Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15](Cl)=[O:16])=[CH:9][CH:8]=1.[CH3:21][NH2:22]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([NH:22][CH3:21])=[O:16])=[CH:9][CH:8]=1
Reactant: CN
Reactant: O=C(Cl)C=Cc1ccc(OCc2cccc(F)c2)cc1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 30 %

Procedure:
500 mg (1.72 mmol) of the crude 3-[4-(3-fluoro-benzyloxy)-phenyl]-acryloyl chloride is dissolved in 2 ml dichloromethane and 0.4 ml of a 41% solution of methylamine in water is added. The reaction mixture is heated under reflux for about 3 hours, cooled, filtered and washed with cold dichloromethane to yield 149 mg (30%) of a colorless solid. MS: m/e=286.2 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:15][C:14]3=[CH:16][S:17][CH:18]=[C:13]3[N:12]=2)[CH:4]=1.[H-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([N:12]1[C:13]2=[CH:18][S:17][CH:16]=[C:14]2[N:15]=[C:11]1[S:10][CH2:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1)=[O:23])[CH3:26]
Reactant: COc1ccnc(CSc2nc3cscc3[nH]2)c1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(SCc2cc(OC)ccn2)nc2cscc21
Temperature: 36 °C

Procedure:
Under nitrogen, 1.4 g (5.0 mmol) of 2-(4-methoxy-2-picolylmercapto)-1H-thieno[3,4-d]imidazole were dissolved in 15 ml of anhydrous dimethylformamide, and 270 mg (6 mmol) of a 60% suspension of NaH in oil were added in portions, and the mixture was heated at 30°-40° C. for 10 minutes. Now, at 25° C., 0.5 ml (5 mmol) of ethyl chloroformate (95%) was added, during which the temperature increases to about 36° C. 30 minutes later the crystalline product was filtered off with suction and washed twice with diethyl ether. Melting point 154°-156° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.92 min; [M+H]+=422.07.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].Br[CH2:28][C:29]#[C:30][Si:31]([CH3:34])([CH3:33])[CH3:32]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)([CH2:28][C:29]#[C:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:8]2=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(F)cc1)C2
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccc(F)cc1)C2

Procedure:
Reaction of ethyl [6,7-dichloro-1-oxo-2-(p-fluorophenyl)-5-indanyloxy]acetate with 1-bromo-3-(trimethylsilyl)-2-propyne according to the procedure of Example 1, STEP (b), affords the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:11]([CH3:10])(=[O:13])=[O:12])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Procedure MM: To a stirring solution of 4-bromo-2-fluoroaniline (1.0 mmol) in 3:1 dichloromethane/pyridine, add methanesulfonyl chloride (1.5 mmol) and stir at room temperature for 18 hours. After this time, wash the reaction with 1N hydrochloric acid while extracting with dichoromethane. Purify the title compound via radial chromatography eluting with ethyl acetate and hexane.
Reaction SMILES: [F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][N:23]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:24][CH:25]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN1C=C2C(=C(C3=CCNCC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C=C2C(=C(C3=CCN(S(C)(=O)=O)CC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of Example 48 (60 mg, 0.17 mmol) in dichloromethane (5 mL) was added triethylamine (0.1 mL, 0.68 mmol) and methanesulfonyl chloride (30 mg, 0.25 mmol) and the mixture was stirred at room temperature overnight. Purification by flash chromatography on silica gel (Teledyne CombiFlash Rf, 0-15% methanol in 2:1 ethyl acetate/hexane) provided the title compound. 1H NMR (400 MHz, DMSO-d6): δ 2.71 (s, 1H), 2.89 (s, 3H), 2.97 (s, 3H), 3.36-3.41 (m, 2H), 3.94-3.95 (m, 2H), 4.08 (s, 2H), 5.90 (s, 1H), 7.28-7.32 (m, 1H), 7.39 (dd, J=9.16, 5.49 Hz, 1H), 7.63-7.67 (m, 1H), 8.27 (d, J=4.88 Hz, 1H), 11.72 (s, 1H). MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:9])[NH2:8].[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[S:14][N:8]=[C:7]([C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: N=C(N)c1cccs1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2cccs2)ns1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of thiophene-2-carboximidamide hydrochloride (1.62 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.40 g (69.3%) of the desired product as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1>>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 1, react imidazole with 1-fluoro-4-nitrobenzene to obtain the title compound.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([Cl:24])[N:21]=[C:20]([O:25][CH3:26])[N:19]=1>O1CCOCC1>[F:16][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:17][C:18]1[N:23]=[C:22]([Cl:24])[N:21]=[C:20]([O:25][CH3:26])[N:19]=1)=[O:15])(=[O:12])=[O:11]
Reactant: COc1nc(N)nc(Cl)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Solvent: C1COCCO1
Product: COc1nc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Yield: 87.9 %

