Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=2)[N:6]=[C:5]1Cl.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].C(O)C>CC(N(C)C)=O>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:21]1[C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:14])[N:4]2[CH2:3][CH2:2]1)=[CH:11][C:10]([Cl:15])=[CH:9][CH:8]=3
Reactant: O=c1c2cc(Cl)ccc2nc(Cl)n1CCCl
Reactant: NCc1ccccc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: O=c1c2cc(Cl)ccc2nc2n1CCN2Cc1ccccc1Cl

Procedure:
A solution of 1.0 g. of 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydroquinazolin-4-one and 1.5 g. of 2-chlorobenzylamine in 50 ml. of ethanol and 1.0 ml of dimethylacetamide is stirred and heated at reflux for 12 hours. The solvent is removed by evaporation in vacuo and the residue dissolved in methylene chloride, washed with water, treated with charcoal, filtered and concentrated in vacuo to obtain a solid which is recrystallized from methylene chloride/pentane and filtered to obtain 1-(o-chlorobenzyl)-7-chloro-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1H)-one, m.p. 173°-174° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:11]Br>O>[Br:11][CH:3]([C:2](=[O:1])[CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CC
Reactant: BrBr
Solvent: O
Product: CCOC(=O)C(Br)C(=O)CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a 0° C. solution of ethyl 3-oxopentanoate (5.0 mL, 34.7 mmol) in water (30 mL) was added bromine (1.8 mL, 35.0 mmol) via syringe pump (0.5 hour). The mixture was stirred at 0° C. for 0.5 hour. The solution was extracted with EtOAc (2×35 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 2-bromo-3-oxopentanoate (7.3 g, 94% yield). The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][N:10]1[CH2:15][CH2:14][C:13](O)([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:9][N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3].[CH2:24]([C@H:8]([NH2:7])[CH2:9][N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:14][CH2:15]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccsc1C1(O)CCN(C[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccsc1C1=CCN(C[C@@H](N)Cc2ccccc2)CC1
Product: COc1ccsc1C1=CCN(C[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.2 g (5 mmol) (S)-{1-benzyl-2-[4-hydroxy-4-(3-methoxy-thiophen-2-yl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester in 20 mL tetrahydrofuran was treated at once with 20 mL 3M hydrochloric acid. The reaction mixture was stirred at ambient temperature overnight and then extracted with 50 mL diethyl ether. The remaining aqueous layer was basefied with sodium bicarbonate powder and extracted with chloroform (3×60 mL). The combined organic extract was dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue was flash chromatographed on 60 g silica gel. Elution with 2% methanol in chloroform yielded both, 100 mg of the title compound as a yellowish oil and 700 mg of (1S)-1-benzyl-2-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethylamine as an amber oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]=1[C:16]([F:19])([F:18])[F:17])[CH3:2].[H-].[Na+].[C:23](Cl)(=[O:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[N:8]([C:23](=[O:25])[CH3:24])[C:7]=1[C:16]([F:17])([F:18])[F:19])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of (5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (4.90 g, 17.2 mmol) in DMF (25 mL) is added a suspension of 60% NaH in mineral oil (824 mg, 20.6 mmol). The reaction mixture is stirred for 1 h at room temperature. After cooling to 0° C. acetylchloride (1.84 mL, 25.8 mmol) is added dropwise. The resulting reaction mixture is stirred for 1 h at room temperature, quenched with an aqueous saturated NH4Cl solution and partitioned between water and EtOAc. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, cyclohexane/EtOAc 95:5) affords the title compound as a yellow solid (2.89 g, 8.83 mmol, 51%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.75 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.91 (q, J=2.2 Hz, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 1.24 (t, J=7.1 Hz, 3H). MS (ES+): 345 (M(C16H16F3NO3)+H2O)+.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4]CC=C.[Br:9]N1C(=O)CCC1=O.[C:17]([OH:21])(C)([CH3:19])[CH3:18].O>>[Br:9][CH2:18][CH:17]([OH:21])[CH2:19][CH2:4][CH2:3][CH2:2][CH2:1][OH:8]
Reactant: CC(C)(C)O
Reactant: C=CCCCCCO
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Product: OCCCCCC(O)CBr
Reaction time: 68 h

