Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[NH4+].[Cl-].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]1[NH:13][N:12]=[N:11][N:7]=1)[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nnn[nH]1
Temperature: 100 °C

Procedure:
To a solution of ethylcyanoacetate (20.0 g, 0.177 mol) in dimethylformamide (DMF) (180 mL) was added NH4Cl (10.4 g, 0.19 mol) and sodium azide (12.6 g, 0.19 mol) sequentially. The mixture was heated for 5 hours at 100° C., allowed to cool, and the DMF removed in vacuo. The residue was taken up in water (150 mL), acidified to pH 2 with concentrated HCl, and filtered. The filtrate was cooled to 5° C. and allowed to crystallize. The solid was filtered, dried in vacuo over self-indicating silica gel to give 10.61 g, 42%, mp 124°-129° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:34][NH:35][CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH3:34][N:35]([CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:36]
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN(C)C)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (19 mg, 0.043 mmol) and dimethylamine (2 M in THF, 0.026 mL, 0.052 mmol) were dissolved in dichloroethane (2 mL) and NaBH(OAc)3 (16 mg, 0.078 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 2 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified with preparative thin layer chromatography (SiO2, 5% Et3N, 5% MeOH, 90% EtOAc) to furnish methyl 6-(2-(3-(4′-((dimethylamino)methyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a tan solid (5 mg, 25%): 1H NMR (CDCl3, 600 MHz) δ 8.12 (d, 1H, J=7.7 Hz), 8.03 (d, 2H, J=9.6 Hz), 7.97 (t, 1H, J=7.8 Hz), 7.53 (dd, 4H, J=8.0, 4.9 Hz), 7.38 (d, 2H, J=7.9 Hz), 7.34 (d, 2H, J=8.0 Hz), 4.03 (s, 3H), 3.51 (t, 4H, J=7.6 Hz), 3.15 (t, 2H, J=7.6 Hz), 2.31 (s, 6H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.4, 138.9, 138.3, 129.6, 128.9, 128.0, 127.2, 126.9, 125.2, 123.3, 63.8, 53.1, 45.1, 40.6, 29.3; HR ESI-TOF m/z 470.2071 (M+H+, C28H27N3O4, requires 470.2074).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].CN(C)C=O>O1CCCC1>[C:27]([O:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH2:11][CH2:12][CH2:13][CH3:14])(=[O:30])[CH:28]=[CH2:29]
Reactant: CCCCC(CO)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)OCC(CCCC)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 50.5 %

Procedure:
To a 100 mL flask stirring under nitrogen was charged 2.88 g (0.0098 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]hexan-1-ol in 25 mL of tetrahydrofuran. To the mixture was added 2.5 mL of pyridine followed by 1.0 g (0.011 mole) of acryloyl chloride after which a precipitate formed. The reaction was monitored by GLC and was 60% complete after I hour. An additional 1.0 g of acryloyl chloride was added followed by 20 mL of dimethylformamide. The reaction was stirred at 60° C. until the precipitate dissolved and was then stirred overnight at room temperature. The reaction was quenched with 20 mL water and extracted with 10 mL ethyl acetate, washed with 2×10 mL water and 2×20 mL saturated sodium bicarbonate. The solvent was dried and concentrated; the residue was chromatographed on 50 g of silica gel. The product was eluted with a 1 to 1 mixture of hexane and ethyl acetate and gave 1.72 g (50.4% yield) of an oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]#[N:11])=[N:2]1.Br[CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.CCOC(C)=O>[F:16][C:15]([F:18])([F:17])[CH2:14][CH2:13][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]#[N:11])=[N:2]1
Reactant: FC(F)(F)CCBr
Reactant: N#Cc1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: N#Cc1nn(CCC(F)(F)F)c2ncccc12
Temperature: 40 °C
Reaction time: 5 h

