Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([CH3:17])=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C[Li].C([Li])CCC.N1C=CC=C(S[S:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)C=1.[NH4+].[Cl-]>C1COCC1>[CH3:17][C:11]1[C:10]([O:9][C:4]2[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([S:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH:3]=2)=[CH:15][CH:14]=[C:13]([CH3:16])[N:12]=1
Reactant: Cc1ccc(Oc2cc(Br)cnc2N)c(C)n1
Reactant: c1ccc(SSc2cccnc2)nc1
Agent: [Cl-]
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Oc2cc(Sc3ccccn3)cnc2N)c(C)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
A 250 mL flask was charged with 5-bromo-3-(2,6-dimethylpyridin-3-yloxy)pyridin-2-amine (5.00 g, 17.66 mmol) and THF (100 mL) and purged with nitrogen. The solution was cooled to −78° C., methyl lithium (1.6 M in hexanes, 12.7 mL, 20.4 mmol) was added and the reaction was stirred for 5 minutes. Butyl lithium (2.5 M in Hexanes, 8.1 mL, 20.4 mmol) was added and the reaction was stirred for 10 minutes at −78° C. (solids formed). 2-(2-(Pyridin-3-yl)disulfanyl)pyridine (4.49 g, 20.4 mmol) was added and the reaction was warmed to ambient temperature and stirred for 18 hours. The reaction was poured into aqueous NH4Cl, extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified over silica gel (5% MeOH in CH2Cl2) to afford 3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (3.5 g, 63%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:13]#[C:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccccc1I
Product: C[Si](C)(C)C#Cc1ccccc1I
Yield: 54 %

Procedure:
The title compound was synthesized as a yellow oil in 54% yield using 1,2-diiodobenzene and (trimethylsilyl)acetylene as the starting materials according to Method A of the above-described General Synthesis Procedures I.
Reaction SMILES: CO[C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:6]([O:7][CH3:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C(O)(=O)C.[CH2:21]([CH2:23][NH2:24])[OH:22]>>[N+:11]([C:10]1[CH:9]=[C:6]([O:7][CH3:8])[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[NH:24][CH2:23][CH2:21][OH:22])([O-:13])=[O:12]
Reactant: NCCO
Reactant: COc1cc([N+](=O)[O-])c(OC)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(NCCO)c([N+](=O)[O-])c1

Procedure:
1 g of 2,6-dinitro-hydroquinone dimethyl ether (B. Relchert and W. Turkewitsch, Arch. der Pharmazie 276, 397, 406 (1938)) was stirred in 15 ml of ethanol amine for one hour at room temperature, whereupon the mixture was poured on ice and neutralized with acetic acid. The precipitated red crystals were filtered with suction. 0.9 g (78 percent of the theoretical yield) of the product was obtained; it has a melting point of 104° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:10](OCC)=[O:11].CC(C)([O-])C.[K+]>>[OH:11]/[CH:10]=[C:4]1/[C:5](=[O:8])[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]/1
Reactant: CC1(C)CCC(=O)CC1
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC1(C)CCC(=O)/C(=C/O)C1

Procedure:
reacting 4,4-dimethylcyclohexanone, ethyl formate and potassium tert-butoxide to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone;
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12]N(C=O)C.S(Cl)(Cl)=O>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 4-hydroxy-3-methylbenzoic acid (10.00 g, 65.7 mmol) and DMF (100 μL) in MeOH (35 mL) was added dropwise thionyl chloride (4.8 mL, 65.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with the addition of aqueous saturated sodium bicarbonate solution (50 mL), and methanol was removed under reduced pressure. The residue was extracted with EtOAc (3×50 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to provide methyl 4-hydroxy-3-methyl-benzoate (10.53 g, 96%) as a light brown solid. ESI-MS m/z calc. 166.0. Found 167.1 (M+1)+; Retention time: 1.09 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].[CH2:23](O)[CH2:24][CH2:25][CH3:26].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:23]([O:22][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2c(=O)n1CC(C)C
Reactant: CCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC(C)C)c(=O)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of ethyl 6-fluoro-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (9.22 g, 30 mmol), 1-butanol (3.3 mL, 45 mmol) and tributylphosphine (14.9 mL, 60 mmol) in tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (15.14 g, 60 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 4-butoxy-6-fluoro-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (9.25 g, 84.9%) as an oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:3])[CH3:2]
