Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:30].[Mg+2]>C(Cl)Cl.CO.C([O-])(O)=O.[Na+]>[CH3:1][S:2]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:25])[F:24])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)=[O:30]
Reactant: CSc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(methylthio)-6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine (1.62 g, 4.39 mmol) in CH2Cl2/MeOH (2:1, 22 mL) was added magnesium monoperoxyphthalate (1.3 g, 2.2 mmol). The mixture was stirred at room temperature for 18 h. Additional magnesium monoperoxyphthalate (300 mg) was added and after 1 h, the mixture was diluted with saturated aqueous NaHCO3 (50 mL), extracted with (3×20 mL) of EtOAc and dried over Na2SO4. Evaporation of the solvent followed by purification by Combiflash chromatography (SiO2, eluant 5% MeOH/EtOAc) afforded the desired product. 1H NMR (500 MHz, acetone-d6): δ 1.92-1.98 (m, 2H), 2.14-2.18 (m, 2H), 2.84 (s, 3H), 3.90-4.08 (m, 5H), 5.01-5.03 (m, 1H), 7.11 (t, 1H), 7.38 (d, 1H), 7.51 (d, 1H), 7.61-7.67 (m, 2H), 7.82 (d, 1H). MS (+ESI) m/z 386 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=1.[NH2:30][C:31]1([CH3:42])[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:38]([O:37][C:35]([N:33]1[CH2:34][C:31]([CH3:42])([NH:30][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=2)[CH2:32]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC1(N)CN(C(=O)OC(C)(C)C)C1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #53, Step E, 0.110 g, 0.223 mmol), tert-butyl 3-amino-3-methylazetidine-1-carboxylate (0.062 g, 0.334 mmol), Pd(OAc)2 (0.010 g, 0.045 mmol), cesium carbonate (0.109 g, 0.334 mmol) and BINAP (0.042 g, 0.067 mmol) in toluene (5 mL) was heated at reflux for 5 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.090 g, 67%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.13 (s, 1H), 5.93 (s, 1H), 5.10 (q, J=10.4 Hz, 2H), 4.62 (d, J=12.8 Hz, 1H), 4.58 (m, 1H), 4.49 (d, J=12.8 Hz, 1H), 4.37 (s, 1H), 4.00 (m, 2H), 3.95 (m, 2H), 3.66 (t, J=8.0 Hz, 2H), 1.63 (s, 3H), 1.47 (d, J=6.8 Hz, 3H) 1.45 (s, 9H), 0.99 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:70])[C@H:41]([CH2:47][C:48]([NH:50]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:49])[NH:42][C:43]([O:45][CH3:46])=[O:44])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:46][O:45][C:43](=[O:44])[NH:42][C@@H:41]([CH2:47][C:48]([NH2:50])=[O:49])[C:40](=[O:70])[NH:39][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:18]=1)[NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29](=[O:30])[O:31][CH3:32]
Reactant: COC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 21 %

Procedure:
A solution of Example 168C (27.7 mg, 0.027 mmol) in dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.25 mL) at 25° C. for 2 h. The solvents were evaporated, and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate, dried over MgSO4, filtered, and the solvents were evaporated. The crude residue was purified by silica gel chromatography eluting with a gradient of dichloromethane, 100% ethyl acetate, and 95% ethyl acetate/7% methanol to give the title compound (4 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81(s, 9H), 1.53(m, 2H), 2.42-2.30(m, 2H), 2.64-2.60(m, 1H), 2.79-2.71(m, 4H), 3.50(s, 3H), 3.54(s, 3H), 3.61(m, 1H), 3.79(d, J=4.04 Hz, 1H), 4.03(m, 4.13(m, 1H), 4.27(m, 1H), 4.57(bs, 1H), 6.17(m, 1H), 6.84(m, 1H), 7.12(m, 1H), 7.21-7.19(m, 7H), 7.27(m, 1H), 7.48(d, J=7.81 Hz, 1H), 7.82(bs, 2H), 7.87-7.86(d, J=7.81 Hz, 2H), 8.62-8.61(d, J=4.39 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][C:41](=[O:43])[CH2:40][N:39]2[CH2:44][CH2:45][CH2:46][C@@H:38]12.CN(C)CN.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu](I)I>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[C:41](=[O:43])[CH2:40][N:39]4[CH2:44][CH2:45][CH2:46][C@H:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1CN2CCC[C@H]2CN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: CN(C)CN
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1-c1cc(N2C[C@@H]3CCCN3CC2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 45.4 %

