Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]([NH:15][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[O:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:26]2[CH2:27][NH:28][CH2:29][CH:25]2[CH2:24][CH2:23]1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[NH:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([N:28]3[CH2:29][CH:25]4[CH:26]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:24]4)[CH2:27]3)=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1cnccn1)Nc1ccnc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC21
Product: CC(C)(C)OC(=O)N1CCC2CN(c3ccc4c(NC(=O)Nc5cnccn5)ccnc4c3)CC21

Procedure:
The compound was prepared by the method described for Example 1 using 1-(7-bromoquinolin-4-yl)-3-(pyrazin-2-yl)urea and tert-butyl hexahydropyrrolo[2,3-c]pyrrole-1(2H)-carboxylate as starting compounds.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>C(Cl)Cl>[Si:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (20.0 g, 0.16 mol) in 200 mL of CH2Cl2 at 0° C., imidazole (24.5 g, 0.36 mol) and tBuSiMe2Cl (27.2 g, 0.18 mol) were added. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was poured into H2O and extracted with CH2Cl2. The organic phase was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes:ethyl acetate=50:1 (v/v)) to give colorless oil (35.1 g, 90.7%). 1H NMR (300 MHz, CDCl3, δ): 9.86 (s, 2H), 7.77 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 0.97 (s, 9H), 0.23 (s, 6H). 13C{1H} NMR (75 MHz, CDCl3, δ): 190.76, 161.49, 131.87, 130.50, 120.47, 25.55, 18.25, −4.37. HRMS-FAB (m/z): [M+H]+ calcd for C14H23O2Si, 251.1467; found, 251.1469.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([C:34](=[O:36])[CH3:35])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[F:21][C:22]1[CH:23]=[C:24]([C:34](=[O:36])[CH3:35])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([C:4](=[O:5])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[F:1])[CH2:30][CH2:29]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A solution of 2-Fluoro-5-nitro-benzoyl chloride (CAS: 7304-32-7; Feng, Y.; Burgess, K.; Chem. Europ. J.; EN; 5; 11; 1999; 3261-3272) (0.054 g, 0.261 mmol) in dioxane (1 ml) was treated with triethylamine (0.073 ml, 0.522 mmol) and then with a solution of 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (CAS: 189763-57-3; WO9714690) (58 mg, 0.261 mmol) in dioxane (1 ml). The mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The crude oil was taken in water. The aqueous layer was extracted 3 times with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude gum was purified on silicagel (eluent: heptane/ethylacetate 0%-20% (10 minutes) to provide the title compound (69 mg, 68%) as a light yellow solid, MS (m/e): 390.2 (MH+, 100%)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][CH:9]([CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(Cl)Cl>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([O:13][CH2:12][CH:9]2[N:8]3[C:33](=[O:34])[NH:1][C:2]4=[CH:3][CH:4]=[CH:5][C:6](=[C:7]34)[O:11][CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3cccc(N)c3N2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc4[nH]c(=O)n2c34)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Toluene-4-sulfonic acid 5-amino-3,4-dihydro-2H-benzo[1,4]oxazin-3-ylmethyl ester (6.7 g , ˜10 mmole) was dissolved in methylene chloride (100 mL), N, N-diisopropylethylamine (5.22 mL, 30.0 mmole) was added, followed by carbonyldiimidazole (4.05 g, 25.0 mmole), and the mixture was stirred at room temperature under nitrogen overnight. The mixture was diluted with methylene chloride (100 mL), washed with water (2×200 mL), saturated sodium bicarbonate (200 mL) saturated sodium chloride (200 mL) and dried (Na2SO4). Filtration, evaporation in vacuum and column chromatography on silica gel with 1% methanol/methylene chloride as eluent gave 2.0 g of the title compound as an off white solid, m.p. 140-142° C. 1H NMR (DMSO-d6): δ 10.7 (s, 1H); 7.63 (d, 2H); 7.47 (d, 2H); 6.82 (t, 1H); 6.57 (d, 1H); 6.52 (d, 1H); 4.53 (m, 1H); 4.43 (dd, 1H); 4.34 (dd, 1H); 4.16 (dd, 1H); 4.10 (dd, 1H); 2.38 (s, 3H). MS (ESI) m/z359 ([M−H]−).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@@H:33]([C:44](O)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([CH2:34][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[C:44](=[O:45])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:36]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (300 mg) and N-tert-butoxycarbonyl-D-tryptophan (294 mg) were used, whereby tert-butyl (2R)-3-(1H-indol-3-yl)-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]propan-2-ylcarbamate was yielded. Subsequently, the procedure of Example 15(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (438 mg) was yielded.
Reaction SMILES: [OH:1][C:2]1[CH2:3][CH:4]([C:17]([OH:19])=[O:18])[CH2:5][C:6](=[O:16])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[CH:22]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:22][O:18][C:17]([CH:4]1[CH2:3][C:2](=[O:1])[C:7]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([OH:16])[CH2:5]1)=[O:19]
Reactant: c1ccccc1
Reactant: O=C1CC(C(=O)O)CC(O)=C1N=Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1CC(=O)C(N=Nc2ccccc2)=C(O)C1

