Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].[CH2:9]([N:11]([CH2:22][CH3:23])[C:12]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH2:21])=[O:13])[CH3:10].[OH-].[Na+]>C1C=CC=CC=1>[CH2:22]([N:11]([CH2:9][CH3:10])[C:12]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH:21][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:13])[CH3:23]
Reactant: CC(C)C(=O)O
Reactant: CCN(CC)C(=O)Oc1cnccc1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCN(CC)C(=O)Oc1cnccc1NCC(C)C
Temperature: 85 °C
Yield: 33 %

Procedure:
A solution of isobutyric acid (49.85 g) in 100 ml of benzene was treated with NaBH4 (6.91 g added portionwise). After the frothing subsided, 4-amino-3-pyridinol N,N-diethylcarbamate (4.90 g) was added and the mixture was heated at 85° C. for 3 hours. The reaction mixture was poured into a dilute NaOH solution and the aqueous phase was extracted with ethyl acetate (3×). The combined organics were washed with water and dried (saturated NaCl, MgSO4). The desired amine was purified via flash chromatography to give 2.05 g of solid. This product was recrystallized from hexane to give analytically pure material, m.p. 71°-75° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])C(O)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)=O>[Cu].N1C2C(=CC=CC=2)C=CC=1>[C:15]([NH:14][CH:10]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:19][CH:18]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)NC(=Cc1ccc(OC(C)=O)cc1)C(=O)O
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Product: CC(=O)NC=Cc1ccc(OC(C)=O)cc1

Procedure:
26.3 g (0.1 mol) of p-acetoxy-α-acetylaminocinnamic acid, 50 ml of quinoline and 2 g of copper powder are heated to 160°-170°C for 3 hours, in the course of which carbon dioxide is evolved. Thereafter, the quinoline is distilled off in vacuo and the residual mass is taken up in ethyl acetate. After filtering off the copper powder, the ethyl acetate solution is extracted with 25 ml of 1 N hydrochloric acid and is then washed with water and sodium bicarbonate solution. The organic phase is dried over sodium sulphate and thereafter the solvent is removed by distillation in vacuo. The resulting oil, on crystallisation from ethyl acetate, yields p-(2-acetylaminovinyl)-acetoxybenzene of melting point 165°-166°C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:58][CH2:57][C:56]([F:60])([F:59])[F:55])=[O:21])=[CH:17][N:16]=1
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (228 mg, 0.71 mmol), N,N-diisopropyl ethyl amine (552 μL, 3.22 mmol) and 2,2,2-trifluoroethylamine 77 μL, 0.77 mmol). The resulting reaction mixture was stirred for 12 h at ambient temperature. After dilution with ethyl acetate (20 mL) it was washed with water (20 mL) and aqueous sodium carbonate (saturated, 40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 20:80) afforded the title compound (213 mg, 84%) as a white solid. MS: m/e=392.2 [M+H]+.
Reaction SMILES: [CH:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)([CH3:3])[CH3:2].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CC(C)Sc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(SC(C)C)n1

