Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[O:10]=[C:11]([CH3:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:11]([C:12]1[CH2:13][O:4][C:3]2[C:2]([CH:1]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:10])[CH3:14]
Reactant: O=Cc1ccccc1O
Reactant: C=CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)C1=Cc2ccccc2OC1

Procedure:
1.22 g (10 mmol) of salicylaldehyde together with 0.66 g (10 mmol) of 3-oxo-1-butene are added at room temperature to a suspension of 0.14 g (1 mmol) of potassium carbonate in 50 ml of 2™butanone. The mixture is brought to reflux with stirring and this temperature is maintained for 4 hours. The reaction medium is evaporated on a water bath under vacuum and the residue taken up with 100 ml of water and extracted three times with 75 ml of diethyl ether. The organic phases are combined, washed to neutrality with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, the filtrate is evaporated on a water bath under vacuum and the product recrystallized in hexane
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O1CCCC1.[CH2:29]([O:36][C:37]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:70][CH2:69][CH:68]([O:71][Si](C(C)(C)C)(C)C)[CH2:67][CH2:66]2)=[CH:61][C:38]=1[C:39]([NH:41][C:42]1[CH:54]=[C:53]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:52]=[CH:51][C:43]=1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(Cl)(Cl)Cl>[CH2:29]([O:36][C:37]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:70][CH2:69][CH:68]([OH:71])[CH2:67][CH2:66]2)=[CH:61][C:38]=1[C:39]([NH:41][C:42]1[CH:54]=[C:53]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:52]=[CH:51][C:43]=1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:40])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)ccc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC(O)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A 1.0 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (0.56 mL) was added to a tetrahydrofuran (3.2 mL) solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)benzamido)-4-phenylbenzoate (0.32 g), followed by stirring at room temperature for 1 hour. A 1.0 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (0.28 mL) was added to the reaction mixture, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture under ice-cooling, and chloroform was added thereto at room temperature. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 90-40% hexane/ethyl acetate] to obtain 0.23 g of tert-butyl 2-(2-(benzyloxy)-5-(4-hydroxypiperidin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)[CH2:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[NH:7][C:6]1=[O:25])=[O:4].[H-].[Na+].CI.[C:30](OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)[CH2:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[N:7]([CH3:30])[C:6]1=[O:25])=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@@H]1C(=O)Nc2ccccc2C[C@H]1c1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CI
Product: COC(=O)[C@@H]1C(=O)N(C)c2ccccc2C[C@H]1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (+/-)-Trans-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(3,4-methylenedioxyphenyl)-2H-1-benzazepine-2-one (0.35 g, 1.03 mmol) in DMF (3 ml) was added to a mixture of sodium hydride (0.036 g, 1.2 mmol, 80% mineral oil dispersion) and the mixture stirred 1 h at ambient temperature. Methyl iodide (0.4 ml, 0.91 g, 6.43 mmol) in DMF (0.5 ml) was added and the mixture stirred 48 h at ambient temperature. The reaction was quenched in water (50 ml) and extracted with ethyl acetate (3×10 ml). The combined extracts were dried (MgSO4), filtered and the solvent removed at reduced pressure to give 0.40 g of crude product. Chromatography on silica gel with 30:70 ethyl acetate-hexane gave 0.335 g of the title compound as a viscous oil. The oil was treated with hexane and the resulting white solid collected and dried to give 0.226 g (62%) of the title compound; mp 