Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6](Cl)=[O:7])[CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([NH2:27])=[N:18][N:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)=[CH:12][C:11]=1[CH3:28]>C(Cl)Cl.N1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([NH:27][C:6](=[O:7])[CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[N:18][N:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)=[CH:12][C:11]=1[CH3:28]
Reactant: O=C(Cl)CCC1CC1
Reactant: Cc1cc(C)n2nc(N)c(-c3ccc(Cl)c(C)c3)c2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(NC(=O)CCC3CC3)c(-c3ccc(Cl)c(C)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A solution of the product from Example 114D (40.9 mg, 0.308 mmol) in CH2Cl2 (2 mL) was added to a stirring solution of the product from Example 47C (49.5 mg, 0.173 mmol) in pyridine (1.5 mL) at room temperature. The solution was stirred at room temperature for 1 hour, and then concentrated under vacuum. Methanol (2 mL) was added, and the mixture was concentrated under vacuum. The residue was crystallized from 60% EtOH-water (8 mL) to provide the title compound (52 mg). 1H NMR (300 MHz, CD3OD) δ ppm 0.01-0.14 (m, 2H) 0.37-0.52 (m, 2H) 0.66-0.82 (m, 1H) 1.48-1.65 (m, 2H) 2.40 (s, 3H) 2.50 (t, J=7.0 Hz, 2H) 2.57 (s, 3H) 2.72 (s, 3H) 6.88 (s, 1H) 7.37 (d, J=8.1 Hz, 1H) 7.55 (dd, J=8.6, 1.5 Hz, 1H) 7.65 (d, J=1.0 Hz, 1H)); MS (ESI) m/z 383/385 (M+H)+; Anal. Calculated for C21H23N4OCl: C, 65.87; H, 6.05; N, 14.63. Found: C, 65.56; H, 6.08; N, 14.63.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][C@@H:10]([OH:15])[C:11]([F:14])([F:13])[F:12])(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:12][C:11]([F:14])([F:13])[C@H:10]([OH:15])[CH2:9][CH2:8][NH:7][CH3:6]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCC[C@@H](O)C(F)(F)F
Reaction time: 1 h
Yield: 76.4 %

Procedure:
A solution of (R)-(4,4,4-trifluoro-3-hydroxybutyl)carbamic acid tert-butyl ester (3.17 g, 13.0 mmol) in THF (130 mL) was treated with lithium aluminium hydride (1.97 g, 52.0 mmol) at ambient temperature, followed by refluxing for 2 h. Heating was stopped, additional lithium aluminium hydride (0.490 g, 12.9 mmol) was added, and refluxing was continued for 1 h. The mixture was cooled to 0–5° C. and carefully quenched with excess sodium sulfate decahydrate. Additional THF and diethyl ether were added to aid stirring. The mixture was filtered through Celite™ and the filtrate was evaporated to a white wax. The wax was purified by trituration with 9:1 hexane/diethyl ether (v/v) to give the product as a white solid (1.56 g, 76%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:7]2[CH:3]1[CH2:4][C:5](=[O:12])[CH:6]2[C:8](=O)[CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)[Cl:34]>C(Cl)(Cl)(Cl)Cl>[Cl:34][C:8](=[C:6]1[C:5](=[O:12])[CH2:4][C@H:3]2[C@@H:7]1[C:2]2([CH3:13])[CH3:1])[CH2:9][CH3:10]
Reactant: CCC(=O)C1C(=O)CC2C1C2(C)C
Reactant: ClC(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Cl)=C1C(=O)C[C@H]2[C@@H]1C2(C)C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(1S,5R)-6,6-dimethyl-2-propionyl-bicyclo[3.1.0]hexan-3-one (14.37 g, 80 mmol) in chloroform (145 mL) and CCl4 (53 mL), triphenylphosphine (41.8 g, 160 mmol) is added. The resulting solution is stirred at 60° C. for 75 min before a second portion of triphenylphosphine (4.2 g, 16 mmol) is added. Stirring is continued at 60° C. for 30 min. The solvent is evaporated and the residue is suspended in pentane. The pentane solution is decanted from the brown oily residue. The residue is once more treated with pentane. The combined pentane fractions are carefully evaporated to leave crude (1R,5S)-2-[1-chloro-propylidene]-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (11.0 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:14]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:31]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[O:32])[CH2:14]3)[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2(CN3CCCC(CNc4ccccc4)C3)CCC2)cc1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCC1)N(CC1CCCN(CC2(c3ccc(Cl)cc3)CCC2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
A solution of 203 (0.276 mmol, 102 mg) in CH2Cl2 (2 mL) at 0° C. was treated with cyclobutanecarbonyl chloride (1.5 equiv, 0.414 mmol, 50 μL) and diisopropylethylamine (1.5 equiv, 0.414 mmol, 72 μL) under Ar. After warming to 25° C. and stirring for 12 h, the reaction mixture was purified directly by chromatography (PTLC, SiO2, 20 cm×20 cm, 1 mm, 8:1 hexane-acetone) which provided 204 (100 mg, 124 mg theoretical, 81%) as a yellow oil: Rf 0.27 (SiO2, 8:1 hexane-acetone); LRMS m/z 451 (M+, C28H35ClN2O, requires 451).
