Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[C@@H:3]1([N:12]2[C:22]3[NH:21][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:15]=3[N:14]=[CH:13]2)[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]1[OH:5].[C:23](Cl)(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:23]([C@@:3]1([N:12]2[C:22]3[NH:21][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:15]=3[N:14]=[CH:13]2)[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]1[OH:5])(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=c1[nH]c(=O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[C@@]1(n2cnc3c(=O)[nH]c(=O)[nH]c32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 50 mL flask was added xanthosine dihydrate (1.0 g, 3.52 mmol) and N,N-dimethyl-4-aminopyridine (0.0086 g, 0.07 mmol). N,N-dimethylformamide (16 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (8 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and palmitoyl chloride (1.6 mL, 9.2 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 18 h, the mixture was poured into 300 mL of ice-cold 0.1 M sodium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×100 mL hot water, air dried, and recrystallized from hot methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(Cl)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(Cl)cc2)n1

Procedure:
60 mg (82.3%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (45.74 mg, 0.165 mmol), 1-(2-fluorophenyl)piperazine (39.16 mL, 0.247 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Cl:6].[CH3:7][C:8]1([OH:18])[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2.C(N(CC)CC)C>C1COCC1>[CH3:7][C:8]1([O:18][CH2:2][O:3][CH2:4][CH2:5][Cl:6])[CH:9]2[CH2:17][CH:13]3[CH2:12][CH:11]([CH2:16][CH:15]1[CH2:14]3)[CH2:10]2
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: ClCCOCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(OCOCCCl)C2CC3CC(C2)CC1C3
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A two neck Kjeldahl flask of 50 ml into which a stirrer was put was charged with 1.55 g (12 mmol) of chloroethyl chloromethyl ether obtained in Example 1 (1), 1.66 g (10 mmol) of 2-methyl-2-adamantanol, 1.52 g (15 mmol) of triethylamine and dried THF, and it was equipped with a coiled condenser to reflux and stir the solution for 8 hours. Triethylamine hydrochloride was filtered, and gas chromatographic analysis was carried out to find that 2-methyl-2-adamantanol was converted by 46.2% and that 2.04 g (7.9 mmol, isolation yield: 78.8%) of a colorless liquid which was the intended product was obtained at a selectivity of 97.3%.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:10])[C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(Cl)CCl.[CH:15]1[CH:16]=CC2N(O)N=[N:21][C:19]=2[CH:20]=1.N1CCCC1>O1CCCC1>[Br:1][C:2]1[N:3]([CH3:10])[C:4]([C:7]([N:21]2[CH2:16][CH2:15][CH2:20][CH2:19]2)=[O:9])=[CH:5][N:6]=1
Reactant: On1nnc2ccccc21
Reactant: Cn1c(C(=O)O)cnc1Br
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: Cn1c(C(=O)N2CCCC2)cnc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of methyl 2-bromo-1-methyl-1H-imidazole-5-carboxylate (2.18 g, 10 mmol) in tetrahydrofuran (60 mL) and water (6 mL) was added lithium hydroxide (0.72 mg, 30 mmol) and the reaction mixture was allowed to stir at room temperature for 2.5 h. The solvent was removed under reduced pressure and water was added followed by formic acid, the resulting precipitate was filtered, washed with water and dried under vacuum overnight to afford the 2-bromo-1-methyl-1H-imidazole-5-carboxylic acid (82%). 1H-NMR (300 MHz, CDCl3): 7.79 (s, 1H), 3.91 (s, 3H). LCMS (ESI+) 205.0 (MH+). To a solution of the carboxylic acid (1.68 g, 8.2 mmol) in anhydrous tetrahydrofuran (24 mL) was added EDC (1.53 g, 9.9 mmol) followed by HOBt (1.22 g, 9.1 mmol) and the reaction mixture was allowed to stir for 1 h at room temperature. A solution of pyrrolidine (1.03 ml, 12.4 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure and residue partitioned between ethyl acetate and 1 M aqueous potassium carbonate. The organic layer was dried (Na2SO4) and solvent evaporated under reduced pressure. Purification by flash column chromatography (silica, EtOAc/MeOH 9:1) afforded the title compound (95%). 1H NMR (300 MHz, CDCl3): 7.79 (s, 1H), 3.92 (s, 3H), δ 3.35 (bs, 4H), δ 1.97 (bs, 4H). LCMS (ESI+) 257.0 (MH+).