Procedure:
1H-pyrazolo[3,4-b]pyridine-3-carbonitrile, as described in Step C of Example 158 (30 g, 208 mmol), 3-bromo-1,1,1-trifluoropropane (44.5 mL, 416 mmol) and potassium carbonate (95 g, 687 mmol) were combined in a flask with acetonitrile (300 mL) and stirred at 40° C. After 5 h, the reaction was cooled to rt and EtOAc and water were added. The layers were separated and the aqueous layer was washed two times with EtOAc. The combined organics were dried (Na2SO4) and filtered. The solvent was removed under reduced pressure and the material was used without further purification. 1H NMR (500 MHz, DMSO-d6): δ 8.77 (d, J=4.50 Hz, 1H); 8.46 (d, J=8.23 Hz, 1H); 7.51 (dd, J=8.22, 4.47 Hz, 1H); 4.86 (t, J=6.66 Hz, 2H); 3.10-2.98 (m, 2H). m/z=241.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][N:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:55]([O:57][C:58](=[O:61])[CH2:59][NH2:60])[CH3:56]>CN(C=O)C.O>[CH2:55]([O:57][C:58](=[O:61])[CH2:59][NH:60][C:20]([C:17]1[CH:16]=[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:19][N:18]=1)=[O:22])[CH3:56]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid (0.7 g, 0.00237 mol) in DMF (4 mL) was added DIPEA (1.226 g, 0.00948 mol), HOBt (0.4 g, 0.0029 mol) and EDCI.HCl (0.57 g, 0.0029 mol) at ambient temperature. After 5 minutes glycine ethyl ester hydrochloride (0.347 g, 0.0024 8 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (65% ethyl acetate in hexane) afforded 0.66 g (73%) of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid ethyl ester. To a stirred solution of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid ethyl ester (0.65 g, 0.00171 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL) was added LiOH.H2O (0.215 g, 0.00512 mol) at ambient temperature. The resulting mixture was stirred overnight. Volatiles were removed by evaporation and the residue was diluted with water acidified with concentrated HCl. The resulting precipitate was isolated by filtration and dried to afford 0.56 g of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid. LCMS: 353.11 (M+1)+, 60.4%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:9]1[CH:11]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH:9][CH:11]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH2:10][N:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: ClC(Cl)(Cl)C1CO1
Reactant: O=c1ncc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ncc(Br)cn1CC(O)C(Cl)(Cl)Cl
Temperature: 80 °C
Yield: 52 %

Procedure:
A stirred mixture of 5-bromopyrimid-2-one (0.009 mol), 1,2-epoxy-3,3,3-trichloropropane (0.009 mol) and K2CO3 (33 mg) in dimethylformamide (40 ml ) was heated at 80° C. for 4 h. The reaction mixture was then evaporated to dryness at reduced pressure (1 mm Hg). The crystalline residue was triturated with a little ether and dissolved in ethyl acetate. The filtered ethyl acetate solution was concentrated to about 50 ml and left in the cold when the product crystallized out in 52% yield. m.p. 210°-212° C. (ethyl acetate).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](O)=[C:5]([O:10][CH3:11])[CH:4]=1)[CH3:2].[Cl:12][CH2:13][CH2:14][CH2:15]Br.C([O-])([O-])=[O:18].[K+].[K+]>CC(C)=O>[CH2:1]([C:3]1([O:18][CH2:15][CH2:14][CH2:13][Cl:12])[CH:8]=[CH:7][CH:6]=[C:5]([O:10][CH3:11])[CH2:4]1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(OCCCCl)C=CC=C(OC)C1
Yield: 115 %