Reaction SMILES: C([O:8][CH2:9][C:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH2:13][OH:14])[CH2:11][OH:12])C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>C(OCC)C>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:10]([CH2:9][OH:8])([CH2:13][OH:14])[CH2:11][OH:12]
Reactant: CC(C)(C)CC(CO)(CO)COCc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)CC(CO)(CO)CO

Procedure:
2-Benzyloxymethyl-2-(2,2-dimethylpropyl)-propan-1,3-diol (5.5 g.) in dry diethyl ether (50 ml.) was added to liquid ammonia (200 ml.) at -70°. Sodium (2.5 g.) was added to the stirred solution. Stirring was maintained at -70°, for 1 hour. The mixture was allowed to warm up to -30° and solid ammonium chloride (15 g.) was added cautiously. The ammonia was removed from the reaction mixture under a current of nitrogen. Methanol (25 ml.) was added to the stirred mixture to destroy residual sodium. Dichloromethane (400 ml.) was added and the mixture was filtered. The filtrates were evaporated in vacuo. 2-(2,2-Dimethylpropyl)-2-hydroxymethyl-propan-1,3-diol was obtained as a colourless solid (3.5 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:19]=2[CH:38]=1)#[N:14].C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.O1CCCC1>[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[N:22]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:21](=[O:23])[N:20]([CH:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:19]=2[CH:38]=1)#[N:14]
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)[nH]c2ccc(C#N)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)OC(C)(C)C)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.63 g (7.87 mmol) of 4-methoxybenzenesulfonyl chloride were added to a solution of 2.50 g (7.16 mmol) of tert-butyl (6-cyano-2-oxo-2,3-dihydro-benzimidazol-1-yl)phenylacetate (XIc), 1.98 ml (14.3 mmol) of triethylamine and a catalytic amount of DMAP in tetrahydrofuran (60 ml) while stirring at room temperature, and the mixture was then stirred at room temperature for 16 h. The reaction solution was mixed with water and extracted with ethyl acetate (3×60 ml). The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase gradient 10-40% ethyl acetate in cyclohexane). Yield: 2.90 g (78%) of colorless solid
Reaction SMILES: C([CH:5]([O:19][SiH](C1C=CC=CC=1)C1C=CC=CC=1)[C@H:6]1[S:10][CH2:9][C@@H:8]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[O:7]1)CCC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:19][CH2:5][C@H:6]1[S:10][CH2:9][C@@H:8]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[O:7]1
Reactant: CCCCC(O[SiH](c1ccccc1)c1ccccc1)[C@@H]1O[C@H](n2ccc(N)nc2=O)CS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ccn([C@@H]2CS[C@H](CO)O2)c(=O)n1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of the β anomer 17 (0.15 g, 0.32 mmol) in THF (25 mL) was added tetrabutylammonium fluoride 1M in THF (0.35 mL, 0.35 mmol, 1.1 eq) and the reaction was allowed to stir at room temperature until TLC indicated the disappearance of starting material (30 min). The reaction mixture was concentrated under reduced pressure and the residue purified by preparative TLC using 12% MeOH/CHCl3 as development solvent to give 0.055 g (75%) of 3 from ethyl ether/MeOH (trace) as a white crystalline solid. [α]23D =-121.6 (c 1.1, MeOH) (for the S,R isomer 2 [α]23D =120.96 (c 1.06, MeOH)); 1H NMR: ((CD3)2SO) δ 3.03 (dd, J5,4a =4.4 Hz, J4a,4b =11.86 Hz, 1 H, 4a-H), 3.43 (dd, J5,4b =5.3 Hz, J4a,4b =11.86 Hz, 1 H, 4b-H), 3.80 (app t on D2O exchange goes to d, J2,2-CH2-OR =4.17 Hz, 2 H, 2-CH2 -OH), 5.27 (t, J2-CH2,OH =4.6 Hz, 1 H, 2-CH2OH), 5.22 (t, J2,2-CH2-OH =4.17 Hz, 1 H, 2-H), 5.88 (d, J5,6 =7.47 Hz, 1 H, H-5), 6.21 (app t, J=5.05 and 4.84 Hz, 1 H, 5-H), 7.19 (bs, 2 H, NH2), 7.89 (d, J5,6 =7.47 Hz, 1 H, H-6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([Cl:16])=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn2cc(F)ccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cn2cc(F)ccc2n1

