Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol from EX-528C (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzene-sulfonyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no free amine starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 20.1 mg (29%) of the desired 4-fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]benzenesulfonamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C24H21F8N2O4S: 585.1094 [M+H]+, found: 585.1083. 1H NMR (CDCl3) δ3.6 (m, 2H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.4 (d, 1H), 6.5-6.6 (m, 3H), 6.9-7.4 (m, 7H), 7.6 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[SH:20][CH2:21][C:22](O)=[O:23].N1CCCCC1>>[NH:8]1[C:4]2[CH:3]=[C:2]([N:1]3[C:22](=[O:23])[CH2:21][S:20][CH:16]3[C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(O)CS
Reactant: O=Cc1ccc(F)cc1
Solvent: C1CCNCC1
Product: O=C1CSC(c2ccc(F)cc2)N1c1ccc2nc[nH]c2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.133 g, 1.0 mmol), 4-fluoro-benzaldehyde (0.108 mL, 1.0 mmol), mercapto acetic acid (0.138 g, 1.5 mmol), piperidine, according to method 9 step A. yield: 69 mg (22%), MS m/z: 314.3 (M+H)+, HPLC [A]): rt 5.86 min (97%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([NH2:20])=[C:16]([C:21]([OH:23])=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:24][O:22][C:21]([C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[CH:19]=[N:18][C:17]=1[NH2:20])=[O:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 5′-amino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4,6′-dicarboxylic acid 4-tert-butyl ester (510 mg, 1.6 mmol; see Example 16 (e) above) in benzene (4 mL) and methanol (4 mL) was added a solution of trimethylsilyldiazomethane (2 M in hexane, 2 mL). The reaction was stirred at room temperature for overnight. The solvent was then removed in vacuo and the residue was purified by flash chromatography using ethyl acetate/hexanes (40:60) as eluant to afford 5′-amino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4,6′-dicarboxylic acid 4-tert-butyl ester 6′-methyl ester as a yellow solid (520 mg, 96%). 1H NMR (300 MHz, CDCl3) δ1.49 (s, 9H), 3.40 (s, 4H), 3.59 (s, 4H), 3.95 (s, 3H), 8.01 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 28.41, 46.30, 52.52, 80.05, 119.69, 135.58, 148.24, 150.00, 154.70, 167.10.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH:46]6[CH2:48][CH2:47]6)[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH:46]6[CH2:48][CH2:47]6)[CH:43]=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CC4CC4)cc2)CCN3CC(C)C)cc1
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CC4CC4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylmethylimidazol-5-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (1.1 g) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (440 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylmethylimidazol-5-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (614 mg) (Compound 386) as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[N:18][C:17]=2[CH:34]=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([CH:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[N:18][C:17]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (300 mg, 0.65 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (1.5 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (300 mg). 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rt for 1 h. To this mixture added cyclobutanol (0.05 ml, 0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60° C. for overnight. Work up (EtOAc/H2O) and purification of the crude by combiflash with gradient mixture of ethyl acetate and petether (1:1) as eluent afforded the titled compound (25 mg) as an off-white solid. M.P.: 165-169° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H), 7.55-7.50 (m, 1H), 4.96 (septet, J 7.8, 1H), 4.20 (d, J 12.4, 2H), 3.22-3.13 (m, 1H), 3.06 (t, J 9.8, 2H), 2.40-2.30 (m, 2H), 2.24-2.15 (m, 2H), 2.15-2.02 (m, 2H), 2.00-1.90 (m, 2H), 1.78 (q, J 10, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1CC(O)=O.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][C:25]1[CH:26]=[C:27](CC(O)=O)[CH:28]=[CH:29][CH:30]=1.CBr>>[CH3:4][CH:3]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1)[C:2]([O:1][CH3:6])=[O:7].[CH3:21][CH:20]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:13]=1)[C:19]([O:18][CH3:23])=[O:24]
Reactant: O=C(O)Cc1ccccc1OC1CCCCO1
Reactant: O=C(O)Cc1cccc(OC2CCCCO2)c1
Agent: CBr
Product: COC(=O)C(C)c1cccc(OC2CCCCO2)c1
Product: COC(=O)C(C)c1ccccc1OC1CCCCO1