Reactant: COC(=O)c1sccc1N
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1sccc1NC(C)=O
Temperature: 0 °C

Procedure:
With simultaneous heating in an oil bath, 567 ml of acetic anhydride are added dropwise to a mixture of 942 g of methyl 3-aminothiophene-2-carboxylate and 1000 ml of toluene, and the mixture is then boiled under reflux conditions for 1½ hours and subsequently cooled in an ice bath to about 0° C. The crystals are filtered off and washed twice with a little isopropanol and twice with diisopropyl ether. Methyl 3-acetylaminothiophene-2-carboxylate can be obtained from the filtrate by further concentration and crystallization. M.p. 93-95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:20][C:21]([CH3:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:20][C:21](=[O:22])[CH3:23]
Reactant: COc1ccccc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1C=CC(C)=O
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
In a 250 ml single neck flask was charged 13.6 g (100 mmoles,1.0 eq) of o-methoxybenzaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 14.5 g of 4-(2-methoxyphenyl)-3-buten-2-one as a faintly yellow oil in 82.3% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:26][C@@H:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
4′-Chloro[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C:1]([S:4][C:5]1[S:9][C:8]([CH3:10])=[N:7][C:6]=1[CH2:11][S:12][C:13](=[O:15])[CH3:14])(=O)[CH3:2].C[O-].[Na+].ICC[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CO>[C:13]([S:12][CH2:11][C:6]1[N:7]=[C:8]([CH3:10])[S:9][C:5]=1[S:4][CH2:1][CH2:2][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])(=[O:15])[CH3:14]
Reactant: O=S(=O)(CCI)c1ccccc1
Reactant: CC(=O)SCc1nc(C)sc1SC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)SCc1nc(C)sc1SCCS(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a solution of 5-acetylthio-4-acetylthiomethyl-2-methyl-1,3-thiazole (600 mg, 2.3 mmol) in methanol (10 mL) was dropwise added 0.5 M sodium methoxide in methanol (4.6 mL) at 0° C. and stirred at the same temperature for 30 min. 2-Iodoethyl phenylsulfone (620 mg, 2.1 mmol) was added and stirred for an additional 30 min. The solvent was removed and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the residue was chromatographed (silica gel, dichloromethane), affording 800 mg of the title compound. 1H NMR (CDCl3) δ 2.30 (s, 3H), 2.64 (s, 3H), 3.00 (t, 2H), 3.30 (t, 2H), 4.23 (s, 2H), 7.58 (2H), 7.69 (1H), 7.89 (2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:34])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[OH:33][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:15]([NH:13][N:14]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:16])=[CH:18][CH:19]=2)=[O:34])[CH:32]=[CH:31][CH:30]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(NC(=O)CCc2cccc(O)c2)cc1
Solvent: CC(=O)O
Product: O=C(CCc1cccc(O)c1)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 63 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]-3-(3-hydroxyphenyl)propanamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 45 mg of the title compound (63%) as a yellow solid in 92.4% purity by HPLC (Rt: 3.88, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>C(O)C.C(COC)OC.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>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:3]#[C:2][CH2:1][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH:20]=1
Reactant: Brc1cccnc1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCC#Cc1cccnc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a pressure tube containing a magnetic stir bar was added 46 (202 mg, 1.3 mmol) and the vial was purged with argon. To the tube is added a solution of tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol) in ethanol/dimethoxyethane (1:1, 2 mL), sodium carbonate(aq) (2 M, 4 mL, 4 mmol), copper(I)iodide (46 mg, 0.24 mmol) and the vial was once again purged with argon. The resultant solution was stirred at room temperature for 5 min when 3-bromopyridine (483 μL, 5 mmol) was added as a neat oil. The tube was purged with argon, capped, heated to 90° C. and stirred for 1 h. The solution was cooled to room temperature and poured into a flask containing anhydrous sodium sulfate (5 g). The solution was dried for 10 min, filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 5/95, Rf=0.43) to afford the title compound 47 (295 mg, 97% yield) as a brown solid: mp=74-78° C.; 1H NMR (CDCl3) δ 8.63 (m, 1H), 8.51 (m, 1H), 7.67 (m, 1H), 7.22 (m, 1H), 5.05 (br s, 1H), 4.15 (m, 2H), 1.45 (s, 9H); LRMS (ESI) m/z calcd for C13H16N2O2 [M+H]+ 233. found 233; m/z calcd for C9H9N2O2 [M+H−CH2C(CH3)2]+ 177. found 177; m/z calcd for C8H9N2 [M+H−t-Boc]+ 133. found 133.