Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CCOCC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
In a 2-(5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 113 μmol), 4-(3-chloropropyl)morpholine (55.5 mg, 339 μmol, Eq: 3.0) and Cs2CO3 (147 mg, 452 μmol) in DMF (2 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min. Then, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62 mg, 94.2 μmol, 83.4%) as an off-white solid. MS (M+Na)+=680; 1H NMR (CDCl3) δ: 9.23 (s, 1H), 8.36 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.05 (s, 1H), 7.59 (d, J=9.1 Hz, 1H), 7.35 (dd, J=8.9, 2.1 Hz, 1H), 6.55 (t, J=74.4 Hz, 1H), 5.75 (s, 2H), 4.61 (t, J=6.4 Hz, 2H), 3.75 (br. s., 4H), 3.55-3.66 (m, 2H), 2.45 (br. s., 6H), 2.25 (br. s., 2H), 1.65 (s, 9H), 0.90-1.06 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[O:26]C(=O)C)=[O:6].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[O:20])[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[OH:26])=[O:6]
Reactant: CC(=O)O[C@@H]1CCc2ccc(NC(=O)N3CCCC3)cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@@H]1c2cc(NC(=O)N3CCCC3)ccc2CC[C@H]1O)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
A solution of 116 (0.27 g) in MeOH (10 mL) was treated with go 0.135 M sodium methoxide (4.9 mL) in MeOH. After 4 h, the solvent was evaporated, the residue was suspended in H2O and the solid was collected by filtration. The solid was crystallized from EtOAc-ether to give a tan powder, m.p. 206-208° C.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH2:9])[N:3]=1.[NH3:10]>C(O)C>[NH2:10][C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH2:9])[N:3]=1
Reactant: N
Reactant: Nc1cnc(Br)c(Cl)n1
Solvent: CCO
Product: Nc1cnc(Br)c(N)n1
Temperature: 160 °C

Procedure:
A suspension of 2-chloro-3-bromo-6-aminopyrazine (15 g, 0.072 mole) in absolute ethanol (150 ml) and 0.880 ammonia (375 ml) was stirred and heated in an autoclave at 160° C. and 20 atm. for 16 hrs The cooled mixture was evaporated in vacuo and extracted with hot methanol (3×100 ml). The combined methanol extracts were evaporated in vacuo. The residue was dissolved in hot chloroform, dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered, and dried in vacuo. Yield 5.51 g (40%), M.p. 176-178° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:19])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH3:19])[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl trans-4-[(t-butoxycarbonyl)(methyl)amino]cyclohexane-carboxylate (44.78 g) obtained in Reference Example 3(1) is dissolved in methanol (300 ml), and thereto is added 2 N aqueous sodium hydroxide solution (100 ml). The mixture is then stirred at room temperature for 6 hours. The reaction solution is concentrated under reduced pressure. To the residue are added ice-water, ethyl acetate and 10% hydrochloric acid under ice-cooling, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in a small amount of ethyl acetate, and n-hexane is poured to the mixture. The resulting crystals are collected by filtration, washed with n-hexane/diisopropyl ether several times and dried to give the title compound (39.20 g).
Reaction SMILES: C1(C([NH:9][CH:10]([CH3:19])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)C)C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[NH2:9][CH:10]([CH3:19])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: CC(Cc1ccc(O)cc1)NC(C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(N)Cc1ccc(O)cc1

Procedure:
5.80 g (20.0 mmol) 4-[2-(1-phenyl-ethylamino)-propyl]-phenol (I37) are added to 300 mL MeOH and charged with 0.60 g palladiumhydroxide (20%) on activated carbon. The mixture is stirred in a hydrogen atmosphere (50 psi) at 50° C. for 1 h 15 min. Then the mixture is filtrated, the solvent is removed in vacuo and the residue is triturated diethylether. The residue is dried at 80° C. in vacuo.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][CH2:5][CH2:6][C:7]1[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:9]=[CH:10][N:11]=1.Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[O:28][CH:29]=1.O>CN(C=O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32](/[CH:31]=[CH:30]/[C:27]2[O:28][CH:29]=[C:25]([CH2:24][O:22][C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:8]4[CH:9]=[CH:10][N:11]=[C:7]4[CH2:6][CH2:5][S:4][CH3:3])=[CH:17][CH:18]=3)[N:26]=2)=[CH:33][CH:34]=1
Reactant: CSCCc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
65% Sodium hydride (63.1 mg) was added to a solution of 4-[[4-[4-[2-[2-(methylsulfanyl)ethyl]-1H-imidazol-1-yl]butyl]phenol (300 mg) in DMF (5 ml) at 0° C., and the mixture was stirred at room temperature for 30 min. 4-Chloromethyl-2-[(E) -2-(4-fluorophenyl)ethenyl]-1,3-oxazole (269 mg) was added to the mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:3 to ethyl acetate) to give the titled compound (374 mg) as a colorless amorphous form.
