Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1[NH:17][C:18]([NH2:21])=[N:19][N:20]=1.[CH2:22]1[O:32][C:25]2([CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[O:24][CH2:23]1.O>C(O)(=O)C>[O:24]1[C:25]2([CH2:30][CH2:29][CH:28]([NH:21][C:18]3[NH:17][C:16]([CH3:15])=[N:20][N:19]=3)[CH2:27][CH2:26]2)[O:32][CH2:22][CH2:23]1
Reactant: Cc1nnc(N)[nH]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Sodium triacetoxyborohydride (32.4 g) was gradually added to a solution (150 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (10.0 g) and 1,4-cyclohexanedione monoethyleneketal (19.1 g) in acetic acid. The mixture was stirred at room temperature for 16 hr, water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue was solidified with diisopropyl ether, and the solid was collected by filtration, and dried to give the title compound (15.6 g).
Reaction SMILES: [CH:1](/[CH:6]([CH2:9][OH:10])[CH2:7][OH:8])=[CH:2]\[CH2:3][CH2:4][CH3:5].[CH2:11]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14].C1(C)C=CC=CC=1>S(=O)(=O)(O)O.C(N(CC)CC)C.O>[CH2:11]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:20]2[O:10][CH2:9][C@H:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:7][O:8]2)=[CH:22][CH:23]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: CCC/C=C/C(CO)CO
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCC/C=C/[C@H]1CO[C@H](c2ccc(OCCCC)cc2)OC1

Procedure:
A mixture of 1.00 g of 2-(trans-1-pentenyl)-1,3-propanediol, 1.11 g of p-butoxybenzaldehyde, 3 drops of 2N sulphuric acid and 40 ml of toluene was heated to reflux for 2 hours with the separation of water. The mixture was subsequently treated with 7 drops of triethylamine, left to cool, washed with 5 ml of saturated sodium hydrogen carbonate solution and three times with 10 ml of water each time, dried over sodium carbonate, filtered and concentrated. The semi-crystalline residue (1.86 g) was chromatographed on silica gel with hexane/diethyl ether (vol. 97:3). The product-containing fractions were pooled (0.99 g) and recrystallized twice from hexane at -25° C. There was obtained 0.44 g of pure trans-2-(p-butoxy-phenyl)-5-(trans-1-pentenyl)-m-dioxan; m.p. (C-N) 60.6° C., cl.p. (N-I) 61.9° C.
Reaction SMILES: [CH:1]1[N:9]=[C:8](N)[C:7]2[C:3](=[C:4]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[NH:5][N:6]=2)[N:2]=1.N([O:22][CH2:23][CH2:24]CC)=O>C1COCC1>[C:14]([O:19][C@@H:12]1[C@H:13]([O:18][C:12](=[O:19])[CH3:11])[C@@H:14]([CH2:16][O:17][C:23](=[O:22])[CH3:24])[O:15][C@H:11]1[C:4]1[C:3]2[N:2]=[CH:1][N:9]=[CH:8][C:7]=2[NH:6][N:5]=1)(=[O:15])[CH3:13]
Reactant: CCCCON=O
Reactant: Nc1ncnc2c([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[nH]nc12
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](c2n[nH]c3cncnc23)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 50 °C

Procedure:
A mixture of 2′,3′,5′-tri-O-acetyl-formycin A (prepared from formycin A by modification of the method from Synthesis (1989) 401) (1.1 g, 2.8 mmol) and n-butyl nitrite (2.6 ml, 22 mmol) in THF (30 ml) was heated at 50° C. for 25 h. After cooling to room temperature, the solvent was removed under reduced pressure. The mixture was dissolved in EtOH and reconcentrated (in each case twice). Silica gel chromatography using 2% MeOH in DCM gave compound (Ia) (0.49 g, 46%), the analysis of which confirmed the chemical identity with the product from method A.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=O)[C@@H:12]2[CH2:17][C@H:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:33][C:34]1[CH:38]=[C:37]([Br:39])[S:36][C:35]=1[C:40]([NH2:42])=[O:41]>O1CCCC1.O>[Br:39][C:37]1[S:36][C:35]2[C:40](=[O:41])[NH:42][C:14]([C@@H:13]3[C@@H:12]4[CH2:17][C@@H:9]([CH2:10][CH2:11]4)[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:33][C:34]=2[CH:38]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a solution (15 mL) of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (0.894 g) and triethylamine (0.541 mL) in tetrahydrofuran was added with stirring isobutyl chloroformate (0.487 mL) under ice-cooling. After stirring at room temperature for 30 min, a solution of 3-amino-5-bromothiophene-2-carboxamide (0.78 g) produced in Example 1, step D, in tetrahydrofuran (3 mL) was added. The reaction system was stirred with heating at 60° C. for 40 hr. Water was poured into the reaction system, and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (7.06 mL) and ethanol (14 mL) were added to the residue, and the mixture was stirred with heating at 70° C. for 5 hr. The reaction system was neutralized with 1M hydrochloric acid (4 mL) while stirring under ice-cooling. Insoluble material was removed by filtration. The mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.06 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[C:20]([Cl:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[ClH:28].[C:20]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:9]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(c2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccccc3)c3ccc([N+](=O)[O-])cc23)CC1
