Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](O)=[O:43])=[O:36])([CH3:33])([CH3:32])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C=O.C(OCC)(=O)C>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](=[O:43])[NH:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)C(N)Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)C1CCCN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A solution of 5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzyl]thiazolidin-2,4-dione hydrochloride (2.03 g, 4.65 mmol) and N-t-butoxycarbonylpyrrolidin-2-carboxylic acid (1 g, 4.65 mmol) in N,N-dimethylformamide (20 ml) was stirred for 1 h at 0° C. N,N′-Dicyclohexylcarbodiimide (0.96 g, 4.65 mmol) was added to this solution and stirring was continued for 2 h at ambient temperature. Water (150 ml) was added to the reaction mixture, stirred for 20 minutes, ethyl acetate (200 ml) was added and stirring continued for another 15 minutes. The organic layer was separated and washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated to give the crude compound, which was purified by column chromatography (1.42 g, yield 51.2%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:4][OH:5].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:2][OH:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COCCOCOCCCCCC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOCCCCCC(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.06 g of 2-hydroxymethyl-7-(2-methoxyethoxy)methoxy-1-heptanol (prepared as described in Preparation 42) dissolved in 20 ml of dimethylformamide was added dropwise to 587 mg of sodium hydride (as a 55% dispersion in mineral oil) dispersed in 40 ml of dimethylformamide, whilst ice-cooling (at 5° to 7° C.). The mixture was then stirred at room temperature for 1 hour, after which 1.60 ml of benzyl bromide were added dropwise, whilst ice-cooling (at 5° to 7° C.). After stirring the reaction mixture at room temperature for 2 hours, it was poured into 300 ml of water and then extracted five times with ethyl acetate. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The oily residue was subjected to column chromatography through 60 g of silica gel, and 2.37 g of the title compound were obtained from the fractions eluted with mixtures of hexane and ethyl acetate ranging from 2:1 to 1:1 by volume, as a colorless oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15](/[CH:19]=[CH:20]/[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C@@H:19]2[O:9][C@H:20]2[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC/C=C/c1cccc(Br)c1
Solvent: ClCCl
Product: OC[C@@H]1O[C@H]1c1cccc(Br)c1
Yield: 71.1 %

