Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1O)[CH3:36].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:1][CH2:2][CH:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4])[CH3:36]
Reactant: CC(CO)N1C(=O)c2ccccc2C1=O
Reactant: CCc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccccc1OCC(C)N1C(=O)c2ccccc2C1=O
Reaction time: 40 h
Yield: 39.7 %

Procedure:
A solution of 5.0 g (24.4 mmol) of 2-(2-hydroxy-1-methylethyl)-1H-isoindole-1,3(2H)-dione (Y. Becker, A. Eisenstadt, J. K. Stille, J. Org. Chem., 1980, 45, 2145) and triphenylphosphine (7.00 g, 27.0 mmol) in 40 mL of dry tetrahydrofuran was stirred at 20° C. for 1 h. To the solution was added 2-ethylphenol (3.90 g, 32.0 mmol) and diethyl azodicarboxylate (5.0 mL, 32.0 mmol) and the solution was stirred an additional 40 h. The reaction mixture was concentrated in vacuo and the residue was diluted in diethyl ether and washed with water and brine. The organic layer was concentrated in vacuo and the crude product was purified by flash silica chromatography using 5% ethyl acetate/hexanes solution as eluent to give 3.0 g (40%) of 2-[2-(2-ethylphenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione as a colorless oil: 1H NMR (CDCl3) δ 0.96 (t, 3H), 1.60 (d, 3H), 2.40 (m, 2H), 4.18 (dd, 1H), 4.48 (t, 1H), 4.84 (m, 1H), 6.80 (m, 1H), 6.90 (m, 1H), 7.10 (m, 2H), 7.70 (m, 2H), 7.84 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=O)[NH:25][CH:24]=[N:23]2)=[CH:18][CH:17]=1.ClC1C=CC(N2C(=O)N([C@H](C)[C@]3(C4C=CC(F)=CC=4F)OC3)C=N2)=CC=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]([O:14][C@@H:12]([C@@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH2:11][O:10]3)[CH3:13])=[N:25][CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]cnn1-c1ccc(Cl)cc1
Agent: C[C@@H](n1cnn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1ncnn1-c1ccc(Cl)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 19.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.34 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl-] ethanol and 1.15 g of 2-(4-chlorophenyl)-3(2H,4H)-1,2,4-triazolone, 2-(4-chlorophenyl)-4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3(2H,4H)-1,2,4-triazolone (519 mg) and 424 mg of (2R)-2-[(1R)-1-[1-(4-chlorophenyl)-1H-1,2,4-triazol-5-yloxy]ethyl]-2-(2,4-difluorophenyl)oxirane were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27](OC)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:32][NH2:33]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:32][NH2:33])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Solvent: O
Solvent: CCO
Product: NNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O

Procedure:
To a solution of 120 mg (0.27 mmol) of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate (Example 47) in EtOH was added hydrazine, monohydrate (135 μl, 2688 μmol). After being refluxed for 14 h, the reaction was concentrated, diluted (H2O) and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (5% MeOH/CH2Cl2, gradient elution) provided the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][C:29](Cl)=[O:30]>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:29](=[O:30])[CH2:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:11]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccs1)Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
2-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-phenylamine (45 mg) was dissolved in a solution of triethylamine in dichloromethane (3 mL, 0.29 M in triethylamine). This solution was added to a test tube containing 2-thiopheneacetyl chloride (50 mg). After standing at ambient temperature for several days, the reaction was directly passed through a small pad of silica and eluted with 10% ethyl acetate in hexanes, then with 50% ethyl acetate in hexanes. Solvent removal left 48.6 mg of the product: MS m/z 459 (M)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:7]([CH2:10]OC(=O)C(CC2C=CC=CC=2)C([O-])=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:33].[K+].O.[CH2:36]([OH:38])[CH3:37]>>[CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:7]([CH2:10][CH:37]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:36]([OH:33])=[O:38])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1ncc(COC(=O)C(Cc2ccccc2)C(=O)[O-])n1Cc1ccccc1Cl
Reactant: CCO
Agent: [K+]
Solvent: O
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Yield: 86 %

Procedure:
A mixture of diethyl [(2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl-2-benzylmalonate (0.72 g, 1.36 mmol), potassium hydroxide (0.83 g, 14.7 mmol), water (15 mL) and ethanol (25 mL) was refluxed for 4 hours. The ethanol was evaporated, the residual aqueous layer was extracted with diethyl ether, and the basic solution was adjusted to pH 3.75 with concentrated hydrochloric acid. The precipitated product was extracted into methylene chloride, dried, and concentrated. This crude product was flash chromatographed on silica gel with 10% methanol in methylene chloride to give 0.51 g (86%) of 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid; mp 118-120° C. (from acetone/diethyl ether as the hydrochloride salt).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N:10]#[C:11]Br>CCOCC.CCCCCC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][N:6]=[C:11]=[NH:10])[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: N#CBr
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(CN=C=N)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the aminoacetaldehyde diethyl acetal (13.16 g, 99 mmol) in ether (35 mL) was added to a suspension of CNBr (10.47 g, 99 mmol) in hexane (35 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The solid was removed by filtration and washed with ether. The combined filtrate was concentrated. Purification by column chromatography (silica gel, eluting with dichloromethane to 4% methanol in dichloromethane, gradient) afforded the title compound (7.0 g, 44.7%, one half of the starting amine served as a sacrificial base in the reaction) (Rf: 2.70, 4% methanol in dichloromethane, stain with 10% ethanolic molybdatophosphoric acid). 1H NMR 400 MHz (CDCl3) δ 4.58 (t, J=5.2 Hz, 1H), 3.77-3.69 (m, 2H), 3.65 (br, s, 1H), 3.60-352 (m, 2H), 3.16 (t, J=5.6 Hz, 1H), 1.23 (t, 6H, J=6.8 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20].[I-:27].[Na+].CC(=O)CC>CCOCC>[I:27][CH2:2][CH2:3][C@H:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20]
Reactant: Cc1cc(OC(=O)OC(C)(C)C)ccc1O[C@H](CCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cc1cc(OC(=O)OC(C)(C)C)ccc1O[C@H](CCI)c1ccccc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A dry 1-L R.B. flask was charged (R)-3-chloro-1-phenyl-1-(2-methyl-4-((tert-butoxycarbonyl)oxy)phenoxy)propane (18.00 g, 47.80 mmol), sodium iodide (90.0 g, 600 mmol) and 2-butanone (550 mL). The reaction flask was protected from light. The reaction mixture was stirred at reflux temperature under nitrogen for 16 hours. The mixture was cooled to room temperature and poured into ether (1 L). The insoluble inorganic salts (white precipitate) were removed by filtration. The filtrate was concentrated under reduced pressure and the crude residue was dissolved in diethyl ether (1 L). The ethereal layer was washed with cold saturated sodium bisulfite solution (2×200 mL), water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluting with 20% ethyl acetate in hexane to provide 20.5 grams (91%) of the desired compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=2)[NH2:41])[CH:36]=[CH:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:38]([CH2:37][N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)[CH:39]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1cccc(Cn2cccn2)c1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(Cn3cccn3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-pyrazol-1-ylmethyl)aniline (Flrochem, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17]([OH:19])=O)[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[N:34](C=O)C.[CH3:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([CH2:44][O:45][C:46]([CH3:59])([CH3:58])[CH2:47][O:48][C:49]2[N:50]=[CH:51][C:52](C(N)=O)=[N:53][CH:54]=2)=[CH:42][CH:41]=1>ClCCl.O.N1C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17]([NH:34][C:52]3[CH:51]=[N:50][C:49]([O:48][CH2:47][C:46]([O:45][CH2:44][C:43]4[CH:60]=[CH:61][C:40]([O:39][CH3:38])=[CH:41][CH:42]=4)([CH3:59])[CH3:58])=[CH:54][N:53]=3)=[O:19])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: COc1ccc(COC(C)(C)COc2cnc(C(N)=O)cn2)cc1
Reactant: CN(C)C=O
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(COC(C)(C)COc2cnc(NC(=O)[C@H](C[C@H]3CCC(=O)C3)c3ccc(S(=O)(=O)C4CC4)c(C4CC4)c3)cn2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoic acid (99 mg) in dichloromethane (2.0 mL) were added oxalyl chloride (27 μL) and DMF (3 μL) under ice-cooling, followed by stirring for 10 minutes. Thereafter, pyridine (28 μL) and 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-amide (53 mg) were added thereto under ice-cooling, followed by stirring for 20 minutes. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:1) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide (82 mg) as a white amorphous substance. A mixture of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide (82 mg), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (56 mg), dichloromethane (7.5 mL), and water (0.38 mL) was stirred at room temperature for 10 minutes. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=80:20). The obtained residue was sonicated with diethyl ether and the resulting precipitate was collected by filtration to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(2-hydroxy-2-methylpropoxy)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide (52 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].O[CH2:15][C@@H:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][N:12]([CH2:15][C@@H:16]([NH2:18])[CH3:17])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2ccn[nH]2)cc1Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)Cn1ccc(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
Into a flask containing 5-(3,4-dichlorophenyl)-1H-pyrazole (1.5 g, 7.04 mmol), (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.357 g, 7.74 mmol) and triphenylphosphine (2.77 g, 10.56 mmol), dry THF (30 ml) was added under nitrogen atmosphere. After few minutes of stirring, DIAD (2.77 ml, 14.08 mmol) was added dropwise through a septum while using icebath to prevent the temperature from rising. The resulting mixture was stirred at RT overnight. The mixture was evaporated. The Boc-protection was removed by adding ethanol (7 ml), 10% HCl/EtOH (50 ml), concentrated HCl (5 ml) and stirring the mixture over the weekend. The mixture was evaporated, extracted with DCM/water. The pH of the water phase was adjusted to ˜12 using 2 M NaOH and extracting the phase again with DCM. The combined organic phases were dried with Na2SO4, filtered and evaporated. 1H-NMR (400 MHz; DMSO-d6): δ 1.00 (d, 3H), 4.70-4.87 (m, 3H), 6.84 (d, 1H), 7.65 (d, 1H), 7.76-7.84 (m, 2H), 8.02 (d, 1H).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[C:27]([C:36]([OH:38])=[O:37])=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:24])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[C:27]([C:36]([OH:38])=[O:37])=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1cc2ccccc2cc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2cc3ccccc3cc2C(=O)O)cc1OC
Yield: 67.6 %

Procedure:
Piperidine (0.23 mL, 2.3 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (0.38 g, 2.3 mmol) and 3-(2-carboxyacetamido)-2-naphthoic acid (0.56 g, 2.0 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-3-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]-2-naphthoic acid (0.51 g, 66%) was obtained as a yellow crystalline solid; mp 212-213° C.; δH (400 MHz, DMSO-d6) 3.80 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 6.82 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, =8.2 Hz, 1H, H5′), 7.25 (dd, 4,6=8.2, J2′,6′=2.0 Hz, 1H, H6′), 7.38 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.49 (t, J6,7=J7,8=8.0 Hz, 1H, H7), 7.58 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (t, J5,6=J6,7=8.0 Hz, 1H, H6), 7.89 (d, J7,8=8.0 Hz, 1H, H8), 8.03 (d, J5,6=8.0 Hz, H5), 8.71 (s, 1H, H1), 9.05 (s, 1H, H4), 11.30 (s, 1H, NH); δC (100 MHz, DMSO-d6) 55.6, 55.7, 110.4, 111.6, 117.1, 117.6, 120.1, 122.6, 125.6, 127.1, 127.3, 128.2, 129.1, 129.3, 133.1, 135.5, 136.3, 141.4, 149.0, 150.6, 164.2, 169.5; HRMS (ESI) Calculated for C22H19NO6 [M+H]+ 378.1336. found 378.1345; vmax 797, 1022, 1134, 1233, 1512, 1665, 1693, 3048 cm−1.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:39]([C:41]1[CH:46]=[CH:45][C:44]([N:47]=[C:48]=[O:49])=[CH:43][CH:42]=1)[CH3:40]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:39]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:49])[O:8][CH2:9][C@@H:10]([N:12]([CH3:20])[C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[CH3:11])=[CH:43][CH:42]=1)[CH3:40]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: CCc1ccc(N=C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OC[C@H](C)N(C)C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)propan-2-yl(methyl)carbamate (301 mg, 1.0 mmol) in THF was added TBAF (1M in THF, 1.5 mL, 1.5 mmol, 1.5 equiv.) and the mixture was stirred for 1 h followed by quenched with saturated NaHCO3 and diluted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude oil, which was re-dissolved in THF (2.0 mL). To this THF solution were added DMAP and 4-ethylphenyl isocyanate. The reaction mixture was stirred for 30 min. LC/MS indicated the completion of the reaction and the mixture was filtered and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-2-(methyl(tert-butoxycarbonyl)amino)propyl 4-ethylphenylcarbamate (118 mg, 30% from 1). LRMS (M-Boc+H+) m/z 237.1.