Reaction SMILES: [CH2:1]([C:3]1([OH:10])[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[CH2:4]1)C.C(C1(O)C=CC=C(O)C1)CC.C(C1(O)C=CC=C(O)C1)CCC.C(C1(O)C=CC=C(O)C1)(C)(C)C.C1(C2(O)C=CC=C(O)C2)C=CC=CC=1.C(C1(O)C=CC=C(O)C1)(C1C=CC=CC=1)(C)C.FC1C(F)(O)C(F)=CC(F)=C1O.BrC1C(Br)(O)C(Br)=CC(Br)=C1O>>[CH3:1][C:3]1([OH:10])[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[CH2:4]1
Reactant: CCC1(O)C=CC=C(O)C1
Agent: CC(C)(C)C1(O)C=CC=C(O)C1
Agent: CC(C)(c1ccccc1)C1(O)C=CC=C(O)C1
Agent: CCCC1(O)C=CC=C(O)C1
Product: CC1(O)C=CC=C(O)C1

Procedure:
3-ethyl resorcinol, 3-propyl resorcinol, 3-butyl resorcinol, 3-t-butyl resorcinol, 3-phenyl resorcinol, 3-cumyl resorcinol, 2,3,4,6-tetrafluroresorcinol, and 2,3,4,6-tetrabromoresorcinol;
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:32][C:33]([C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][CH2:38][C@H:39]2[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[NH:34]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH2:13][C:14]1[O:16][N:34]=[C:33]([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][CH2:38][C@H:39]3[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[N:32]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C(=N)NO)cccc21
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)no2)cc1OCC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared using General Procedure 2. A solution of 2-(3,4-diethoxyphenyl)acetic acid (150.0 mg, 0.67 mmol) in DMF (3 mL) was treated with HOBt (164.8 mg, 1.22 mmol) and EDC (172.7 mg, 0.9 mmol) at room temperature. The reaction was stirred for 2 h until the complete formation of the HOBt-acid complex. (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-54 (233.8 mg, 0.8 mmol) was added and stirred at room temperature for 2 h and then mixture was heated to 80° C. for 16 h. The reaction was diluted with NaHCO3 (10 mL) and extracted with EA (3×10 ml). The organic phase was dried over MgSO4 and the crude product was purified by a chromatography (EA/hexanes) to produce (R)-tert-butyl 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-56 (187 mg, 58%) as off-white solid and used directly in the next step. LCMS-ESI (m/z) calculated for C27H33N3O5: 479.2; found 502.2 [M+Na]+, tR=4.11 min. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 6.81 (ddd, J=20.2, 12.8, 5.1 Hz, 3H), 5.18 (d, J=8.4 Hz, 1H), 4.69 (d, J=8.3 Hz, 1H), 4.15 (d, J=6.1 Hz, 2H), 4.06-3.93 (m, 4H), 3.32 (ddd, J=17.4, 8.8, 3.4 Hz, 1H), 3.14-2.91 (m, 1H), 2.65-2.40 (m, 1H), 1.75 (dq, J=12.9, 8.4 Hz, 1H), 1.36 (ddd, J=40.2, 26.9, 22.6 Hz, 15H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.NC(N)=[S:13].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[OH-].[Na+]>[SH:13][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: NC(N)=S
Reactant: Clc1nccn2ccnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nccn2ccnc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 3.10 g(0.02 mol) of 8-chloroimidazo[1,2-a]pyrazine in 70 ml of ethanol was added 1.52 g (0.02 mol) of thiourea and the mixture was refluxed. After 3 hours, the reaction mixture was cooled to 0° C. The thiouronium salt was collected by filtration, dried and suspended in 80 ml of water. To this was added 3.46 g (33 mmol) of sodium carbonate. The reaction mixture was stirred for 15 minutes and then diluted with 30 ml of 5% sodium hydroxide solution. The aqueous solution was washed with 50 ml of chloroform, made acidic with acetic acid and then extracted with 2×50 ml of chloroform. The organic extracts were dried (Na2SO4), filtered, and concentrated to yield the crystalline product.
