Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[Br:17])(=O)=O.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21].[Li+].[Cl-].[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[Br:17][C:8]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[C:12]([CH3:13])[C:7]=1[CH:20]=[CH2:21]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc([N+](=O)[O-])cc1Br
Temperature: 70 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
The reaction mixture of 2-Bromo-6-methyl-4-nitrophenyl trifluoromethanesulfonate (10.0 g, 27.5 mmol), vinyl-tri-n-butyltin (8.7 g, 27.5 mmol), LiCl (1.4 g, 33.0 mmol), Pd(dppf)Cl2 (673 mg, 0.92 mmol) and DMF (50 mL) was stirred at 70° C. for 3 h under N2. Then 2 N aq. NaOH (30 mL) was added and stirred at 70° C. for 10 min. The reaction mixture was cooled down, washed with saturated aqueous NaHCO3 (100 mL), and extracted with EtOAc (3×50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column (Petroleum Ether→Petroleum Ether:EtOAc (50:1)) to afford 1-Bromo-3-methyl-5-nitro-2-vinylbenzene (2.01 g, 30%) as yellow oil. 1H-NMR: 400 MHz, (CDCl3) δ: 8.29 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 6.67 (dd, J=17.6, 11.6 Hz, 1H), δ 5.75 (d, J=11.6 Hz, 1H), δ 5.49 (d, J=18.0 Hz, 1H), δ 2.48 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:19])=[C:9]2[C:14]=1[CH2:13][CH:12]([O:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>FC(F)(F)C(O)=O>[C:1]([NH:4][C:5]1[C:6]([N+:20]([O-:22])=[O:21])=[CH:7][C:8]([Br:19])=[C:9]2[C:14]=1[CH2:13][CH:12]([O:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Br)c2c1CC(OC(C)=O)CC2
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CC(OC(C)=O)CC2
Reaction time: 2.5 h
Yield: 81 %

Procedure:
A solution of acetic acid 8-acetylamino-5-bromo-1,2,3,4-tetrahydronaphthalen-2-yl ester (2.6 g, 8 mmol) in 40 mL of trifluoroacetic acid was cooled in an ice bath. Fuming nitric acid (2 mL) was added dropwise and the mixture was stirred for 2.5 h. The solvent was removed by rotoevaporation, and water was added to the residue which induced solidification. The solid was collected by filtration, washed with ether and dried to give the product (2.4 g) in 81% yield.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]([CH3:22])[CH:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:10]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(C#Cc1nc(Br)cnc1N)cn2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3[nH]1)cn2C
Reaction time: 5 h
Yield: 45.5 %