Procedure:
A mixture of 5.75 g. 3-isopropylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 2.5 hours. The reaction mixture was worked up as described in Example 1 to produce an oily residue which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-isopropylthio-1,2,4-triazole, b.p. 133° C./0.4 mm. - 144° C./0.9 mm. (97.2% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])[CH:2]=C.[O:13]=[O+][O-].[BH4-].[Na+]>ClCCl>[Br:11][C:6]1[CH:7]=[C:8]([Cl:10])[CH:9]=[C:4]([CH2:1][CH2:2][OH:13])[C:5]=1[OH:12]
Reactant: C=CCc1cc(Cl)cc(Br)c1O
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: OCCc1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of 2-allyl-6-bromo-4-chlorophenol (1.378 g, 5.567 mmol) in 20 mL dichloromethane was cooled at −78° C. While stirring at this temperature, ozone was bubbled through the reaction solution for 6.5 hours. After flushing the reaction vessel with oxygen, while still at −78° C., the reaction was quenched with sodium tetrahydroborate (1.064 g, 28.12 mmol). The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (10 to 60% ethyl acetate in heptanes) to yield 0.5911 g (42%) of 2-bromo-4-chloro-6-(2-hydroxyethyl)phenol. 1H NMR (400 MHz, CDCl3) δ: 7.38 (d, J=2.5, 1H), 7.27 (s, 1H), 7.06 (d, J=2.4, 1H), 3.96 (br s, 2H), 2.91 (t, J=5.7, 2H), 1.98 (s, 1H).
Reaction SMILES: C(N=[CH:6][C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH3:16])CCC.[OH:17]S(O)(=O)=O>O.CCOC(C)=O>[CH2:15]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:7]=1[CH:6]=[O:17])[CH3:16]
Reactant: CCCCN=Cc1c(CC)cccc1CC
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cccc(CC)c1C=O
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a solution of butyl-(2,6-diethyl-benzylidene)-amine (1.10 g; 5.06 mmol) in water (20 mL) was added H2SO4 (5.00 ml; 93.80 mmol), and the resulting mixture was heated under reflux for 2 hours. After cooling to RT the mixture was diluted with EtOAc, and washed with water, a 5% aqueous NaHCO3-solution and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 2,6-diethyl-benzaldehyde (0.72 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]=[N-:13].[O-]CC.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:14]([N:11]=[N+:12]=[N-:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1cc(C)cc(C=O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=Cc1cc(C)cc(C)c1)N=[N+]=[N-]
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of 5 g of 3,5-dimethylbenzaldehyde and 19.3 g of ethyl azidoacetate is added, at −10° C. under dry nitrogen, to a mixture of 25 ml of ethanol and 50 ml of a 21% solution of sodium ethoxide in ethanol. The mixture is left stirring for 1 hour at −10° C. and for fourteen and a half hours at +5° C. It is poured into 100 ml of water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in ether and this solution is dried over MgSO4 and then evaporated to give the product, which is used without further purification in the subsequent step.
Reaction SMILES: [OH-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([NH:21][C:22](=[O:34])[NH:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>CO>[C:3]12([C:13]3[CH:14]=[C:15]([NH:21][C:22](=[O:34])[NH:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(NC(=O)Nc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
6 g (0.15 mol) of sodium hydroxide are added to a solution of 6.08 g (14 mmol) of methyl 4-[3-(1-adamantyl)-4-methoxyphenylureido]benzoate in 75 ml of methanol and the mixture is stirred at room temperature for 3 hours and then heated to reflux for 3.5 hours. The reaction mixture is evaporated, the residue is then taken up with 100 ml of water and the mixture is acidified to pH 1. The solid is filtered off, rinsed with water, dried and recrystallized in a tetrahydrofuran/hexane mixture to yield 2.78 g (87%) of 4-[3-(1-adamantyl)-4-methoxyphenylureido]benzoic acid, melting point 279°-282° C.
Reaction SMILES: [CH:1]([C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:10]1=[O:26])=[O:2].CO.[BH4-].[Na+]>C1COCC1>[OH:2][CH2:1][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]2)[C:10]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(C=O)C(=O)OC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(CO)C(=O)OC1)C2=O
Reaction time: 0.25 h