Procedure:
To a suspension of the product of step (b) (20 g) in toluene (250 ml) and tetrabutylammonium chloride (0.3 g) was added thionyl chloride (40 ml) and the mixture refluxed for 4 hrs. A further aliquot of thionyl chloride-(40 ml) was added and the mixture was refluxed for a further 4 hrs. Solvents were evaporated and the residue was azeotroped with toluene to give the sub-title compound as a solid (20 g). This was used without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]2[C:14](=[CH:15][C:16]=1Cl)[N:13]=[C:12]([CH3:18])[CH:11]=[CH:10]2)(=[O:5])=[O:4].Cl[C:29]1C=CC(C2C(O)=C(C)C=C3C=2C=CC(C)=N3)=CC=1>>[F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:29])[N:13]=[C:12]([CH3:18])[CH:11]=[CH:10]2)(=[O:5])=[O:4]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(C)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1

Procedure:
Compound 2E was prepared following the procedure used to prepare compound 1F of Example 1, except that 5-(4-chlorophenyl)-2,7-dimethylquinolin-6-ol (2D) was used instead of compound 1E. LCMS-ESI+ (m/z): 416.0, 418.0 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:18])[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9]1)C.Cl>O.C(O)C>[C:14]([N:11]1[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([OH:18])=[O:5])[CH2:13][CH2:12]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)CC1CCN(C(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)N1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To a solution of NaOH in water/ethanol (v/v=40/10, 50 mL) (1-tert-butyl-piperidin-4-yl)-acetic acid ethyl ester (4.03 g, 17.8 mmol) was added and the mixture was stirred at r.t. overnight. 1 N aq. HCl was added to adjust the pH to 5. Volotiles were evaporated in vacuo, the residue was diluted with methanol (30 mL), and the insoluble inorganic salts were removed by filtration. The filtrate was concentrated and purified by column chromatography on silica gel (CH2Cl2/MeOH=20/1 to 5/1) to give 0.7 g of title compound as a light grey powder. 1H NMR (400 MHz, DMSO-d6): 3.15-3.08 (br m, 2H), 2.30 (br t, J=11.2 Hz, 2H), 2.05 (d, J=6.4 Hz, 2H), 1.71-1.68 (m, 3H), 1.30-1.27 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[C:22]1([C:28]#[C:29][C:30]2[O:34][C:33]([C:35](ON3C(=O)CCC3=O)=[O:36])=[CH:32][CH:31]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][C:35]([C:33]2[O:34][C:30]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:31][CH:32]=2)=[O:36])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(C#Cc2ccccc2)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1(NC(=O)c2ccc(C#Cc3ccccc3)o2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (53 mg, 0.263 mmol) in CH2Cl2 (2 mL) was treated with NEt3 (0.11 mL, 0.789 mmol), and 2,5-dioxopyrrolidin-1-yl 5-(phenylethynyl)furan-2-carboxylate, prepared as described in Preparation 5 (89 mg, 0.289 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the product purified by column chromatography to obtain the title compound (51 mg, 49%). 1H NMR (400 MHz, CD3OD) δ 7.57-7.53 (m, 2H), 7.44-7.40 (m, 3H), 7.16 (s, 1H), 6.84 (s, 1H), 4.08 (q, 2H, J=7.2 Hz), 2.89 (s, 2H), 2.70-2.65 (m, 2H), 2.54-2.47 (m, 2H), 2.39-2.25 (m, 5H), 1.85-1.80 (m, 2H), 1.17 (t, 3H, J=7.2 Hz); MS ESI 395.2 [M+H]+, calcd for [C23H26N2O4+H]+ 395.47.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:9][OH:10])[C:2]=1[NH:1][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH3:11]
