Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(O)(=O)C.[Br:16]Br>>[Br:16][CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11]
Reactant: COc1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cccc(C(=O)CBr)c1
Yield: 32.8 %

Procedure:
Reaction of 1-(3-methoxy-phenyl)-ethanone (5.0 g, 33.30 mmol), acetic acid (1.9 mL, 33.30 mmol), and bromine (1.9 mL, 38.30 mmol) followed by recrystallisation from cold EtOAc/Hexane gave the title compound (2.5 g, 33%) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 3.87 (s, 3H), 4.46 (s, 2H), 7.16 (d, 1H, J=8.4 Hz), 7.63 (dd, 1H, J=8.1, 8.1 Hz), 7.52 (s, 1H), 7.56 (d, 1H, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=[O:15])[N:5]2[CH:16]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][C:6]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[O:15])[NH:5][CH:16]=1
Reactant: Cc1cn2c(n1)Cc1ccccc1NC2=O
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: Cc1c[nH]c(Cc2ccccc2NC(=O)N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 16 g of 2-methyl-11H-imidazo[1,2-c][1,3]bezodiazepine-5-(6H)-one, 9.58 g of N-methylpiperazine and 160 ml of methylene chloride is stirred at room temperature overnight. The mixture is decolorized with charcoal and evaporated to dryness. The residue is crystallized from methanol-ether to give 1-[2-(4-methyl-2-imidazolylmethyl) phenylcarbamoyl]-4-methylpiperazine, m.p. 177°-179°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9]>>[C:7]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])(=[O:10])[CH:8]=[CH2:9]
Reactant: C=CC(=O)Cl
Reactant: O=C1CCCN1
Product: C=CC(=O)N1CCCC1=O
Yield: 70 %

Procedure:
The title compound was synthesized by using the similar procedure as described in Reference Example 1 except that 2-pyrrolidone and acryloyl chloride were used. The yield was 70%.
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11]
Reactant: [H][H]
Reactant: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCC(c2ccccc2)CC1
Yield: 91.2 %

Procedure:
A mixture of (2S,3S,5S)-N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1 (2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide TFA salt (4 mg, 0.00001 mol) in 1 mL of MeOH was hydrogenated in the presence of 5% Pd/BaSO4, under balloon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was concentrated to dry to yield the titled compound (4 mg, 100%). MS (ESI): (M+H)+=439.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)([O-])=O.[NH2:16][C:17]1C=CC=CC=1>>[NH:1]1[C:4]2[C:13]3[C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9][C:8]=3[CH:7]=[CH:6][C:5]=2[N:16]=[CH:17]1
Reactant: Nc1ccccc1
Reactant: O=C1Cc2cccc([N+](=O)[O-])c2C(=O)N1
Product: O=C1Cc2ccc3nc[nH]c3c2C(=O)N1

Procedure:
The general synthesis described in Scheme 1 is similar to the one described in U.S. Pat. No. 4,176,184. Briefly, reduction of 8-nitroisoquinoline-1,3(2H,4H)-dione 1(i) (prepared according to the procedure described in DE 3410168) to the corresponding aniline 1(ii) followed by acylation with acyl chloride and cyclization of the resulting amide gave 1H-imidazol[4,5-h]isoquinoline-7,9(6H,8H)-dione 1 (iii). Alkylation of 1(iii) with 1-bromo-3-chloropropane gave 1(iv), which reacted with a primary amine to give 1(v). If necessary, the transformation of R1a and R3a to R1 and R3 by methods known to the skilled in the art (including, but not limited to, removal of protective group, alkylation, oxidation and reduction) gave the compounds of formula (I) or (Ia).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH2:2][CH3:3].N[C:26]1C=C(C2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1.C1(C(Cl)=O)CC1>>[CH:2]1([C:1]([NH:5][C:6]2[CH:7]=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[CH:9]=[CH:10][CH:11]=2)=[O:4])[CH2:26][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: CCC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=C(Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Yield: 100 %