Procedure:
By the same method but using 2-(tetrahydropyran-2-yloxy) phenylacetic acid and 3-(tetrahydropyran-2-yloxy)-phenylacetic acid in place of 4-(tetrahydropyran-2-yloxy)-phenylacetic acid and methyl bromide as alkylating agent there are obtained methyl 2-methyl-2-(2-tetrahydropyran-2-yloxyphenyl)acetate and methyl 2-methyl-2-(3-tetrahydropyran-2-yloxyphenyl)acetate, respectively.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][O:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]=1[OH:46].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])[C:7]=4[C:8]=3[CH:9]=2)[CH:34]=[CH:33][C:32]=1[OH:46]
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(O)c(OC)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.6 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.5 mg, 0.12 mmol) in toluene/ethanol (1:1, 8 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-Methoxy-4-[6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenol as brown solid in 60% yield.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(N(CC)C(C)C)(C)C.Br[C:19]([CH3:26])([CH3:25])[C:20](OCC)=[O:21].O>CN(C)C=O>[CH3:25][C:19]1([CH3:26])[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][C:20]1=[O:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccccc1N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)Nc2ccccc2NC1=O
Temperature: 110 °C
Yield: 57.5 %

Procedure:
To a solution of 1,2-phenylenediamine (16.96 g) in N,N-dimethylformamide (80 mL) were added successively N,N-diisopropylethylamine (36.4 mL) and ethyl α-bromoisobutyrate (39.8 g), and the mixture was heated at 110° C. for 3 days. After cooling, to the reaction mixture was added cold water and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed successively with an aqueous 10% HCl solution, water, an aqueous saturated sodium hydrogencarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was recrystallized from dichloromethane-n-hexane to give 3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (15.90 g) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:9]([CH3:11])[CH3:10])[CH:3]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:22][O:23][CH3:24].O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:22][O:23][CH3:24])=[C:4]([N:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CN(C)c1cc(Br)ccc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(Br)cc1N(C)C
Yield: 98.7 %

Procedure:
To a stirring solution of 4-bromo-2-dimethylamino-phenol (3.7 g, 17.13 mmol) in CH2Cl2 (100 mL) at room temperature was added ethyl-diisopropyl-amine (4.47 mL, 25.7 mmol) and chloro-methoxy-methane (1.69 mL, 22.27 mmol). The mixture was refluxed for 16 hrs, added water. The organic layer was collected and dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude N-(5-bromo-2-methoxymethoxyphenyl)dimethylamine as a red oil (4.4 g, 99%): 1H NMR (200 MHz, DMSO-d6): 6.96 (m, 3 H), 5.17 (s, 2 H), 3.40 (s, 3 H), 2.72 (s, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=15% ethyl acetate in hexanes; Rf=0.59.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23]CC2C=COC=2)=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[OH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:39](=[O:40])[C:33]3[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[C:42]2=[O:41])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1
Reactant: Nc1ccc(OCc2ccoc2)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1ccc(O)c(-c3nc4cc(-c5ccccc5)ccc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-(3-furanylmethoxy)phenyl)-5-phenylbenzoxazole (144 mg, 0.28 mmol) and 1,2,4-benzenetricarboxylic anhydride (73 mg, 0.38 mmol) the title compound was obtained (100 mg, 55%). 1H NMR (DMSO) δ 8.48(dd, 1H), 8.39(s, 1H), 8.25(d, 1H), 8.21(d, 1H), 8.17(d, 1H), 8.00(d, 1H), 7.82(m, 3H), 7.70(dd, 1H), 7.57(t, 2H), 7.46(t, 1H), 7.38(d, 1H). MS 477 m/z (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[CH3:23].C[Si](C)(C)[O-].[K+].C(OCC)(=O)C.C(OCC)C>O1CCCC1>[F:1][C:2]1[C:10]2[O:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[CH3:23]
Reactant: COC(=O)c1cc2ncoc2c(F)c1Nc1ccc(I)cc1C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(I)ccc1Nc1c(C(=O)O)cc2ncoc2c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution comprised of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5-carboxylate (0.024 M) in tetrahydrofuran is added solid potassium trimethylsilanolate (5.14 equiv.). The reaction mixture is stirred at ambient temperature under argon for 16 hours. An additional equivalent of potassium trimethylsilanolate is added and the mixture stirred 30 minutes. The reaction mixture is concentrated in vacuo to give a residue that is then taken up into 1:1 (v/v) ethyl acetate-diethyl ether. The organic phase is washed with dilute aqueous hydrochloric acid, water, and brine, is dried (MgSO4), is concentrated in vacuo, and chased with chloroform to give a crude product. Recrystallization from an appropriate solvent like ethanol gives the purified desired product.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[N:16]=[C:15]([C:17](O)=O)[CH:14]=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([C:11]1[N:16]=[C:15]([C:17]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCc1cccc(C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cccc(-c2nc3ccccc3[nH]2)n1

