaction was adjusted to 1 by 1N HCl and the organic phase was removed in vacuo. The resulting mixture was extracted with EtOAc (3×3 mL) and the combined organic phases were dried over Na2SO4 before concentration in vacuo. The residue was purified on column (silica gel, gradient elution, CHCl3/MeOH/AcOH from 1:0:0 to 90:10:1) to give N-[3,5-dibromo-4-[4-hydroxy-5-isopropyl-3-methylphenoxy]-2-trifluoromethylphenyl]malonamic acid as a white solid (6 mg, 42%)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]I)=[CH:5][CH:4]=1)#[N:2].[I:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(O)C>[I:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][CH2:8][C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(C(=O)CI)cc1
Reactant: Nc1ccc(I)cc1
Solvent: CCO
Product: N#Cc1ccc(C(=O)CNc2ccc(I)cc2)cc1
Reaction time: 16 h

Procedure:
p-Cyanophenacyl iodide (18.0 g, 0.08 mole) was combined with p-iodoaniline (35.2 g, 0.16 mole) in 32.1 g of absolute ethanol and stirred 16 hours. Precipitated title product was recovered by filtration and repulped in 400 ml ether: 42.4 g; m.p. 160°-165°; ms 362, 232, 219.
Reaction SMILES: C(O[C:4](OCC)([CH3:17])[CH2:5][CH2:6][N:7]1[CH:12]=[C:11]([C:13]#[N:14])[C:10](=[O:15])[NH:9][C:8]1=[O:16])C.[O:21]1CCOCC1>>[O:16]=[C:8]1[NH:9][C:10](=[O:15])[C:11]([C:13]#[N:14])=[CH:12][N:7]1[CH2:6][CH2:5][CH2:4][CH:17]=[O:21]
Reactant: C1COCCO1
Reactant: CCOC(C)(CCn1cc(C#N)c(=O)[nH]c1=O)OCC
Product: N#Cc1cn(CCCC=O)c(=O)[nH]c1=O
Temperature: 60 °C

Procedure:
1-(3,3-Diethoxy-butyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (Prep 54, 200 mg, 0.71 mmol) was dissolved in dioxane (8 mL) and 1N HClaq (1 mL) was added. The mixture was warmed at 60° C. for 20 minutes. The solvents were evaporated, the residue was submitted to lyophilization, to give 150 mg of the title compound that was used in the next step without further purification (quantitative yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11](OC3C=CC=CC=3)=[O:12])[C:5]=2[C:4]2([C:31]3[C:22](=[CH:23][C:24]4[O:29][CH2:28][CH2:27][O:26][C:25]=4[CH:30]=3)[O:21][CH2:20]2)[C:3]1=[O:32].Cl.[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:34]1([NH:38][C:11]([C:6]2[C:5]3[C:4]4([C:31]5[C:22](=[CH:23][C:24]6[O:29][CH2:28][CH2:27][O:26][C:25]=6[CH:30]=5)[O:21][CH2:20]4)[C:3](=[O:32])[N:2]([CH3:1])[C:10]=3[CH:9]=[CH:8][CH:7]=2)=[O:12])[CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCC1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)Oc3ccccc3)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)NC3CCC3)cccc21
Temperature: 110 °C
Yield: 15.8 %

Procedure:
Phenyl 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate (0.30 g, 0.70 mmol), cyclobutylamine hydrochloride (0.23 g, 2.1 mmol), potassium carbonate (0.39 g, 2.8 mmol) and N,N-dimethylformamide (3.0 mL) were added to a microwave reaction vessel. The reaction was heated at 110° C. for 1 h in a microwave reactor, allowed to cool to ambient temperature, poured into water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with 1 M hydrochloric acid (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 20% to 100% gradient of ethyl acetate in hexanes followed by recrystallization from dichloromethane/diethyl ether to afford N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.045 g, 17%) as a colorless solid: mp 128-129° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.41-7.33 (m, 1H), 7.26-7.21 (m, 1H), 6.97-6.93 (m, 1H), 6.51 (s, 1H), 6.20 (s, 1H), 5.46 (d, J=6.65 Hz, 1H), 4.96-4.81 (m, 2H), 4.35-4.01 (m, 5H), 3.25 (s, 3H), 2.27-2.09 (m, 2H), 1.70-1.40 (m, 4H); MS (ES+) m/z 407.0 (M+1). N,N,1′-trimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.12 g, 37%) was isolated as a byproduct from the synthesis of N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide, obtained as colorless solid: mp 218-221° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.32 (dd, J=7.8, 7.8 Hz, 1H), 6.91-6.84 (m, 2H), 6.44 (s, 1H), 6.22 (s, 1H), 5.05 (d, J=8.8 Hz, 1H), 4.79 (d, J=8.8 Hz, 1H), 4.20-4.04 (m, 4H), 3.28 (s, 3H), 2.79 (s, 3H), 2.19 (s, 3H); MS (ES+) m/z 381.0 (M+1).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[C:9]([CH3:14])[C:8]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH3:5].[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:14][O:19][C:16](=[O:18])[CH3:17])[C:8]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCOc1cc[n+]([O-])c(C)c1C
Product: CCCCCOc1ccnc(COC(C)=O)c1C
Yield: 79.6 %

