Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:75]=[C:74]([O:76][CH3:77])[CH:73]=[C:72]([O:78][CH3:79])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:31]([CH:34](/[CH:58]=[CH:59]/[C:60]1[C:65]([O:66][CH3:67])=[CH:64][C:63]([O:68][CH3:69])=[CH:62][C:61]=1[O:70][CH3:71])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([NH:43][C:44](=[O:57])[C:45]2[CH:50]=[C:49]([N+:51]([O-])=O)[CH:48]=[C:47]([N+:54]([O-])=O)[CH:46]=2)[CH:36]=1)(=[O:33])=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[C:20]([N+:27]([O-])=O)[CH:19]=2)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>O.CC(C)=O>[CH3:79][O:78][C:72]1[CH:73]=[C:74]([O:76][CH3:77])[CH:75]=[C:3]([O:2][CH3:1])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:31]([CH:34](/[CH:58]=[CH:59]/[C:60]1[C:61]([O:70][CH3:71])=[CH:62][C:63]([O:68][CH3:69])=[CH:64][C:65]=1[O:66][CH3:67])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([NH:43][C:44](=[O:57])[C:45]2[CH:50]=[C:49]([NH2:51])[CH:48]=[C:47]([NH2:54])[CH:46]=2)[CH:36]=1)(=[O:32])=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:30])[C:18]2[CH:19]=[C:20]([NH2:27])[CH:21]=[C:22]([NH2:24])[CH:23]=2)[CH:9]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc(N)cc(N)c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc(N)cc(N)c3)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4,6-trimethoxystyryl-3-(3,5-dinitrobenzamido)-4-methoxybenzylsulfone (example 5) (1.3 mmol) in acetone water (10:5) was heated to 50° C. After 30 min, sodiumhydrosulfite (Na2S2O4) (26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C., 1 h.), cooled to room temperature and water was added. The product was rinsed with NaHCO3, and then isolated by extraction with ethyl acetate. The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was recrystallized from 2-propanol to yield pure (E)-2,4,6-trimethoxystyryl-3-(3,5,diaminobenzamido)-4-methoxybenzylsulfone. m.p. 208-210° C. NMR (DMSO-d6) δ 3.76(s, 3H), 3.80(s, 6H), 3.82(s, 3H), 4.4(s, 2H), 5.9(s, 1H), 6.2(s, 2H), 7.05-8.26(m, aromatic), 8.85(s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][CH2:29]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([O:27][CH2:28][CH2:29][N:15]1[CH2:16][CH2:17][O:18][CH:13]([CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:14]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCCBr)c1ccccc1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: O=C(NCC1CN(CCOC(=O)c2ccccc2)CCO1)Nc1ccc(Cl)cc1

Procedure:
Example 39 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 2-bromoethyl benzoate (6.5 μl) to give the title compound (0.007 g). LC-MS (System A): Rt 2.69 mins, Mass Spectrum m/z 418 [MH+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[OH:35]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[Cl:27])=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1cc(F)ccc1Cl
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cc(F)ccc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 2-chloro-5-fluorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 8.06–8.04 (1H, m), 7.97–7.94 (2H, m), 7.51–7.45 (1H, m), 7.43–7.40 (2H, m), 7.12–7.00 (2H, m), 5.43–5.32 (1H, m), 1.61–1.58 (12H, m); MS (ESI) m/z 505 (M+H)+, 503 (M−H)−.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[N:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.C(O)(=O)C.O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[N:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][CH:9]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(Oc2ccc(SC)cc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CSc1ccc(Oc2cccc(C=O)n2)cc1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A solution of 38.7 g (0.141 mol) of methyl 6-(4-(methylthio)phenoxy)picolinate in 250 mL of toluene was cooled to a minus 70° C. in a dry ice-acetone bath. To the thus prepared slurry was added dropwise 285 mL of 1 Molar DIBAL-H in hexane over 1.5 hours. The solution was stirred at minus 70° C. for 20 minutes and an additional 20 mL of 1 Molar DIBAL-H in hexane was added. After 15 minutes, a solution of 187.5 mL of diether ether, 62.5 mL of glacial acetic acid and 15 mL of water was added dropwise over 1.5 hours at minus 65° C. with a white solid forming. The thus formed slurry was allowed to stir at ambient temperature overnight and the white solid was