Procedure:
According to the procedure used for the synthesis of tert-butyl 4-[3-(propionylamino)phenyl]-1-piperidinecarboxylate, tert-butyl 4-(3-aminophenyl)-1-piperidinecarboxylate (16.47 g 0.0596 mol) and cyclopropanecarbonyl chloride (6.27 g, 0.0597 mol) provided the tert-butyl 4-{3-[(cyclopropylcarbonyl)amino]phenyl}-1-piperidinecarboxylate (18.1 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.55-7.46 (m, 2H), 7.29-7.21 (m, 2H), 6.96-6.89 (m, 1H), 2.79 (t, 2H, J 12.1 Hz), 2.68-2.58 (m, 1H), 1.84 (d, 2H, J=12.6 Hz), 1.83-1.76 (m, 4H), 1.48 (s, 9H), 1.19-1.12 (m, 1H), 1.09-1.05 (m, 2H), 0.89-0.75 (m, 2H); ESMS m/e: 345.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]([C:20]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]4[C:21]=3[N:22]=[CH:23][N:24]4C3CCCCO3)=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:5][CH:4]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]([C:20]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]4[C:21]=3[N:22]=[CH:23][NH:24]4)=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nc3ccccc3cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2nc3ccccc3cc2-c2nc(C)nc3[nH]cnc23)cn1

Procedure:
A solution of N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)quinolin-2-amine (21 mg, 0.045 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 30 min. The solvents were removed under vacuum and the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate (2×), water, and brine. The organic layer was dried over Na2SO4. The crude material was adsorbed onto a plug of silica gel and purified by silica gel chromatography (1 to 4% MeOH/CH2Cl2). The title compound was obtained as a yellow solid. m/z (ESI, +ve ion) 384 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 13.71 (s, 1H); 12.73 (s, 1H); 10.24 (s, 1H); 8.86 (s, 1H); 8.71 (s, 1H); 8.40 (d, J=7.0 Hz, 1H); 7.92 (d, J=7.8 Hz, 1H); 7.71 (br. s., 2H); 7.37 (br. s., 1H); 6.92 (d, J=8.6 Hz, 1H); 3.88 (s, 3H); 2.91 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[C:7]([CH3:13])=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[O:3]1.[CH3:15][O:16]C(Cl)Cl>ClCCl>[CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[C:7]([CH3:13])=[C:8]([CH3:12])[C:9]([CH3:11])=[C:10]([CH:15]=[O:16])[C:4]=2[O:3]1
Reactant: COC(Cl)Cl
Reactant: Cc1cc2c(c(C)c1C)CC(C)(C)O2
Solvent: ClCCl
Product: Cc1c(C)c(C=O)c2c(c1C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 22 g of the 2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran in 150 ml of absolute dichloromethane was added 12.8 ml of titanium chloride(IV) and 15.8 ml of a α,α-dichloromethyl methyl ether at 0° C. With stirring at room temperature for 1 hour, the reaction mixture was quenched with 300 ml of water and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 20 g of 2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran-7-carboxaldehyde as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.O.[NH2:10][NH2:11]>O1CCOCC1.C(O)(C)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:10][NH2:11]
Reactant: Clc1ccncc1Br
Reactant: NN
Solvent: CC(C)O
Solvent: O
Solvent: C1COCCO1
Product: NNc1ccncc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 3-bromo-4-chloropyridine (5 g, 0.026 mol) and hydrazine hydrate (80% in water, 80 mL) in dioxane (100 mL) was stirred at 100° C. overnight. After cooling down to RT, the mixture was concentrated. The residue was partitioned between 300 mL of EA and 300 mL of aq. sat. NH4Cl. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to get crude product which was suspended in 30 mL of cold isopropyl alcohol and filtered. The collected solid was dried in air to get 4.2 g (87%) of 3-bromo-4-hydrazinylpyridine as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.07 (d, J=5.6 Hz, 1H), 7.37 (s, 1H), 7.01 (d, J=5.6 Hz, 1H), 4.36 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]1[O:25][CH2:26][CH:27]=[CH2:28].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]2[O:25][CH2:26][CH:27]=[CH2:28])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1N
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 562 mg, 3.07 mmol) and ethyl (3S,4R)-4-amino-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 18, 700 mg, 3.07 mmol) in dichloromethane (150 mL) were added HOBt (470 mg, 3.07 mmol) and N-methyl morpholine (1.01 mL, 9.21 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (1.05 g, 5.52 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of 2 N HCl (100 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, and dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum. Purification by column chromatography (silica, 35% ethyl acetate in pet ether) afforded Ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate 1.1 g (90%) as brown solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10](Cl)(=[O:12])=[O:11])#[N:2].[S:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>O1CCCC1>[F:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10]([N:16]2[CH2:17][CH2:18][S:14][CH2:15]2)(=[O:12])=[O:11])[C:3]=1[C:1]#[N:2]
Reactant: N#Cc1c(F)cccc1S(=O)(=O)Cl
Reactant: C1CSCN1
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1S(=O)(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
440 mg of 2-cyano-3-fluoro-benzenesulfonyl chloride in 10 ml of tetrahydrofuran are treated with 0.36 ml of thiazolidine and the mixture is stirred for 16 hours at room temperature. The reaction mixture is concentrated in vacuo. Purification by Flash chromatography (eluent: cyclohexane/ethyl acetate 1:1) followed by acidic washing with a 1M HCl solution affords 318 mg of 2-fluoro-6-(thiazolidine-3-sulfonyl)-benzonitrile.
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>O1CCCC1>[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: NCc1cccc(Cl)c1Cl
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cccc(Cl)c2Cl)c(=O)c1=O
Yield: 90.8 %