Procedure:
To 26.7 g (0.11 mol, 1.0 eq.) of 4-pentyloxy-2,3-dimethylpyridine-N-oxide, 44.0 g (0.43 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 7 hours at 90 to 100° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 22.0 g of 4-pentyloxy-2-acetoxymethyl-3-methylpyridine as an oily matter (yield 79.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9]C([C@@H](NC([C@@H](N)CC(O)=O)=O)CC1C=CC=CC=1)=O>>[CH:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: Nc1ccccc1
Product: O=CNc1ccccc1
Yield: 65 %

Procedure:
The reaction was run as described in Example 1, however, 0.70 g (7.6 mmol) aniline was used. Analysis of the reaction showed that aspartame was formed in 65-70% yield. Formanilide was also formed.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.C(Cl)Cl.S(Cl)(Cl)=O.[N:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][C:45]=1[S:54]([O-:56])=[O:55].[Li+]>O.CCOC(C)=O.CC(C)=O>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:26][CH2:25]5)=[N:22][CH:23]=4)=[C:3]([CH2:2][S:54]([C:45]4[CH:46]=[CH:47][C:48]5[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=5)[N:44]=4)(=[O:55])=[O:56])[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15]1
Reactant: O=S([O-])c1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Agent: [Li+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CS(=O)(=O)c4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound 21a (152 mg, 0.307 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added and the solid dissolved. Thionyl chloride (54.7 μL, 0.750 mmol) was added dropwise via microsyringe and then the reaction was stirred at rt for 5 min. The solvent was removed under reduced pressure. The residue was placed in a 40 mL vial equipped with a stir bar and then acetone was added. Compound 24a (199 mg, 1.00 mmol) was dissolved in water (5 mL) and added to the stirred acetone solution. The reaction turned yellow immediately. The reaction was stirred at rt for 18 h and then diluted with EtOAc (30 mL). The organic layer was separated and then the aqueous layer was extracted with EtOAc (3×20 mL). The aqueous layer was then extracted with DCM (3×30 mL). The organic extracts were combined, dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude residue was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-80% ACN/DCM to afford compound 24b. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.47 (d, J=2.2 Hz, 1H), 8.33 (d, J=8.6 Hz, 1H), 8.29 (d, J=8.6 Hz, 1H), 7.93-7.98 (m, 2H), 7.92 (d, J=5.6 Hz, 1H), 7.85-7.90 (m, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.72-7.78 (m, 1H), 6.68 (d, J=8.8 Hz, 1H), 5.93 (d, J=5.6 Hz, 1H), 5.07 (s, 2H), 3.59-3.64 (m, 4H), 3.55-3.59 (m, 4H), 3.36-3.41 (m, 4H), 3.29-3.36 (m, 4H), 1.51 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H38N8O5S: 671.3 (M+H). Found: 671.3.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].CN(C=O)C.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[N:20][N:19]=1>O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([O:1][CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:19][N:20]=2)=[CH:34][CH:33]=1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Reactant: OCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Nc2nnc(OCc3ccncc3)c3ccccc23)cc1
Reaction time: 0.33 h

Procedure:
A mixture of 1 g (9.16 mmol) 4-hydroxymethylpyridine, 0.44 g (11.0 mmol) sodium hydride (60% dispersion in oil) and 15 ml DMF is incubated for 20 min at 0° C. while stirring in a nitrogen atmosphere. At RT, 1 g (3.07 mmol) 1-chloro-4-(4-chloroanilino)phthalazine hydrochloride is added to the mixture, which is stirred for about 1 h at 50° C. and for 15 h at 80° C. Addition to the reaction mixture of a little water, evaporation under vacuum, recrystallization of the residue from methanol, and drying under HV yield the title compound with a water content of 3.36%; m.p. 139-141° C.; ESI-MS: (M+H)+=363.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CC2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Yield: 56.9 %

Procedure:
Under a nitrogen atmosphere, 13.98 g of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-thioxo-4-thiazolidinone, 13.17 g of diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate and 600 ml of toluene were stirred to effect solution. Forty grams of silica gel 60 (finer than 230 mesh) previously dried in vacuo at 50° C. for 7 hours were added to the reaction. The reaction was heated at reflux for 18 hours and filtered hot. The filtrate was evaporated to dryness. The residue was dissolved in 500 ml of ethyl acetate, washed 5 times each with 400 ml of 1N hydrochloric acid, dried over sodium sulfate, filtered, and evaporated in vacuo to provide a yellow solid. Chromatography over silica gel eluting with 2.5% ethyl acetate in toluene provided 8.0 g of the desired title product, m.p. 178-179° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](O)=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([Cl:28])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(-c2nn(Cc3ccccc3)c3ncnc(O)c23)c1
Product: COc1cccc(-c2nn(Cc3ccccc3)c3ncnc(Cl)c23)c1
Temperature: 0 °C

Procedure:
A mixture of 2.48 g (7.46 mmol) of 1-benzyl-4-hydroxy-3-(3-methoxy-phenyl)-pyrazolo[3,4-d]pyrimidine and 30 ml of phosphorus oxychloride is heated under reflux for 10 hours and then, with stirring, poured slowly into ice-water. The reaction mixture is stirred for a further 2 hours at 0-10° C. and filtered and the filter residue is washed with water. The crude product is dissolved in methylene chloride and the organic phase is washed with brine, dried over sodium sulfate and concentrated by evaporation in vacuo. Purification of the residue by flash chromatography on silica gel (230-400 mesh) using methylene chloride and methylene chloride/methanol mixtures (99:1 and 49:1) yields the title compound; m.p. 99-101° C.; FAB-MS: (M+H)+ =351.