Procedure:
A magnetically stirred solution of m-chloroperbenzoic acid (3.57 g, 10.33 mmol) in dichloromethane (60.0 ml) at 25° C. was treated dropwise with a solution of trans-3-(3-bromophenyl)-2-propenol (2.0 g, 9.39 mmol) in dichloromethane (20.0 ml). After stirring. for 16 h the mixture was diluted with dichloromethane (200 ml), washed with aqueous 1M NaOH (2×200 ml), brine (2×200 ml) and dried (Na2SO4). Evaporation of the solvent in vacuo returned the crude epoxide as a pale yellow oil (2.06 g). Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 3:7) provided the title compound (1.53 g, 71%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4][N:5]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7](=[O:9])[NH2:8].CN(C)[CH:21]=[O:22]>>[CH2:13]([O:12][CH2:11][CH2:10][N:5]1[C:6]2[C:7](=[O:9])[NH:8][C:21](=[O:22])[NH:1][C:2]=2[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4]1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CCOCCn1nc(C(=O)OC)c(N)c1C(N)=O
Product: CCOCCn1nc(C(=O)OC)c2[nH]c(=O)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the amide of step 4 (570 mg, 3.38 mmol) in N,N-dimethylformamide (30 mL) was treated with N,N′-carbonyldiimidazole (658 mg, 4.06 mmol) and the reaction mixture stirred at room temperature for 1 hour and then at 90° C. for 18 hours. The reaction mixture was concentrated in vacuo and the crude product suspended in acetone and sonicated for 30 minutes. The solid product was filtered off and dried in vacuo to yield the dione product. 1H NMR (DMSO-D6, 400 MHz) δ: 1.02 (t, 3H), 3.37 (m, 2H), 3.77 (m, 2H), 3.83 (s, 3H), 4.63 (m, 2H), 10.75 (s, 1H), 11.40 (s, 1H). MS ES− m/z 281 [M-H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[N:17]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[Cl:16][C:15]1[CH:14]=[CH:13][C:4]([CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:3][C:2]=1[NH:1][NH2:17]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(NN)c1
Yield: 65169.4 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-61 by using N-(3-amino-4-chlorobenzyl)pivalamide (1.80 g), NaNO2 (0.62 g, 0.009 mmol), SnCl2.2H2O (4.2 g, 0.018 mmol) and conc. HCl (30 mL) to afford 1.5 g of the desired product.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])(OCC1C=CC=CC=1)=O>>[NH2:34][C@H:35]([CH:36]([CH3:38])[CH3:37])[C:39]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:40]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)[C@@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 4 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-D-valine as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.15-4.01 (m, 1H), 3.58 (d, 1H), 3.55-3.43 (m, 1H), 3.32-3.15 (m, 1H), 2.25-2.07 (m, 1H), 2.02-1.85 (m, 2H), 1.83-1.58 (m, 6H), 1.56-1.45 (m, 2H), 1.42-1.18 (m, 3H), 1.10 (d, 6H), 1.08-0.96 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 40.91. LCMS m/z: [M+H]+=335.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][S:8]2(=[O:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>O1CCCC1>[O:17]=[S:8]1(=[O:16])[N:9]([CH2:19][CH:20]2[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:21]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CN2c3ccccc3N(c3ccccc3)S2(=O)=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared analogously as in general procedure I, 246 mg, 1.00 mmol), tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (228 mg, 1.05 mmol, 1.05 equiv.) and triphenylphosphine (289 mg, 1.10 mmol, 1.1 equiv.) in tetrahydrofuran (5 mL) was cooled to 0° C. in an ice bath. Diispropyl azodicarboxylate (0.22 mL, 1.1 mmol, 1.1 equiv.) was added dropwise via a syringe. The reaction mixture was stirred overnight while warming to room temperature. Solvent was removed under reduced pressure and the residue was purified by Isco flash column chromatography (silica gel, 3-30% ethyl acetate/hexane) to give 398 mg (89%) of tert-butyl 2-[(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)methyl]morpholine-4-carboxylate as a white foam. MS (ESI) m/z 445.9 ([M+H]+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1cccc(Cl)c1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1c(F)cccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-6-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29]>C1COCC1.C(Cl)Cl>[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:29][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccco1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccco1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
To a solution of furan-2-carboxylic acid (2.0 g, 17.8 mmols) and N-methylmorpholine (1.95 ml, 17.8 mmols) in anhydrous THF (10 ml), cooled at −15° C. was added dropwise under stirring an equivalent quantity of isobutylchloroformate (2.33 ml, 17.8 mmols). After 30 minutes a solution of L-leucine methylester hydrochloride (3.23 g, 17.8 mmol) and N-metylmorpholine (1.95 ml, 17.7 mmols in anhydrous THF (15 ml) was slowly added, maintaining the mixture under stirring at −15° C. for two hours. The reaction mixture was diluted with CH2Cl2 (100 ml) and washed with HCl 1N (30 ml×2), NaHCO3 saturated solution (30 ml×2), and NaCl saturated solution (30 ml). After drying the organic phase on Na2SO4 and removal of the solvent at a reduced pressure, the raw product was obtained as an oily residue which spontaneously solidified. By grinding the solid substance in petroleum ether, white crystals of either N-[(furan-2-yl) carbonyl]- L-leucine methylester were obtained: 3.32 g (80%); m.p. 88-90° C., [a] D22=−23° C. (1, methanol); IR (CHCl3): 3424, 2956, 1741, 1663, 1595, 1517, 1351, 1177 cm−1; 1H-NMR (CLCl3): d 0.95 and 1.02 [two s, 6, CH2CH(CH3)2], 1.45-2.00 [m, 3, CH2CH(CH3)2], 3.85 (s, 3, OCH3), 4.73-5.13 (m, 1, aCH), 6.39-7.45 [m, 3, furan aromatics and 6.89 (d, 1, NH, J=8 Hz)]. Calculated for C12H17NO4: C, 60.24; H 7.16; N 5.85. Found C 60.15; H 7.22; N 5.88%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N:30]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[C:31]=[O:32]>C(Cl)Cl>[CH:33]1([NH:30][C:31]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (63 pt, 0.36 mmol) in DCM (2 mL) was added isocyanatocyclohexane (46 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 give the title compound as a white solid. MS (ESI, positive ion) m/z: 403 (M+H).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH2:18][CH2:19][F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:21]([CH3:23])[CH3:22])[S:14]2)[C@H:10]1[O:24]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[CH3:23][N:21]([CH3:22])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([CH2:18][CH2:19][F:20])[C@@H:9]([OH:8])[C@H:10]([OH:24])[C@H:11]2[N:12]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CCF)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CCF)O[C@@H]2S1
Yield: 18.9 %