Procedure:
A mixture of 4-ethyl-2-methoxyphenol (9.0 g, 59 mmol), 3-chloro-1-bromopropane (13.0 g, 83 mmol), K2CO3 (6.2 g) and acetone (200 ml) was stirred and refluxed for 16 hours. The reaction was allowed to cool, and then it was filtered. The filtrate was concentrated to a clear liquid. The liquid was diluted with dilute aqueous NaOH, and the basic mixture was extracted with diethyl ether. The diethyl ether was washed (water), dried (MgSO4), and the solvent was concentrated to afford 11.9 g of a golden liquid. The liquid was flash chromatographed. This gave a colorless liquid, 9.9 g of 4-ethyl-2-methoxy+(3-chloropropoxy)benzene.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:10][N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([NH2:21])=[N:15][C:16]=2[Cl:20])[CH2:5][C:6](OC)=[O:7].[BH4-].[Li+].O>C(O)(C)(C)C>[NH2:21][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[CH2:10][CH:4]([CH2:5][CH2:6][OH:7])[CH2:3][OH:2])=[C:16]([Cl:20])[N:15]=1
Reactant: COC(=O)CC(Cn1cnc2c(Cl)nc(N)nc21)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1nc(Cl)c2ncn(CC(CO)CCO)c2n1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (-)-dimethyl-2-(2-amino-6-chloropurin-9-ylmethyl)succinate (enantiomeric excess 85%; 19.9 mg, 0.0607 mmol), dissolved in tert. butanol (2.0 ml) at 40° C., was added lithium borohydride (30 mg, 1.38 mmol) in portions with stirring. After 1 h at ambient temperature, water (0.3 ml) was added slowly and stirring continued over night. Inorganic salts were filtered, washed carefully with tert. butanol and the solution was evaporated to dryness. Preparative thin-layer chromatography (PSC-Fertigplatten, Merck) with chloroform+methanol (5+1) as mobile phase afforded 16.5 mg (theoretical yield) of (-)-2-(2-amino-6-chloropurin-9-ylmethyl)-1,4-butanediol. [α]D200 -5.20°, [α]54620 -5.92° (c 0.625, ethanol). TLC on silica (chloroform+methanol 5+1): Rf 0.40, identical to that of the racemate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[CH2:7](Cl)[C:8](=[CH2:10])[CH3:9].[CH2:12]([OH:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>O>[C:12]([CH:2]([CH2:7][C:8]([CH3:9])=[CH2:10])[C:1]([O:4][CH2:5][CH3:6])=[O:3])(=[O:14])[CH3:13]
Reactant: CCOC(C)=O
Reactant: CCO
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(C)CC(C(C)=O)C(=O)OCC