Procedure:
5-Bromo-3-((5-methoxy-1-methyl-1H-indol-3-yl)ethynyl)pyrazin-2-amine (3.25 g, 9.10 mmol) in DMF (35 mL) was treated with NaH (60% dispersion in mineral oil, 0.36 g, 9.1 mmol). After about 5 h at ambient temperature, the mixture was treated with another portion of NaH (60% dispersion in mineral oil, 0.036 g, 0.91 mmol) and stirred for about 16 h. The mixture was concentrated and stirred with water (50 mL) and EtOAc (40 mL). The mixture was filtered and the solids were washed until an insoluble tar remained. The filtrate layers were separated and the organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The material was dissolved in a minimum amount of warm DMF and purified by silica gel chromatography (120 g silica gel column) eluting with 95:5 DCM/MeOH. The product-containing fractions were combined and concentrated to give an oil which was purified by silica gel chromatography (120 g silica column) eluting with EtOAc. The product-containing fractions were combined and concentrated to give an oily residue which was triturated with EtOAc (20 mL) then filtered to give a yellow solid. The material was dried to give 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine (1.48 g, 45%): LC/MS (Table 2, Method a) Rt=2.50 min; MS m/z: 357 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH:18]2[CH2:19][O:20]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC2CO2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (2.71 g) in dimethylformamide (20 mL) under argon was treated with 55% sodium hydride (0.65 g) , stirred for 15 minutes and treated with epichlorohydrin (12 mL). The mixture was heated at 60° C. for four hours and worked up as in Example 20. The material was purified by HPLC (dichloromethane-diethyl ether; 50:1) to provide 2.4 g of 4-(oxiranylmethoxy)alpha-oxobenzeneacetic acid methyl ester, as an oil.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:41](=[O:42])[CH:40]=[C:38]([NH2:39])[NH:37][C:35]1=[O:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:43]([O-])=O.[Na+].C(O)(=O)C>C(O)(C)=O.O.[Zn]>[NH2:43][C:40]1[C:41](=[O:42])[N:34]([C@@H:11]2[O:12][C@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:14]([O:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:10]2[O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:35](=[O:36])[NH:37][C:38]=1[NH2:39]
Reactant: Nc1cc(=O)n([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1[nH]c(=O)n([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)c1N
Temperature: -5 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 49 (238 mg, 0.42 mmol) in AcOH—H2O (5: 0.5 mL) was added NaNO2 over 10 min at −5° C. The resulting mixture was stirred at −5° C. for 1 hr, concentrated, and co-evaporated with toluene to give a purple solid, which was treated with acetic acid (5 mL) and Zn dust (460 mg, 7.04 mmol), and heated at 70° C. for 30 mm. The mixture was filtered through a Celite pad, and the filtrate concentrated to a slightly green solid, which was purified by silica gel column chromatography (CHCl3:MeOH=10:1 v/v) to give compound 50 (217 mg, 88%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.Cl.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(O)C.C([O-])(O)=O.[Na+]>O>[CH:14]1[CH:15]=[CH:16][CH:17]=[C:12]2[C:13]=1[C:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C:2]=1[NH:18]2
Reactant: NNc1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: c1ccc2c(c1)Cc1[nH]c3ccccc3c1-2
Temperature: 80 °C

Procedure:
In a 1-L flask were charged 36.55 g of 2-indanone (Aldrich, Mw=−132.16, 276.6 mmol), 40.00 g of phenyl-hydrazine hydrochloride (Aldrich, 99%, Mw=144.61, 276.6 mmol) and 0.3 L of i-PrOH. The suspension was warmed to 80° C. in about 30 minutes and the slurry changed color from yellow to dark brown under stirring. The reaction mixture was stirred at 80° C. for 1.5 hours and then was cooled to room temperature in about 30 minutes. The slurry was siphoned into 1.0 L of water containing 34.85 g of NaHCO3, thus obtaining a fine dispersion of a green product (no heat evolution was observed). The slurry was then filtered on a G4 frit, washed with water, dried in air under moderate vacuum for 24 h until to achieve constant weight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:11]
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Reactant: COc1cccc(C(CN)CCCCCCc2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(CCCCCCc2ccccc2)CNC(=O)Cc2c(Cl)cncc2Cl)c1
Yield: 84.6 %

Procedure:
By working in a way similar to that described in example 4 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (1.65 g, 8.026 mmoles), carbonyldiimidazole (1.43 g, 8.829 mmoles), THF (25 ml) and 2-(3-methoxy-phenyl)-8-phenyl-octylamine (2.5 g, 8.026 mmoles), obtained as described in example 13, 3.39 g of the title compound were obtained (yield: 84.6%), m.p.: 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([CH:21]3[CH2:23][CH2:22]3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)O)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[CH:21]3[CH2:22][CH2:23]3)\[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccc(F)cc2)C2CC2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C(\c2ccc(F)cc2)C2CC2)C1
Temperature: 5 °C