Reactant: Nc1c(Cl)cccc1CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1c(Cl)cccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To the crude (2-amino-3-chlorophenyl)methanol (1.08 g, 6.88 mmol) in CH2Cl2(15 mL) was fast dropwise added trimethylacetyl chloride (0.89 mL, 7.23 mmol), followed by DIEA (2.4 mL, 13.8 mmol) at 0° C. 5 min later, the reaction mixture was stirred at room temperature for 1 hr. Normal aqueous work-up to afford the expected product as a white solid (1.58 g, 95% yield), which was pure enough to be used in next step; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (s, 9 H), 3.35 (s, 2 H), 4.36 (d, J=6.29 Hz, 1 H), 7.06-7.22 (m, J=7.81, 7.81 Hz, 1 H), 7.29-7.33 (m, 2 H), 7.58 (s, 1 H); Mass spec. 242.08 (MH+), Calc. for C12H16ClNO2 241.09.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([CH3:19])=[CH2:18])=[CH:15][C:14]([OH:20])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1>CCOC(C)=O.C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:16]([CH:17]([CH3:18])[CH3:19])=[CH:15][C:14]([OH:20])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: C=C(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 3 h
Yield: 89.7 %

Procedure:
2-(4-Hydroxyphenyl)-7-isopropenyl-1,3-benzoxazol-5-ol (64 mg, 0.24 mmol) was dissolved in a mixture of EtOAc (5 mL) and absolute ethanol (5 mL) and placed under an inert atmosphere with argon. To this mixture was added 10% Pd—C (25 mg). The solution was, hydrogenated on a Parr apparatus at 25 psi for 3 h. The solution was filtered through celite and rinsed with ethanol. The filtrate was concentrated and the residue purified by flash chromatography (50% EtOAc/petroleum ether) to give (58 mg, 90% yield) of the product as a tan solid, m.p. 200° C.; MS m/e 270 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@H:11]1[CH2:20][C:19]23[CH2:21][CH2:22][C@:12]1([OH:36])[CH:13]1[O:30][C:28]4=[C:29]5[C@@:14]12[CH2:15][CH2:16][N:17]([CH2:32][CH:33]1[CH2:35][CH2:34]1)[C@@H:18]3[CH2:23][C:24]5=[CH:25][CH:26]=[C:27]4[OH:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:38]1[N:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:41]=[N:40][N:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C@H:11]1[CH2:20][C:19]23[CH2:21][CH2:22][C@:12]1([OH:36])[CH:13]1[O:30][C:28]4=[C:29]5[C@@:14]12[CH2:15][CH2:16][N:17]([CH2:32][CH:33]1[CH2:34][CH2:35]1)[C@@H:18]3[CH2:23][C:24]5=[CH:25][CH:26]=[C:27]4[O:31][C:38]1[N:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:41]=[N:40][N:39]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)[C@H]1CC23CC[C@]1(O)C1Oc4c(O)ccc5c4[C@@]12CCN(CC1CC1)[C@@H]3C5
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)[C@H]1CC23CC[C@]1(O)C1Oc4c(Oc5nnnn5-c5ccccc5)ccc5c4[C@@]12CCN(CC1CC1)[C@@H]3C5
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
Under an argon atmosphere, the compound 111 (2 g, 4.11 mmol) was dissolved in DMF (40 mL), the solution was added with 5-chloro-1-phenyl-1H-tetrazole (891 mg, 4.93 mmol), and potassium carbonate (1.42 g, 10.3 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The obtained crude product was purified by silica gel column chromatography to give the title compound 112 (2.5 g, 96%).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[CH3:7][N:8]1[C:16]2[N:15]=[C:14]([Cl:17])[NH:13][C:12]=2[C:11](=[O:18])[NH:10][C:9]1=[O:19].CCN(C(C)C)C(C)C.O>CN(C)C=O>[CH3:7][N:8]1[C:16]2[N:15]=[C:14]([Cl:17])[N:13]([CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])[C:12]=2[C:11](=[O:18])[NH:10][C:9]1=[O:19]