Reaction SMILES: [O:1](N=[N+]=[N-])S(N=[N+]=[N-])(=O)=O.[CH2:11]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]=[N+:26]=[N-:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:12](=[CH2:14])[CH3:13].C(OO)(=O)C.C([O-])(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[N:25]([S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:11][C:12]2([CH3:13])[O:1][CH2:14]2)=[CH:21][CH:20]=1)(=[O:23])=[O:24])=[N+:26]=[N-:27]
Reactant: C=C(C)COc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: [N-]=[N+]=NOS(=O)(=O)N=[N+]=[N-]
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(COc2ccc(S(=O)(=O)N=[N+]=[N-])cc2)CO1
Temperature: 41 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
To show another example of the epoxy-sulfonylazide of the instant invention, a solution of p-methallyloxybenzenesulfonylazide (506 parts) in methylene chloride (1,450) parts is stirred and heated to reflux (41° C.) then a solution of 35% peracetic acid in acetic acid (521.5 parts) containing sodium acetate (15.6 parts) is added slowly from an addition funnel over 15 minutes. An additional 40 parts of methylene chloride is added to adjust the reflux temperature to 45° C. After 6 hrs stirring and refluxing at 45° C. the reaction is quenched with 835 parts of distilled water. The layers are separated and the organic phase is washed with 555 parts of 10% sodium sulfite, 835 parts of sodium bicarbonate, and 565 parts of distilled water containing 23 parts of trioctylammonium chloride. The solution is dried azeotropically, and the solvent is removed at 55° C. and 20 mm to yield 528 parts of 3-(p-azidosulfonylphenoxy)-2-methylpropylene oxide as a white, crystalline solid. This represents a yield of 98%.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25](O)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CCN=C=NCCCN(C)C.Cl>C1COCC1>[CH2:25]([CH:2]([CH2:1][CH2:7][CH2:8][CH3:9])[C:3]([OH:4])=[O:16])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5]
Reactant: CCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: OCC(O)CO
Product: CCCCCCC(CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous THF (50 mL). Hexanoic acid (11.96 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) was dissolved in the solution. When the catalyst was fully dissolved, EDC HCl (18.32 g, 95.6 mmol) was added into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was stripped of THF via rotoevaporation and redissolved into chloroform. The organic layer was washed 2× with sodium bicarbonate buffer and 2× with deionized water to remove unreacted starting materials. The chloroform was removed to yield a clear viscous liquid. NMR analysis supported full conversion of hydroxyl groups to the hexanoic esters.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](Cl)=[O:32])=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH3:21].N1C=CC=C[CH:35]=1>O>[CH3:35][CH:30]([CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:24][CH:25]=1)[C:31]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:32]
Reactant: c1ccncc1
Reactant: CCCCCOc1ccc(CCC(=O)Cl)cc1
Reactant: CCCc1ccc(-c2ccc(O)cc2)cc1
Solvent: O
Product: CCCCCOc1ccc(CC(C)C(=O)Oc2ccc(-c3ccc(CCC)cc3)cc2)cc1
Reaction time: 8 h

Procedure:
4-Hydroxy-4'-propylbiphenyl (2.5 g, 0.012 mol) was dissolved in pyridine (10 ml) and to the solution was added β-(4-pentyloxyphenyl)propionic acid chloride (2.5 g, 0.01 mol) with sufficient shaking, followed by allowing the resulting reaction solution to stand overnight, pouring it in water (100 ml), extracting the resulting oily material with toluene (100 ml), washing the toluene layer with 6N-HCl, then with 2N-NaOH and further with water till the washing water became neutral, filtering, distilling off toluene under reduced pressure, and recrystallizing residual crystals from ethanol to obtain the objective 4'-propyl-4-biphenylyl α-methyl-β-(4-pentyloxyphenyl)propionate. m.p. 84.0°-84.5° C. N-I point 46.0° C. (extrapolated value).