Procedure:
124.6 g of 2-difluoromethoxyphenyl-sulfonyl isocyanate in 100 ml of dioxane are added dropwise to a suspension of 80.3 g of 2-amino-4-chloro-6-methoxy-1,3,5-triazine in 400 ml of absolute dioxane in the course of 10 minutes. The reaction mixture is warmed to 90°-100° for 3 hours, and the solution is then cooled and concentrated to give 180 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-chloro-6-methoxy-1,3,5-triazin-2-yl)-urea of melting point 167°-168°.
Reaction SMILES: C([C:9]1[C:13]([NH:14][C:15](=[O:28])[CH2:16][N:17]2[C:21](=O)[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3C2=O)=[CH:12][N:11](C)[CH:10]=1)(=O)C1C=CC=CC=1.NN.[CH3:32]O>>[CH3:32][C:10]1[NH:11][CH:12]=[C:13]2[C:9]=1[C:21]([C:20]1[CH:19]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:17][CH2:16][C:15](=[O:28])[NH:14]2
Reactant: CO
Reactant: Cn1cc(NC(=O)CN2C(=O)c3ccccc3C2=O)c(C(=O)c2ccccc2)c1
Agent: NN
Product: Cc1[nH]cc2c1C(c1ccccc1)=NCC(=O)N2

Procedure:
3-Benzoyl-1-methyl-4-(phthalimidoacetamido)pyrrole (38 g.) is reacted with 6 g. of anhydrous hydrazine in 300 ml. of methanol according to the procedure of the foregoing example. After evaporation of the solvent and refluxing the residue with concentrated hydrochloric acid, the reaction mixture is filtered and the filtrate is alkalinized with dilute sodium hydroxide. The precipitate is crystallized from methanol. Yield 19 g. The compound decomposes at 400° C. without melting.
Reaction SMILES: [CH3:1]I.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[S:10])[NH2:9]>CC(C)=O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([S:10][CH3:1])=[NH:9]
Reactant: NC(=S)c1cccs1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=N)c1cccs1
Temperature: 23 °C
Yield: 97 %

Procedure:
Methyl iodide (66 g; 0.46 mol) is added drop wise at 0° C. to a solution of thiophene-2-carbothioamide (50 g; 0.33 mol) in 500 ml of acetone. After the addition, stirring is maintained for two hours at 23° C. The precipitate formed is filtered on frit and washed twice with 100 ml of acetone before being dried under vacuum (in a bell jar). A yellow powder is obtained with a yield of 97%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.C(N(CC)CC)C>CS(C)=O>[CH:2]([CH2:3][N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:1]
Reactant: COc1cccc(C(=O)N(CCO)c2ccccc2OC)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cccc(C(=O)N(CC=O)c2ccccc2OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
In an atmosphere of argon, N-(2-hydroxyethyl)-3-methoxy-N-(2-methoxyphenyl)benzamide (339 mg, 1.12 mmol) was dissolved in DMSO (4 ml) to which were subsequently added dropwise triethylamine (0.724 ml, 5.20 mmol) and a DMSO solution (8 ml) of a sulfur trioxide-pyridine complex (844 mg, 5.20 mmol) at room temperature. After 20 minutes of stirring at the same temperature, this was mixed with ice water (40 ml) and extracted with ethyl acetate, and then washed with water and saturated brine. The resulting organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by evaporation to obtain 220 mg (65.6%) of the title compound the form of light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH3:11].Br[CH:13]([OH:16])[CH2:14][CH3:15]>>[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:15][CH2:14][CH2:13][OH:16])=[CH:5][C:4]=1[O:10][CH3:11]
Reactant: COc1cc(O)ccc1CN
Reactant: CCC(O)Br
Product: COc1cc(OCCCO)ccc1CN

Procedure:
3-(4-Aminomethyl-3-methoxy-phenoxy)-propan-1-ol is prepared starting from 4-aminomethyl-3-methoxy-phenol and 1-bromo-propanol in analogy to the procedures given in Example 18, steps a to c. LC-MS: tR=0.67 min, [M+1]+=212.16.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([OH:18])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[CH2:19](O)[CH3:20].Cl>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:2][CH2:3]1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1