Procedure:
60 G. of 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-carboxylic acid, 200 ml. of methanol, 1200 ml. of benzene and 5 g. of p-toluenesulfonic acid were heated together at reflux for 18 hours on a water separator. After cooling, the solution was washed with 500 ml. of a 5% sodium bicarbonate solution, washed with water, dried and evaporated. The residue was dissolved in ethyl acetate and purified on an aluminum oxide column (500 g., activity stage I). After evaporation of the ethyl acetate, there was obtained 3-hydroxy-5-keto-4-phenylazo-3-cyclohexenecarboxylic acid methyl ester of melting point 144° C. (from benzene/petroleum ether).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Fe+2].[Fe+2].O>[OH2:2].[OH:2][C:1]1[C:3]([OH:4])=[CH:5][C:6]2[C:7]3[C:6](=[CH:5][C:3]([OH:4])=[C:1]([OH:2])[CH:8]=3)[C:6]3[C:7](=[CH:8][C:1]([OH:2])=[C:3]([OH:2])[CH:5]=3)[C:7]=2[CH:8]=1
Reactant: Oc1ccccc1O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Temperature: 30 °C
Yield: 61.6 %

Procedure:
Catechol (22.0 g, 0.2 moles) and diiron trioxide (ferric oxide) (31.9 g, 0.2 moles) were added into water (44 mL), and 98% sulfuric acid (176 g, 1.76 moles) was added dropwise to the solution while temperature of the solution is maintained at 30° C. or lower, to adjust the concentration in percent by weight of sulfuric acid in the reaction system at 80%. The solution was reacted at 30° C. for 6 hours with stirring. After completion of the reaction, water (200 mL) was added dropwise to the reaction solution while temperature of the solution was maintained at 30° C. or lower, and the reaction solution was stirred at the same temperature for another 30 minutes. The resultant precipitate was collected by filtration, and the obtained crude crystal was washed with water. The crude crystal was further dispersed in water (400 mL), and the dispersion liquid was stirred for 30 minutes, and then filtered to collect crystal. After the collected crystal was dispersed in acetone (400 mL), the dispersion liquid was stirred for 30 minutes. After that, the dispersion liquid was filtered to filter off insoluble matter, and activated charcoal (10.81 g) was added to the filtrate, which was then stirred for 30 minutes. After stirring, the filtrate was concentrated under reduced pressure to distill off acetone, and evaporated to dryness. After the residue after evaporation to dryness was dissolved by adding the acetone (40 mL) and the water (20 mL) thereto at room temperature, water (380 mL) was slowly added dropwise at the same temperature. By cooling down the solution after the addition to 10° C., crystal precipitated. The crystal thus precipitated was collected by filtration, and then dried, to give type C crystal of 2,3,6,7,10,11-hexahydroxytriphenylene monohydrate (8.43 g, theoretical yield from catechol: 36.9%) in reddish purple powder form. Also, water content of the obtained the type C crystal was measured by Karl-Fischer method in the same way as in Example 4, and the type C crystal was confirmed to be monohydrate of 2,3,6,7,10,11-hexahydroxytriphenylene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[C:20]1([S:26]([N:29]2[C:37]3[CH:36]=[C:35]([Sn](C)(C)C)[CH:34]=[C:33]([NH2:42])[C:32]=3[CH:31]=[N:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>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.CN(C=O)C>[C:20]1([S:26]([N:29]2[C:37]3[CH:36]=[C:35]([C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[N:8]([S:11]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=45)[CH:34]=[C:33]([NH2:42])[C:32]=3[CH:31]=[N:30]2)(=[O:27])=[O:28])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Yield: 27.3 %

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.546 g), 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (2 g) and Pd(PPh3)4 (0.265 g) were added to DMF (30 ml) under nitrogen. The mixture was heated at 100° C. for 2 days then cooled to RT and concentrated in vacuo. The mixture was purified by column chromatography on silica (70 g) eluting with ammonia and methanol in DCM, then again using the ISCO Companion, eluting with a gradient of 30-85% MeCN (+0.1% TFA): H2O (0.1% TFA). Fractions containing desired product were combined and the solvent was removed to afford the title compound as a brown solid (663 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[CH2:19][OH:20])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21]I>C1COCC1.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[CH2:19][O:20][CH3:21])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@@H]1Cc2ccccc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a slurry of sodium hydride (60%) (1.623 g, 40.5 mmol, 1.3 eq) in THF (15 mL) was added (S)-2-hydroxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (7.760 g, 31.1 mmol, 1 eq) (J. Org. Chem, 62, 7679, 1997) in THF (100 mL) and the mixture was stirred at room temperature for 1 hr. Methyl iodide (3 mL, 48.2 mmol, 1.5 eq) was added and the reaction was stirred at room temperature overnight. It was then poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated. The crude residue purified by column chromatography using ethyl acetate/hexanes (10/90) as an eluent to give the title compound as a colorless oil (3.863 g, 47% ). NMR (400 Mz, DMSO-d6): consistent.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11]Br)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1c(C(C)(C)C)cc(CBr)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1c(C(C)(C)C)cc(COc2ccc(C=O)cc2)cc1C(C)(C)C
Yield: 81.8 %