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]1C=CC=CC=1[P+](C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:27]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])O.[Na+].O>C(OCC)C>[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH:7]=[CH:48][C:45]1[CH:44]=[CH:43][C:42]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:41][CH:40]=2)=[N:47][CH:46]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)cn2)cc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1C1OCCO1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc(C=CC3OCCO3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6.44 g of (1,3-dioxolan-2-yl)-methyl-triphenylphosphonium bromide in 70 ml of diethyl ether is treated with 1.68 g of potassium t-butylate within 5 minutes while gassing with nitrogen. The orange suspension is stirred for 30 minutes, then cooled to 0° C. and treated within 10 minutes with a solution of 3.11 g of 6-[4-(octyloxy)phenyl]-3-pyridinecarboxaldehyde (prepared in accordance with Example 2) in 25 ml of diethyl ether. The reaction mixture is stirred at room temperature for a further 3 hours and then treated with 0.6 g of sodium hydrogen carbonate and with 20 ml of water. The organic phase is washed with water, dried over sodium sulfate and concentrated. The residue is taken up in hexane and 20 ml of 80 percent aqueous methanol. The phases are separated and the hexane phase is washed with 10 ml of 80 percent methanol, dried over sodium sulfate and concentrated. Chromatographic purification of the residue on 50 g of silica gel with hexane/ethyl acetate (vol. 9:1) gives 5-[2-(1,3-dioxolan-2-yl)vinyl]-2-[4-(octyloxy)phenyl]-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1ccc2nc(NC(=O)N3CCN(c4cc(C)cc(C)c4)CC3)c(OC)nc2c1
Yield: 90 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.26 (s, 4H), 3.75 (s, 4H), 3.90 (s, 3H), 4.14 (s, 3H), 6.59 (s, 3H), 6.99-7.20 (m, 3H), 7.73-7.75 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([OH:16])=O)=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]([C:22]([F:25])([F:24])[F:23])=[N:10]2)=[CH:5][CH:4]=1.[C:26](Cl)(=O)[C:27](Cl)=O.[CH2:32](Cl)Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[O:16][CH:32]=[CH:26][CH:27]=3)=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]([C:22]([F:23])([F:25])[F:24])=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Reactant: CCOC(=O)c1c(C(F)(F)F)nn(-c2ccc(OC)cc2)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nn(-c2ccc(OC)cc2)c1-c1ccco1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-(trifluoromethyl)-4-(ethoxycarbonyl)-pyrazole-5-carboxylic acid (0.5 g, 1.4 mmol) in 10 mL of methylene chloride was added oxalyl chloride (0.18 mL, 2.1 mmol) and 2 drops of dimethylformamide. The reaction was stirred at ambient temperature for 6 h and then the volatiles were removed in vacuo. The residue was dissolved in 20 mL of methylene chloride and then there was added 4-dimethylaminopyridine (0.51 g, 4.2 mmol). The reaction was stirred for 10 min and then there was added (2′-methylsulfonyl-3-fluoro-[1,1′]-biphen-4-yl)amine hydrochloride (0.42 g, 1.4 mmol). The resulting mixture was allowed to stir at ambient temperature for 16 h. The reaction was diluted with ethyl acetate and the organics were washed with 10% aq HCl, sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 0.6 g (70%) of the compound of Example 169 as a solid. A portion was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford the title compound as a white powder. LRMS (ES+): 628.1 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.C(N(CC)CC)C.[CH3:54][Si:55]([C:58]#[CH:59])([CH3:57])[CH3:56]>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:59]#[C:58][Si:55]([CH3:57])([CH3:56])[CH3:54])[CH:33]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH3:13])=[N:7]2
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#C[Si](C)(C)C)c3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was purged with nitrogen and charged with compound 138 (220 mg, 0.33 mmol), dichlorobis(triphenylphosphine) palladium(II) (27.1 mg, 0.039 mmol), and anhydrous DMF (1 mL). Triethylamine (146 mg, 1.44 mmol) and (trimethylsilyl) acetylene (102 mg, 1.04 mmol) were added, and the reaction mixture was stirred for 10 h at 90° C. and an additional 8 h at 100° C. Evaporation of the reaction mixture to dryness followed by column chromatography purification afforded 63% yield of compound 139 as an off-white solid. 1H NMR (CD3OΔ) δ (ppm) 7.43-8.33 (m, 8H), 7.30 (d, 1H, J=6.6 Hz), 5.64 (s, 2H), 5.14 (bs, 1H), 3.68 (t, 2H, J=8.0 Hz), 2.81 (s, 3H), 1.59-1.64 (m, 3H), 0.94 (m, 2H), 0.32 (s, 9H), −0.09 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1)=[O:4].CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:46]=[CH:47][C:48]2[CH:52]=[C:51]([S:53](Cl)(=[O:55])=[O:54])[S:50][C:49]=2[CH:57]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:53]([C:51]2[S:50][C:49]3[CH:57]=[C:45]([Cl:44])[CH:46]=[CH:47][C:48]=3[CH:52]=2)(=[O:55])=[O:54])[CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=1)=[O:4]