collected by filtration and washed with diether ether. The filtrate was washed thrice with 250 mL portions of water followed by washing with 250 mL of a 10 percent sodium bicarbonate solution and then with 250 mL of water. The organic layer was then dried over sodium sulfate and the solvent removed in vacuo leaving 32.4 g (94.1 percent of theoretical) of the above named compound, a white crystalline solid, melting at 60° -63° C.; 1H NMR (CDCl3) δ2.40 (s, 3H, CH3S--), 6.9-7.9 (m, 7H, ArH),9.75 (s, 1H, --CH=O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:38])(=[O:37])[CH:30]([CH:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:34]([CH:32]([CH:30]([C:29]([O-:38])=[O:37])[OH:31])[OH:33])([O-:36])=[O:35]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of tartaric acid (0.75 g) in absolute ethanol (35 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 168.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[BrH:16]>O>[Br:16][CH2:12][CH2:11][CH2:10][N:6]1[C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Reactant: Br
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCBr

Procedure:
A mixture of 9.3 parts of 5-chloro-1,3-dihydro-1(3-hydroxypropyl)-2H-benzimidazol-2-one and 83 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 6 hours. The reaction mixture was cooled and allowed to crystallize overnight at room temperature. The precipitated product was filtered off and stirred a few times in 100 parts of water till the pH of the filtrate was greater than 2. The product was stirred and refluxed for 1 hour in 55 parts of chlorobenzene with 1.3 parts of activated charcoal. The latter was filtered off and the filtrate was allowed to crystallize overnight in an ice-box. The product was filtered off and recrystallized twice: first from chlorobenzene (activated charcoal) and then from methylbenzene (activated charcoal), yielding 4.9 parts of 1-(3-bromo- propyl)-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 161.5° C. (intermediate 29).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH3:12][N:13]([CH3:21])[CH:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[C:10]2[C:9]([NH:20][CH:17]3[CH2:18][CH2:19][CH:14]([N:13]([CH3:21])[CH3:12])[CH2:15][CH2:16]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: CN(C)C1CCC(N)CC1
Reactant: Clc1ncnc2scc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCC(Nc2ncnc3scc(Br)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50-mL round-bottom flask was charged with commercially available 5-bromo-4-chlorothieno[2,3-d]pyrimidine (300 mg, 1.20 mmol, 1.00 equiv), 1-N,1-N-dimethylcyclohexane-1,4-diamine (205 mg, 1.44 mmol, 1.20 equiv), potassium carbonate (497 mg, 3.60 mmol, 3.00 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 250 mg (59%) of 4-N-[5-bromothieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:12](=[CH2:13])[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:3][CH:4]=1)#[N:10]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: N#CCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC(C)(C)C)c1ccc(CC#N)cc1
Temperature: 25 °C

Procedure:
p-Bromophenylacetonitrile (50 g), t-butyl acrylate (46 ml), palladium (II) acetate (575 mg) and tri-o-tolylphosphine (3.1 g) are combined with 125 ml triethylamine in a steel pressure reactor and heated at 140° for 16 hours. The reaction mixture is cooled to room temperature and poured into 500 ml 3N hydrochloric acid at 0°. The solids are extracted into ethyl acetate and the ethyl acetate solution is extracted with saturated NaCl solution and dried over magnesium sulfate. The crude product is triturated with ether:hexane (1:1), filtered and dried under vacuum to yield t-butyl p-(cyanomethyl)-phenylacrylate; m.p. 80°-82°; NMR (CDCl3): 7.5 (2H,d), 7.32 (2H,d), 6.39 (2H,d), 3.78 (2H,s), 1.52 (9H,s).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.[C:36]([OH:39])(=[O:38])[CH3:37].[H][H]>CO.[Pd]>[C:13]([OH:15])(=[O:14])[CH3:12].[C:36]([OH:39])(=[O:38])[CH3:37].[C:13]([OH:15])(=[O:14])[CH3:12].[NH2:11][C@@H:12]([CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@H](CCCNC1CCN(c2ccncc2)CC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H](N)CCCNC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of the product of step (iii) (1.34 g) and acetic acid (0.48 ml) in methanol under argon was added 10% Pd on C.