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[O:14]1.N1C=CC=CC=1.Cl>C(Cl)Cl.O>[OH:10][C:9](=[C:16]1[C:17](=[O:19])[O:18][C:13]([CH3:21])([CH3:12])[O:14][C:15]1=[O:20])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=C(O)COc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
93.8 g (0.55 mol) of phenoxyacetyl chloride are added dropwise to a solution, cooled to 8° C., of 72.1 g (0.5 mol) of 2,2-dimethyl-1,3-dioxane-4,6-dione and 79.1 g (1.0 mol) of pyridine in 250 ml of methylene chloride so that the temperature does not rise above 10° C. The mixture is subsequently stirred at room temperature for 2.5 hours, a mixture of 250 g of ice, 250 ml of water and 30 ml of concentrated hydrochloric acid is added and the mixture is extracted by shaking. The organic phase is washed twice with 100 ml of water each time and dried over magnesium sulfate. The solvent is distilled off, a solid remaining, which is recrystallized from t-butyl methyl ether. 72 g (52% of theory) of white crystals of the compound (6), which melt at 85°-87° C., with decomposition, are obtained.
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH2:50])=[CH:44][C:43]=2[O:51][CH3:52])=[CH:34][CH:33]=1.Cl>O1CCCC1>[NH2:8][C@@H:9]([CH:10]([CH3:11])[CH3:12])[C:13]([NH:50][CH2:49][CH2:48][C:45]1[CH:46]=[CH:47][C:42]([O:41][CH2:40][CH2:39][CH2:38][C:35]2[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][CH:36]=2)=[C:43]([O:51][CH3:52])[CH:44]=1)=[O:15]
Reactant: COc1cc(CCN)ccc1OCC=Cc1ccc(Cl)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OCCCc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
BOC-L-Valine (31.4 g) and N-methylmorpholine (15.9 ml) are dissolved in tetrahydrofuran (250 ml) and cooled to −20° C. Isobutyl chloroformate (18.9 ml) is added dropwise during 20 minutes. The resulting mixture is stirred for 15 min and allowed to warm to −7° C. It is then cooled again to −20° C. and a solution of 2-{4-[3-(4-chloro-phenyl)-allyloxy]-3-methoxy-phenyl}-ethylamine (41.7 g) in tetrahydrofuran (150 ml) is added dropwise during 40 min. The reaction mixture is stirred at room temperature during 4 hours. 1M Hydrochloric acid (500 ml) is added carefully. It is extracted with ethyl acetate (2×500 ml). The organic layers are washed with 1M hydrochloric acid (500 ml) and brine (500 ml), dried (MgSO4) and evaporated. The residue is dissolved in tetrahydrofuran (500 ml) and hydrogenated over palladium (5% on charcoal, 0.14 g) at room temperature and normal pressure. The reaction mixture is filtered and evaporated. The residue is dissolved in dioxane (130 ml) and added dropwise to 4M sulfuric acid (650 ml). The resulting mixture is stirred for 8 hours at +50° C. After cooling it is extracted with diethyl ether (2×1000 ml). The aqueous phase is saturated with potassium carbonate and then extracted with diethyl ether (2×1500 ml). The organic layers are dried (K2CO3) and evaporated. (S)-2-Amino-N-(2-{4-[3-(4-chloro-phenyl)-propoxy]-3-methoxy-phenyl}-ethyl)-3-methyl-butyramide is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34].C1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[OH:36][CH2:35][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH3:34]
Reactant: C[C@@H](N)CO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)CO)[nH]2)c1
Reaction time: 30 h
Yield: 86 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (2.00 g, 4.48 mmol) synthesized in Example (78k), D-alaninol (0.52 mL, 6.72 mmol), HOBT.H2O (0.73 g, 5.38 mmol) and N-methylmorpholine (0.99 mL, 8.96 mmol) were dissolved in methylene chloride (40 mL), and WSCI.HCl (0.94 g, 4.93 mmol) was added at room temperature, followed by stirring for 30 hours under nitrogen atmosphere. The reaction solution was diluted with methylene chloride (100 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired compound (1.94 g, 86%) as a white solid.