Procedure:
Under a nitrogen atmosphere 1,3-di (t-butyl)-2-methoxy-5-bromomethylbenzene (6.26 g, 20 mmol) is then reacted with 4-hydroxybenzaldehyde (2.44 g, 20 mmol) and potassium carbonate (3.04 g) in 140 ml of methyl ethyl ketone. The reaction mixture is heated to reflux and maintained at this temperature for about 18 hours at which time the reaction mixture is cooled. The inorganics are removed by filtration and the filtrate is concentrated in vacuo. The concentrated reaction products are purified by silica gel chromatography to yield 5.8 grams (81%) of 4-[[3,5-di (t-butyl)-4-methoxyphenyl]methoxy]benzaldehyde.
Reaction SMILES: I[C:2]1[N:3]([CH3:13])[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1.[CH3:14][C:15]1[S:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CN(C=O)C>[CH3:13][N:3]1[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=[C:2]1[C:18]1[S:19][C:15]([CH3:14])=[CH:16][CH:17]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1ccc(-c2cn(C)c(I)n2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cn(C)c(-c3ccc(C)s3)n2)s1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 2-iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 6 (1.31 g, 4.31 mmol), 5-methylthiophene-2-boronic acid pinacol ester (1.35 g, 6.03 mmol), Na2CO3 (1.80 g, 17.2 mmol) in H2O (10 mL) and DMF (40 mL) was degassed (N2 bubbling). Pd(PPh3)4 (125 mg) was added and the mixture was heated to reflux for 5 h. The mixture was allowed to cool to room temperature and concentrated. The mixture was diluted with EtOAc and H2O and the organic phase was separated. The aqueous phase was re-extracted (EtOAc) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 10:90 then 15:85 then 20:80) to give 1-methyl-2,4-bis(5-methylthiophen-2-yl)-1H-imidazole 7 (930 mg, 79%) as a colourless solid. A portion of this material was further purified by, firstly, recrystallisation (EtOAc/hexanes) and, secondly, by sublimation (130° C., 10−6 mBar): m.p. 138-140° C. 1H NMR (CDCl3, 400 MHz) δ2.48 (d, J=0.7 Hz, 3H), 2.51 (d, J=0.7 Hz, 3H), 3.76 (s, 3H), 6.64-6.67 (m, 1H), 6.73-6.77 (m, 1H), 7.00 (s, 1H), 7.10 (d, J=3.4 Hz, 1H), 7.14 (d, J=3.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ15.2, 15.3, 34.5, 117.0, 122.1, 125.5, 125.6, 126.7, 136.3, 137.7, 141.5, 142.4; HRMS (EI) m/z 274.0589 C14H14N2S2 [M]+. requires 274.0593.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9]Br)=[CH:2]1.[C:14]([C:19]1[N:20]=[C:21]([SH:24])[S:22][CH:23]=1)(OCC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][S:24][C:21]2[S:22][CH:23]=[C:19]([CH2:14][OH:15])[N:20]=2)=[CH:2]1
Reactant: CCOC(=O)c1csc(S)n1
Reactant: BrCc1cccc(-c2ccsc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1csc(SCc2cccc(-c3ccsc3)c2)n1

Procedure:
The same reaction as in Referential Example 57 is carried out except using 3-(3-thienyl)benzyl bromide [prepared by reducing 3-(3-thienyl)benzaldehyde with sodium borohydride, followed by reacting with phosphorus tribromide] and 4-carboethoxy-2-mercaptothiazole [J. Org. Chem., 25, 1337 (1960)], and the resulting ester compound is reduced with lithium aluminium hydride to give the captioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:16])[N:13]=1
Reactant: Fc1ccc(Br)c(-c2nnn[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc(-c2cc(F)ccc2Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol), iodomethane (1.12 g, 10 mmol) and potassium carbonate (1.5 g) in dimethylformamide (5 mL) was stirred at room temperature for 16 hrs, then concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to provide 650 mg (Yield 61%) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm: 4.45 (3H, s) 7.03–7.11 (1H, m) 7.63 (1H, dd, J=8.9, 3.1 Hz) 7.69 (1H, dd, J=8.9, 5.5 Hz); 13C NMR (126 MHz, CDCl3) δ ppm: 39.86, 116.28, 118.66, 118.76, 130.13, 135.73, 161.74, 163.53; LC/MS m/z 257/259.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([CH:8]([O:15][C:16](OC2C=CC=CC=2)=[O:17])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:31]>C(O)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]2[NH:31][C:16](=[O:17])[O:15][C:8]=2[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(Cl)cc1
Yield: 80 %