Product: Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A mixture of 3-(1-methyl-4-piperidinyl)-5-nitro-1H-indazole (4.0 g, 0.015 mol) of Example 105 and benzoyl chloride (12 ml) was heated at 100° C. (steam bath) for 4 hours. After cooling to ambient temperature, ether was added, the mixture stirred for 1 hour and then 4.9 g of a solid was collected. The solid was recrystallized twice from DMF and once from methanol to yield 2.3 g (38%) of 1-benzoyl-3-(1-methyl-4-piperidinyl)-5-nitro-1H-indazole hydrochloride, mp 297°-299° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][O:30][CH:31]([C:33]1[NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]=1)[CH3:32]>>[CH3:29][O:30][C@H:31]([C:33]1[N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32]
Reactant: COC(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CO[C@@H](C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Yield: 15.9 %

Procedure:
2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.15 g) was reacted with 2-(1-methoxyethyl)-1H-benzo[d]imidazole (97 mg) via General Procedure I for Buchwald coupling to give 32.1 mg of 516 [MS (Q1) 549.4 (M)+] and 32.4 mg of 519 [MS (Q1) 549.3 (M)+] following reverse phase purification and subsequent chiral separation.
Reaction SMILES: [CH3:1][C@:2]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH3:16])[N:9]=1.CO>C(=O)=O>[CH3:1][C@:2]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH3:16])[N:9]=1.[CH3:1][C@:2]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH3:16])[N:9]=1
Reactant: CC(Nc1nccc(N2C(=O)OC[C@]2(C)c2ccccc2)n1)c1ccc(N2CCCCC2)cc1
Agent: O=C=O
Solvent: CO
Product: C[C@@H](Nc1nccc(N2C(=O)OC[C@]2(C)c2ccccc2)n1)c1ccc(N2CCCCC2)cc1
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@]2(C)c2ccccc2)n1)c1ccc(N2CCCCC2)cc1

Procedure:
(4S)-4-methyl-4-phenyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (example 141, 51 mg) was resolved on a column (IA 4.6×100 mm) using 45% MeOH in CO2 to give (S)-4-methyl-4-phenyl-3-(2-((S)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-methyl-4-phenyl-3-(2-((R)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.[N:31]12[C:37](=[O:38])[CH2:36][CH:35]1[CH2:34][C:33](=O)[CH:32]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([O:10][C:33]2[CH2:34][CH:35]3[N:31]([C:37](=[O:38])[CH2:36]3)[C:32]=2[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[O:41])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
p-toluenesulfonic anhydride (520 mg, 1.59 mmol) and N,N-diisopropylethylamine (300 μl, 1.72 mmol) are added to an ice-cold, stirring solution of p-nitrobenzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (484 mg, 1.59 mmol) in anhydrous methylene chloride (17 ml). The resulting solution is stirred in the cold for 2 hours, then diluted with more methylene chloride, washed with water, 1μ ph 3.4 phosphate buffer and saturated aqueous sodium bicarbonate, dried with magnesium sulfate, filtered, and evaporated under vacuum. Addition of cold ethyl acetate and a few seed crystals to the oily residue induces crystallization. The product is collected, washed with cold ethyl acetate, and dried under vacuum to afford p-nitrobenzyl 3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (446 mg, 61%) as off-white crystals: mp 99°-102° (dec.); IR (neat) 1790, 1725, 1521, 1345, and 1172 cm-1 ; UV (CH2Cl2) 272 nm; NMR (CDCl3) δ 2.40 (s, 3, ArCH3), 3.06 (dd, 1, J=3.0 and 17.2, H6β), 3.16 (dd, 1, J=9.0 and 9.0, H4a), 3.31 (dd, 1, J=9.0 and 10.0, H4b), 3.59 (dd, 1, J=5.8 and 17.2, H6α), 4.24 (m, I, H5), 5.20 and 5.32 (ABq, 2, J=14.0, CH2Ar), 7.32 and 7.77 (two d's, 4, J=8.0, p-MeC6H4), 7.51 and 8.19 (two d's, 4, J=8.0, p-NO2C6H4).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C@@H:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28]([O:32][C:33]([NH:35][C:36]([CH3:41])([C:38](O)=[O:39])[CH3:37])=[O:34])([CH3:31])([CH3:30])[CH3:29].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(Cl)Cl>[CH2:1]([O:8][C:9](=[O:20])[C@H:10]([NH:11][C:38](=[O:39])[C:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])([CH3:41])[CH3:37])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