Procedure:
tert-butyl 2-(4-formyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.18 g, 3.24 mmol) was dissolved in THF (13 mL) and MeOH (13 mL) and the mixture was cooled to −78° C. and stirred for 15 min. Sodium borohydride (0.147 g, 3.89 mmol) was added in two equal portions and the resulting mixture was stirred for ˜15 min. at −78° C. LC-MS after 15 minutes stirring at −78° C. showed complete consumption of starting material. The reaction mixture was diluted with ethyl acetate and quenched with aqueous ammonium chloride solution at −78° C. The aqueous layer was extracted with EtOAc (2×), combined organic layers were washed with water, brine, then dried (MgSO4) and filtered, and the solvent was evaporated under reduced pressure to obtain the product, which was taken to the next step without purification.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1([O:45][C@H:44]([CH2:46]O)[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]1[O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:67]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:9][CH2:10][C:11]1([O:45][C@H:44]([CH2:46][I:67])[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]1[O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC1(COC(=O)c2ccccc2)O[C@H](CO)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC1(COC(=O)c2ccccc2)O[C@H](CI)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
In DMF (16 ml) was dissolved methyl 1,3,4,5-tetra-O-benzoyl-D-ido-2-heptulopyranoside (950 mg). To the solution were added triphenyl phosphine (1.65 g) and N-iodosuccinimide (1.2 g). The mixture was stirred at room temperature overnight. To the mixture was added ice-water (100 ml). The resulting oily substance was subjected to extraction with ethyl acetate. The ethyl acetate extract was washed with saturated sodium thiosulfate solution, 2N hydrochloric acid and saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was chromatographed on a column of silica gel (200 ml) with toluene-ethyl acetate (10:1). The eluate was concentrated to dryness under reduced pressure to give a white powder (780 mg) of methyl 1,3,4,5-tetra-O-benzoyl-7-deoxy-7-iodo-D-ido-2-heptulopyranoside.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:34])(=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=3)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:35])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[K+].Br[CH2:39][CH:40]=[CH:41][CH3:42]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:33])(=[O:34])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=3)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:35][CH2:39][CH:40]=[CH:41][CH3:42])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC=CCBr
Reactant: CC(=O)Nc1ccc(Nc2c(N)cc(C(=O)O)cc2S(=O)(=O)Nc2ccc(NC(C)=O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC=CCNc1cc(C(=O)O)cc(S(=O)(=O)Nc2ccc(NC(C)=O)cc2)c1Nc1ccc(NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: To the solution of 2.5 g of 4-(4-acetamidophenylamino)-3-amino-5-(4-acetamidophenylsulfamoyl)-benzoic acid in 60 ml of water and 5 ml of N potassium hydroxide, 0.7 g of 1-bromo-2-butene are added dropwise while stirring. The pH of the mixture is kept at 7.4 by subsequent addition of 4 N aqueous potassium hydroxide. After about 15 minutes the mixture is filtered, the filtrate acidified with glacial acetic acid to pH = 4, the precipitate formed filtered off and recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylamino)-3-but-2-enylamino-5-(4-acetamidophenylsulfamoyl)-benzoic acid melting at 265° with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([CH3:22])=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH3:25])[C:13]([CH3:22])=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: CI
Reactant: COc1ccc(-c2nc(-c3cccnc3)c(C)[nH]2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(-c3cccnc3)c(C)n2C)c(OC)c1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2,4-dimethoxyphenyl)-5-methyl-4-(3-pyridyl)imidazole (0.80 g) in N,N-dimethylformamide (12 ml) was added sodium hydride (0.13 g, 60% suspension in oil), and the mixture was stirred for 10 minutes. Then methyl iodide (0.34 ml) was added thereto, and the reaction was stirred at ambient temperature for 5 hours. The solution was poured into water (100 ml), and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and chromatographed on silica gel (25 g) eluting with chloroform. The fractions were collected and evaporated, and the residue was triturated with a mixture of ethyl acetate and diisopropyl ether (1:1 V/V) to give 2-(2,4-dimethoxyphenyl)-1,5-dimethyl-4-(3-pyridyl)imidazole (70 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH2:26][CH2:27]2)[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]1=[O:17]
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CC(CCN2CCN(c3ccccn3)CC2)c2nc3ccccc3n2C1=O

Procedure:
To 50 mL of toluene was added 5.0 g (0.019 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one, 6.19 g (0.038 mol) of 1-(2-pyridyl)piperazine, and 3.8 g (0.038 mol) of triethylamine. The reaction mixture was heated to reflux for 24 hours. The reaction mixture was washed with 2×50 mL of NaOH, dried over Na2SO4, filtered and concentrated by rotary evaporation. The residue was crystallized from isopropyl alcohol to afford 5.5 g (75%) of analytically pure crystals, mp 158°-59° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH:33]=[O:34])=[C:18]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([C:31]#[N:32])=[CH:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].BrC1C(C=[O:54])=C(N2C3C(=CC=CC=3)C(C#N)=C2)C=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:33][OH:34])=[C:18]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([C:31]([NH2:32])=[O:54])=[CH:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c5ccccc54)c3C=O)ncc2c1
Reactant: N#Cc1cn(-c2cccc(Br)c2C=O)c2ccccc12
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccccc54)c3CO)ncc2c1
Yield: 66 %