Procedure:
2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (40 g, 143 mmol) was dissolved in 20% EtOH—HCl solution (200 ml) and refluxed for 3 h to convert the starting material to ester. The volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate (×2). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by recrystallization to ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (38 g) as pale yellow solid.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([O:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[O:7])[CH2:2]1.[C:18](=O)([O:26]C1C=CC=CC=1)[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[O:1]1[CH2:4][CH:3]([O:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH:17][C:18](=[O:26])[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:16])=[O:15])=[O:7])[CH2:2]1
Reactant: NS(=O)(=O)c1ccccc1C(=O)OC1COC1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1C(=O)OC1COC1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A mixture of 2.57 g of 2-(oxetan-3-oxycarbonyl)phenylsulfonamide, 2.14 g of diphenyl carbonate, 1.38 g of potassium carbonate and 13 ml of dimethylformamide is stirred at a temperature of 20°-25° C. for 15 hours. The reaction mixture is then poured into ice-water, the pH is brought to a value of 5-6 by dropwise addition of 10% hydrochloric acid and the mixture is extracted with ethyl acetate and washed with water. After drying over sodium sulfate, evaporation and crystallisation of the residue from diethyl ether, 2.2 g of phenyl N-[2-(oxetan-3-oxycarbonyl)phenylsulfonyl)carbamate (compound 1.030) of melting point 91°-92° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[C@H:4]([CH:41]([CH3:43])[CH3:42])[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33]CC5C=CC=CC=5)[C:27]=4[CH:28]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:44])[C@H:4]([CH:41]([CH3:42])[CH3:43])[NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[C:27]=4[CH:28]=3)=[O:23])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4c(OCc5ccccc5)cccc4o3)cc2)cc1)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4c(O)cccc4o3)cc2)cc1)C(C)C
Reaction time: 5 h
Yield: 80 %

Procedure:
The product of Example 13-Step 1, 4′-[(4-benzyloxy-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl-L-valine methyl ester (0.32 mmol), was dissolved in 3 mL of ethyl acetate-MeOH (2:1) and 10% Pd/C (20 mg) was added. The reaction was stirred under a hydrogen atmosphere for 5 h. The reaction mixture was filtered through celite and then concentrated to give 4′-[(4-hydroxy-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl-L-valine methyl ester in 80% yield. The product (0.13 mmol) was dissolved in anhydrous DMF (1 mL), and Cs2CO3 (0.26 mmol) was added, followed by 2-bromo-propionic acid ethyl ester (0.13 mmol). After the reaction was complete by TLC the reaction was diluted with ethyl acetate and acidified with 1N hydrochloric acid. The organic layer was washed with brine (2×), dried (magnesium sulfate), filtered and concentrated to afford 79 mg of 4′-{[4-(1-ethoxycarbonyl-ethoxy)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonyl-L-valine methyl ester. The ester was taken up in THF:MeOH (2:1, 2 mL) and treated with NaOH (5N, 5 eq). The reaction was stirred overnight, diluted with ethyl acetate and acidified with 1N HCl. The organic layer was isolated and washed with brine (2×), dried (magnesium sulfate), filtered and concentrated to afford 4′-{[4-(1-carboxy-ethoxy)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonyl-L-valine. LCMS MH+ (m/z) 581. 1H NMR (300 MHz, CD3OD): δ 7.91-7.68 ppm (m, 6H), 7.40-7.09 ppm (m, 3H), 6.70 ppm (d, 1H, J=8 Hz), 4.99 ppm (q, 1H, J=13 Hz), 3.69 ppm (d, 1H, J=5.8 Hz), 2.08-2.00 ppm (m, 1H), 1.69 ppm (d, 3H, J=6.9 Hz), 0.97 ppm (d, 3H, J=7.0 Hz), 0.96 ppm (d, 3H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CO.[C].[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of di-tert-butyl (2-fluoro-5-nitrophenyl)imidodicarbonate (256 mg, 0.718 mmol) in methanol (10 mL) was added 10% palladium-carbon (50 mg), and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (150 mg, 64%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=2[F:24])[O:14][C:15]=1[CH3:16])C1C=CC=CC=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>O1CCCC1.[OH-].[OH-].[Pd+2]>[F:24][C:18]1[CH:19]=[C:20]([C:32]2[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=2)[CH:21]=[CH:22][C:17]=1[C:13]1[O:14][C:15]([CH3:16])=[C:11]([CH2:10][CH2:9][OH:8])[N:12]=1
Reactant: Cc1oc(-c2ccc(Br)cc2F)nc1CCOCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)nc1CCO

Procedure:
Using 4-(2-benzyloxy-ethyl)-2-(4-bromo-2-fluoro-phenyl)-5-methyl-oxazole (see Intermediate 37) and 4-methylsulfonylphenylboronic acid, follow a procedure in substantial accordance with that found in Example 4. Take this product and hydrogenate using 20% palladium hydroxide on carbon in tetrahydrofuran for 36 hours at 40° C. and 60 psi. After this time, filter the reaction and concentrate in vacuo. Purify via radial chromatography eluting with methanol and dichloromethane. MS (m/e): 376.2 (M+1)
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH3+:5].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1)([O-:8])=[O:7]>>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]=[C:16]2[NH:5][CH2:4][CH2:3][S:17]2)=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: [NH3+]CCCl
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Agent: [Cl-]
Product: O=[N+]([O-])c1ccc(N=C2NCCS2)cc1