Procedure:
2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-cyclopropyl-1-(4-fluorophenyl)ethanol (1 g, 2.51 mmol, 1 equiv) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.40 (s, 1H), 7.20 (d, 1H), 7.10 (m, 3H), 6.90 (m, 2H), 6.70 (s, 1H), 4.60 (m, 1H), 4.22 (m, 1H), 3.70 (m, 1H), 3.40 (m, 1H), 3.0 (s, 3H), 2.80 (m, 2H), 1.80 (m, 1H), 1.0 (m, 2H), 0.8 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].I[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[CH:15]\[CH2:16][O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:20]([CH3:30])[CH:19]=2)=[CH:10][CH:9]=1>O1CCCC1.C(N(CC)CC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]([CH2:3][C:4]#[C:5][C:8]1[CH:9]=[CH:10][C:11](/[C:14](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)=[CH:15]\[CH2:16][O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:20]([CH3:30])[CH:19]=2)=[CH:12][CH:13]=1)[CH3:6]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethyl(prop-2-ynyl)amine (114 mg, 1.374 mmol) was added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.687 mmol; prepared as described in example 34) in a mixture of tetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture was degassed and copper(I) iodide (20 mg, 0.109 mmol) and tetrakis(triphenylphosphine)palladium (63 mg, 0.054 mmol) were added. The reaction mixture was stirred at ambient temperature for 24 h. Further portions of dimethyl(prop-2-ynyl)amine (57 mg, 0.687 mmol), copper(I) iodide (10 mg, 0.0545 mmol) and tetrakis(triphenylphosphine)palladium (31.5 mg, 0.027 mmol) were added and the reaction mixture was stirred under argon for additional 20 h. The mixture was evaporated in vacuo; the residue was dissolved in ethyl acetate (30 mL) and was washed with water (2×15 mL) and brine (10 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 3:5) yielding methyl (E)-[4-[3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-3-(3-trifluoromethyl phenyl)allyloxy]-2-methylphenoxy]acetate as oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:8][C:9]#[N:10])[CH2:3][CH2:2]1.[Cl:25][C:26]1[C:31]([CH3:32])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C.C(O)C>>[Cl:25][C:26]1[N:27]=[CH:28][N:29]=[C:30]([N:1]2[CH2:2][CH2:3][CH:4]([CH:7]([N:11]3[CH:15]=[C:14]([C:16]4[C:17]5[CH:24]=[CH:23][NH:22][C:18]=5[N:19]=[CH:20][N:21]=4)[CH:13]=[N:12]3)[CH2:8][C:9]#[N:10])[CH2:5][CH2:6]2)[C:31]=1[CH3:32]
Reactant: N#CCC(C1CCNCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reactant: Cc1c(Cl)ncnc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Yield: 44.3 %

Procedure:
A solution of 3-piperidin-4-yl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.20 g, 0.00062 mol), 4,6-dichloro-5-methylpyrimidine (0.11 g, 0.00067 mol) and N,N-diisopropylethylamine (130 microL, 0.00076 mol) in ethanol (2.0 mL, 0.034 mol) was heated to reflux for 1.2 hours, then the reaction was purified by preparative-LCMS (pH 10) to give 123 mg white solid (44% yield). LCMS (M+1): 448.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1cc2ccccc2o1
Yield: 48.7 %

Procedure:
To a solution of benzofuran (4.55 g, 38.5 mmol) in 100 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° C. was added a 1.3 M hexanes solution of n-butyllithium (29.6 mL, 38.5 mmol). The reaction was warmed to 0° C. and stirred for 30 minutes. Sulfur dioxide gas was bubbled through this mixture for 20 minutes at 0° C. and the reaction was concentrated under vacuum. The residue was dissolved in 100 mL of water, to which were added 304 millimoles of sodium acetate and 100 millimoles of hydroxylamine-0-sulphonic acid. This reaction was stirred at room temperature for 1.5 hours. The mixture was diluted with 200 mL of water, and the aqueous layer was separated and poured into 600 mL of diethyl ether. The ether layer was extracted with 1 N sodium hydroxide (3×100 mL). The combined aqueous extract was acidified with about 300 mL of 1 N hydrochloric acid, and then extracted with methylene chloride. The combined methylene chloride extract was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide 2.3 g of 2benzofuransulfonamide. The sulfonamide (11.7 mmol) was reacted with 4-chlorophenylisocyanate (11.7 mmol) as described in Method A above to obtain 2 grams of the title product as a solid. 1H NMR (CD3SOCD3); δ9.23 (s, 1 H), 7.87 (d, J=9 Hz, 1 H), 7.82 (s, 1 H), 7.78 (d, J=9 Hz, 1 H), 7.58 (dd, J=9, 9 Hz, 1 H), 7.46 (m, 1 H), 7.44 (d, J=9 Hz, 2 H), 7.32 (d, J=9 Hz, 2 H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(F)c(C=O)c1
Product: COc1ccc(F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-fluoro-5-methoxy benzaldehyde. MS (ESI) m/z 517.
Reaction SMILES: [NH:1]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O:52][C:53]([CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][NH-:62])=[O:54])(C)(C)C>FC(F)(F)C(O)=O>[NH:1]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:53]([CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][NH-:62])([OH:54])=[O:52]
Reactant: CC(C)(C)OC(=O)CCCCCCC[NH-]
Agent: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: [NH-]CCCCCCCC(=O)O