D-Homophenylalanine benzyl ester (0.87 g; 3.23 mmol), triethylamine (900 ml) and N-(t-butoxycarbonyl)-α-methylalanine (656 mg; 3.23 mmol) were dissolved in dry methylene chloride (6.5 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP-reagent) (1.43 g; 3.23 mmol) was added with stirring in small batches over 10 minutes. The reaction mixture was stirred at room temperature for 2.5 h then quenched by adding saturated brine (25 ml). The two phase system was extracted with methylene chloride (3×25 ml) and the combined methylene chloride extracts dried over magnesium sulfate powder, filtered and evaporated on a rotary evaporator under reduced pressure to give a colorless oil that solidified to an off white solid on standing at room temperature. This solid material was taken up in the minimum volume of methylene chloride and chromatographed on silica gel using an eluant composed of ethyl acetate and hexanes in the ratio 1:3 v/v. The product was isolated after evaporation of the volatiles as a white solid. The yield of the desired product was 1.30 g (88.5%). FAB-MS: -calculated for C26H34N2O5 454.2; found 455.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Yield: 88 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylate (see reference example 1) (10.2 g, 0.55 mmol) in THF (3 ml) and methanol (5 ml) was treated with 1N aqueous sodium hydroxide solution (2.7 ml) and was heated to 40° C. for 24 hours. The solvents were evaporated at reduced pressure, the residue treated with 1N acetic acid (2.7 ml) and the precipitate filtered, washed with water and air dried to give the title compound (0.17 g, 92%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg+2].[Br-].[Br-].C[Si](C)(C)O[CH:18]=[CH:19][C:20]([O:22][Si](C)(C)C)=[CH2:21].[CH3:29]C(O)=O>C1COCC1>[CH2:1]([O:8][CH2:9][CH:10]1[O:11][C:18]([CH3:29])=[CH:19][C:20](=[O:22])[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C=CO[Si](C)(C)C)O[Si](C)(C)C
Reactant: CC(=O)O
Reactant: O=CCOCc1ccccc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC1=CC(=O)CC(COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A solution of 10.4 g of the aldehyde from Step 1 in 250 ml of THF was cooled to 0° C. and 1.0 eq. of freshly prepared MgBr2 was added dropwise. The mixture was warmed to r.t. and 40.6 g of 1,3-bis(trimethylsilyloxy)-1,3-butadiene (Emde, et al., Synthesis, p. 6 (1982)) was added. After 3 h., 50% aqueous HOAc was added and the mixture was stirred 10 min. and then extracted with Et2O (2x). After the ether was evaporated, the resultant oil was taken back up in 300 ml of CH2Cl2 and 12 ml of TFA. After 3 hours, the solution was washed with H2O, saturated NaHCO3, brine and finally dried over MgSO4. After flash chromatography, 9.5 g (60%) of the title compound was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc(CO)cs2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared as in Example 3(B)(b), 130 mg, 0.29 mmol) in diethyl ether (2 mL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride (17 mg, 0.44 mmol). The reaction mixture was allowed to warm to 25° C. where it was stirred for 4 h. After 4 h at 25° C., thin layer chromatography indicated the presence of starting material. An additional amount of lithium aluminum hydride (11 mg, 0.29 mmol) was added to the reaction mixture. The resulting reaction mixture was allowed to stir at 25° C. for 15 h. The reaction mixture was then slowly quenched by the dropwise addition of water. The resulting mixture was then partitioned between water and ethyl acetate. The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, ethyl acetate) afforded 3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide (55 mg, 46%) as a white solid: mp 124–126° C.; EI-HRMS m/e calcd for C19H24N2O4S2 (M+) 408.11–78, found 408.1164.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7]([N-:10]Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Na+].II.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1.ClCCl>C(#N)C.O>[C:4]1([S:7]([N:10]2[CH2:21][CH:20]2[C:19]2[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][CH:18]=2)(=[O:9])=[O:8])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=S(=O)([N-]Cl)c1ccccc1