Procedure:
In a reaction vessel of 1.5 l equipped with a mechanical stirrer, a condenser, a thermometer and an inlet tube for nitrogen, 600 g (4.61M) of ethyl acetate, 375.9 g (4.15M) of methallyl chloride, 500 ml of ethanol and 636.9 g (4.61M) of potassium carbonate are mixed together. The resulting suspension is heated at reflux for 2 h while the mixture becomes slightly yellow and thick. Ethanol is stripped off and the obtained residue is dissolved in 900 ml of water. The two layers thus formed are separated and the organic phase is washed with 900 ml of water.
Reaction SMILES: O[CH2:2][NH:3]C(=O)C[Cl:6].[CH3:8][S:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:20].S(=O)(=O)(O)O.Cl>C(O)(=O)C.C(O)C>[ClH:6].[NH2:3][CH2:2][C:12]1[CH:13]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[CH:15]=[C:10]([S:9][CH3:8])[C:11]=1[OH:20]
Reactant: O=C(CCl)NCO
Reactant: CSc1cc(C(C)(C)C)ccc1O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1cc(C(C)(C)C)cc(CN)c1O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Pulverized N-hydroxymethyl-2-chloroacetamide (3.32 g., 0.027 mole) is added portionwise over 15 minutes to a solution of 2-methylthio-4-(1,1-dimethylethyl)phenol (5.3 g., 0.027 mole) and conc. sulfuric acid (10 ml.) in acetic acid (150 ml.) cooled in an ice bath. The resulting reaction mixture is stirred at 20° C. for 16 hours and then poured into ice-water (1 l.) whereupon a white gum is deposited. The gum is extracted with ether and the etheral extract, washed well with water and saturated brine. Removal of the solvent under reduced pressure leaves a residual solid which is dissolved in ethanol (30 ml.). The resulting solution is treated with 12 N hydrochloric acid (15 ml.) and heated at reflux for 4 hours. Evaporation in vacuo affords a residual solid which is triturated with ether and collected by filtration to give crude 2-aminomethyl-4-(1,1-dimethylethyl)-6-(methylthio)phenol hydrochloride (5.4 g., 76.4%), m.p. 150°-177° C. Two recrystallizations from ether-ethanol (10:1; v:v) followed by recrystallization from 12 N hydrochloric acid provides analytically pure 2-aminomethyl-4-(1,1-dimethylethyl)6-(methylthio)phenol hydrochloride as colorless crystals, m.p. 180°-181.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:16]([N:22]=[C:23]=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[N:12]([C:23]([NH:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:24])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCN=C=O
Reactant: O=c1[nH]cc(-c2ccc(F)cc2)c(=O)[nH]1
Product: CCCCCCNC(=O)n1cc(-c2ccc(F)cc2)c(=O)[nH]c1=O
Temperature: 110 °C
Yield: 22 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 6, starting from 5-(4-fluorophenyl)-1H-pyrimidine-2,4-dione (0.10 g, 0.48 mmol); 4.5 equivalents of hexyl isocyanate were used herein, splitted into two aliquots (2.2 equiv each) and the reaction mixture was heated under microwave irradiation to 110° C. for 1 hr (2 cycles of 30 min each). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 84:16) to afford the title compound (0.03 g, 22% over two steps) as white powder. 1H NMR (400 MHz, CDCl3) δ 0.91 (d, J=6.3 Hz, 3H), 1.27-1.42 (m, 6H), 1.58-1.68 (m, 2H), 3.41 (td, J=7.1, 5.6 Hz, 2H), 7.06-7.17 (m, 2H), 7.45-7.63 (m, 2H), 8.35 (s, 1H), 8.55 (s, 1H), 8.93-9.16 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 14.41, 22.33, 26.62, 29.26, 31.38, 41.46, 115.62, 126.97, 130.27, 135.83, 149.57, 150.60, 160.93, 162.81 (d, J=250.5 Hz). MS (ESI) m/z: 207 [M-H]+.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.[CH2:35](N1C[C@H]2C(N)CC[C@H]2C1)[C:36]1C=CC=CC=1>>[CH:11]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]([NH:29][C@@H:26]2[C@H:24]3[C@H:23]([CH2:22][N:21]([CH2:20][C:19]4[CH:30]=[CH:31][CH:32]=[C:17]([C:16]([F:33])([F:15])[F:34])[CH:18]=4)[CH2:25]3)[CH2:28][CH2:27]2)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:36][CH2:35]1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1