125°-127°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9]/[CH:10]=[C:11](/[C:19]1[N:20]=[C:21]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])\[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:19]1[N:20]=[C:21]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1/C(=C/CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1sc(N2CCOCC2)nc1C(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of ethyl 4-[(1E)-3-[(tert-butoxycarbonyl)amino]-1-(4-chlorophenyl)prop-1-en-1-yl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (0.328 g, 0.646 mmol) in ethanol (8 mL) in a Parr bottle under an atmosphere of argon was added palladium hydroxide (0.0323 g, 0.230 mmol). The flask was purged several times with argon then filled with hydrogen to 60 psi and rapidly stirred at room temperature for 3 hours. The reaction was incomplete by LCMS. An additional portion of palladium hydroxide (0.0300 g, 0.214 mmol) was added and the reaction was stirred at room temperature under 60 psi hydrogen for 16 hours. There was further progress by LCMS but still incomplete reaction, so another portion of palladium hydroxide (0.0300 g, 0.214 mmol) was added and the reaction was stirred at room temperature under 60 psi hydrogen for 3 days. The mixture was filtered through celite, the celite was washed with methanol to extract all product, and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (24 g Analogix column, gradient hexane to 40% EA in hexane over 15 minutes) to give the product (0.286 g, 87%). LCMS: (AA) ES+ 510, 512. 1H NMR (300 MHz, d4-MeOH) δ: 7.40 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 5.02 (dd, J=8.9, 6.6 Hz, 1H), 4.24 (q, J=6.8 Hz, 2H), 3.86-3.70 (m, 4H), 3.61-3.45 (m, 4H), 3.02-2.85 (m, 2H), 2.42-2.21 (m, 1H), 2.18-2.01 (m, 1H), 1.40 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [BrH:1].[NH2:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].BrBr>CC(O)=O>[BrH:1].[NH2:2][C@@H:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([Br:1])[CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccc(O)c(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 216 h
Yield: 85 %

Procedure:
To a 250 mL r.b. flask equipped with a stir bar was added acetic acid (50 mL) and hydrobromic acid in AcOH (27 mL, 149 mmol), then (S)-2-amino-3-(4-hydroxyphenyl)propanoic acid (13.47 g, 74.3 mmol). To the stirred solution was added dropwise over 3 hr via an addition funnel bromine (4.14 mL, 80 mmol) in AcOH (20 mL). The solution was stirred at room temperature. After 9 days, stirring was stopped and the mixture was filtered (reaction time not optimized). The filter cake washed with AcOH (100 mL) and then Et2O (150 mL). The isolated off-white solids were dried under vacuum to afford the product (S)-2-amino-3-(3-bromo-4-hydroxyphenyl)propanoic acid, hydrobromide (23.9 g, 85% yield) as a pale yellow powder. 1H NMR (500 MHz, methanol-d4) d 7.47-7.41 (m, 1H), 7.12 (dd, J=8.2, 2.2 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.22 (dd, J=7.6, 5.4 Hz, 1H), 3.23 (dd, J=14.8, 5.4 Hz, 1H), 3.08 (dd, J=14.7, 7.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[C:8]2=[O:17]
Reactant: O=C(Cc1cccc(F)c1)c1cc(Br)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
Intermediate 33 (3.0 g, 9.70 mmoles) was taken in a RB flask and to this triethylamine (30 ml) and propionic anhydride (3.94 g, 30.37 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (1.30 g, 39% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.10 (d, J=2.3 Hz, 1H), 7.99 (dd, J=8.9, 2.4 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.51 (q, J=7.9 Hz, 1H), 7.25 (dt, J=10.8, 2.4 Hz, 1H), 7.15 (t, J=12.2 Hz, 2H), 2.57 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[CH:6][C:7]=1[F:8].O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([B:9]2[O:10][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(O)C(C)(C)O
Product: CC1(C)OB(c2ccc(F)c(Cl)c2)OC1(C)C
Yield: 77 %

Procedure:
The title compound (77%, oil) was prepared from 3-chloro-4-fluorophenylboronic acid and pinacol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:35]([N:32]1[CH2:33][CH2:34][N:29]([C:26]2[CH:27]=[CH:28][C:23]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][C:10]=3[Cl:11])[NH:7][N:6]=[C:5]4[C:12]([OH:14])=[O:13])=[CH:24][CH:25]=2)[CH2:30][CH2:31]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(-c3cc4c(C(=O)O)n[nH]c4cc3Cl)cc2)CC1