Procedure:
The title compound was prepared starting from 100 mg (0.187 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 79 mg (0.563 mmol) of (8aS)-hexahydropyrrolo[1,2-a]pyrazin-3(4H)-one (D12), 72 mg of copper iodide (0.378 mmol), 40 μl (0.375 mmol) of N,N-dimethylmethanediamine, 112.4 mg (0.375 mmol) of cesium carbonate; the reagents were dissolved in 4 ml of dioxane and heated at 80° C. for 4 h and then at 120° C. overnight. The crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 54 mg of the title compound as pale yellow solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Si:7]([O:14][C@H:15]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])/[CH:16]=[N:17]/[S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>CCOCC>[Si:7]([O:14][C@H:15]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@@H:16]([NH:17][S@:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: Brc1nccs1
Solvent: CCOCC
Product: CC(C)(C)[S@](=O)N[C@@H](c1nccs1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 2-bromothiazole (7.9 ml, 89 mmol) in 200 mL ether was cooled to −78° C. and treated with a solution of n-butylithium (36 ml, 89 mmol) (2.5N in hexanes). After stirring for 30 minutes the reaction mixture was slowly added to a cooled (−78° C.) suspension of (S,E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (25.000 g, 59 mmol) in 100 mL ether. The reaction mixture was allowed to stir at −78° C. for one hour. The reaction mixture was quenched with MeOH and saturated NH4Cl solution. The organic solution was washed with water, brine, dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography gave (S)-N-((1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (24.81 g, 83% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:21])=[N-]>CCOCC>[CH3:21][O:17][C:16](=[O:18])[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(N-Boc-piperidine-4-yl)-propionic acid (4.0 g, 15.6 mmol) in ether (100 mL) was added a solution of diazomethane in ether (0.2 M, 100 ml) in portions until the solution became lightly yellow. The mixture was stirred at room temperature for 1 hr and the solvents were evaporated to give 3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (4.2 g) as an oil.
Reaction SMILES: C(O[C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[NH:29][C:30]5[C:35]([CH:36]=4)=[CH:34][C:33]([Cl:37])=[CH:32][CH:31]=5)(=[O:27])=[O:26])[CH2:21][CH2:20]3)=[O:18])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl.O1CCCC1>C(Cl)Cl.CO>[ClH:37].[Cl:37][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([S:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]([C:15]3[O:14][C:11]4[CH2:12][NH:13][CH:8]([CH3:6])[CH2:9][C:10]=4[N:16]=3)=[O:18])[CH2:20][CH2:21]1)(=[O:27])=[O:26])=[CH:36]2
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)oc2CN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)oc2CN1
Reaction time: 0.25 h

Procedure:
To a solution of 1-[[6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (100 mg) in methylene chloride (3.0 ml) was added trifluoroacetic acid (3.0 ml) at room temperature, followed by stirring for 15 minutes. The reaction mixture was concentrated under reduced pressure. To the residue were added methylene chloride (4.0 ml), triethylamine (50.0 μl), acetic acid (21.0 μl), formalin (23.5 μl) and sodium triacetoxyborohydride (58.0 mg) at room temperature. After stirring for 1 hour, methylene chloride (20 ml) and a saturated aqueous solution (50 ml) of sodium bicarbonate were added to the reaction mixture to separate it into layers. The water layer was extracted with methylene chloride (20 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (chloroform : methanol=10:1) using silica gel, whereby the free form (82.6 mg) of the title compound was obtained as a colorless solid. To the resulting compound were added a 1N aqueous solution of hydrochloric acid, tetrahydrofuran and methanol, followed by concentration under reduced pressure, whereby the title compound was obtained as a colorless solid.
Reaction SMILES: C(O)(=O)C.Br.C(OC([NH:16][C:17](=[CH:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])=O)C1C=CC=CC=1>>[NH2:16][C:17](=[CH:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19]
Reactant: CC(C)C=C(NC(=O)OCc1ccccc1)C(N)=O
Agent: Br
Solvent: CC(=O)O
Product: CC(C)C=C(N)C(N)=O
Reaction time: 2 h

