Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15](=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:14]=[CH:13][N:12]=[C:11]3[NH2:25])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].[CH2:30]([O:32]CC)[CH3:31]>FC(F)(F)C(O)=O>[C:26]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:16]=[C:15]3[C:10]([C:11]([NH2:25])=[N:12][CH:13]=[N:14]3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([O:1][C:30](=[O:32])[CH3:31])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCOCC
Reactant: Nc1ncnc2nc(-c3ccc(O)cc3)c(-c3ccc(O)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(-c2nc3ncnc(N)c3nc2-c2ccc(OC(C)=O)cc2)cc1
Temperature: 80 °C
Yield: 97.7 %

Procedure:
662.6 mg (2.0 mmol) of 6,7-bis(4-hydroxyphenyl)-pteridin-4-ylamine was dissolved in 20 ml of trifluoroacetic acid. 1.0 mL (14.06 mmol, 7.0 eq) of acetyl chloride was added via syringe to this mixture. Upon heating to 80° C. bubbling of the reaction mixture and evolution of HCl gas was observed. The reaction mixture was heated at 80° C. for 40 min, at which point LC/MS indicated a complete conversion of the starting material to the di-acetate. Solvent was removed in vacuo to give bright-yellow oil, which upon standing solidified. 40 mL of diethyl ether was added, the solid was crushed with spatula, centrifuged down, washed with 45 mL of diethyl ether twice and dried in vacuo to give 1.034 g (97.7%) of the product as a light-yellow solid. 97.5% purity by LC/MS (230 DAD). Mass-spec [ES+]=416.5. 1H NMR (DMSO-d6) 2.280 (3H, s), 2.284 (3H, s), 7.16–7.21 (4H, dd), 7.56–7.62 (4H, dd), 8.80 (1H, s), 9.46 (1H, br.s), 9.52 (1H, br, s).
Reaction SMILES: C(O[C:4]([C:6]1[S:14][C:9]2=[CH:10]N=C[CH:13]=[C:8]2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])C.[OH-].[Na+].[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH2:34])[CH2:29][O:28]1.C[CH2:37][N:38]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(O)C>[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH:34][C:4]([C:6]2[S:14][C:9]3[CH:10]=[CH:37][N:38]=[CH:13][C:8]=3[C:7]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])=[O:5])[CH2:29][O:28]1
Reactant: CCOC(=O)c1sc2cnccc2c1Nc1ccc(I)cc1F
Reactant: CCN=C=NCCCN(C)C
Reactant: CC1(C)OC[C@H](CON)O1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)OC[C@H](CONC(=O)c2sc3ccncc3c2Nc2ccc(I)cc2F)O1
Temperature: 65 °C
Reaction time: 19 h
Yield: 30.1 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester (50 mg, 0.11 mmol), 1N aqueous NaOH solution (0.12 ml, 0.12 mmol) and ethanol (2 ml) was heated at 65° C. for 45 minutes. The reaction mixture was concentrated then azeotroped with toluene (2×2 ml) to give a solid residue. The solid residue was dissolved in anhydrous THF (2 ml) and O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (27 mg, 0.23 mmol), EDCI (27 mg, 0.14 mmol), HOBt (21 mg, 0.16 mmol) and DIPEA (59 μl, 0.34 mmol) were added. After stirring for 19 hours the solvent was evaporated and the residue partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was dried over sodium sulphate, filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 80:20 to 50:50) to afford the title compound as a yellow solid (18 mg, 30%). LCMS (method B): RT=3.09 min, M+H+=544.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:42])(=[O:41])[NH:36]C(C)(C)C)=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:42])(=[O:41])[NH2:36])=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 65 %

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2-[5-(carbomethoxy)-2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step B) according to the procedure of Example 13, Step B, and was obtained in 65% yield as a white solid after flash chromatography, mp 182°-184° C., homogenous by TLC (19:1 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 555 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:11][O:12][NH:13][CH3:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:13]([O:12][CH3:11])[CH3:14])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 5-bromo-nicotinic acid (2.02 g, 10 mmol) and O,N-dimethyl-hydroxylamine (670 mg, 11 mmol) in DMF (100 mL) was added HOBt (400 mg, 0.3 mmol), EDCI (2.09 g, 11 mmol) and Et3N (1.11 g, 11 mmol). The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, dried by anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography to give the title compound (2.08 g, 85%) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[C:6]([O:8]C)=[O:7])[CH3:2].[OH-].[Li+]>[Pd].CO.CO.O1CCCC1.O>[F:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(C(=O)OC)ccc1F
