Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[C:20]([O:19][C@@H:18]1[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:29][C@H:17]1[N:6]1[C:5]2[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=[C:2]1[Cl:1])(=[O:22])[CH3:21]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1cc(Cl)c2[nH]c(Cl)nc2c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Cl)cc(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
To a suspension of 1.362 g (6.15 mmol) of 2,4,6-trichlorobenzimidazole in 31 mL of MeCN, was added 1.52 mL (6.15 mmol) of BSA. The reaction mixture was stirred at 80° C. for 15 min to give a clear solution. This solution was treated with 2.153 g (6.675 mmol) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 1.426 mL (7.380 mmol) of TMSOTf at 80° C. for 1 hr. The reaction mixture was cooled and diluted with EtOAc (150 mL). The EtOAc solution was washed with sat. NaHCO3 solution (150 mL×2), sat. NaCl solution (150 mL), dried (Na2SO4), and evaporated. The residue was coevaporated with MeOH and then suspended in 50 mL of hot MeOH. The suspension was cooled, filtered, and the solid product was washed with MeOH to give 2.103 g of 80 as white crystals (This product showed one spot on TLC). The mother liquor was evaporated and the residue was chromatographed on a silica column (2.5×20 cm, eluted with CHCl3 and 0.5% MeOH/CHCl3). Evaporation of fractions 20-24 (20 mL per fraction) and recrystallization from MeOH gave an additional 0.258 g of 80 as white crystals. The total yield of 80 was 2.361 g (80%). MP: 198°-200° C. MS: (El) m/e 480.0069 (4%, for C18H1735Cl237ClN2 O7 : M+ =480.0072). 1H NMR (DMSO-d6): δ7.89 (d, 1, 7-H, J7-5 =2.0 Hz), 7.58 (d, 1, 5H), 6.26 (d, 1, 1'-H, J1'-2' =7.0 Hz), 5.54 (t, 1, 2'-H, J2'-3' =7.0 Hz), 5.44 (dd,1, 3'H, J3'-4' =4.5 Hz), 4.48, 4.38 (2×m, 3, 4'-H and 5'-H), 2.14, 202 (2×s, 9, 3×Ac). 13H NMR (DMSO-d6): δ169.84, 169.37, 169.09 (3×COCH3), 140.91 (C2), 137.39 (C3a), 134.14 (C7a), 128.47 (C6), 123.66 (C4), 123.25 (C5), 111.06 (C7), 86.91 (C1'), 79.58 (C4'), 70.54 (C2'), 68.55 (C3'), 62.47 (C5'), 20.48, 20.19, 19.90 (3×COCH3). Anal. Calcd. for C18H17Cl3N2 O7 : C, 45.07; H, 3.57; N, 5.84. Found: C, 45.08; H, 3.62; N, 5.87.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[I:17].N(OC(C)(C)C)=O.[Si]([N:29]=[N+:30]=[N-])(C)(C)C>CC#N>[N:1]([C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[I:17])=[N+:29]=[N-:30]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)c(I)c1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1ccc(N=[N+]=[N-])c(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
tert-Butyl 4-amino-3-iodobenzylcarbamate (1.0 g, 2.87 mmol) was dissolved in CH3CN (6.0 ml). The solution was cooled to 0° C., tert-butyl nitrite (444.3 mg, 4.30 mmol) and TMS azide (397.1 mg, 3.45 mmol) were added. The mixture was then stirred at r.t for 2.0 h. The solvents were removed under vacuum and the residue purified by flash chromatography (Pet. Ether/EtOAc 85:15) affording 936 mg (87%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]2[N:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([N:21]5[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)[CH3:2].[CH:30]1([NH2:33])[CH2:32][CH2:31]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:30]1([NH:33][CH:24]2[CH2:23][CH2:22][N:21]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[N:12]=[C:11]([N:8]3[C:7]5[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=5[N:10]=[CH:9]3)[CH:20]=[CH:19]4)[CH2:26][CH2:25]2)[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: CCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(=O)CC3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(NC4CC4)CC3)c2n1
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
1-[2-(5-Ethoxy-benzoimidazol-1-yl)quinolin-8-yl]-piperidin-4-one 18 (130 mg, 0.340 mMol) was dissolved in 1.5 mL of DCE under an atmosphere of dry N2. To this solution was added cyclopropyl amine (110 μL, 1.70 mMol) and 200 μL of AcOH and the solution was stirred for 10 minutes. To this solution was added NaHB(OAc)3 (107 mg, 0.50 mMol) and the solution was stirred at ambient temperature for 5 hours. The reaction mixture was then partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was again washed with aqueous 0.1 N NaOH, dried over Na2SO4, filtered and concentrated under vacuum to give 150 mg of a green foam. The foam was chromatographed on flash silica gel eluting with a gradient from MeOH/DCM (299) to MeOH/DCM (496) to give the title compound 20 as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:13]C(OC(C)(C)C)=O)[CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]([F:12])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(F)cc(Cl)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Cl)cc(F)c1C(=O)O
Reaction time: 72 h
Yield: 69 %