Procedure:
Tetrahydrofuran (12 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5.0 mmol) and 2,3-dichlorobenzylamine (0.88 g, 5.0 mmol) were stirred together at room temperature for 64 hours. The residue remaining after removal of solvent was trituated thoroughly with diethyl ether and dried to give 1.55 g of a white solid. Recrystallization (four times) of the crude product from acetonitrile provided 0.796 g of the title compound as a white solid: mp 222°-223° C. (softens 218° C.). MS (m/z) 340/342/344 (M+). HPLC indicates a major component (96.2%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:16])=O)=[CH:10]2)[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCCC1>[CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](=[S:37])[NH2:16])=[CH:10]2)[CH3:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 117.6 %

Procedure:
To a solution of 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (700 mg) in tetrahydrofuran (40 mL) was added Lawesson's reagent (729 mg) and the mixture was stirred at 60° C. for 40 min. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95 to 50/50, volume ratio) to give the title compound (857 mg, 100%) as a yellow amorphous solid. MS 405 (MH+).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:29]([NH:31][C@H:32]([C:43]([O:45][CH3:46])=[O:44])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:30])[CH2:11][C:12]1[N:16]=[CH:15][N:14](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:13]=1)=[O:8]>CN(C=O)C.O.SC(O)C>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:29]([NH:31][C@H:32]([C:43]([O:45][CH3:46])=[O:44])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:30])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)NC(=O)[C@@H]1CCC(=O)N1
Agent: CC(O)S
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To the solution containing 15.84 g (25 mmoles) of Glp-His(DNP)-Trp-OMe protected tripeptide in 100 ml of DMF and 40 ml of water, 4 ml of mercaptoethanol are added, then the pH-value of the solution is adjusted to 8 by adding TEA. The solution is left to stand at room temperature for 30 minutes, then evaporated to dryness under reduced pressure. The oily residue is thoroughly triturated with ether, filtered and dried. The thus-obtained product is dissolved in a little volume of methanol and crystallized by adding ether. The crystals are filtered and dried to give 10.92 g (93.5% yield) of the aimed compound, m.p.: 228°-232° C.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=3[Cl:26])[CH:12]=[CH:11][C:10]=2[O:27]C)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([NH:5][S:6]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:17]([Cl:26])=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][C:21]=3[Cl:22])[CH:12]=[CH:11][C:10]=2[OH:27])(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4]1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)NC1CCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)NC3CCC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of N-Cyclobutyl-5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfonamide (451 mg, 1.0 mmol) in methylene chloride (9 mL) at 0° C. was added boron tribromide (1M in methylene chloride, 2.0 mL, 2.0 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (25 mL) and stirred at room temperature for 1 hour, then extracted with ethyl acetate (3 times 40 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (5% ethyl acetate in CH2Cl2) to afford the title compound (403 mg). 1H NMR (400 MHz, CDCl3) δ8.39 (s, 1H), 8.28 (s, 2H), 7.05-6.94 (m, 3H), 4.77 (d, 1H), 3.77-3.71 (m, 1H), 2.14-2.07 (m, 2H), 1.75-1.56 (m, 4H). MS (APCI−) Calc: 432.1, Found: 431.2 (M−1).
Reaction SMILES: [C:1]([C@H:4]([N:9]([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([C@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:1]([NH2:2])=[O:3])[CH2:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:27])=[CH:23][CH:22]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: C1COCCN1
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(C(=O)O)cc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(C(=O)N2CCOCC2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a 0° C. solution of 4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}benzoic acid (50.0 mg, 0.114 mmol) in DMF (0.3 mL) was added morpholine (12.9 mg, 0.148 mmol), followed by 1-hydroxybenzotriazole (18.5 mg, 0.137 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.2 mg, 0.137 mmol), and iPr2NEt (26 μL, 0.15 mmol). After 2 h, the solution was warmed to rt. After 4 h, the solution was poured into 10% aq. citric acid and extracted with EtOAc (2×). The combined organic layers were washed sequentially with water and sat. aq. NaHCO3, then dried (MgSO4) and concentrated. Flash column chromatography (SiO2, 40 to 100% EtOAc/hexanes) gave the title compound as a white solid (46.0 mg, 79%). MS (ESI), (M+H)+ 508.22; 1H NMR (CDCl3, 300 MHz) δ 7.68 (d, 2H, J=8.6), 7.29-7.47 (m, 6H), 6.38 (br s, 1H), 5.75 (br s, 1H), 4.65 (d, 1H, J=16.0), 4.42 (d, 1H, J=16.0), 4.32 (t, 1H, J=7.5), 3.30-3.85 (br in, 8H), 1.69-1.78 (m, 1H), 1.28-1.37 (m, 1H), 1.08-1.14 (m, 1H), 0.76 (d, 3H, J=6.5), 0.63 (d, 3H, J=6.6).
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][NH2:5]
Reactant: N#CCC(O)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
35.5 g of β-hydroxy-β,β-diphenyl-propionitrile are added portionwise to the stirred suspension of 12.9 g of lithium aluminum hydride in 800 ml of diethyl ether while cooling with an ice bath. After stirring for 15 hours at room temperature and 2 hours at the boil, it is cooled again and 12.9 ml of water, 12.9 ml of 15% aqueous sodium hydroxide and 38.7 ml of water are added in this order. The mixture is filtered, the residue washed 3 times with 150 ml of methylene chloride, the filtrate dried, evaporated and the residue recrystallized from ethanol, to yield the 3-hydroxy-3,3-diphenyl-propylamine melting at 134°-136°.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+:20]>CO>[C:1]([O-:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[K+:20]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)[O-]
Yield: 143.2 %