Procedure:
In a hydrogen bromide acetic acid solution was dispersed 1 g of the 2-(benzyloxycarbonyl)aminoisopropyl acrylamide synthesized in Example 8 and stirred for two hours. After hydrogen bromide and acetic acid were thoroughly distilled off, water was added to the residue. The protective group benzyl bromide eliminated with the use of ether was removed by extraction and subsequently, the aqueous layer was concentrated. Methanol was added to the residue and stirred for two hours. Only the methanol layer was separated and condensed to obtain the desired 2-aminoisopropyl acrylamide hydrobromate as a white solid. The structure was confirmed by using 1H-NMR.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:11][C:12]1[CH:27]=[CH:26][C:15]2[NH:16][C:17]([C:19]([O:21]C(C)(C)C)=[O:20])=[N:18][C:14]=2[CH:13]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([NH:11][C:12]1[CH:27]=[CH:26][C:15]2[NH:16][C:17]([C:19]([OH:21])=[O:20])=[N:18][C:14]=2[CH:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc2[nH]c(C(=O)OC(C)(C)C)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc2[nH]c(C(=O)O)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.5 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a suspension of 1,1-dimethylethyl 5-(acetylamino)-1H-benzimidazole-2-carboxylate (0.155 g, 0.563 mmol) in dichloromethane (2 mL). After stirring at RT overnight, the solvent was evaporated to give the title compound (0.166 g, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.17 (s, 1H), 8.19 (d, 1H), 7.61 (d, 1H), 7.40 (dd, 1H), 2.1 (s, 3 H). MS: m/z 218 (M−1).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[C:10](OC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.O.C(OCC)(=O)C>CCCCCC.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1cccc(Cl)c1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
A solution of 26 g of methyl (R)-α-t-butyldimethylsilyloxy-3-chlorophenylacetate (prepared as described in Preparation 48) in a mixture of 1000 ml of anhydrous hexane and 500 ml of dry toluene was cooled to -60° C., and then 124 ml of a 1M solution of diisobutylaluminum hydride in hexane were added dropwise to the cooled solution. The resulting mixture was stirred at the same temperature for 3 hours, after which 10 ml of water were added to it, and the temperature of the mixture was gradually allowed to rise to room temperature. The reaction mixture was then mixed with water and ethyl acetate, after which it was stirred for 30 minutes. Insoluble materials were filtered off using a Celite (trade mark) filter aid, and the ethyl acetate layer was separated from the filtrate and dried over anhydrous sodium sulfate. The ethyl acetate solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound having an Rf=0.36 (thin layer chromatography over silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=O)=[CH:3][CH:2]=1.Cl.[CH2:21]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[CH2:22][CH2:23][CH3:24]>O>[CH2:21]([O:25][C:26](=[O:29])[CH2:27][N:28]1[C:17](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[C:8]([S:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:9]=2)[C:12]1=[O:14])[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)c1ccc(Sc2ccncc2)cc1C(=O)O
Reactant: CCCCOC(=O)CN
Agent: Cl
Solvent: O
Product: CCCCOC(=O)CN1C(=O)c2ccc(Sc3ccncc3)cc2C1=O
Temperature: 250 °C
Yield: 69.8 %

Procedure:
A solid mixture of 4-(pyridin-4-ylsulfanyl)-phthalic acid (11.40 g) and glycine n-butyl ester hydrochloride salt (6.95 g) was heated in a oil bath (250° C.) with efficient stirring for 20 min. until the water bubble evaporation ceased. After cooling, it was partitioned between ethyl acetate (300 ml) and saturated sodium bicarbonate aqueous solution (150 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (300 ml). Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound 10.70 g. MS-(+)-ion: M+1=371.2.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:23][O:24][C:25](=[O:31])[CH:26]([F:30])[C:27](O)=[O:28].[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:23][O:24][C:25](=[O:31])[CH:26]([F:30])[C:27]([NH:38][C:35]1[CH:34]=[CH:33][C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:37][CH:36]=1)=[O:28]
Reactant: COC(=O)C(F)C(=O)O
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(F)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
HOBt (83 mg, 0.61 mmol), DMAP (125 mg, 1.02 mmol) and EDCI.HCl (118 mg, 0.61 mmole) were added to a stirred solution of 2-fluoro-malonic acid monomethyl ester (70 mg, 0.514 mmol) in DMF (2 mL). Biphenyl-4-ylamine (100 mg, 0.61 mmol) was then added and the resulting mixture was stirred at ambient temperature overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 114 mg (80%) of N-biphenyl-4-yl-2-fluoro-malonamic acid methyl ester
Reaction SMILES: F[B-](F)(F)F.[NH4+].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([CH3:15])[CH:9]=1.Cl.[N:17]([O-])=O.[Na+].CC([O-])=O.[K+].C1OCCOCCOCCOCCOCCOC1>C(O)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:13][CH:14]=1)[NH:12][N:17]=[CH:15]2
Reactant: O=N[O-]
Reactant: Cc1cc(Br)ccc1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Brc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 152.3 %