Procedure:
2.2 g. of o-phenylenediamine, 3 g. of 6-ethylpicolinic acid and 15 g. of polyphosphoric acid were heated at 160°-180° C. under nitrogen gas current for 2 hours with stirring. The reaction mixture was diluted with 200 ml. of water and neutralized with sodium carbonate. The resulting precipitate was filtered off, dried, subjected to silica gel column chromatography (developed with 1:1 by volume mixture of benzene and ethyl acetate) and recrystallized from benzene. 3.3 g. of colorless needles of the product (74% of theory) was obtained. M.P. 161°-161.5° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Nn1nc(-c2ccccn2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccn2)c2ccccc2c1=O

Procedure:
The product from Example 18A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.78 (ddd, J=4.8, 1.7, 0.9, 1H), 8.46-8.30 (m, 2H), 7.99 (dddd, J=16.4, 15.3, 7.5, 1.6, 3H), 7.80 (dt, J=7.8, 1.0, 1H), 7.59 (ddd, J=7.6, 4.8, 1.1, 1H), 7.23-7.09 (m, 3H), 3.79 (s, 2H); MS (APCI) M/Z 393 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS([O-])(=O)=O.O.C(O[CH2:28][CH3:29])(=O)C>CN(C=O)C>[CH:28]1([CH2:29][N:9]2[C:10]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:7]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:8]2=3)[CH2:4][CH2:3][CH2:2][CH2:10]1
Reactant: CCOC(C)=O
Reactant: O=C1NCCc2[nH]c3c(F)cccc3c21
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCc2c1c1cccc(F)c1n2CC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (1.023 g) in dry DMF (50 ml) was treated with sodium hydride (73.2% dispersion in oil; 331 mg) and stirred under nitrogen at room temperature for 30 min. A solution of cyclopentylmethyl(methyl sulphonate (893 mg) in dry DMF (20 ml) was then added over 15 min and stirring was continued for 5 days. Water (20 ml) was added to the reaction mixture which was then concentrated in vacuo to give a solid. This was dissolved in ethyl acetate (300 ml) and methanol (1 ml), and the resulting solution was washed with saturated sodium chloride solution (3×100 ml) and then adsorbed onto silica. Purification by FCC eluting with System A (150:8:1) gave a solid (283 mg) which was recrystallised from ethyl acetate to give the title compound (237 mg) m.p. 175°-176°.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12].[CH2:13]([OH:15])[CH3:14]>>[ClH:12].[C:1]1([CH:7]([CH3:11])[CH2:8][C:9](=[NH:10])[O:15][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC(CC#N)c1ccccc1
Agent: Cl
Product: CCOC(=N)CC(C)c1ccccc1
Reaction time: 8 h

Procedure:
Through a stirred solution of Example 52A (3.9 g, 26.8 mmol) in absolute ethanol (30 mL) was bubbled with hydrogen chloride gas for 20 min. The mixture was allowed to stand for overnight in the refrigerator. The product was precipitated with anhydrous ether and filtered to obtain 4.8 g of the title compound. MS (ESI/NH3) m/Z 192 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.O>CC(O)=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH:16]=[CH:20][CH:19]=[CH:18]2)[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([O-:3])=[O:2]
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(-n2cccc2)cc([N+](=O)[O-])c1

Procedure:
According to Scheme 16, a solution of 3,5-dinitroaniline (1.83 g, 10 mmol) and 2,5-dimethoxytetrahydrofuran in 20 mL of HOAc was refluxed overnight. The reaction mixture was poured into water and extracted with EtOAc. The ethyl acetate layer was washed with water followed by aq NaHCO3 and brine. After drying, the solvent was removed to provide 1.52 g of 1-(3,5-dinitrophenyl)pyrrole.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[C:21]=1[O:22]C)[C:6]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].B(Br)(Br)Br.C(O)C>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[C:21]=1[OH:22])[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.1 g of diethyl (3,4-dimethoxy-5-nitrobenzoyl)malonate are dissolved in 200 ml of methylene chloride, whereupon the solution is cooled to -20° and at this temperature there is added dropwise while stirring within 15 minutes a solution of 68.1 g of boron tribromide in 120 ml of methylene chloride. The mixture is subsequently stirred at room temperature overnight. After cooling to -20°, the mixture is treated with 300 ml of ethanol and stirred at room temperature for 30 minutes. The solvent is distilled in a water-jet vacuum at 40°. The residue is treated with 300 ml of ice-water and methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product obtained is chromatographed on a 10-fold amount of silica gel with toluene. After crystallization from methylene chloride/hexane there is obtained ethyl (3,4-dihydroxy-5-nitrobenzoyl)acetate in the form of yellow crystals of m.p. 136°-137°.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([OH:39])=O)=[CH:35][CH:36]=1>>[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with p-toluic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(4-methylbenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 484 (M+H)+.