Procedure:
A solution of 108 (300 mg, 0.7 mmol) in dichloromethane (20 mL) was treated with BCl3 (7 mL, 7 mmol, 1 M in dichloromethane) for 2 hours at −60° C., then quenched by the addition of methanol (10 mL). Volatiles were distilled out under vacuum to give a residue, which was dissolved into methanol (5 mL) and neutralized by Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give the title compound as a white solid (35 mg, 20%); (ES, m/z) [M+H]+ 265.0; 1HNMR (300 MHz, D2O) δ 6.16 (d, J=6.3 Hz, 1H), 4.60 (t, J=4.8 Hz, 1H), 4.45 (t, J=4.8 Hz, 1H), 4.10 (t, J=6.0 Hz, 1H), 3.92 (t, J=4.8 Hz, 1H), 3.62-3.66 (m, 1H), 3.42-3.60 (m, 1H), 2.90 (s, 6H), 2.06-2.20 (m, 1H), 1.67-1.88 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([OH:17])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[C:24]([O-])([O-])=O.[K+].[K+].IC>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:17][CH3:24])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Reaction time: 18 h
Yield: 99 %

Procedure:
At ambient temperature, to a stirred mixture containing 2'-hydroxy-[1,1';3',1"]terphenyl-5'-carboxylic acid methyl ester (1.232 g, 4.049 mmol) and K2CO3 (0.6155 g, 4.454 mmol) in N,N-DMF (10.1 mL) was added iodomethane (0.353 mL, 5.67 mmol). After 18 h, the reaction was diluted with H2O (100 mL) and the reaction was stirred vigorously. The resulting precipitate was collected, dissolved in CH2Cl2, dried (K2CO3) and concentrated to give 1.167 g, (99%) of the title compound. 1H NMR (DMSO-d6) δ 3.16 (s, 3 H), 3.87 (s, 3 H), 7.41-7.53 (m, 6 H), 7.58-7.60 (m, 4 H), 7.89 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:37][CH2:38][C:39]1[C:40]([OH:47])=[N:41][C:42]([CH3:46])=[CH:43][C:44]=1[CH3:45]>ClCCl.O>[OH:47][C:40]1[C:39]([CH2:38][NH:37][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:2]=2[CH3:1])=[O:12])=[C:44]([CH3:45])[CH:43]=[C:42]([CH3:46])[N:41]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1-c1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(-c3ccccc3)c3ccccc23)c(O)n1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 2-methyl-1-phenyl-1H-indole-3-carboxylic acid (115 mg, 0.46 mmol) in anhydrous dichloromethane (3 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (75 mg, 0.55 mmol), 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (106 mg, 0.55 mmol) and triethylamine (0.16 mL, 1.15 mmol). The mixture was stirred at room temperature for half an hour, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (70 mg, 0.46 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was added water (20 mL), extracted with dichloromethane (20 mL×2), combined and concentrated the organic layers to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=25:1) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1-phenyl-1H-indole-3-carboxamide (12 mg, 50% yield. LRMS (M+H+) m/z: calcd for 385.18. found 385. 1H NMR (300 MHz, CDCl3) δ 12.62 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.77-7.40 (m, 3H), 7.43-7.18 (m, 3H), 7.22-7.00 (m, 2H), 5.98 (s, 1H), 4.65 (s, 2H), 2.60-2.52 (m, 3H), 2.45 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: Cl[C:2]1[S:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[Cl:12].C([Li])CCC.Cl>CCOCC.CCCCCC>[Cl:12][C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[S:6][CH:2]=1
Reactant: Cc1cccc2c(Cl)c(Cl)sc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cccc2c(Cl)csc12

Procedure:
10 g of 2,3-Dichloro-7-methylbenzo[b]thiophene are dissolved in 200 ml ether and 28.8 ml of a 1.6M solution of butyllithium in hexane added dropwise at 0°. After one hour the mixture is poured into dilute aqueous HCl, the organic phase separated, washed, dried and concentrated on a rotary evaporator. The raw title product thus obtained is reacted directed further (B.p.=60°-62°/0.13 Pascal. 3-Chloro-4-methylbenzo[b]thiophene may be prepared analogously.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[S:11]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:13])=[O:12].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][S:11]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:12])=[O:13]
Reactant: COc1ccccc1/C=C/S(=O)(=O)Nc1ccccc1S(N)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1CCS(=O)(=O)Nc1ccccc1S(N)(=O)=O
Yield: 71.6 %