(100 mg). The mixture was covered with a blanket. of hydrogen and stirred at room temperature for 4 hr. The catalyst was then removed by filtration through a pad of kieselguhr and the pH of the filtrate was adjusted to 4 by addition of acetic acid. To this mixture, under argon, was then added a further quantity of 10% Pd on C (100 mg), it was covered again with hydrogen and stirred at room temperature for 3 days. The catalyst was filtered off through a pad of kieselguhr and the filtrate was evaporated to dryness. Toluene (100 ml) was then added to the residue and the solvents were again removed in vacuo to give tert. butyl (S)-2-amino-5-[1-(4-pyridyl)piperidin-4-yl]aminopentanoate, triacetate salt (1.68 g) as a yellow gum: NMR (d6-DMSO+CD3CO2D) δ 1.49 (9H, s), 1.70 (6H, m), 2.23 (2H, m), 3.03 (2H, m), 3.25 (2H, m), 3.50 (1H, m), 3.96 (1H, m), 4.30 (2H, m), 7.18 (2H, d), 8.20 (2H, d); m/Z 349 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]1([C:36](Cl)=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 1-naphthoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.NN>CO>[N+:11]([C:5]1[CH:4]=[N:3][CH:2]=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: NN
Solvent: CO
Product: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
A sample of 2-chloro-3,5-dinitropyridine is dissolved in methanol, hydrazine is added, and the reaction mixture is stirred for 16 hours. The solvent is removed, the residue is dissolved in water, silver acetate is added, and the mixture is heated at reflux for 3 hours. The solution is adjusted to a basic pH, and product is extracted with CHCl3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28]C)[C:25]=1[O:26]C)[C:6]([NH:8][C:9]1[S:10][C:11]([CH3:22])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[N:13]=1)=[O:7].B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([OH:28])[C:25]=1[OH:26])[C:6]([NH:8][C:9]1[S:10][C:11]([CH3:22])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)=[O:7]
Reactant: COc1ccc(-c2nc(NC(=O)c3cc(OC)c(OC)c(OC)c3)sc2C)cc1
Agent: BrB(Br)Br
Product: Cc1sc(NC(=O)c2cc(O)c(O)c(O)c2)nc1-c1ccc(O)cc1
Yield: 60.5 %

Procedure:
A procedure similar to that in Example 7 was used. 3,4,5-trimethoxy-N-[4-(4-methoxy-phenyl)-5-methyl-thiazol-2-yl]-benzamide prepared in Example 53 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 60.5%, mp: 262-263 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 2.36 (3H, s, CH3), 6.76 (2H, d, J=8.80 Hz, ArH), 7.02 (2H, s, ArH), 7.41 (2H, d, J=8.80 Hz, ArH), 9.10 (2H, br, OH), 9.50 (1H, br, OH), 12.06 (1H, br, CONH); EI-MS m/e (%): 358.1 (M+, 25), 206.2 (100), 153.1 (20); HREI-MS Calcd. for C17H14N2O5S: 358.0623. found: 358.0621.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]([NH:9]C(OC)=O)[CH2:5][CH2:6][CH2:7][CH3:8].[ClH:15].C(O)=O>O>[ClH:15].[NH2:9][CH:4]([C:3]([OH:14])=[O:2])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(NC(=O)OC)C(=O)OC
Agent: Cl
Solvent: O=CO
Solvent: O
Product: CCCCC(N)C(=O)O
Yield: 97.3 %

Procedure:
4.07 grams of 2-methoxycarbonylaminohexanoic acid methyl ester were heated in 15 ml of a mixture consisting of equal parts of concentrated hydrochloric acid, 100 weight percent formic acid and water for 24 hours under reflux. The acid mixture was removed in a vacuum, the oily residue treated twice with 20 ml of acetone and freed from acetone again in a vacuum. The now crystalline residue was intensively stirred with 10 ml of acetone, filtered with suction and dried over diphosphorus pentoxide. There were obtained 3.26 grams (97.3%) of D,L-norleucine hydrochloride pure by thin layer chromatography.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][C@@H:16]([C:25]([OH:27])=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.Cl.[N:30]1([C:36]2[N:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]3=[N:38][CH:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>CN(C=O)C.O>[C:11]([O:10][C:8](=[O:9])[NH:15][C@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:25]([N:33]1[CH2:34][CH2:35][N:30]([C:36]2[N:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]3=[N:38][CH:37]=2)[CH2:31][CH2:32]1)=[O:27])([CH3:12])([CH3:13])[CH3:14]
Reactant: c1ccn2c(N3CCNCC3)cnc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2cnc3ccccn23)CC1