Reactant: COC(=O)C1CNCC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution containing (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (55 mg, 0.12 mmol) in CH2Cl2 (1 mL) is cooled to 0° C. DIPEA (24 mg, 0.18 mmol) is then added followed by the addition of 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (32 mg, 0.12 mmol), EXAMPLE 1. The reaction mixture is warmed to ambient temperature. After 16 h, the reaction mixture is absorbed directly onto silica gel and chromatographed (CH2Cl2 to 2% MeOH/CH2Cl2) to provide 60 mg (73%) of the title compound. 1H NMR (300 MHz, CDCl3) δ2.77 (dd, J=12.3, 3.4 Hz, 1H), 3.50-3.72 (m, 3H), 3.79 (s, 3H), 4.15 (dd, J=12.3, 1.4 Hz, 1H), 4.24 (d, J=16.9 Hz, 1H), 5.41 (d, J=15.3 Hz, 1H), 6.50 (s, 1H), 6.76 (dd, J=7.9, 1.4 Hz, 1H), 7.11-7.86 (m, 15H) ppm; MS (ISP loop): m/z 683 (M+H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=[N:25]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([NH2:25])=[O:18])[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 2-phenylbenzo[d]oxazole-4-carboxylic acid in DMF (15 mL) was added HOBt (148 mg, 1.1 mmol), NH4Cl (54 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol) and EDCI (211 mg, 1.1 mmol). The mixture was stirred at 25° C. for 10 hr. Then water (10 mL) was added and aqueous hydrochloric acid (1 N) to pH=3 and extracted with ethyl acetate (100 mL×4). The organic phase was washed with saturated sodium bicarbonate solution and brine, concentrated and dried in vacuum. The crude product was purified by pre-HPLC to obtain 2-phenylbenzo[d]oxazole-4-carboxamide as a white solid (40 mg). 1H-NMR (400 MHz, DMSO-d6) δ 7.47-7.56 (m, 1H), 7.63-7.68 (m, 3H), 7.93-8.01 (m, 3H), 8.28-8.30 (d, J=8 Hz, 2H), 8.47 (s, 1H); LC-MS (ESI) m/z 239 [M+1]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[CH2:18]([N:7]([CH2:5][CH3:6])[C:8](=[O:17])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:22](=[O:23])[CH2:21][Cl:20])=[CH:13][CH:12]=1)[CH3:19]
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)C(=O)COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCN(CC)C(=O)COc1ccc(C(=O)CCl)cc1
Reaction time: 16 h

Procedure:
Aluminium chloride (83.3g.) was added in portions over 30 minutes to a rapidly stirred solution of N,N-diethylphenoxyacetamide (51.6g.) and chloroacetyl chloride (31.0g.) in methylene dichloride (200ml.) at 0° C. The mixture was stirred and allowed to reach room temperature over 16 hours. The solvent was evaporated and the residue poured into a mixture of ice (300g.) and concentrated hydrochloric acid (15ml.). The mixture was extracted with methylene dichloride (5 × 100ml.), and the extracts washed with water (2 × 50ml.) dried and evaporated. The residue was chromatographed on alumina to give N,N-diethyl-4-(chloroacetyl)phenoxyacetamide, m.p. 89°-91° C.
Reaction SMILES: [NH:1]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14](O)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl.[NH2:29][CH:30]1[CH2:38][CH2:37][C:36]2[C:32](=[CH:33][NH:34][N:35]=2)[CH2:31]1>>[CH2:3]([C@@H:2]([NH:1][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])[C:10](=[O:11])[N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([NH:29][CH:30]1[CH2:38][CH2:37][C:36]2[C:32](=[CH:33][NH:34][N:35]=2)[CH2:31]1)=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NC1CCc2n[nH]cc2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCc2n[nH]cc2C1
Yield: 80 %

Procedure:
The title compound was prepared from Boc-D-PheL-Pro-OH and 5-amino-4,5,6,7-tetrahydro-2H-indazole dihydrochloride using the procedure of EXAMPLE 6, and was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([NH:16][C:17]([NH:19][NH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)=[O:22])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([NH:20][NH:19][C:17]([NH:16][C:7]2[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)=[O:18])=[O:22])=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 75 %

Procedure:
In a 250 ml Parr flask, 0.72 g (1.68 mmoles) of N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)carbonylamino]-urea is dissolved in 30 ml of absolute ethanol in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for. two hours. After filtration on celite, the filtrate is concentrated under vacuum. The evaporation residue is suspended in diethyl ether (20 ml), agitated and filtered to produce a pale yellow powder with a yield of 75%. Melting point: 245-246° C.
Reaction SMILES: [OH:1][C:2]1[C:15]([CH2:16][CH:17]=[CH2:18])=[C:14]([OH:19])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]([OH:19])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: C=CCc1c(O)ccc(C(=O)c2ccccc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc(C(=O)c2ccccc2)c1O

Procedure:
A solution of 2,4-dihydroxy-3-(2-propenyl)benzophenone (3 grams) was reduced under ˜1 atmosphere of H2 in ethyl acetate (100 mL) over 10% Pd/C catalyst (0.3 grams) for 3 hours. The product was purified by crystallization from methanol/water to give the title compound.