Reactant: C=Cc1ccc(Br)cc1
Agent: II
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: O=S(=O)(c1ccccc1)N1CC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 48.7 %

Procedure:
To a stirred suspension of chloramine B (CAS [127-52-6], 1.35 g) in acetonitrile (18 mL) under argon was added iodine (0.16 g). 4-Bromostyrene (2.41 g) was added and the mixture was stirred for 19 h at room temperature. Dichloromethane (240 mL) and water (120 mL) were added and the mixture was extracted with dichloromethane. The org. phase was washed with water and brine, dried over MgSO4 and K2CO3 and filtered. The filtrate was concentrated and the product was purified using column chromatography (SiO2, cyclohexane/ethyl acetate 95:5=>ethyl acetate) to give 1-benzenesulfonyl-2-(4-bromo-phenyl)-aziridine (1.04 g) as a colorless oil. MS: 340.0 ([M+H]+)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:11][C:12]([C:14]1[CH:36]=[CH:35][C:17]([O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]([C:29]([O:31]C)=[O:30])[CH2:24][CH2:25][O:26]3)=[CH:21][C:20]=2[C:33]#[N:34])=[CH:16][CH:15]=1)=[O:13].[OH-].[Na+].CO>C1COCC1.C(OCC)(=O)C.Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:11][C:12]([C:14]1[CH:36]=[CH:35][C:17]([O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][O:26]3)=[CH:21][C:20]=2[C:33]#[N:34])=[CH:16][CH:15]=1)=[O:13]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCc5ccccc5C4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NC3CCc4ccccc4C3)cc1)OCCC2C(=O)O
Reaction time: 1 h
Yield: 30.5 %

Procedure:
Methyl 7-(4-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (10 mg, 0.021 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (0.12 ml, 0.12 mmol) and methanol (100 μL). After stirring for 1 hour, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 7-(4-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid (3.0 mg, 31% yield). MS (ESI)=469.0 (M+H).
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:11]([Cl:23])=[CH:10][N:9]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:24]1([S:30]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:12]3[C:11]([Cl:23])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=3)=[CH:15]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Sodium tert-butoxide (529 mg, 5.50 mmol) was added portionwise over a period of 2 minutes to a mixture of 3-(2,5-dichloro-pyrimidin-4-yl)-1H-indole (Intermediate 11, 1.321 g, 5.0 mmol) and benzenesulfonyl chloride (0.645 mL, 5.00 mmol) in DMF (30 mL) at r.t. under N2. The resulting solution was stirred at r.t. for 1 h. Further benzenesulfonyl chloride (0.064 mL, 0.50 mmol) and sodium tert-butoxide (0.053 g, 0.055 mmol) were added and the mixture was stirred at r.t. for a further 0.25 h. The reaction was quenched by the addition of CH3OH (6 mL) and neutralised by the addition of solid CO2 pellets until reaching pH=7. The solvent was then removed in vacuo and the resulting residue was dissolved in CH2Cl2 (100 mL). This solution was filtered through a 20 g silica pad, and the eluted solution was diluted with isohexane (50 mL). This solution was concentrated in vacuo to give a volume of 70 mL and was then cooled. A resulting crystalline precipitate was collected by filtration, washed with isohexane/CH2Cl2 (4:1, 50 mL) and dried by suction to give the title compound (923 mg, 46%) as an off-white crystalline solid, which was used without further purification; 1H NMR: 7.39-7.53 (2H, m), 7.64 (2H, t), 7.75 (1H, t), 8.04 (1H, d), 8.11-8.17 (2H, m), 8.28 (1H, d), 8.79 (1H, s), 9.00 (1H, s); m/z: ES+ MH+ 404.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])([O-:25])=[O:24]
Reactant: COC(=O)c1ccccc1O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of methyl salicylate (15.2 g, 0.1 mol), 4-chloro-3-nitrobenzotrifluoride (22.6 g, 0.1 mol), and potassium carbonate (8.3 g, 0.06 mol) in dimethylformamide (100 mL) was stirred under argon and heated in an oil bath to 150° C. for 70 min. The reaction mixture was diluted with ethyl acetate (300 mL), filtered, and the residue washed with ethyl acetate. The combined filtrates were evaporated, and the crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane) to give the title compound as a pale yellow solid; mp 69°-70° C.