Procedure:
Ammonium tetrafluoroborate (20.97 g, 200 mmol) was dissolved in aqueous acetic acid (500 mL AcOH/250 mL water) and cooled to 0° C. 2-Methyl-4-bromoaniline (compound 1f, 18.61 g, 100 mmol) and 42 mL of aqueous concentrated HCl (36% w/w, 12N, 500 mmol) were sequentially added. The mixture was stirred for 20 minutes at 0° C. and NaNO2 (7.59 g, 110 mmol) was added. The reaction was stirred for 1 hour at 0° C. and warmed to room temperature. After 16 hours at room temperature, the mixture was concentrated under reduced pressure and the residue was azeotroped with toluene and dried under high vacuum. The solid was suspended in 500 mL of CHCl3 and KOAc (12.76 g, 130 mmol) and 18-crown-6 (7.93 g, 30 mmol) were added. The reaction was stirred for 1.5 hours at room temperature. The mixture was washed with water, dried over anhydrous MgSO4, filtered through Celite and concentrated under reduced pressure to provide 30 g of 5-bromo-1H-indazole (compound 2f) as a tan solid. The crude material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=1[Cl:1])=[O:6])[CH2:47][CH2:48][CH3:49]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,3-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.83-0.92 (m, 3 H) 1.25-1.37 (m, 2 H) 1.67-1.75 (m, 2 H) 2.50 (s, 3 H) 4.15 (t, 2 H) 6.18 (s, 1 H) 7.37-7.48 (m, 2 H) 7.64-7.69 (m, 1 H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [CH2:1]([C:7]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:19]=[CH:18][C:8]=1[O:9][CH2:10][CH:11]1[CH2:15][O:14]C(C)(C)[O:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl>O1CCCC1>[CH2:1]([C:7]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:19]=[CH:18][C:8]=1[O:9][CH2:10][CH:11]([OH:12])[CH2:15][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC2COC(C)(C)O2)c(CCCCCC)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CCCCCC)c1
Yield: 98.5 %

Procedure:
A mixture of 13.6 g of 4-[(2-hexyl-4-tetradecylphenoxy)methyl]-2,2-dimethyl-1,3-dioxolane, 10 ml of 5% hydrochloric acid and 250 ml of tetrahydrofuran was heated at reflux for 4 hours, then allowed to cool and the tetrahydrofuran removed under reduced pressure. The mixture was then extracted several times with ethyl acetate. The organic extracts were combined, washed with aqueous sodium bicarbonate, dried and the solvent evaporated, giving 12.3 g of the desired compound.
Reaction SMILES: [S-2].[Na+].[Na+].[N+:4]([C:7]1[CH:12]=[C:11]([S:13][C:14]#N)[CH:10]=[CH:9][C:8]=1[OH:16])([O-:6])=[O:5].BrC[CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].Cl>CS(C)=O.CO>[OH:16][C:8]1[CH:9]=[CH:10][C:11]([S:13][CH2:14][CH2:19][N:20]2[C:21](=[O:30])[C:22]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]3[C:24]2=[O:25])=[CH:12][C:7]=1[N+:4]([O-:6])=[O:5]
Reactant: N#CSc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCSc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
A methanol solution (15 ml) containing sodium sulfide. 9 hydrate (3.60 g) was added to 2-nitro-4-thiocyanophenol (1.96 g), which was prepared according to the method described in U.S. Pat. No. 2,562,948 (1951), in dimethyl sulfoxide (10 ml). Then N-(2-bromoethyl)phthalimide (2.54 g) was added, and the mixture was agitated for 3 hrs at room temperature, and was poured into ice water. The pH of the solution was adjusted to 5 with diluted hydrochloric acid, and the precipitate was collected to obtain N-[2-(4-hydroxy-3-nitrophenylthio)ethyl]phthalimide (2.3 g). The compound (3.5 g) was subjected to reduction under increased pressure at 70 atm in the presence of a 5% palladium carbon catalyst, and was subsequently caused to react with cyanogen bromide to yield 2-amino-5-[2-<2-(1,3-(2H)-dioxo-1H-isoindolyl)>ethylthio]benzoxazole (2 g). The benzoxazole derivative (2 g) was heated with hydrazine hydrate to yield 2-amino-5-(2-aminoethylthio)benzoxazole (1.1 g).