Procedure:
To a solution of 3 (500 mg, 4.38 mmol) in t-butanol-water (24 mL-4 mL) in the dark was added N-bromosuccinimide (NBS) (858 mg, 4.82 mmol) in small portions. Additional NBS (312 mg) was added after 4 hours and 16 hours later another 400 mg of NBS was added. The reaction mixture was stirred for 68 hours. After removal of t-butanol in vacuo, the residue was diluted with ether, washed with saturated sodium thiosulfite solution, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was purified by HPLC to give 123 mg of 7-bromo-6-hydroxy-1-heptanol (4).
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].CS[C:19]([N:33]([CH3:42])[N:34]=CC1C=CC=CC=1)=[N:20][C:21](=O)[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)=O>[CH3:42][N:33]1[C:19]([NH:13][CH2:12][CH2:11][CH2:10][O:9][C:8]2[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=2)[CH:2]=[O:3])=[N:20][C:21]([CH2:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:34]1
Reactant: NCCCOc1cccc(C2OCCO2)c1
Reactant: CSC(=NC(=O)CS(=O)(=O)c1ccccc1)N(C)N=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Cn1nc(CS(=O)(=O)c2ccccc2)nc1NCCCOc1cccc(C=O)c1
Yield: 70.5 %

Procedure:
A mixture of 3-[3-(1,3-dioxolan-2-yl)phenoxy]propanamine (2.3 g) and methyl-1-methyl-2-(phenylmethylene)-N-[2-(phenylsulphonyl)acetyl]hydrazine carboximidothioate (4.0 g) was heated at 60° under water pump vacuum for 3 h. The reaction mixture was dissolved in toluene (100 ml), 5N hydrochloric acid (100 ml) and acetone (50 ml) and stirred at room temperature for 18 h. The aqueous layer was basified to pH 9 with potassium carbonate and extracted with ethyl acetate. The organic extract was evaporated to give the title compound as an amber gum (3.0 g) T.l.c. Methanol; Rf 0.8.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:6]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8]=1[CH:9]([CH3:11])[CH3:10].C1(C)C=CC=CC=1.[C:32]1([PH2:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:39]CC)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[C:32]1([P:38](=[O:39])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:2][C:3]2[C:4]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:5][C:6]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8]=2[CH:9]([CH3:11])[CH3:10])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCO[PH2](c1ccccc1)c1ccccc1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Reaction time: 9 h
Yield: 72.8 %

Procedure:
N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (10.0 g), toluene (100.0 mL), and diphenyl(ethoxy)phosphorane (6.2 g) were added to a reactor. The reaction mixture was stirred at 90˜100° C. for 9 hours and then water (80.0 mL) was added thereto. The separated organic layer was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1:1) to obtain diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide as a white solid (9.4 g, yield 73%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([OH:13])[CH2:9][CH2:10][CH2:11][OH:12].[OH-].[Na+].C(Cl)C1C=CC=CC=1>O>[CH2:7]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: OCCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCc1ccccc1
Solvent: O
Product: OCCCCOCc1ccccc1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A mixture of toluene (50 ml), 1,4-butanediol (212 g, 2.35 mol) and sodium hydroxide (47.7 g) was heated up to 95° C., and thermally insulated at the same temperature for 30 minutes. Thereafter, benzyl chloride (150 g, 1.185 mol) was added and the mixture was thermally insulated at 95 to 105° C. for 4 hours, then, poured into water (250 ml). After neutralization with 35% hydrochloric acid, the organic layer was liquid-partitioned and the aqueous layer was extracted with toluene (100 ml). The organic layers were combined and washed with saline (100 ml). The organic layer was concentrated under reduced pressure, and the residue was distilled under reduced pressure, to obtain a title compound (115 g, yield 53.8%).
Reaction SMILES: [CH:1]1(/[C:6](/[N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)=[CH:7]\[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1>[CH:1]1([C@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: C1CCOC1
Product: COC(=O)C[C@H](C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 35 °C
Reaction time: 22 h