Reactant: CC(C)=CCBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.87 mL of 1-bromo-3-methyl-2-butene is added to 10.56 g of 3-methyl-8-chloroxanthine and 17 mL of Hünig base in 100 mL of N,N-dimethylformamide. The reaction mixture is stirred for approximately 10 minutes at ambient temperature and then combined with 800 mL of water. The light-colored precipitate formed is suction filtered, washed with ethanol and diethyl ether and dried. Yield: 10.56 g (81% of theory); mass spectrum (ESI+): m/z=269, 271 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([SH:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21]Cl)[CH:16]=1>CO.O>[F:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][CH2:21][C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[CH:19][N:18]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2[nH]c(S)nc12
Reactant: COc1ccnc(CCl)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccnc(CSc2nc3c(F)cccc3[nH]2)c1

Procedure:
To a solution of 4-fluoro-2-mercapto-1H-benzimidazole (1.15 g, 0.0068 mol) in methanol (60 ml) NAOH (0.54 g, 0.014 mol) dissolved in water (3 ml) and 4-methoxy-2-chloromethylpyridine hydrochloride (1.32 g, 0.0068 mol) dissolved in methanol (20 ml) were added in the given order. The mixture was refluxed for one hour whereupon the solution was evaporated. The residue was partitioned between methylene chloride and water. After separation the organic solution was dried over MGSO4 and evaporated giving an oil which was purified on silica gel (50 g) using 1% methanol in methylene chloride as eluent. In this way the title compound was obtained (1.35 g, 69%). NMR data for the product is given below.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:25])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][CH:40]=[N:41]3)=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].ClCCl>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([N:16]1[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:43]=[C:42]5[C:37]([CH:38]=[CH:39][CH:40]=[N:41]5)=[CH:36][CH:35]=4)=[CH:3][CH:4]=3)[C:9](=[O:25])[NH:10][N:11]=2)[CH2:15]1)=[O:24]
Reactant: CC(C)(C)C(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2)C1
Temperature: 110 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of 4-(4-bromophenyl)-5-{[(3S)-1-(2,2-dimethylpropanoyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.277 mmol) in dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.294 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (20 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with the dropwise addition of 6N aq HCl, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) and then reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The combined product fractions were concentrated in vacuo for 30 min to remove the acetonitrile. The aqueous solution was neutralized with the addition of saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (49 mg, 38% yield). MS(ES)+ m/e 456.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:51])([CH3:50])[CH2:3][C:4]1[N:5]=[C:6]([CH2:28][C:29]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)([OH:34])[C:30]([F:33])([F:32])[F:31])[N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:59]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][N:60]=1.O>CN(C)C=O.O>[CH3:1][C:2]([CH3:51])([CH3:50])[CH2:3][C:4]1[N:5]=[C:6]([CH2:28][C:29]([C:35]2[CH:40]=[CH:39][C:38]([C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][N:60]=3)=[CH:37][CH:36]=2)([OH:34])[C:30]([F:31])([F:32])[F:33])[N:7]([C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(F)(F)F)n1
Reactant: Fc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)(F)F)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (458 mg, 0.56 mmol) was added to a degassed, ambient temperature solution of 3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol, sodium carbonate (2.4 g, 22.5 mmol) and 2-bromo-5-fluoropyridine (3.0 g, 16.8 mmol) in N,N-dimethylformamide/water (4:1) (150 mL). After stirring at 90° C. for 2 h, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]propan-2-ol.