Procedure:
A solution of methyl 4-chloro-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-fluorobenzoate in methylene chloride (150 mL) and trifluoroacetic acid (25 mL) was stirred for six hours. All solvents were removed under reduced pressure on a rotoevaporator, and the resulting residue was dissolved in THF (150 mL) and water (100 mL) and lithium hydroxide (2.5 g) were added. The biphasic mixture was stirred rapidly for three days, at which time no starting materials remain by TLC. The organic layer was washed with 2.0N sodium hydroxide and then the organic layers are discarded. The aqueous layer was adjusted to pH=2 by careful addition of 1.0N hydrochloric acid and then extracted with ethyl acetate. The combined ethyl acetate washes were dried over sodium sulfate, and volatiles were removed under reduced pressure to afford 2-amino-4-chloro-6-fluorobenzoic acid as a white solid (3.3 g, 69% yield) of sufficient purity for use in the next transformation. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.38 (dd, J=11.17, 1.47 Hz, 1 H), 6.60 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:11]([N:18]1[CH:22]=[C:21]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[C:7]#[N:8])[CH:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(-c2cnn(Cc3ccccc3)c2)ccc1F
Temperature: 110 °C

Procedure:
5-Bromo-2-fluorobenzonitrile (484 mg, 2.42 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (736 mg, 2.59 mmol), dichlorobis(triphenylphosphine)palladium(II) (174 mg, 0.248 mmol), and potassium carbonate (1.36 g, 9.84 mmol) were combined in a sealed vial with dioxane (10 mL) and water (1 mL) under an inert atmosphere of nitrogen, and the mixture was heated to 110° C. overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 290.0 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+].[CH:4]1([C:7](=[O:28])[C:8](=[CH:24][N:25](C)C)[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([NH:21][CH3:22])[C:12]=2[CH3:23])=[O:10])[CH2:6][CH2:5]1>C(O)C>[CH:4]1([C:7]2[O:28][N:25]=[CH:24][C:8]=2[C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([NH:21][CH3:22])[C:12]=2[CH3:23])[CH2:6][CH2:5]1
Reactant: CNc1c(S(C)(=O)=O)ccc(C(=O)C(=CN(C)C)C(=O)C2CC2)c1C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Product: CNc1c(S(C)(=O)=O)ccc(C(=O)c2cnoc2C2CC2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.19 g (2.8 mmol) of hydroxylammonium chloride was added to a solution of 0.85 g (2.3 mmol) of 1-cyclopropyl-2-(dimethylaminomethylidene)-3-(3-methylamino-2-methyl-4-methylsulfonylphenyl)propane-1,3-dione in 100 ml of ethanol. The mixture was stirred for 3 h at RT, and the solvent was removed in vacuo. The residue was taken up in CH2Cl2, washed with 10% strength H2SO4 and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel. This gave 0.50 g of product in 95% purity.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:34]2[N:33]=[CH:32][N:31]=[C:23]([NH:24][CH:25]3[CH2:29][CH2:28][C:27](=[O:30])[NH:26]3)[C:22]=2[N:21]=[CH:20]1)(=O)C>N>[O:30]=[C:27]1[NH:26][CH:25]([NH:24][C:23]2[C:22]3[N:21]=[CH:20][N:19]([C:34]=3[N:33]=[CH:32][N:31]=2)[C@@H:6]2[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]2[OH:4])[CH2:29][CH2:28]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCC(=O)N4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Product: O=C1CCC(Nc2ncnc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)N1
Yield: 67.9 %