Procedure:
A solution of (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 815 mg) in tetrahydrofuran (THF, 8.0 mL) in a pressure glass tube was treated with the catalyst [Rh(COD)(−)-DuanPhos](BF4) (4.6 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 50 bar pressure. The reaction mixture was stirred at 35° C. under this hydrogen pressure for 22 h. When HPLC analysis showed that the substrate was almost completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 94.7% ee (97.35% of the second peak, (R)-22; 2.65% of the first peak, (S)-22) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with tetrahydrofuran (THF, 5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (778 mg) was analyzed by chiral HPLC analysis and result showed a 94.7% of enantiomeric excess favoring the second peak (97.35% of the second peak, (R)-22; 2.65% of the first peak, (S)-22).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11]([S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[CH2:12]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:17][CH2:16][S:13](=[O:15])(=[O:14])[CH2:11][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C=CS(=O)(=O)C=C
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: CCO
Product: C[C@@H](c1ccc(Br)cc1)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A solution of (S)-1-(4-bromophenyl)ethanamine (0.144 ml, 1.0 mmol) and vinylsulfonylethene (0.100 ml, 1.0 mmol) in EtOH (4.0 ml) was heated at 100° C. and stirred for 3 h. The reaction mixture was cooled to RT and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (gradient elution, heptane AcOEt 95:5 to 4:6) to yield the title compound (256 mg, 0.804 mmol, 80% yield) as a colorless oil which crystallized on standing into a colorless solid. TLC: RF=0.40 (heptane AcOEt 1:1); HPLC: BtRet=1.29 min; LC-MS: m/z 320.2 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.39 (d, J=6.8, 3H), 2.92-3.09 (m, 8H), 3.76 (q, J=6.8, 1H), 7.19-7.26 (m, 2H), 7.45-7.53 (m, 2H).
Reaction SMILES: C([C:6]1[C:7](=[O:17])[NH:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1[OH:16])(OCC)=O>Cl>[OH:16][C:15]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7](=[O:17])[CH:6]=1
Reactant: CCOC(=O)c1c(O)c2c([nH]c1=O)CCCC2
Agent: Cl
Product: O=c1cc(O)c2c([nH]1)CCCC2

Procedure:
A suspension of 3-carboethoxy-4-hydroxy-5,6,7,8-tetrahydrocarbostyril (19.4g; 0.082 mole) in 2N hydrochloric acid (200 ml) was refluxed 30 hrs. and the clear solution evaporated to dryness. Water was added and the solution brought to pH 4.0 with dilute sodium hydroxide solution. The precipitated white product was filtered off, washed well with water and recrystallised from glacial acetic acid, m.p. >330° C.
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].[C:10]1(=[O:23])[N:14]([CH2:15][C:16]#[N:17])[C:13](=[O:18])[C:12]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:11]12.S(=O)(=O)(O)[OH:25].O>C(O)(=O)C>[C:13]1(=[O:18])[N:14]([CH2:15][C:16]([NH:17][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:25])[C:10](=[O:23])[C:11]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:12]12
Reactant: O=S(=O)(O)O
Reactant: CCCCCC(C)(C)O
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCC(C)(C)NC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
2-Methylheptan-2-ol (56.53 g.; 0.43 mole) and phthalimidoacetonitrile (80.27 g.; 0.43 mole) were dissolved in glacial acetic acid (220 ml.) and the solution warmed to about 60° C. with stirring. Concentrated sulphuric acid (59 ml.; 1.1 mole) was then added gradually; at first the temperature fell but as the addition proceeded a vigorous exothermal reaction took place, the temperature of the reaction was controlled at 70° C. by regulating the addition of the sulphuric acid and coolingas necessary. When the addition was complete the resulting dark brown solution was stirred for 11/2 hours and then added dropwise to a mixture of ice and water. The precipitated solid was filtered off, pressed well, washed with fresh water and dried in vacuo. The residue was recrystallisedfrom benzene with filtering, to afford 2-phthalimido-N-(1,1-dimethylhexyl)acetamide m.p. 142° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C4CCCCO4)=[CH:13][CH:12]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.C1(S)C=CC=CC=1.Cl>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(OC4CCCCO4)cc3)c3cc(Br)cnc32)cc1
Agent: Cl
Agent: Sc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(O)cc3)c3cc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
575 g (1.09 mmol) of 5-bromo-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 250 ml of dichloromethane. To this solution was added 2.50 g (3.53 mmol) of PS-thiophenol (Argonaut Technologies) and 1.5 ml of a 2 M solution of hydrochloric acid in ether. The mixture was stirred at room temperature for 3 hours before the resin was filtered off, washing extensively with dichloromethane. The filtrate was evaporated to afford 389 mg (877 μmol, 81%) of 4-[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-phenol as a pale yellow solid. 1H-NMR (d6-DMSO) δ: 9.67 [1H] s, 8.52 [1H] d, 8.43 [IH] d, 8.11 [1H] s, 8.03 [2H] d, 7.58 [2H] d(m), 7.43 [2H] d, 6.89 [2H] d(m), 2.35 [3H] s. MS, m/z: 443 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[C:7]([F:17])([C:13]([F:16])([F:15])[F:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[C:7]([F:17])([C:13]([F:14])([F:15])[F:16])[C:6]=2[CH:5]=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)C1(F)c2cccc(Cl)c2OC1(F)F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)c2c(c1)C(F)(C(F)(F)F)C(F)(F)O2
Temperature: 80 °C

