Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[N:4]([CH3:18])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:9]=2[CH3:17])[CH:7]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>[Fe].C(O)C>[NH2:14][C:10]1[C:9]([CH3:17])=[C:8]([C:6]2[CH:7]=[C:2]([Br:1])[C:3](=[O:19])[N:4]([CH3:18])[CH:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1c(-c2cc(Br)c(=O)n(C)c2)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cc1c(N)cccc1-c1cc(Br)c(=O)n(C)c1
Temperature: 25 °C
Yield: 111.6 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a mechanical stirrer was charged with 3-bromo-1-methyl-5-(2-methyl-3-nitrophenyl)pyridin-2-one (11) (0.70 g, 2.17 mmol), ethanol (15 mL), iron powder (−325 mesh, 1.20 g, 21.7 mmol), 2N hydrochloric acid (1.09 mL, 2.17 mmol) and stirred at reflux for 4 h. After this time the reaction was cooled to room temperature and solid potassium carbonate (0.738 g, 5.35 mmol) was added. The suspension was stirred for 0.5 h and then filtered through a pad of Celite 521. The filter cake was washed with ethanol (3×15 mL) and the combined filtrates were concentrated to a constant weight under reduced pressure to afford 0.71 g (88%) of 5-(3-amino-2-methylphenyl)-3-bromo-1-methylpyridin-2-one (12) as a yellow oil: 1H NMR (300 MHz, CDCl3) 7.75 (dd, 1H, J=2.1 Hz), 7.23 (d, 1H, J=2.1 Hz), 7.05 (t, 1H, J=7.8 Hz), 6.72 (d, 1H, J=7.8 Hz), 6.60 (d, 1H, J=7.2 Hz), 3.75 (br s, 2H), 3.66 (s, 3H), 2.07 (s, 3H); MS (ESI+) m/z 293 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36]>C1COCC1.CC#N>[C:35]([NH:39][C:9]([C:6]1[CH:5]=[C:4]([CH2:3][C:2]([CH3:1])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:11])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)Cc1cc(C(=O)O)no1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)Cc1cc(C(=O)NC(C)(C)C)no1
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2,2-dimethyl-propyl)-isoxazole-3-carboxylic acid (125.4 g, 0.685 mol) in THF (1500 ml) and MeCN (1500 ml) is added HOBT (101.75 g, 0.753 mol) and EDCI (144.3 g, 0.753 mol). After stirred 30 min, tert-butyl amine (86.7 ml, 0.821 mol) is added dropwise under nitrogen atmosphere and then the reaction is stirred at rt for 1.5 h. The solvents are evaporated under reduced pressure and the residue is taken into DCM (2000 ml). The mixture is washed with saturated aq sodium bicarbonate (500 ml×2), the organic layer is dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica (DCM) to give the product as white solid.
Reaction SMILES: [NH:1](C(C)=O)[C@H](C(N[C@H](C(O)=O)CCCCN)=O)CC1C=CC=CC=1.N(C(C)=O)[C@H](C(N[C@H](C(O)=O)CCCCNC(=C1C(=O)CC(C)(C)CC1=O)CC(C)C)=O)CC1C=CC=CC=1.C(O)(C(F)(F)F)=O.N1CCCCC1.NN.[NH2:79][C@H:80]([C:88]([OH:90])=[O:89])[CH2:81][C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1.N[C@H](C(O)=O)CCCCN>C(Cl)Cl.CS(C)=O>[NH3:1].[NH2:79][C@H:80]([C:88]([OH:90])=[O:89])[CH2:81][C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(CC(C)C)=C1C(=O)CC(C)(C)CC1=O)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Agent: NN
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N

Procedure:
Ac-Phe-Lys-OH and Ac-Phe-Lys(ivDde)-OH. Cleavage of the synthesized peptides from resin was accomplished using 1% TFA in DCM (twice resin bed volume) for 2 min. For each sample, aliquots were dried on a speed-vac and directly used for HPLC or MALDI-TOF analysis. HPLC Column was reverse phase (Waters RP-18, 8C1810μ). Elute solvents were water and acetonitrile containing 0.1% or 0.08% TFA, respectively. The gradient used was 15 to 95% of water in acetonitrile in 16 min with a flow rate of 3 mL/min. Ac-Phe-Lys(ivDde)-OH by photogenerated piperidine synthesis, Rt=8.55 min; piperidine synthesis, Rt=8.57 min. Ac-Phe-Lys-OH, by photogenerated piperidine and hydrazine synthesis, Rt=3.55 min; regular synthesis (piperidine and hydrazine) Rt=3.54 min 1H NMR (300 MHz, DMSO d6): Ac-Phe-Lys(ivDde)-OH synthesized using either photogenerated piperidine or piperidine gave identical NMR spectra; δ 13.60 (s, 1H, NH), 12.62 (br s, COOH), 8.27 (d, J=8.1 Hz, 1H, CONH), 8.06 (d, J=7.8 Hz, 1H, CONH), 7.22 (m, 5H, ArH), 4.51 (m, 1H, αCH), 4.18 (m, 1H, αCH), 3.38 (m, Phe βCH2, Lys εCH2), 3.00 (m, 2H; ivDde CH2), 2.25 (s, 4H, ivDde CH2), 1.80 (m, βCH2), 1.72 (s, CH3), 1.58 (m, ivDde CH, Lys δCH2), 1.40 (m, 2H, γCH2), 0.92 (s, 6H, CH3), 0.88 (s, 6H, CH3). Ac-Phe-Lys-OH (both dipeptides synthesized using either photogenerated piperidine and hydrazine versus piperidine and hydrazine-gave identical NMR spectra), δ 12.67 (br s, COOH), 8.31 (d, J=7.8 Hz, 1H, CONH), 8.09 (d, J=7.8 Hz, 1H, CONH), 7.65 (s, NH3)H, 7.22 (m, 5H, ArH), 4.51 (m, 1H, αCH), 4.18 (m, 1H, αCH), 3.34 (m, 1H, Phe βCH), 2.98 (m, 1H, Phe βCH), 2.74 (m, 2H, εCH2), 1.72 (s, 3H, CH3), 1.58 (m, βCH2), 1.55 (m, δCH2), 1.34(m, γCH2). Mass analysis (MALDI-TOF): calculated for Ac-Phe-Lys(ivDde)-OH 541.7, found 541.9 for that by photogenerated piperidine synthesis and found 541.8 for that by piperidine; calculated for Ac-Phe-Lys-OH 335.4, found 335.5 for that by photogenerated piperidine and hydrazine, found 335.5 for that by piperidine and hydrazine.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1>CSC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:3][CH2:2][CH2:1][N:4]=[C:5]=[O:6])=[CH:10][CH:9]=1
Reactant: C=CCN=C=O
Reactant: Sc1ccc(Cl)cc1
Solvent: CSC
Product: O=C=NCCCSc1ccc(Cl)cc1

Procedure:
A solution of 41.5 grams (0.5 mole) of allyl isocyanate and 72.25 grams (0.5 mole) of p-chlorobenzenethiol in 50 ml dimethyl sulfide was irradiated with an ultraviolet lamp in the manner described in Example 1. Nmr indicated that in 48 hours 32% of the allylic double bonds reacted with the thiol to form the allylic monoadduct, i.e. 3-p-chlorophenylthiopropyl isocyanate. No other products could be observed.
Reaction SMILES: N1C=[CH:4][CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10]CC[CH2:7]1>>[CH3:10][N:6]([CH2:11][C@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH2:3][CH3:4])[CH3:7]
Reactant: c1cn[nH]c1
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Product: CC[C@H](CN(C)C)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (R)—N,N-dimethyl-1,2-butanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: [CH2:1]([O:19][P:20]([C:41](=[CH2:52])[CH2:42][CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:21])[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][CH2:16][CH2:17][CH3:18].[S].[H-].[Na+]>[P].C1COCC1>[CH2:1]([O:19][P:20]([CH:41]([CH2:52][CH2:41][P:20]([O:19][CH2:1][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][CH2:16][CH2:17][CH3:18])([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:21])[CH2:42][CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:21])[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][CH2:16][CH2:17][CH3:18]
Reactant: C=C(CCCC(=O)OC(C)(C)C)P(=O)(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC
Agent: [H-]
Agent: [Na+]
Agent: [P]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOP(=O)(CCC(CCCC(=O)OC(C)(C)C)P(=O)(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC

Procedure:
Dioctadecyl hydrogen phosphonate may be reacted with tert-butyl 5-(bis(octadecyloxy)phosphoryl)hex-5-enoate, D, prepared in Example 4 using substantially the conditions found in Phosphorus, Sulfur and Silicon and the Related Elements, 83 (1-4), 77-98:1993 and outlined in FIG. 6. Thus, dioctadecyl hydrogen phosphonate (MW 586.95, 1.56 g, 2.66 mmol), dissolved in THF (30 mL) and sodium hydride (95%, FW 24.0, 2.66 mmol, 0.064 g) are allowed to react under inert atmosphere at RT with stirring. Then tert-butyl 5-(bis(octadecyloxy)phosphoryl)hex-5-enoate (MW 1356.2, 3.65 g, 2.69 mmol) in THF is added and allowed to react under an inert atmosphere until the reaction is complete. The reaction progress may be followed by TLC, rphplc or 31P nmr. At the completion of reaction the solvent may be removed by evaporation and the crude product purified by normal phase flash chromatography using a suitable solvent system (e.g., hexanes-ethyl acetate gradient (ELSD detection) to yield substantially pure product. The crude product may also be purified using reverse phase HPLC (e.g., C4, 300 A, and a suitable solvent gradient, e.g., water;isopropanol). The MS of the desired product is M+H+ 1357.2, M+Na+ 1379.2.