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-fluoro-3-ethylbenzoyl chloride was prepared in 5 steps from 3-bromo-4-fluorobenzoic acid. 3-bromo-4-fluorobenzoic acid was converted to methyl 3-bromo-4-fluorobenzoate by treatment with trimethylsilyl diazomethane (1.5 equivalents) in benzene/methanol (4/1) at room temperature. Subsequent reaction with tributyl(vinyl) tin (1.2 equivalents) in DMF in the presence of catalytic dichlororbis(triphenylphosphine)palladium(II) (0.1 equivalents) at 80° C. under an argon atmosphere, followed by aqueous work up and standard chromatography (10% ethyl acetate/hexanes), yielded methyl 4-fluoro-3-vinylbenzoate. Hydrogenation of the vinyl group by treatment of this material with palladium on carbon (10% palladium on carbon, 10% by mass) in methanol under an hydrogen atmosphere then afforded methyl 3-ethyl-4-fluorobenzoate. This material was dissolved in methanol/tetrahydrofuran/water (2/1/1) then lithium hydroxide (5.0 equivalents) was added and reaction mixture stirred at room temperature for 2 hours. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-fluoro-3-ethylbenzoic acid. This material was directly converted to 4-fluoro-3-ethylbenzoyl chloride by treatment with thionyl chloride (2.2 equivalents) in dichloromethane at room temperature for 2 hours followed by removal of the volatiles in vaccuo). The rest of the procedures were followed as indicated in general procedure B to afford N-(4-chlorophenyl)-N-[(2S,4R)-1-(3-ethyl-4-fluorobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:22][C:23]1[C:27]([CH:28]=[O:29])=[CH:26][N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:22][C:23]3[C:27]([CH:28]=[O:29])=[CH:26][N:25]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:24]=3)=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
A mixture of 4-[(4-chloromethylphenoxy)methyl]-2-(2-furyl)-5-methyloxazole (3.01 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.70 g), potassium carbonate (1.24 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (2.66 g, 65%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 148-149° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@@H:25]([OH:28])[C:24]([CH3:30])([CH3:29])[CH2:23]1>C1COCC1>[OH:28][C@@H:25]1[CH2:26][CH2:27][C@H:22]([NH:21][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:23][C:24]1([CH3:30])[CH3:29]
Reactant: CC1(C)C[C@@H](N)CC[C@H]1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.0 equiv.) and DIEA (3.0 equiv) in THF (0.05 M) was added (1R,4S)-4-amino-2,2-dimethylcyclohexanol (stereochemistry determined as described herein) (1.2 equiv.). The mixture was stirred at 50° C. overnight. After reaction completion, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (82% yield) as a white solid. MS (ESI) m/z 293.1 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:42][N:43]=[C:44]=[O:45].C(NC(C)C)(C)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:44]([NH:43][CH3:42])=[O:45])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CNC(=O)Oc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (80 mg), methyl isocyanate (0.5 mL), dichloromethane (3 mL) and diisopropylamine (0.05 mL) was stirred at ambient temperature for 1 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, hexanes/ethyl acetate, 3:1) to provide the title compound as a solid foam (57 mg). 1H NMR (DMSO-d6) δ 0.78 (3H, d), 0.82 (3H, d), 1.17 (1H, dd), 1.30-1.45 (1H, m), 1.9-2.0 (1H, m), 2.42 (1H, t), 2.6 (3H, d), 2.62-2.80 (3H, m), 2.99 (2H, dd), 3.15-3.20 (1H, m), 3.50-3.63 (4H, m), 3.7 (13H, t), 3.8 (1H, dd), 4.8 (1H, dd), 5.04 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.95 (2H, d), 7.05 (1H, d), 7.15 (2H, d), 7.2 (1H, s), 7.25 (1H, d), 7.5 (1H, quartet), 8.08 (1H, d); MS: 650 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[N:6]=1.[Br-].[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1.[CH3:22][C:23](C)([O-:25])C.[K+]>>[N:13]1([CH2:22][C:23]([NH:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)=[O:25])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)(C)[O-]
Reactant: Cc1nc2cc(N)ccc2s1
Agent: [Br-]
Agent: [K+]
Product: Cc1nc2cc(NC(=O)Cn3cnc4ccccc43)ccc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.2 %

Procedure:
2-Methyl-benzothiazol-5-ylamine (32 mg, 0.2 mmol) and bromoacethyl bromide were added to a suspension of (N,N-diisopropyl)aminomethylpolystyrene resin (170 mg) in anhydrous TBF (2 mL) and the reaction mixture was shaken for 4 h at ambient temperature. The resin was then filtered off. 1H-benzoimidazole (35 mg, 0.3 mmol) and potassium tert-butoxide (0.36 mL of 1 M solution in THF, 0.36 mmol,) were added and the mixture was stirred at 55° C. for 24 h. The crude product was purified on a preparative LC/MS (XTerra C8 column 19×100 mm, 0.1 M aqueous NH4Ac/CH3CN). The pooled to fractions were lyophilized to afford 4 mg (6%) of the title compound. Calculated for C17H14N4OS m/z: 322.39, found 323.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([OH:18])=O.C(N(CC)CC)C.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([NH:32][CH3:33])=[CH:30][CH:29]=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:33][N:32]([C:31]1[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=1)[C:16]([C:3]1[C:4](=[O:15])[N:5]([CH3:14])[C:6]2[C:11]([C:2]=1[OH:1])=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: CNc1ccc(C(F)(F)F)cc1
Reactant: COc1cccc2c1c(O)c(C(=O)O)c(=O)n2C
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1c(O)c(C(=O)N(C)c1ccc(C(F)(F)F)cc1)c(=O)n2C
Temperature: 0 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To an ice-cold solution of 1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid (8 g, 0.032 mol), triethylamine (15.5 ml, 0.11 mol) and 4-trifluoromethyl-N-methylaniline (6.1 g, 0.035 mol) in 150 ml of methylene chloride was added dropwise during 0.5 hours a solution of thionyl chloride (3.0 ml, 0.042 mol) in 10 ml of methylene chloride. The stirring was continued at 4° C. for 4 hours. The solution was diluted with 10 ml of methylene chloride, washed with cold 1 M sulphuric acid and then extracted with 1 M sodium hydroxide. The pH of the aqueous phase was adjusted to 8-8.5, clarified by filtration and then acidified with hydrochloric acid to pH 4. On standing a crystalline precipitate was formed which was filtered off, washed with water and dried to give the title compound (8.5 g) yield 65%.
Reaction SMILES: IC.[Cl:3][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=S)[O:10][C:6]=2[CH:5]=1.[C:14]([O-])([O-])=O.[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1.[S:31]([O-:35])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([S:31]([CH3:14])=[O:35])[O:10][C:6]=2[CH:5]=1
Reactant: O=S([O-])([O-])=S
Reactant: O=C([O-])[O-]
Reactant: S=c1[nH]c2ccc(Cl)cc2o1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CS(=O)c1nc2ccc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodomethane (1.35 mL, 21.6 mmol) was added to a mixture of 6-chlorobenzo[d]oxazole-2(3H)-thione (2.00 g, 10.8 mmol) and K2CO3 (2.99 g, 21.6 mmol) in THF (43 mL). After 2 h, the reaction mixture was filtered and concentrated under reduced pressure. The crude material was dissolved in CH2Cl2 (40 mL) and meta-chloroperbenzoic acid (50-55%, 3.73 g, 10.8 mmol) was added at 0° C. The reaction was allowed to warm to rt. After stirring overnight, the reaction mixture was diluted with sodium thiosulfate (saturated, aqueous) and the organics were separated. The organics were washed with NaHCO3 (saturated, aqueous, 50 mL) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 3.22 g (>100% crude yield) of the desired product as an orange solid. The material was used without further purification. LC-MS: RT=6.57 min., [M+H]+=216.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH2:24][NH2:25])([CH3:23])[CH2:20][C:19]=4[C:26]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH2:24][NH:25][C:37](=[O:39])[CH3:38])([CH3:23])[CH2:20][C:19]=4[C:26]=3[CH3:27])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN)O4)CC2)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CNC(C)=O)O4)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of THF (2.0 mL) containing 1-{5-[4-(4-Methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}methaneamine (110 mg, 0.278 mmol) synthesized in Example 108, triethylamine (42 mg, 0.417 mmol) and acetylchloride (26 mg, 0.337 mmol) were serially added under ice-cooling condition, and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was diluted with water, and THF was removed under reduced pressure, followed by extraction using ethyl acetate. The extract was washed with saturated saline and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 7:3-3:7) and crystallized from ethyl acetate-hexane to obtain 90 mg of the title compound (yield 74%). Melting point was 146 to 152° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Br>C(O)(C)C>[Br-:8].[C:11]1([CH2:16][N+:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1.[Br-:8]