Procedure:
GPC in an amount of 5.14 g, 350 ml of methanol, 10.44 g of palmitic acid and 2.28 g of potassium hydroxide were mixed to give a uniform solution at 40° C. and then concentrated to dryness to obtain 17.14 g of potassium palmitate-supported GPC.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH:13]1([N:19]=[C:20]=S)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:19][C:20]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=3[N:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: S=C=NC1CCCCC1
Product: Cn1c(NC2CCCCC2)nc2cc([N+](=O)[O-])ccc21
Yield: 73.2 %

Procedure:
N1-methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and cylcohexyl isothiocyanate (1.80 ml, 13.2 mmol) were coupled using the procedure of intermediate example one part B to give the title compound as a yellow solid (2.41 g, 73%). 1H NMR (300 MHz, d6-DMSO) δ 7.98 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.7 and 2.4 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.74 (m, 1H), 3.56 (s, 3H), 2.00 (M, 2H), 1.75 (m, 2H), 1.63 (m, 1H), 1.25-1.36 (M, 4H), 1.17 (M, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:15])=[C:10]([C:12]([OH:14])=O)[O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:16][O:17]C(=O)C(F)(F)F.[C:24]([O:28][C:29](=[O:51])[C@@H:30]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH:31]([CH3:33])[CH3:32])([CH3:27])([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[C:24]([O:28][C:29](=[O:51])[C@@H:30]([NH:34][S:35]([C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][C:4]([CH2:16][OH:17])=[C:3]([O:2][CH3:1])[C:8]=4[C:9]=3[CH3:15])=[O:14])=[CH:48][CH:49]=2)=[CH:42][CH:43]=1)(=[O:37])=[O:36])[CH:31]([CH3:33])[CH3:32])([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: COc1c(COC(=O)C(F)(F)F)ccc2oc(C(=O)O)c(C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(CO)ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To 100 mg (0.42 mmol) of 4-methoxy-3-methyl-5-(2,2,2-trifluoro-acetoxymethyl)-benzofuran-2-carboxylic acid was added 256 mg (1.5 eq) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester, BOP (185 mg, 1 eq), N,N-diisopropylethylamine (54 mg, 1 eq) and 4 mL of DMF. The mixture was stirred at room temperature for 48 h. Brine was added and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2N HCl and water. Removal of the solvent from the organic solution gave the crude product, which was purified by column chromatography on silica gel to give 89 mg of (S)-2-{4′-[(5-hydroxymethyl-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester as an off white solid.