Reaction SMILES: [CH:1]1([OH:12])[CH:6]([OH:7])[CH:5]([OH:8])[CH:4]([OH:9])[CH:3]([OH:10])[CH:2]1[OH:11].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].B(OB([O-])[O-])([O-])[O-]>O.[Ni]>[C@@H:6]1([OH:7])[C@@H:5]([OH:8])[C@H:4]([OH:9])[C@@H:3]([OH:10])[C@H:2]([OH:11])[C@H:1]1[OH:12]
Reactant: OC1C(O)C(O)C(O)C(O)C1O
Agent: [Ni]
Agent: [Na+]
Agent: [O-]B([O-])OB([O-])[O-]
Solvent: O
Product: O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 97.5 °C

Procedure:
The first step for the preparation of scyllitol diborate involves a sponge nickel mediated isomerization of myo-inositol in water near reflux to yield a mixture of inositols consisting of roughly 22% scyllitol (as judged by HPLC). After separating the crude reaction mixture from the nickel, scyllitol is selectively converted to scyllitol diborate by treatment with sodium tetraborate at 80-90° C. and pH 9-10. Scyllitol diborate is then crystallized by cooling and is isolated in 17-20% yield and >99% HPLC purity (AUC). All six batches of diborate proceeded as expected (Table 1). The isomerization reactions required 2-3 hours to heat to 95-100° C. and each were sampled for analysis after 1, 2, and 3 hours. All five reactions resulted in myo/scyllo ratios of 2-3:1 (typical) by 1H NMR and all but one batch resulted in >20% AUC (HPLC Analysis) scyllo-inositol (Table 2). The diborate formations resulted in myo/scyllo ratios of >60:1 (typical) by 1H NMR (Table 2) within one hour and the subsequent crystallizations were allowed to proceed over 14-16 hours (overnight). The resulting diborate slurries filtered very fast and were isolated as large white crystals. The diborate filter cakes were found to have consistent 1H NMR spectra, HPLC purities of 98.7%-99.2% AUC and moisture levels of 46.8%-56.4%. Nickel and aluminum analysis revealed levels ranging from <1 ppm to 17 ppm for nickel and <1 ppm to 28 ppm for aluminum. The yields corrected for moisture content ranged from 17.1% to 20.3%.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)CCOC(=O)[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:34])[CH3:33])=[C:28]([Cl:35])[CH:27]=1>O1CCCC1>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:34])[CH3:33])=[C:28]([Cl:35])[CH:27]=1
Reactant: CC(O)c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)c1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL) is added to [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester (0.5 g) and the mixture is stirred at room temperature for approximately 3.5 hours. The solution is then concentrated under reduced pressure, dissolved in a 1:1 mixture of ethyl acetate and hexanes, washed successively with water then saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure followed by chromatography over silica gel (40% ethyl acetate in hexanes is used as the eluant) provides the product as an amber oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccncc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
To a suspension of 3.05 g of 60% sodium hydride (76.0 mmol) in toluene (50 mL) in a 250 mL RB flask was added 12.2 g of diethyl malonate (76.0 mmol) dropwise. The reaction mixture was stirred for 30 min under nitrogen, and a solution of 10.8 g of 4-chloro-3-nitropyridine (prepared according to the procedure of Houston et al. J. Med. Chem. 1985, 28, 467) in toluene (50 mL) was added dropwise and the resulting mixture refluxed for 4 hours. The reaction mixture was concentrate, and the residue was partitioned between 100 mL each of dilute hydrochloric acid and diethyl ether. The aqueous phase was extracted twice with 100 mL of ether, and the combined ether phases were dried over magnesium sulfate and concentrated to give a dark oil. This was chromatographed on silica gel eluting with a hexane-30% hexane/EtOAc gradient to give 3.5 g of the title compound as a colorless oil which crystallized on standing. 1H NMR (DMSO-d6): δ 1.15 (t, J=7.1 Hz, 6H), 4.16 (q, J=7.1 Hz, 4H), 5.55 (s, 1H), 7.59 (d, J=5.1 Hz, 1H), 8.89 (d, J=5.1 Hz, 1H), 9.24 (s, 1H); C12H14N2O6: APES-MS m/z 281 (M−H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[C:3]([CH:12]=O)=[N:2]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:12]1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[NH:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)[NH:1][N:2]=1