Yield: 7.1 %

Procedure:
To 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (75.0 mg, 0.27 mmol) in a 5 mL microwave vial was sequentially added 1-{4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]piperazin-1-yl}ethanone (89.8 mg, 0.27 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.0 mg, 0.027 mmol), 1,4-dioxane (2 mL) and 2N aqueous potassium carbonate solution (0.4 mL, 0.81 mmol). The reaction mixture was degassed with argon and subjected to microwave irradiation at 110° C. for 50 minutes. The cooled reaction mixture was acidified to pH 5 with 1N HCl and diluted with EtOAc (10 mL). The organic layer was washed with brine (6 mL), dried over MgSO4 and concentrated in vacuo. The resulting solid was purified by reversed phase HPLC (Column: Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: HOLD at 80.0% H2O/20.0% MeCN for 1.0 min. 80.0% H2O/20.0% MeCN linear to 60.0% H2O/40.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min.) to afford the title compound (7.6 mg, 7% yield). MS (ES+) 399.1 (M+H)+. Retention time=2.25 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)C4CCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclopentanecarbonyl chloride (0.29 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the solid was stirred with ether (20 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}cyclopentylcarboxamide (0.59 g, 83%) as a white solid: mp 175-177° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.41 (t, J=5.7 Hz, 1H), 7.87-7.78 (m, 2H), 7.66-7.63 (m, 1H), 5.19-5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.72 (d, J=5.8 Hz, 2H), 2.98-2.83 (m, 1H), 2.73-2.51 (m, 3H), 2.08-2.04 (m, 1H), 1.81-1.51 (m, 8H); 13C NMR (DMSO-d6) δ 175.71, 172.75, 169.82, 167.49, 166.95, 139.68, 134.76, 132.91, 131.50, 127.01, 121.77, 48.84, 44.20, 37.60, 30.93, 29.96, 25.60, 21.97; Anal. Calcd. For C20H21N3O5: C, 62.65; H, 5.52; N, 10.96. Found: C, 62.52; H, 5.55; N, 10.81.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([OH:19])[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(OCC)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]([CH3:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([OH:19])[CH2:17][O:18][S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CCCCCC[C@@H](O)CO)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)CCCCCC[C@H](C)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To an ice cold solution of 4.6 g (16.4 mmol) (2R,9S)-9-benzyloxydecane-1,2-diol in 50 ml abs. pyridine was slowly added a solution of 2.9 g (15 mmol) p-toluene sulfonyl chloride in 20 ml abs. pyridine. Stirring was continued for 5 h at 0° C. and 12 h at 4° C. Subsequently, 150 ml ice water (brought to pH 5 with 0.1% hydrochloric acid) were added and 60 ml diethyl ether. Subsequently, the aqueous layer was extracted four times with 120 ml diethyl ether. The combined organic layers were washed three times with 100 ml of an aqueous, saturated solution of copper-II-sulphate and two times with 100 ml brine. The organic layer was dried over magnesium sulphate and concentrated in vacuo. Flash chromatography (10% ethyl acetate in hexane) furnished 4.6 g (10.5 mmol, 64%) (2R,9S)-9-benzyloxy-1 (p-tolylsulfonyloxy)decane-2-ol.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:27]=[CH:26][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=O)=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH2:4][CH3:5].Cl.[OH-].[Na+]>C1COCC1>[CH3:6][C:2]([C:7]1[CH:27]=[CH:26][C:10]([CH2:11][NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=2)=[CH:9][CH:8]=1)([CH3:1])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)(C)c1ccc(C(=O)NCCc2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 440 mg of 4-(1,1-dimethyl-butyl)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (1.17 mmol) in 10 ml of THF was added dropwise to 4.66 ml of a 1 molar solution of BH3-THF complex in THF at 0° C. The reaction mixture was stirred for 1 h at rt and then heated to reflux overnight. Upon cooling to rt 2 ml of 6N HCl were added and the mixture was stirred for 1 h. Then the pH was adjusted to 9 by addition of 1 N sodium hydroxide solution and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated. This gave 422 mg (100%) of [4-(1,1-dimethyl-butyl)-benzyl]-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine as a light yellow oil which was used in the following coupling step without further purification. MS (ISP) 364.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19]>C1C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20][CH3:21])=[O:19])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: c1ccccc1