Reaction SMILES: C(N[C:9]([C:11]1[C:16]([NH:17][C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])C1C=CC=CC=1.NC1C(C(O)=[O:32])=NC=CN=1.C(N(C(C)C)CC)(C)C.C(Cl)(=O)CC(C)C>CN(C=O)C>[CH3:21][CH:20]([CH3:22])[CH2:19][C:18]([NH:17][C:16]1[C:11]([C:9]([OH:10])=[O:32])=[N:12][CH:13]=[CH:14][N:15]=1)=[O:23]
Reactant: CC(C)CC(=O)Nc1nccnc1C(=O)NCc1ccccc1
Reactant: Nc1nccnc1C(=O)O
Agent: CC(C)CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(=O)Nc1nccnc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(3-Methyl-butyrylamino)-pyrazine-2-carboxylic acid benzylamide: To a solution of DMF (200 mL), 3-aminopyrazine-2-carboxylic acid (10.0 g, 71.9 mmol) and diisopropylethyl amine (25.0 mL, 144 mmol) was added isovaleryl chloride (12.4 mL, 86.3 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for two hours after which the solvent was removed under reduced pressure and the residue dried under vacuum overnight, to afford 3-(3-methyl-butyrylamino)-pyrazine-2-carboxylic acid as a solid residue. The solid residue was dissolved in acetic anhydride (200 mL) and the mixture stirred at 100° C. overnight. The excess acetic anhydride was removed by distillation under reduced pressure, leaving a residue that was then cooled to room temperature and washed with hexane to give the corresponding oxazinone compound of Formula 103, 2-isobutyl-pyrazino[2,3-d][1,3]-oxazin-4-one, which was carried forward without additional purification. A solution of chloroform (200 mL), the oxazinone of Formula 103, and benzylamine (16.0 mL, 144 mmol) was stirred at 60° C. for two hours. After the complete consumption of the oxazinone, as monitored by reverse phase HPLC, the chloroform was removed under reduced pressure and the residue purified by silica gel chromatography using hexane-EtOAc (1:2) as eluent to obtain the title bis amide, 3-(3-methyl-butyrylamino)-pyrazine-2-carboxylic acid benzylamide (4.5 g 20.0%, three steps). MS (Cl) M/E: 313.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:16])[N:10]=[CH:11][C:12]=2[C:13](O)=O)=[C:4]([CH:17]([O:25][CH3:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1.S(Cl)(Cl)=O.C([N:34](C(C)C)CC)(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:16])[N:10]=[CH:11][C:12]=2[CH2:13][NH2:34])=[C:4]([CH:17]([O:25][CH3:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1
Reactant: COC(c1ccccc1Cl)c1cc(Cl)ccc1-c1c(C(=O)O)cnn1C
Reactant: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(c1ccccc1Cl)c1cc(Cl)ccc1-c1c(CN)cnn1C
Product: Cl
Reaction time: 16 h

Procedure:
The solution of 7.8 g of 3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-2-methylpyrazole-4-carboxylic acid in 75 ml of methylene chloride and 6.7 ml diisopropyl ethylamine is stirred in an ice bath and 4.7 ml of thionyl chloride are added. The mixture is refluxed for 40 minutes, cooled and washed with icewater. The organic layer is dried, evaporated and the residue taken up in 65 ml of tetrahydrofuran and the solution saturated with ammonia. After stirring at 25° for 16 hours, the mixture is diluted in diethyl ether, washed with water and brine, dried and evaporated. The resdiue is dissolved in 300 ml of diethyl ether and the solution refluxed for 16 hours with 2 g of lithium aluminum hydride. After destroying the excess reagent and filtering off the precipitate, the filtrate is washed with diluted hydrochloric acid. The acidic layer is basified with aqueous sodium hydroxide and extracted with methylene chloride. The extract is dried, evaporated, the residue taken up in ethyl acetate and the solution acidified with hydrogen chloride, to yield the 3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-4-aminomethyl-2-methylpyrazole hydrochloride melting at 260°-262°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: Cc1ccccc1N
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1ccccc1NC(=O)c1c(N)cccc1Cl
Yield: 55.3 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (1.0 g, 5.83 mmol) and SOCl2 (1.1 mL, 14.6 mmol) in benzene (30 mL), followed by o-toluidine (1.4 mL, 12.8 mmol) and CHCl3 (30 mL). The product was chromatographed in CH2Cl2 to provide 840 mg of an oily yellow solid (55%). NMR (CDCl3) δ: 7.96 (d, J=7.9 Hz, 1H); 7.60 (br s, 1H); 7.23-7.30 (m, 2H); 7.14 (t, J=7.5 Hz, 1H); 7.11 (t, J=8.3 Hz, 1H); 6.78 (d, J=7.9 Hz, 1H); 6.64 (d, J=8.2 Hz, 1H); 4.73 (br s, 2H); 2.35 (s, 3H). MS (ES): m/z 261.0 (M+).