Reactant: O=Cc1cccc2[nH]nc(C=O)c12
Reactant: Nc1ccccc1N
Product: c1ccc2[nH]c(-c3cccc4[nH]nc(-c5nc6ccccc6[nH]5)c34)nc2c1

Procedure:
The title compound is prepared using the procedure described in Example 4 from 1H-indazole-3,4-dicarbaldehyde and an excess of 1,2-diaminobenzene.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([O:8][C:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(O)CC1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCC(Oc2ncnc3c([N+](=O)[O-])cccc23)CC1
Reaction time: 0.33 h
Yield: 48.4 %

Procedure:
To a solution of 4,4-dimethylcyclohexanol (140 mg, 1.097 mmol) in THF (2 mL) was added NaH (43 mg, 1.097 mmol, 60% in mineral oil) at 0° C. Then the reaction mixture was stirred at that temperature for 20 min and 4-chloro-8-nitroquinazoline (Intermediate-7, step 2, 115 mg, 0.549 mmol) was added to the reaction mixture. Then the reaction mixture was stirred at 0-5° C. for 4 h and then at rt for 12 h. Then the reaction mixture was quenched with water and was extracted with chloroform. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography using chloroform to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.89 (s, 1H), 8.49-8.46 (d, J=7.8 Hz, 1H), 8.45-8.42 (d, J=7.8 Hz, 1H), 7.86-7.80 (t, J=8.4 Hz, 1H), 5.41 (m, 1H), 1.94 (m, 2H), 1.82-1.79 (m, 2H), 1.54 (m, 2H), 1.37-1.34 (m, 2H), 0.99 (s, 3H), 0.67 (s, 3H); MS (m/z): 301.93 (M+H)+.
Reaction SMILES: ClCCl.C([O:6][C:7](=[O:37])[CH:8]([NH:30][C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH:11]=1)C.[Cl:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:40]=1[C:41](Cl)=[O:42].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:34]([O:33][C:31]([NH:30][CH:8]([CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:29])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:41](=[O:42])[C:40]3[C:39]([Cl:38])=[CH:47][CH:46]=[CH:45][C:44]=3[Cl:48])=[CH:26][CH:27]=2)[CH:11]=1)[C:7]([OH:6])=[O:37])=[O:32])[CH:35]=[CH2:36]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc(N)cc2)no1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
A dichloromethane (1 mL) solution 2-allyloxycarbonylamino-3-(3-{1-[(4-amino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic acid ethyl ester (80 mg, 0.170 mmol) was cooled to 0° C. and 2,6-dichlorobenzoylchloride (39 mg, 0.187 mmol) was added. The mixture was stirred for 15 minutes then pyridine (28 μL, 0.34 mmol) was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water, 1M sodium hydroxide and brine. The organic portion was dried over magnesium sulfate and concentrated to give the title compound (84 mg, 78%). MS (Cl) m/z 635.3 (M+1), 632.5 (M−1) C. 2-Allyloxycarbonylamino-3-(3-{1-[(4-amino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)propionic acid ethyl ester