Procedure:
The title compound was prepared by substituting 2,2-dicyclohexylacetic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.73 (s, 1H), 7.65 (d, J=7.6, 1H), 7.57-7.44 (m, 3H), 4.46 (dt, J=6.4, 12.6, 1H), 3.55 (d, J=12.9, 1H), 3.47 (d, J=12.8, 1H), 2.75 (d, J=8.1, 2H), 2.53-2.39 (m, 2H), 2.32 (t, J=8.2, 1H), 2.21 (t, J=8.3, 1H), 1.97-1.53 (m, 15H), 1.50-1.04 (m, 11H), 0.98 (dd, J=11.3, 23.1, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[C:26]([F:29])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]([CH3:20])([CH3:19])[O:10][C:9]3=[O:21])=[CH:4][CH:3]=2)[C:26]([F:29])=[N:27][CH:28]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(Br)cnc3F)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A microwave vial was charged with (S)-3-(4-iodophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (Intermediate C)(0.200 g, 0.509 mmol), 5-bromo-2-fluoropyridine-3-boronic acid (0.224 g, 1.017 mmol)(commercially available from Alfa Aesar, Ward Hill, Mass.), sodium carbonate (0.162 g, 1.526 mmol), dioxane (3.0 mL), and water (0.600 mL). Tetrakis(triphenylphosphine)palladium(0) (0.059 g, 0.051 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. in the microwave for 1 hour. The resulting reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford a yellow oil. The residual oil was purified by column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-25% EtOAc-hexane) to afford (S)-3-(4-(5-bromo-2-fluoropyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.104 g, 0.236 mmol, 46% yield) as a pale tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3H), 1.64 (s, 3H), 5.52 (s, 1H), 7.07-7.47 (m, 5H), 7.51-7.75 (m, 4H), 8.15-8.44 (m, 2H). m/z (ESI) 441, 443 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:11]([CH3:27])=[C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:15])[N:13]=1.C(N(CC)CC)C.[F:42][C:43]([F:51])([F:50])[CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47].O>ClCCl>[F:42][C:43]([F:51])([F:50])[CH2:44][CH2:45][S:46]([O:34][C:31]1[CH:30]=[CH:29][C:28]([N:10]2[C:11]([CH3:27])=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)=[O:15])[N:13]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:33][CH:32]=1)(=[O:48])=[O:47]
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: Cc1c(C(=O)Nc2ccc(C(F)(F)F)cn2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(C(F)(F)F)cn2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxamide (136 mg, 0.27 mmol) and triethylamine (40 μl, 0.32 mmol) in dichloromethane (4.0 ml) were cooled to −78° C. 3,3,3-trifluoropropane-1-sulfonyl chloride (63 mg, 0.32 mmol) was carefully added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h, and then allowed to reach room temperature. Water was added to the reaction, and the phases were separated. The organic phase was washed with NaHCO3, brine and dried with Na2SO4. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (88 mg, 49%) as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][O:47]S(C)(=O)=O)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[CH:46]([OH:47])=[O:55].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCN3CCOCC3)c2)n1
Product: O=CO

Procedure:
The title compound was prepared starting from Intermediate 108e and morpholine using analogous procedures to those described in Example 108. LCMS (Method 5): Rt 3.37 min, m/z 708 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.24 (9H, s), 1.55-1.65 (2H, m), 1.67-1.76 (4H, m),1.79-2.19 (4H, m), 2.41 (4H, d, J=4.7 Hz), 2.72 (2H, t, J=6.7 Hz), 3.13 (4H, t, J=5.3 Hz), 3.53 (4H, t, J=4.6 Hz), 4.23 (2H, t, J=6.6 Hz), 4.78-4.87 (1H, m), 5.55 (1H, t, J=4.4 Hz), 6.25 (1H, s), 7.11-7.18 (2H, m), 7.25-7.41 (4H, m), 7.58-7.64 (3H, m), 8.00 (1H, s), 8.05 (1H, s), 8.16 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11]([Br:17])[CH:12]=[C:13]([I:16])[CH:14]=2)[C:9]([OH:28])([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:8]1=[O:29].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>ClCCl>[CH3:37][S:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11]([Br:17])[CH:12]=[C:13]([I:16])[CH:14]=2)[C:9]([OH:28])([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:8]1=[O:29])(=[O:40])=[O:39]
Reactant: O=C1N(CCCCCO)c2cc(I)cc(Br)c2C1(O)c1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(Br)cc(I)cc21
Yield: 64.5 %

Procedure:
To a solution of 1-(5-hydroxypentyl)-4-bromo-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole (155 mg, 0.279 mmol) and triethylamine (0.06 mL, 0.43 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (0.025 mL, 0.323 mmol) at 0° C. The mixture was stirred for 5 min at the same temperature and water was added. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 3:2 hexane/ethyl acetate to give the mixture (116 mg) of the title compound and dimesylate.