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.Cl.Cl>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
Agent: Cl
Solvent: O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Temperature: 45 °C
Yield: 124.8 %

Procedure:
A solution of 15.65 kg of levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (30.02 mol) dissolved in 20.3 l water and 3,15 l sodium hydroxide 19.5 molar aqueous solution was extracted with 30.4 l of methylbenzene at 40° C. and the aqueous layer was washed with 7.5 l methylbenzene. Weighing of the combined water layers and determination of the concentration of the di-sodium salt of L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid yields a 97% amount of di-sodium salt of L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid. To the combined water layers were added 25.2 l water and 13.48 kg of tetramisole hydrochloride. After warming up at about 45° C. the aqueous solution was adjusted to pH 4.2 with hydrochloric acid and cooled at 15° C. After 18 hours the precipitate was filtered off, washed and dried under vacuo at 50° C. yielding 14.27 kg of levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield: 97.7%); αD20 =- 64.1 (c5. 1N HCl); mp. 127.8°-129.3° C..
Reaction SMILES: Cl[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][NH2:16])[CH3:13].O.Cl>C(OCC)C>[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][N:16]1[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2]1)[CH3:13]
Reactant: CCCCC(CC)CN
Reactant: O=C(Cl)c1ccccc1SCl
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCCCC(CC)Cn1sc2ccccc2c1=O
Reaction time: 8 h
Yield: 64 %

Procedure:
2-chlorosulphenylbenzoyl chloride (10.35 parts; 0.005M) was slowly added to a stirred solution of 2-ethylhexylamine (29.8 parts; 0.23M;) in diethylether (150 ml) at below 5° C. The reactants were then stirred overnight, allowing the temperature to rise to 18° to 20° C. Iced water was then added and the mix made just acid to Congo red by dropwise addition of of concentrated hydrochloric acid, keeping the temperature below 5° C. The ether layer was then separated and dried over magnesium sulphate. The solution was then filtered and the ether evaporated leaving a syrupy oil. This was boiled with petroleum ether (bp 60°-80° C.), the ether layer decanted from some tarry material and then evaporated to dryness leaving a dark yellow oil. This oil was purified by high vacuum distillation in a Kugelrohr and 8.4 parts pale yellow liquid obtained (Yield 64% theory).
Reaction SMILES: O[C:2]1[C:7]2[C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.[H-].[Na+].ClC1C2C(=CC=CC=2)N=C(C2C=CC=CC=2)[N:31]=1.[OH-].[K+]>O.C(O)CO.CN(C)C=O>[NH2:31][C:2]1[C:7]2[C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: OCCO
Solvent: O
Product: CCCCCC(C)C(C)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 7.07 g. (0.02 mole) of 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-5H-[1]benzopyrano[4,3-c]-pyridine in 100 ml. of dimethylformamide was added to a stirred suspension of 1.06 g. (0.022 mole) of 50% sodium hydride (dispersed in mineral oil), in 20 ml. of dimethylformamide. The mixture was stirred at 80° C. for 1-1/2 hour and after cooling to room temperature, 4.8 g. (0.02 mole) of 4-chloro-2-phenylquinazoline was added. The mixture was stirred at 100° C. for 15 hours, and then at 150° C. for 4 hours. The cooled mixture was poured into water and extracted with ether. The combined ether extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a Florisil (60-100 mesh) column using chloroform to give 7.5 g. of the O-alkylated product. The O-alkylated product was heated in a Woods' metal bath at 330° C. under nitrogen for 3 hours. The crude product was purified by chromatography on a Florisil column using graded chloroform-methanol mixtures to give 6.6 g. of the rearranged product. A mixture of 6.6 g. of the rearranged product and 60 g. of potassium hydroxide in 40 ml. of water and 800 ml. of ethylene glycol was stirred and heated at 150° C. for 18 hours. The mixture was diluted with water and extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on a Florisil column using chloroform to yield the pure product.