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:29]1[C:37]2[C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[S:34][C:33]=2[C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:32]3[C:33]4[S:34][C:35]5[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=5[C:37]=4[CH:29]=[CH:30][CH:31]=3)=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Product: O=C(O)c1c(-c2ccccc2)c2cc(Nc3cccc4c3sc3ccccc34)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and 4-dibenzothiopheneboronic acid according to the procedure of Example 1 Step 3 as a black solid: 1H NMR (DMSO-d6) δ 5.82 (s, 2 H), 7.00-8.20 (m, 27 H); MS (ESI) m/z 525 (MH+); HRMS calcd. for C34H25N2O2S: 525.1637; found (ESI+): 525.1622; Anal. calcd. for C34H24N2O2S.0.3ACN: C, 74.88; H, 4.89; N, 5.81. Found: C, 75.14; H, 4.53; N, 5.82.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Product: O=[N+]([O-])c1cc(Cl)ccc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,5-dichloronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:24][CH3:25])[N:20]=[C:21]([O:22]C)[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:24][CH3:25])[NH:20][C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1nc(SC)nc2c1ccn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Temperature: 105 °C
Reaction time: 36 h
Yield: 68.1 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-4-methoxy-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (0.615 g) was dissolved in dioxane (6 ml) followed by addition of 4,41-thiobis(6-t-butyl-m-cresol) (7 mg). Then, 0.5N-HCl (1.2 ml) was added and the mixture was stirred at 105° C. for 36 hours. Thereafter, 0.5N-HCl (1.2 ml) was added again and the mixture was further stirred at the same temperature as above for 24 hours. After cooling to room temperature, the precipitate was collected by filtration, washed with methanol and ether, and dried to provide the title compound (0.405 g) 1H-NMR (DMSO-d6) δ: 2.53(3H,s), 5.42(2H,s), 6.44(1H,d,J=3.4Hz), 7.15(1H,d,J=3.4Hz), 7.45(2H,d,J=8.OHz), 7.60(2H,d,J=8.4Hz), 7.72(2H,d,J=8.OHz), 7.73(2H,d,J=8.4Hz), 12.18(1H,s).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH3:18])=[CH:4][CH:3]=1.ClC(Cl)C(O)=O.[CH2:27]([C@@H:34]1N[C@H](C(C)(C)C)N(C)[C:35]1=[O:44])[C:28]1C=CC=CC=1.C(=O)/C=C/C>C(O)(C)C.C(Cl)Cl>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C@H:27]([CH3:28])[CH2:34][CH:35]=[O:44])=[C:8]2[CH3:18])=[CH:4][CH:3]=1
Reactant: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Reactant: COc1ccc2c(c1)cc(C)n2Cc1ccc(Br)cc1
Agent: C/C=C/C=O
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc2c(c1)c([C@H](C)CC=O)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 420.1 %

Procedure:
To 1-(4-bromo-benzyl)-5-methoxy-2-methyl-1H-indole (110 mg, 0.333 mmol) in a 2-dram amber vial was added CH2Cl2 (0.60 mL), isopropanol (0.066 mL), dichloroacetic acid (5.5 μL, 0.066 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (16.4 mg, 0.066 mmol). This solution was stirred for 10 min at room temperature, then placed in a −70° C. bath for an additional 10 min. At this time, crotonaldehyde (82 μL, 1.0 mmol) was added and the reaction was stirred at −70° C. for 9 h. The reaction mixture was then transferred cold through a silica plug into a flask and concentrated to provide, after silica gel chromatography (20:80 EtOAc/hexanes), the title compound as a colorless oil (111 mg, 84% yield, 87% ee). IR (film) 2930, 2823, 2730, 1722, 1618, 1581, 1530, 1483, 1452, 1405, 1229, 1156, 1073, 1037, 1011, 902, 798, 476 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.69 (dd, J=1.8, 1.8 Hz, 1H, CHO), 7.38 (dt, J=2.4, 9.0 Hz, 2H, ArH), 7.12 (d, J=2.1 Hz, 1H, ArH), 7.05 (d, J=9.0, 1H, ArH), 6.79-6.75 (m, 3H, ArH), 5.19 (s, 2H NCH2), 3.88 (s, 3H, OCH3), 3.66 (dt, J=7.2, 22.2 Hz, 1H ArCH), 3.02 (ddd, J=1.8, 8.1, 16.5 Hz, 1H, CH2CO); 2.85 (ddd, J=2.1, 6.6, 16.5 Hz, 1H, CH2CO); 2.30 (s, 3H, ArCH3) 1.48 (d, J=7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 202.5, 153.6, 137.0, 132.7, 132.0, 131.9, 127.6, 126.6, 121.1, 114.5, 110.0, 109.8, 102.3, 56.2, 50.6, 46.2, 26.4, 21.4, 10.9; HRMS (CI) exact mass calcd for (C21H22BrNO2) requires m/z 399.0834, found m/z 399.0833. [α]D=−20.8 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel OD-H and OD guard column (4:96 ethanol/hexanes, 1 mL/min); S isomer tr=45.1 min and R isomer tr=35.9 min.