Reactant: BrCc1ccccc1CBr
Reactant: Cc1ccncc1
Solvent: CC(C)O
Product: Cc1cc[n+](Cc2ccccc2C[n+]2ccc(C)cc2)cc1
Product: [Br-]
Temperature: 120 °C
Yield: 87 %

Procedure:
A mixture of 4-methylpyridine (1.02 g) and 1,2-bis-bromomethyl-benzene (1.32 g) was heated during 2.5 hours at 120° C. To the reaction mixture 5 mL of isopropyl alcohol was added and the mixture was refluxed for 2 hours. After cooling the product was filtered, washed with diethyl ether and dried under vacuum to provide Compound 4 in 87% yield. The structure of Compound 4 is given below:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].C1(N)CCCCC1.C(N)C(C)C>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: CC(C)CN
Solvent: NC1CCCCC1
Product: CC(=O)Nc1ccccc1-c1ccc(C(O)CCC(=O)O)cc1
Yield: 60 %

Procedure:
Prepared analogous to Example 25 from 4-(2'-acetamido-4-biphenylyl)-4-oxo-butyric acid (m.p. 209°-210° C.). Melting point of the cyclohexylamine salt: 143° C.; melting point of the isobutylamine salt: 125°-126° C.; yield: 60% of theory.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([CH2:26][Cl:25])[CH:28]=2)[CH:10]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccccc2)cc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
Triethylamine (2.0 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)benzamide (3.0 g), 3-chloromethylbenzoyl chloride (2.76 g), 4-dimethylaminopyridine (0.162 g) and methylene chloride (50 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under 2N aqueous hydrochloric acid solution. The solid so obtained was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution, water and isohexane and dried under vacuum at 55° C. There was thus obtained the title compound (5.1 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 4.85 (s, 2H), 7.23 (d, 1H), 7.55 (m, 5H), 7.66 (d, 1H), 7.84 (s, 1H), 7.95 (m, 3H), 8.05 (s, 1H), 9.96 (s, 1H), 10.22 (s, 1H); Mass Spectrum: M−H− 377.
Reaction SMILES: C(NC(C)C)(C)C.C(N)CCC.[CH3:13][N:14]([CH3:18])[C:15](=[O:17])[CH3:16].C([O:21][C:22](=O)[CH2:23][C@H:24]([OH:38])[CH2:25][S:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[N:29][N:28]=1)C>C1COCC1>[OH:38][C@H:24]([CH2:25][S:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[N:29][N:28]=1)[CH2:23][C:22](=[O:21])[CH2:16][C:15]([N:14]([CH3:18])[CH3:13])=[O:17]
Reactant: CCOC(=O)C[C@H](O)CSc1nnnn1-c1ccccc1
Reactant: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCCCN
Solvent: CC(C)NC(C)C
Product: CN(C)C(=O)CC(=O)C[C@H](O)CSc1nnnn1-c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
1000 mL THF and 132.27 g diisopropyl amine were taken in round bottom flask at 25° C. The reaction mixture was cooled to −10° C. and 531 mL of n-butyl amine was added to it. The reaction mixture was stirred for 30 minutes and further cooled to −40° C. 113 g N,N-dimethylacetamide solution in 1000 mL THF was gradually added to the reaction mixture and stirred for 2 hours. 100 g (S)-Ethyl-3-hydroxy-4-(1-phenyl-1H-tetrazol-5-ylthio)butanoate (11a) solution in 200 mL THF was added to the reaction mixture and stirred for 2 hours. After the completion of the reaction as monitored by TLC, the reaction mixture was quenched with 20% 1000 mL ammonium chloride solution at about −25° C. The separated aqueous layer was extracted with 400 mL ethyl acetate. The separated organic layer was washed with 1000 mL 1N HCl solution followed by washing with 1000 mL of water at 25° C. The organic layer was distilled under vacuum below 50° C. to obtain 100 g residue as an oil. The oily residue was taken in 400 mL hexane and distilled to obtain oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH3:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([CH3:32])[CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1.CO.CS(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([CH3:32])[CH:22]=2)(=[O:20])=[O:19])=[C:7]([CH3:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1OCC(=O)O
Reactant: CCCCc1ccc(NCC(C)C)c(C)c1
Solvent: CO
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCCCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC(=O)O)c(C)c2)c(C)c1
Reaction time: 2 h

Procedure:
To (4-butyl-2-methylphenyl)(2-methylpropyl)amine (21.94 mg, 0.100 mmol) in pyridine (1 mL) was added {[4-(chlorosulfonyl)-2-methylphenyl]oxy}acetic acid (26.5 mg, 0.100 mmol) and reaction stood for 2 hours at room temperature. The sample was then dissolved in a 1:1 mixture of MeOH and DMSO and purified by MDAP Method A2, to provide the desired product, 11 mg. LCMS (M+1) 448, RT 1.44 mins.