Procedure:
To N6 -(5-oxo-2-pyrrolidinyl)adenosine 2',3',5'-triacetate (2.2 g) was added cold ammonia-saturated methanol (40 ml), and the resulting mixture was allowed to stand in a refrigerator (at 4° C.) overnight. Next morning the solvent was removed at room temperature. To the residue was added a small amount of methanol and the mixture was allowed to stand at room temperature. The resulting precipitate was recovered by filtration and dried to give N6 -(5-oxo-2-pyrrolidinyl)adenosine as crystals (1.098 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH:6]([O:7]2)[C:5](=[O:9])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:13]O>O>[CH3:13][O:7][C:6]1[C:5](=[O:9])[CH2:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:8]=1
Reactant: CO
Reactant: CC1(C)CCC(=O)C2OC21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC1=CC(C)(C)CCC1=O
Reaction time: 20 h
Yield: 45.9 %

Procedure:
A solution of 5,5-dimethyl-7-oxabicyclo[4.1.0]heptan-2-one (19.4 g, 138.4 mmol) in methanol (95 mL) was added to a solution of 85% potassium hydroxide (9.1 g, 138.4 mmol) in methanol (285 mL) at room temperature. The mixture was kept at this temperature for 20 hours and was then heated to reflux for 30 minutes. After cooling, the solution was diluted with water (750 mL) and extracted with diethyl ether (350 mL×4). The organic extracts were collected, washed with brine, dried on Na2SO4 and evaporated to dryness. The crude material was taken up with hexane (380 mL), maintained under vigorous stirring for 30 minutes and filtered to remove the solid material. The filtrate was evaporated under vacuum to obtain the pure title compound (9.8 g, 45.9% yield) as a pale yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Br:11]N1C(C)(C)C(=O)N(Br)C1=O.FC(F)(F)S(O)(=O)=O>ClCCl>[Br:11][C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2ccc(Br)cc2o1
Reaction time: 1 h

Procedure:
A mixture of 2-benzoxazolinone (3.00 g, 22.2 mmol), 1,3-dibromo-5,5-dimethylhydantoin (3.49 g, 12.2 mmol), and trifluoromethanesulfonic acid (5.00 g, 33.3 mmol) in dichloromethane (100 mL) at room temperature was protected from light, stirred for 1 hour, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:40])[N:21]([CH3:39])[C@@H:22]([C:30](=[O:38])[NH:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:39][N:21]([C@@H:22]([C:30](=[O:38])[NH:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:20](=[O:40])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccc2ccccc12)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN[C@H](Cc1cccc2ccccc12)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Reaction time: 0.08 h
Yield: 98.3 %

Procedure:
Methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(1-naphtyl)ethyl)carbamic acid tert butylester (0.84 g; 1.46 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 5 min at roomtemperature. Water (3 mL) and methylene chloride (5 mL) was added. Sodium hydrogen carbonate (solid) was added until pH 8. The reaction mixture was extracted with methylene chloride (3×10 mL). The combined organic layers were dried (magnesium sulfate) and evaporated in vacuo to afford 0.68 g of (2R)-N-methyl-2-methylamino-3-(1-naphtyl)-N-((1R)-2-phenyl-1-((tetrahydrofuran-2-yl-methyl)carbamoyl)ethyl)propionamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[K+:15].O.[OH-].[Na+].[CH3:19][O:20][CH2:21][CH2:22][OH:23]>[O-2].[O-2].[Mn+4]>[N+:1]([C:4]1[CH:5]=[C:6]([S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[O:23][CH2:22][CH2:21][O:20][CH3:19])([O-:3])=[O:2].[K+:15]
Reactant: COCCO
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1Cl
Agent: [Mn+4]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COCCOc1ccc(S(=O)(=O)[O-])cc1[N+](=O)[O-]
Reaction time: 0.83 h