Procedure:
(E)-2-(2-(2-Methoxyphenyl)vinylsulfonamido)benzenesulfonamide (94 mg, 0.26 mmol) was dissolved in methanol (5 mL) in a 5 mL syringe. The solution was injected to the H-cube (1 ml/min, full hydrogen; 10% Pd/C). The solvent was then removed under reduced pressure and the crude material was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (69 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][N:3]=1.ClC1C=CC=[C:18]([C:22]([O:24]O)=[O:23])C=1>ClCCl>[C:22]([O:24][CH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])=[CH:4][N:3]=1)(=[O:23])[CH3:18]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.1 g of t-butyl 6-methylnicotinate in 100 ml of dichloromethane, 9.8 g of m-chloroperbenzoic acid is added slowly, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed successively with 10% sodium carbonate solution and water, dried over magnesium sulfate, and concentrated. The residue is slowly added to 7.1 g of acetic anhydride at 100°-120° C., and the mixture is refluxed with stirring for 1 hour. After cooling, the remaining acetic anhydride is decomposed with ethanol, and the mixture is concentrated. The residue is neutralized with saturated aqueous potassium bicarbonate and extracted with three 50-ml portions of chloroform. The combined extracts are dried over magnesium sulfate and concentrated to give crude 5-t-butoxycarbonyl-2-pyridylmethanol acetate.
Reaction SMILES: [N+]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N+:7]([O-])=[CH:6][CH:5]=1)([O-])=O.P(Cl)(Cl)[Cl:16].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:16][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=[CH:6][CH:5]=1
Reactant: ClP(Cl)Cl
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Clc1ccnc2c1CCCC2
Temperature: 25 °C

Procedure:
A solution of the crude product of Step 1 (36.5 g, 188 mmol) in chloroform (500 ml) was treated over 30 min with phosphorus trichloride (80 g, 580 mmol) at 0°, heated under reflux for 1 h, cooled to room temperature, and poured onto ice (2 Kg). The mixture was basified with sodium hydroxide and the layers separated. The aqueous phase was extracted with chloroform (500 ml).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[C:3]=1[Br:11]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cn1c(N)c(Br)c(=O)[nH]c1=O
Temperature: 80 °C
Yield: 81.8 %

Procedure:
A mixture of 6-amino-1-methyluracil (14.0 g, 100 mmol), N-bromosuccinimide (21.0 g, 118 mmol), and dry DMF (250 mL) was heated at 80° C. for 3 h. The reaction mixture was evaporated in vacuo and the residue was slurried with ice-cold 50% aqueous ethanol (150 mL) and filtered. The resulting off-white solid was washed with ethanol, then ether and dried to yield 18.0 g 2a (83%). mp 274° C. dec; UV pH 1 λmax 276 nm; NMR δ (DMSO-d6) 3.26 (s, 3H, CH3), 7.02 (s, 2H, NH2), 10.89 (s, 1H, NH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=1>>[N:1]1([C:15]([C:14]2[CH:19]=[CH:20][C:11]([O:10][CH2:9][CH2:8][OH:7])=[CH:12][CH:13]=2)=[O:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(OCCO)cc1
Product: O=C(c1ccc(OCCO)cc1)N1CCOCC1
Yield: 26.9 %

Procedure:
Using morpholine (1.25 mL, 14.3 mmol) and methyl 4-(2-hydroxyethoxy)benzoate (1.00 g, 5.10 mmol), the desired title compound (345 mg, yield 27%) was obtained by the same method as in Reference Example 8.
Reaction SMILES: C(C1OC2C=CC=CC=2C=1)C.COC1C=CC(S(Cl)(=O)=O)=CC=1.[CH2:24]([C:26]1[O:27][C:28]2[CH:45]=[CH:44][CH:43]=[CH:42][C:29]=2[C:30]=1[S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40]C)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH3:25]>>[CH2:24]([C:26]1[O:27][C:28]2[CH:45]=[CH:44][CH:43]=[CH:42][C:29]=2[C:30]=1[S:31]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH3:25]
Reactant: CCc1oc2ccccc2c1S(=O)(=O)c1ccc(OC)cc1
Agent: CCc1cc2ccccc2o1
Agent: COc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1oc2ccccc2c1S(=O)(=O)c1ccc(O)cc1

Procedure:
2-Ethyl-3-(4-hydroxyphenylsulfonyl)benzofuran is prepared by acylation of 2-ethylbenzofuran with 4-methoxybenzenesulfonyl chloride followed by demethylation of the 2-ethyl-3-(4-methoxyphenylsulfonyl)benzofuran thus formed as described hereinabove.