Procedure:
2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method C1a to give 2-(4-nitrophenylimino) -1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2-(4-nitrophenylimino)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[C:7]=1[C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH3:2].Cl.[NH2:18][OH:19].C[O-].[Na+]>>[CH2:1]([C:3]1[O:4][C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[C:7]=1[C:8]([CH3:12])([CH3:11])[C:9](=[N:18][OH:19])[NH2:10])[CH3:2]
Reactant: NO
Reactant: CCc1oc2ccccc2c1C(C)(C)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1oc2ccccc2c1C(C)(C)C(N)=NO
Yield: 41 %

Procedure:
The above-named compound was prepared from 2-(2-ethyl-3-benzofuranyl)-2-methyl-propionitrile by the procedure described in Example 1(a), but using 1.5 mol of hydroxylamine hydrochloride and sodium methylate for each mole of 2-(2-ethyl-3-benzofuranyl)-2-methylpropionitrile and continuing the reaction for 72 hours. Yield: 41%; m.p. 118°-120° C. after recrystallization from a mixture of ethyl acetate and light petroleum ether.
Reaction SMILES: NN.[CH2:3]([O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][C:42](=[CH2:44])[CH2:41][C@H:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[N+:47]([O-])=O)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][C:20](=[CH2:22])[CH2:19][CH:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[N+:25]([O-])=O.C(Cl)(Cl)Cl.CO>CO.[Ni]>[CH2:5]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][C@@H:20]([CH3:22])[CH2:19][C@H:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[NH2:25])[CH2:4][CH2:3][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][CH:42]([CH3:44])[CH2:41][CH:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[NH2:47]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3[N+](=O)[O-])cc2OC)C1
Agent: [Ni]
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(OCCCOc2cc(OC)c(C(=O)N3C[C@@H](C)C[C@H]3CO)cc2N)c(N)cc1C(=O)N1CC(C)CC1CO
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of hydrazine (23 mg, 23 μL, 0.72 mmol) in MeOH (5 mL) was added dropwise to a solution of the diol 76 (95 mg, 0.145 mmol) and Raney Ni (20 mg) in MeOH (15 mL) heated at reflux. After 1 hour at reflux TLC (90% CHCl3/MeOH) revealed some amine formation. The reaction mixture was treated with further Raney Ni (20 mg) and hydrazine (23 mg, 23,L, 0.72 mmol) in MeOH (5 mL) and was heated at reflux for an additional 30 minutes at which point TLC revealed complete reaction. The reaction mixture was then treated with enough Raney Ni to decompose any remaining hydrazine and heated at reflux for a further 1.5 hours. Following cooling to room temperature the mixture was filtered through a sinter and the resulting filtrate evaporated in vacuo. The resulting residue was then treated with CH2Cl2 (30 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the bis-amine (77) as a yellow oil (54 mg, 63%): 1H NMR (270 MHz, CDCl3) (diastereoisomers) δ6.73 (s, 2Harom), 6.32 (s, 2Harom), 4.60-4.30 (m, 2H, NCHCH2OH), 4.19 (t, 4H, J=5.87 Hz, OCH2CH2CH2O), 3.78-3.50 (m, 14H, NCHCH2OH, NCH2CHCH3 and OCH3), 2.40-1.55 (m, 8H, NCH2CHCH3, OCH2CH2CH2O and NCH2CHCH3CH2), 1.00-0. 95 (m, 6H, NCH2CHCH3); MS (EI), m/z (relative intensity) 600 (M+., 16), 459 (46), 345 (16), 206 (13), 186 (17), 180 (31), 166 (37), 149 (6), 142 (76), 100 (6), 98 (13), 97 (29), 84 (81), 69 (7), 55 (100).
Reaction SMILES: CC([O-])(C)C.[K+].Br[CH2:8][CH2:9][CH2:10][OH:11].[N+:12]([C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:11][CH2:10][CH2:9][CH2:8][N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:23]=2)[CH:19]=[CH:20]1
Reactant: OCCCBr
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2ccn(CCCO)c2c1
Temperature: 80 °C

Procedure:
0.13 mol of potassium tert-butylate and 0.13 mol of 3-bromopropanol are added to a solution of 0.11 mol of 6-nitroindole in 400 ml of dimethylformamide. The reaction mixture is heated at 80° C. for 3 hours. After cooling, 300 ml of a 10% potassium carbonate solution are added, and the mixture is diluted with ethyl acetate. After decanting, the aqueous phase is extracted with dichloromethane, and the combined organic phases are then concentrated and purified by chromatography on silica gel to yield the expected product.