Procedure:
63 mg of Z-Phe-His-Leu-Val-7-tert.-butoxycarbonylheptyl amide (Example 28) are stirred for 10 minutes at room temperature in 1.5 ml of trifluoroacetic acid. The resulting solution is concentrated. The residue is purified by flash chromatography (30 g of silica gel 60, 40-63 μm, approximately 0.4 bar, eluant B1). The productcontaining fractions are combined and concentrated by evaporation. The residue is stirred in 2 ml of water, the solid portion is filtered off with suction and dried in a high vacuμmand the title compound is obtained in the form of a white powder. Rf (B11)=0.14.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([C:18]4[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[CH:20][CH:19]=4)[NH:15]3)=[CH:11][CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Br[CH2:41][CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].[F-].[Cs+]>CC#N>[Br:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([C:18]4[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[CH:20][CH:19]=4)[N:15]3[CH2:41][CH2:42][CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]4[C:47](=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:46]3=[O:55])=[CH:11][CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)[nH]c3c2)sc1Br
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Yield: 57.4 %

Procedure:
To a stirred solution of 4 (76 mg, 0.13 mmol), N-(4-bromobutyl)-phthalimide (71 mg, 0.25 mmol) in 10 mL CH3CN, CsF (96 mg, 0.63 mmol) was added. The resulting mixture was refluxed for 5 hours and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the residue gave 5 as a yellow amorphous solid (60 mg, 69%). 1H NMR (400 MHZ, CDCl3) δ 8.13 (d, J=8.4 Hz, 2H), 7.96 (s, 1H), 7.74-7.35 (m, 14H), 6.62 (s, 1H), 5.39 (s, 2H), 4.30 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.66 (s, 2H), 3.49 (t, J=6.8 Hz, 2H), 1.70-1.66 (m, 2H), 1.48-1.45 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.27, 169.94, 168.47, 166.11, 144.12, 143.76, 137.30, 137.13, 136.11, 135.81, 135.11, 134.22, 132.06, 131.88, 131.24, 130.37, 130.20, 129.31, 128.90, 128.61, 128.53, 123.43, 121.63, 120.86, 112.60, 104.17, 67.17, 61.49, 43.90, 37.22, 35.32, 27.38, 25.80, and 14.43.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[N+:7]([O-:9])=[O:8].C(=O)(O)[O-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:6]1[C:2]([Br:1])=[C:3]([N+:7]([O-:9])=[O:8])[N:4]=[CH:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1nc[nH]c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncn(Cc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
A solution of the product of Example 312A (2.3 g, 11.98 mmol) in anhydrous N,N-dimethylformamide (40 mL) at 25° C. was reacted with sodium bicarbonate (2.0 g, 24 mmol) and dropwise addition of benzyl bromide (1.58 mL, 13.17 mmol). The reaction was stirred for an additional 12 hours at 25° C. The reaction was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography on a C18 column, eluting with a gradient of acetonitrile in water containing 0.1% trifluoroacetic acid (5:95 to 100) to give the title compound (1.63 g, 48%). MS (ESI+) m/z 284 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.38 (s, 2H), 7.24-7.42 (m, 5H), 8.28 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Yield: 81.8 %

Procedure:
3-t-Butoxycarbonylaminopropanol (10.0 g) is dissolved in methylene chloride (100 ml) and thereto are added triethylamine (8.66 g) and tosyl chloride (16.3 g) with stirring under ice cooling. The mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is dissolved in water-ethyl acetate, and the organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate, and then distilled off the solvent. The residue is purified with a silica gel column chromatography to give 3-t-butoxycarbonylaminopropyl tosylate (15.37 g) as pale yellow oil.