Product: COC(=O)c1sccc1Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared using the process of Example 1(a) but with 2,5-difluoronitrobenzene and methyl 3-aminothiophene-2-carboxylate as starting materials, m.p. 172°-175° C. (benzene).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33](O)=[O:34])=[CH:23][N:22]=1>>[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:23][N:22]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Product: Cc1ncc(C(=O)N2[C@H](CNC(=O)c3c(C)nc4sccn34)C[C@@H]3C[C@@H]32)c(-c2ccccc2)n1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-4-phenyl-pyrimidine-5-carboxylic acid. LC-MS (basic): tR=1.19 min; [M+H]+=473.2.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22](=[O:34])[NH:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:35][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([CH3:12])[C:9]=1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22](=[O:34])[NH:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)[O:5][CH2:4][C:3]([OH:36])=[O:2]
Reactant: COC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCC(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenoxy}-acetic acid methyl ester (200 mg, 0.41 mmol) in MeOH (5 mL) was added NaOH (1N, 5 ml) and the solution was stirred at ambient temperature for 3 h. The solution was carefully acidified to pH 3-4 with 1N HCl and the suspension was filtered, washed with water, and the white solid was dried in vacuum oven to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 13.02 (s, 1H), 11.13 (s, 1H), 8.44 (m, 3H), 8.04 (d, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.77 (m, 2H), 7.56 (m, 1H), 6.81 (s, 2H), 4.76 (s, 2H), 2.13 (s, 6H). MS (m/z) 467.2 (M+1); Retention time: 1.03 min (Method 10).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][C:4]3[C:5]4[C:10](=[N:9][CH:8]=[CH:7][N:6]=4)[N:1]=[CH:2][N:3]=3)=[CH:15][CH:16]=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)cc1
Reaction time: 20 h
Yield: 10.7 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (500 mg, 1.9 mmol), 4-isopropylphenylboronic acid (400 mg, 2.4 mmol), anh. Cu(OAc)2 (360 mg, 2.0 mmol) and powdered, freshly activated 4 Å molecular sieves (approximately 1 g) were combined in CH2Cl2 (15 mL), treated with pyridine (920 μL, 900 mg, 11.4 mmol) and sealed and stirred for 20 h with a moisture trap. The reaction was suction filtered and the filtrate shaken with dilute aqueous NH4OH. The organic phase was washed with H2O and brine and concentrated in vacuo. The residue was purified by preparative RP-HPLC using 80% MeCN/H2O to yield {2-[4-(4-isopropylphenoxy)-phenyl]-ethyl}-pteridin-4-yl-amine (78 mg, 11%) as a tan solid: mp 105-106.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>O>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:13][C:14](=[O:15])[NH:1]2)=[CH:7][C:8]=1[F:12]
Reactant: NC(N)=O
Reactant: Nc1cc(Br)c(F)cc1C(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(F)c(Br)cc2[nH]1
Temperature: 200 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a 100 mL round bottom flask, 2-amino-4-bromo-5-fluoro-benzoic acid (0.7 g, 0.003 mol) and urea (1.07 g, 0.0018 mol) were added. The reaction mixture was stirred at 200° C. for 2 h. The reaction mixture was allowed to reach 100° C. and water was added. The aqueous reaction mixture was refluxed for 5-10 min, cooled to room temperature, to get the precipitate. The solid was filtered and dried to afford the title compound (400 mg, 51%). This material was taken for next step without any further purification.