Procedure:
A stirred mixture of 3.3 g (0.012 mole) 7-chloro-2,2,3-trifluoro-3-trifluoromethyl-2,3-dihydrobenzofuran, 10 ml of concentrated sulfuric acid and 15 ml of concentrated nitric acid was heated at 80° C. for approximately 18 hours. The mixture was cooled and poured into ice water. The aqueous mixture was extracted with three 100 ml portions of diethyl ether and the extracts were combined. After drying over anhydrous magnesium sulfate the extract was filtered. The filtrate was evaporated under reduced pressure leaving an oil which crystallized upon standing. Recrystallization from n-heptane yielded 1.65 g of 7-chloro-2,2,3-trifluoro-3-trifluoromethyl-2,3-dihydro-5-nitrobenzofuran (mp 46°-47° C.). The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][C:14]([O-:16])=O)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([O:47][Si](C(C)(C)C)(C)C)[CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:33]1=[O:55].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:47][C:44]1[CH:45]=[C:46]2[C:41]([CH:40]=[CH:39][CH:38]=[C:37]2[N:34]2[CH2:35][CH2:36][C@H:32]([NH:31][C:14](=[O:16])[CH2:13][C:11]3[N:10]=[CH:9][N:8]([C:7]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:12]=3)[C:33]2=[O:55])=[CH:42][CH:43]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cccc(N3CC[C@H](N)C3=O)c2c1
Reactant: O=C([O-])Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N[C@H]1CCN(c2cccc3ccc(O)cc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of lithium [1-(triphenylmethyl)-1H-imidazol-4-yl]acetate, as described above in Step B, (4.40 g, 11.6 mmol), (S)-3-amino-1-[7-(tert-butyldimethylsilyloxy)naphthalen-1-yl]-2-oxopyrrolidine hydrochloride, as described above in Step A (3.86 g, 9.84 mmol), HOBT (1.60 g, 11.8 mmol), EDC (2.30 g, 12.0 mmol), and N,N-diisopropylethylamine (6.00 mL, 34.4 mmol) was stirred in DMF (80 mL) at ambient temperature for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (50 mL) and CHCl3 (75 mL). The aqueous layer was extracted further with CHCl3 (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was dissolved in dry THF (75 mL) and TBAF (5 mL of a 1.0 M solution in TBF, 5 mmol) was added. The resulting mixture was stirred at ambient temperature for 30 min, then quenched with saturated aqueous NH4Cl (30 mL) and most of the TBF was removed under reduced pressure. The residual mixture was poured into saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (100 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—2% to 4% MeOH to yield the titled product.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([NH:13][C:14]([C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:16]([C:14]([NH:13][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=3)=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:26])=[O:15])[N:17]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc2ccccc2cn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O)c1cc2ccccc2cn1
Yield: 71.8 %

Procedure:
The resulting amide (100 mg, 0.24 mmol) was reacted with 4-trifluoromethylphenyl boronic acid (95 mg, 0.5 mmol) as described in general procedure D yielding the title compound (80 mg, 80%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]([CH3:16])[C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[CH:9]=2)[C:4](=O)[CH2:3]1.C([O-])(=O)C.[Na+].Cl.[NH2:27][OH:28]>C(O)C.O>[OH:28]/[N:27]=[C:4]1\[CH2:3][C:2]([CH3:20])([CH3:1])[C:10]2[C:5]\1=[CH:6][CH:7]=[C:8]([C:11]1[N:15]([CH3:16])[C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH:9]=2
Reactant: NO
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)C/C2=N\O
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a stirred mixture of 5-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.07 g, 0.26 mmol) in ethanol (1.6 mL)/water (0.4 mL) was added sodium acetate (0.03 g, 0.34 mmol) and hydroxylamine hydrochloride (0.02 g, 0.32 mmol). The resulting mixture was heated to reflux for 5 hours. The solution was allowed to cool to room temperature, diluted with water, and filtered to give 5-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile as a white solid (0.04 g, 55%). MS (ES) m/z 280.1. HRMS: calcd for C17H17N3O+H+, 280.14444; found (ESI, [M+H]+), 280.145.