Procedure:
A mixture of methyl 4-(4-chlorobenzoyl)-4-phenoxycarbonyloxybutyrate (61.2 g), ammonium acetate (62.2 g) and acetic acid (300 ml) was stirred under reflux for 1.5 hours. The reaction mixture was concentrated, water was added to the resulting residue, and the crystals thus precipitated were collected by filtration. These were recrystallized from methanol to give colorless needles of methyl 3-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]propionate (36.6 g, 79%). m.p. 147-148° C.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.BrC(F)(F)C[OH:17].C(N(CC)CC)C>O1CCCC1>[C:1]12([C:11]([OH:12])=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OCC(F)(F)Br
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)C12CC3CC(CC(C3)C1)C2

Procedure:
1-adamantanecarbonyl chloride and 2-bromo-2,2-difluoroethanol were mixed in tetrahydrofuran, and ice-cooled. Triethylamine was added into the mixture, and then a typical liquid separating operation and a distillation removal of solvent were conducted, to obtain 1-adamantanecarboxylic acid=2-bromo-2,2-difluoroethyl. Next, conversion into sodium sulfinate by sodium dithionite and oxidation by hydrogen peroxide were conducted for the mixture, to obtain intended sodium 2-(1-adamantanecarbonyloxy)-1,1-difluoroethanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][CH:7]=1.[Cl:29]NC(=O)CCC(N)=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23][C:24]([CH3:25])([CH3:27])[CH3:26])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][C:7]=1[Cl:29]
Reactant: NC(=O)CCC(=O)NCl
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)c(Cl)n2)c(F)c1
Temperature: 60 °C
Yield: 52.4 %

Procedure:
To a 25 mL round-bottomed flask were added a stirbar, 52 mg (0.13 mmol) 4′-(5-aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide, 27 mg (0.20 mmol) N-chlorosuccinamide, and dry DMF (2.0 mL). The flask was sparged with nitrogen and heated at 60° Celsius for 18 hours before cooling to rt and subjecting the reaction mixture (after syringe filtration) to HPLC purification to give the title compound (29.6 mg, 52%). MS (ESI): mass calcd. for C20H20ClFN4O2S, 434.10; m/z found, 435.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.44 (d, J=2.0, 1H), 8.06 (dd, J=8.1, 1.5, 1H), 7.85 (dd, J=9.4, 6.8, 1H), 7.70-7.64 (m, 1H), 7.64-7.57 (m, 1H), 7.43-7.27 (m, 3H), 7.13 (s, 2H), 6.98 (d, J=3.7, 1H), 1.02 (s, 9H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH2:8])C.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH:21]N)[CH:17]=[CH:18][C:19]=1[F:20]>CO>[Br:13][C:14]1[CH:15]=[C:16]2[C:17]([C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][NH:21]2)=[CH:18][C:19]=1[F:20]
Reactant: NNc1ccc(F)c(Br)c1
Reactant: CCOC(CCCN)OCC
Agent: Cl
Solvent: CO
Product: NCCc1c[nH]c2cc(Br)c(F)cc12
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 116.7 %

Procedure:
4,4-Diethoxybutan-1-amine (4.72 g, 29.3 mmol) was added to (3-bromo-4-fluorophenyl)hydrazine hydrochloride (6.4 g, 27 mmol). The resulting mixture in an open round bottom flask was placed into a preheated oil bath at 180° C. The mixture was stirred at 180° C. for 2.5 h and then cooled to 120° C. Methanol (300 mL) was added, and the mixture was stirred at ambient temperature for 18 h. The resulting suspension was filtered through a silica gel plug, and the silica gel was then washed with methanol (5×300 mL). The combined methanol fractions were concentrated under vacuum to provide the crude title compound (8.1 g) as a yellow solid, which was used in the next step without further purification: ESI MS m/z 257 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]>C(O)C>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Yield: 95.3 %

Procedure:
A solution of N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (253 mg, 0.575 mmol) in 10 mL of ethanol was hydrogenated at atmospheric pressure over 45 mg of 10% Pd(C) for 3 hours. The reaction mixture was filtered through a pad of celite and evaporated to dryness to give 4-amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (225 mg, 95%) as a white solid suitable for use in the next step, HR-FAB-MS: Obs mass, 410.2196. Calcd mass, 410.2200 (M+).