Procedure:
The preparation of 1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3-carbonitrile, via reaction of 1-(3-bromo-2-formylphenyl)-1H-indole-3-carbonitrile (222 mg, 40% pure, 0.27 mmol, synthesis described above in Example 18, step 1) with 6-tert-butylphthalzin-1(2H)-one (138 mg, 0.68 mmol) was carried out in a procedure analogous to that described in Example 18. Similar work up and purification provided desired product as a light yellow-white solid (82 mg, 66% yield). LC/MS calcd for C28H22N4O2 (m/e) 446.51, obsd 447.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 7.23-7.40 (m, 3H) 7.55 (dd, J=7.93, 1.13 Hz, 2H) 7.72-7.94 (m, 6H) 8.32 (s, 1H) 8.39 (d, J=8.31 Hz, 1H) 9.59 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:28]>CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:14]3[C:10]4[C:9]5[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=[C:2]([NH2:28])[C:11]=4[N:12]=[CH:13]3)[O:20][N:19]=2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(-c2cc(Cn3cnc4c(Cl)nc5ccccc5c43)on2)cc1
Reactant: N
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2Cc1cc(-c2ccc(F)cc2)no1
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinoline (0.2322 g, 0.6130 mmol) and 7 N ammonia in methanol (10 mL) was sealed in a pressure vessel and heated at 150° C. for 22 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the resulting orange solid was triturated with diethyl ether. The solid was then purified by column chromatography on silica gel (7 g, eluting with 10% to 20% CMA in chloroform), triturated with diethyl ether, isolated by filtration, and dried. The solid was then boiled in methanol in the presence of a small amount of 0.5 N sodium hydroxide in methanol. The mixture was allowed to cool to room temperature, and the solid was isolated by filtration and dried to provide 0.0259 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder, mp 259.0-260.0° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([C:13]#[N:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>C(#N)C>[C:13]([CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:15])#[N:14]
Reactant: Oc1cccc(CBr)c1
Reactant: COC(=O)C(C#N)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C#N)Cc1ccc(OCc2cccc(O)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.44 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged 10 mL of acetonitrile. To the stirred solvent was added 2-cyano-3-(4-hydroxy-phenyl)-propanoic acid methyl ester (0.3 g, 1.57 mmol), followed by K2CO3 (0.65 g, 4.71 mmol) and 3-bromomethyl-phenol (0.294 g, 1.57 mmol). After addition, the RM was heated at 50° C. for 1 h. After 1 h, the RM was concentrated to distill off the solvent, water (20 mL) was added and the aqueous layer was extracted with ethyl acetate (15 mL×2). The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The product was obtained as yellow liquid. (0.32 g, yield: 65.44%); MS (ESI, 120 eV): m/z=310.0 (M−H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:17])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN1CCCc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1CCCc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A solution of 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (134 mg, 0.57 mmol), HBTU (327 mg, 0.86 mmol), and diisopropylethylamine (150 μL, 0.86 mmol) was stirred in methylene chloride (3.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (Example SP-272) (234 mg, 0.57 mmol) and diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (3.0 mL) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (10 mL), saturated sodium bicarbonate (10 mL), and brine. The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1,2,3,4-tetrahydroquinoline-7-carboxamide (130 mg): ESI MS m/z 550 [M+H]+
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:5][CH:6]=1>CC(O)C.O>[CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Solvent: CC(C)O
Solvent: O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Yield: 128.1 %

Procedure:
A suspension of 31.73 g of L-N-[(4-methoxyphenyl)sulfonyl]-glutamic acid (0.1 mol) in 400 ml of 2-propanol and 20 ml of water was stirred and heated till all solid entered solution. Then there were added 20.43 g of tetramisole. The whole was stirred and heated till an homogeneous solution was obtained. The solution was further stirred for 4 hours while the temperature was allowed to reach room temperature. The precipitate was filtered off, washed with 100 ml of 2-propanol and 5 ml of water and dried under vacuo at 50° C., yielding 26.17 g levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield 100.3%) αD20 =-62.8° (c5. 1N HCl); mp. 127.4°-129.1° C.