Reaction SMILES: C(OC(=O)[N:7]=[C:8]([NH:25]C(OC(C)(C)C)=O)[N:9]([CH3:24])[CH2:10][C:11](=[O:23])[N:12]1[CH2:17][C@H:16]([OH:18])[C@@H:15]([OH:19])[C@@H:14]([OH:20])[CH:13]1[CH2:21][OH:22])(C)(C)C>FC(F)(F)C(O)=O.O>[CH3:24][N:9]([CH2:10][C:11](=[O:23])[N:12]1[CH2:17][C@H:16]([OH:18])[C@@H:15]([OH:19])[C@@H:14]([OH:20])[CH:13]1[CH2:21][OH:22])[C:8]([NH2:25])=[NH:7]
Reactant: CN(CC(=O)N1C[C@H](O)[C@@H](O)[C@@H](O)C1CO)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(CC(=O)N1C[C@H](O)[C@@H](O)[C@@H](O)C1CO)C(=N)N

Procedure:
In a dry, round bottomed flask, equipped with a magnetic stirrer, 23.81 g (0.050 mol) of tert-butyl(tert-butoxycarbonylamino)(methyl(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)ethyl)amino)methylenecarbamate is dissolved in 275 mL of a trifluoroacetic acid:H2O (1:1) mixture. The resultant mixture is stirred for 2 hours at room temperature, after which it is concentrated under reduced pressure and then purified by flash chromatography (ethyl acetate/hexanes; 2/3) to yield the creatine deoxygalactonojirimycin amide, 1-methyl-1-(2-oxo-2-((3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)ethyl)guanidine.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C@H:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:20][CH:21]=C)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].C[N+]1([O-])CC[O:34]CC1.S([O-])([O-])(=O)=S.[Na+].[Na+].I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.C(OCC)(=O)C.O.O1CCCC1.CC(C)=O.C(O)(C)(C)C.O>[CH3:1][N:2]([CH2:18][C@H:19]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH2:20][CH:21]=[O:34])[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(-n2cnnn2)ccc1OC)c1ccc(F)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N(C)C[C@@H](CC=O)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
Combine (S)-N-methyl-N-(2-(4-fluorophenyl)pent-4-enyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide (4.46 g, 11.3 mmol), acetone/t-butanol/water (2/1/1, 64 mL), and a solution of N-methylmorpholine N-oxide (3.0 mL, 50% in water, 14.5 mmol). Add a solution of osmium tetraoxide (3.0 mL, 4% in water, 0.5 mmol). After 3 hours, evaporate in vacuo to remove most of the acetone and partition the evaporated reaction mixture between dichloromethane and an aqueous 10% solution of sodium thiosulfate. Separate the layer, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Combine the residue, tetrahydrofuran (80 mL), and water (20 mL). Add sodium meta-periodate (3.63 g). After 1.5 hours, filter the reaction mixture, rinse the solids with dichloromethane, and evaporate the filtrate to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf =0.22 (silica gel, ethyl acetate).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=3[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]([OH:68])=O>>[NH:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]([NH:18][C@H:19]([C:44]([NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:68]
Reactant: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2cc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-2,5-dimethoxyaniline (620 mg, 0.83 mmol, example 82, step A) as described for example 82 (step B) using indole-2-carboxylic acid (201 mg, 1.25 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using initially 10% then 20% EtOAc/CH2Cl2. The title compound was obtained as white crystals (200 mg, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:14])[CH2:12]O)=[O:4].C(OC([N+](C(OCC)=O)=[N-])=O)C.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:14])[CH2:12][N:47]=[N+:48]=[N-:49])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CN=[N+]=[N-]

Procedure:
A mixture of 3-(2-Hydroxy-1-methyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (213 mg, 0.257 mmol), diethyldiazodicarboxylate (250 μL, 1.59 mmol, 2 eq), diphenylphosphoryl azide (343 μL, 1.59 mmol, 2 eq) and triphenyl phosphine (417 mg, 1.59 mmol, 2 eq) was stirred at 21° until all starting alcohol was consumed. The reaction was evaporated to dryness and the crude residue purified on biotage with 5% EtOAc/hexane followed by 100% toluene as eluent. 3-(2-Azido-1-methyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester was isolated as a solid (181 mg, 78%); 1H NMR (300 MHz, CDCl3) 1.33 (d, J=6.6 Hz, 3H), 3.38-3.46 (m, 2H), 3.78-3.81 (m, 1H), 6.82 (s, 1H), 7.36-7.41 (m, 3H), 7.60-7.62 (m, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:31]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:31])=[O:32])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and 2-bromo-N-(tert-butyl)benzenesulfonamide. MS (ESI): mass calcd. for C19H21N5O2S, 383.14; m/z found, 384.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.96 (s, 2H), 8.62 (dd, J=2.3, 0.9, 1H), 8.34 (d, J=1.8, 1H), 8.01 (dd, J=8.0, 1.6, 1H), 7.94 (dd, J=8.2, 2.3, 1H), 7.87 (dd, J=8.2, 0.9, 1H), 7.65 (d, J=7.9, 1H), 2.84 (q, J=7.2, 2H), 1.01 (t, J=7.2, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:23][C:24]1[CH:28]=[CH:27][N:26]([CH2:29][C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[CH:34][CH:35]=2)[N:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:37]([NH:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:26]1[CH:27]=[CH:28][C:24]([NH:23][C:13](=[O:15])/[C:12](/[C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)=[N:16]/[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:25]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Nc1cccc(Cn2ccc(N)n2)c1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Cn2ccc(NC(=O)/C(=N/OC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Yield: 41.4 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 100 mg, 0.29 mmol), N-[3-(3-amino-pyrazol-1-ylmethyl)-phenyl]-acetamide (67 mg, 0.29 mmol) and N,N-diisopropylethylamine (151 μL, 0.87 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol) was added and the ice bath was removed. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/chloroform to 80% ethyl acetate/hexanes) to afford (E)-N-[1-(3-acetylamino-benzyl)-1H-pyrazol-3-yl]-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetamide (67 mg, 42%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C26H28ClN5O5S [M+] 557.15, found 558 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.63 (m, 4 H, 2×CH2), 1.84 (m, 4 H, 2×CH2), 2.16 (s, 3 H, CO2CH3), 3.29 (s, 3 H, SO2CH3), 4.86 (m, 1 H, OCH), 5.20 (s, 2H, NCH2), 6.75 (d, J=2.3 Hz, 1 H, Ar), 6.92 (brd, J=7.7 Hz, 1 H, Ar), 7.29 (brt, J=8.0 Hz, 1 H, Ar), 7.37 (m, 3 H, 2 Ar and NH), 7.43 (brd, J=7.9 Hz, 1 H, Ar), 7.54 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.64 (d, Jm=1.5 Hz, 1 H, Ar), 8.17 (d, Jo=8.2 Hz, 1 H, Ar), 9.20 (s, 1 H, NH).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:21][NH:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-methylbenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 163 mg of the title compound (80%) as a yellow solid in 99.99% purity by HPLC (Rt: 5.7, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O-:14])=[O:13]>C(#N)C>[C:8]([C:7]1[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])(=[O:22])=[O:23])=[O:26])=[N:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH3:10])#[N:9]
Reactant: O=C=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1cc(C)c(C#N)c(N)n1
Solvent: CC#N
Product: Cc1cc(C)c(C#N)c(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 0.5 g (3.4 mmol) 2-amino-4,6-dimethyl-3-pyridinecarbonitrile [Archiv. Pharm., 288, 174 (1955)] in 20 ml of acetonitrile was added 1.3 g (5.7 mmol) o-nitrobenzenesulfonyl isocyanate. The mixture was then heated to reflux (80°) for four hours followed by stirring at ambient temperature overnight. A crystalline product was collected, 0.5 g, m.p. 174°-176° dec. An infrared spectrum (nujol mull) exhibited absorptions at 1700, 1720 and 2240 cm-1 ; and a proton magnetic resonance spectrum (90 MHz NMR) exhibited absorptions at 2.5 (s, 3H), 2.6 (s, 3H), 7.05 (s, 1H), 7.7 (s br, NH), 7.8 (m, 3H), 8.4 (m, 1H), 9.7 (s br, NH) ppm indicating the title compound.