Reaction time: 12 h
Yield: 66.3 %

Procedure:
Triethylamine (0.30 mL, 2.18 mmol) was added to a solution of (R)—N-Boc-4-chlorophenylalanine (392 mg, 1.31 mmol), 3-piperazin-1-yl-imidazo[1,2-a]pyridine dihydrochloride (300 mg, 1.09 mmol), and 1-hydroxybenzotriazole (177 mg, 1.31 mmol) in DMF (5 mL) followed by the addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (251 mg, 1.31 mmol) in a single portion. After being stirred for 12 hours, the mixture was diluted with H2O, basified to pH 12 with 1.0 M NaOH, and extracted with DCM. The DCM extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was chromatographed (SiO2) using DCM:Et2O (1:1) followed by 10% MeOH/DCM as eluent to give (R)-[1-(4-chlorobenzyl)-2-(4-imidazo[1,2-a]pyridin-3-yl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (350 mg).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29].CN(C1C=CC=CN=1)C.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:28]([Si:32]([CH3:34])([CH3:33])[O:27][CH2:26][CH2:25][C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1-trityl-1H-imidazol-4-yl)-ethanol (5.21 g, 14.7 mmol) in DMF (20 mL) is added tert-butylchlorodimethylsilane (2.44 g, 16.1 mmol), dimethylaminopyridine (0.179 g, 1.47 mmol) and imidazole (3.00 g, 44.1 mmol). The reaction mixture is stirred for 2 h at room temperature. It is then diluted with ethyl acetate and washed with water thrice. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane-ethanol, 7:3) to give 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1-trityl-1H-imidazole product, which is used in the next step without further purification; MS (ESI) m/z 469.3 (M+H)
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:4]=1)=O.C([N:17](CC)CC)C.Cl.NO>C(OC(=O)C)(=O)C>[C:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:4]=1)#[N:17]
Reactant: O=Cc1ccn(-c2ccccc2O)c1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccn(-c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
2-(3-Formyl-1-pyrrolyl)phenol (3 g, 16 mmol) and triethylamine (17.6 mmol) are added to a suspension of hydroxylamine hydrochloride (1.22 g, 17.6 mmol) in acetic anhydride (7.7 ml) and is allowed to stir overnight at ambient temperature. The mixture is refluxed for 5 hours, concentrated, dissolved in 50 ml ethanol and stirred for 10 minutes with 50 ml 2 M aqueous sodium hydroxide. After neutralisation with aqueous hydrochloric acid, and extraction with ethyl acetate, the organic layer is dried and concentrated. The residue is purified by chromatography (toluene/ethanol 9:1) to yield 2.4 g of 2-(3-cyano-1-pyrrolyl)phenol (92%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH3:14])([CH3:13])[O:11][B:10]([OH:15])[C:9]=2[CH:16]=1)([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:50][C:51]1[CH:59]=[C:58]([C:60]2[CH2:64][C:63]([C:69]3[CH:74]=[C:73]([Cl:75])[C:72]([Cl:76])=[C:71]([Cl:77])[CH:70]=3)([C:65]([F:68])([F:67])[F:66])[O:62][N:61]=2)[CH:57]=[CH:56][C:52]=1[C:53](O)=[O:54]>C1COCC1.CC(=O)OCC>[OH:15][B:10]1[C:9]2[CH:16]=[C:5]([C:2]([NH:1][C:53](=[O:54])[C:52]3[CH:56]=[CH:57][C:58]([C:60]4[CH2:64][C:63]([C:69]5[CH:74]=[C:73]([Cl:75])[C:72]([Cl:76])=[C:71]([Cl:77])[CH:70]=5)([C:65]([F:68])([F:67])[F:66])[O:62][N:61]=4)=[CH:59][C:51]=3[CH3:50])([CH3:4])[CH3:3])[CH:6]=[CH:7][C:8]=2[C:12]([CH3:14])([CH3:13])[O:11]1
Reactant: CC(C)(N)c1ccc2c(c1)B(O)OC2(C)C
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC(C)(C)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of 6-(2-aminopropan-2-yl)-3,3-dimethylbenzo[c][1,2]-oxaborol-1(3H)-ol (100 mg), HATU (277 mg, 0.73 mmol) and DIPEA (0.2 mL, 1.1 mmol) in THF (5 mL) was added 2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (80 mg, 0.37 mmol). The reaction mixture was stirred at rt overnight. EA was added and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the final title compound N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)propan-2-yl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (100 mg; yield 38% over 3 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.64 (s, 1H), 7.85 (s, 2H), 7.74 (s, 1H), 7.47-7.55 (m, 4H), 7.36 (d, J=8.4 Hz, 1H), 4.41 (d, J=18.4 Hz, 1H), 4.34 (d, J=18.4 Hz, 1H), 2.33 (s, 3H), 1.66 (s, 6H), 1.44 (s, 6H) ppm; HPLC purity: 99.29% at 220 nm and 99.63% at 254 nm; MS: m/z=653.8 (M+1, ESI+).