Procedure:
Potassium 3-nitro-4-chlorobenzensulfonate (47.2 g (0.17 moles)) and manganese dioxide (15 g) were added to a mixed solvent of 500 ml of methyl Cellosolve and 75 ml of water and the resulting mixture was heated at a temperature of 65° to 70° C. with stirring. The mixture was admixed with 17.5 ml of an aqueous solution of 17.5 g (0.44 moles) of sodium hydroxide diluted with 50 ml of methyl Cellosolve, and the reaction was continued for another 50 minutes. After completion of the reaction, while the reaction mixture was sitll hot, insoluble matter was removed by filtration with sellaite. Isopropyl alcohol (750 ml) and toluene (1,250 ml) were added to the filtrate and crystals which separated out were collected by filtration, washed with isopropyl alcohol and dried.
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28](OC)[O:29]C)[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Cl>C(#N)C>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[O:29])[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: COC(CCCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1)OC
Agent: Cl
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCCCCCC=O)C1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a three-necked 500 mL flask equipped with a mechanical stirrer, a nitrogen inlet, cooling bath, and a thermometer was added (S)-3-(1-carbamoyl-1,1-diphenylmethyl)-1-(7,7-dimethoxyhept-1-yl)pyrrolidine (16 g, 0.036 mol) and acetonitrile (100 mL). This mixture was cooled to about 10° C. and 100 mL of 1N aqueous hydrochloric acid was added while maintaining the reaction temperature at 20° C. or less. The resulting mixture was stirred at 20±5° C. for 2 hours. The reaction mixture was then extracted with dichloromethane (1×200 mL and 2×100 mL). The combined organic layers were washed with brine (200 mL) and dried with sodium sulfate (40 g). The organic layer was then concentrated under vacuum at about 25° C. to a volume of about 200 mL. This solution, containing the title intermediate as the hydrochloride salt, was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1.O>[O:33]1[CH2:38][CH2:37][CH:36]([O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:11])([F:12])[F:13])[CH2:35][CH2:34]1
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(OC2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g 4-Hydroxy-3-trifluoromethyl-benzonitrile, 5.6 g triphenylphosphine and 1.2 g tetrahydro-4H-pyran-4-ol was suspended in 15 mL tetrahydrofuran at 0° C. before 4.92 g di-tert-butylazodicarboxylate (DBAD) as a solution in 5 mL tetrahydrofuran was added over 15 min. The reaction was warmed to ambient temperature. Additional 2.8 g triphenylphosphine, 0.55 g (5.3 mmol) tetrahydro-4H-pyran-4-ol and 2.46 g di-tert-butylazodicarboxylate (DBAD) in tetrahydrofuran were added and the reaction was stirred overnight. After this time, the reaction was diluted with water and extracted with ethyl acetate (×2). The organic phase was separated and then it was washed with 2N sodium hydroxide, water and saturated sodium chloride, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel chromatography (SiO2: heptane/ethyl acetate) to provide the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:11][C:12]1[CH:17]=[C:16]([O:18][C:2]2[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=2[CH:4]=[O:5])[CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: Cc1cc(O)cc(C)n1
Reactant: O=Cc1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(I)cc2C=O)cc(C)n1
Yield: 93.1 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (2 g, 8 mmol) (Aldrich) was reacted with 2,6-dimethyl-4-hydroxypyridine (1.08 g, 8.8 mmol) and K2CO3 in N,N-dimethylacetamide to give 2-(2,6-dimethyl-pyridin-4-yloxy)-5-iodo-benzaldehyde as a yellow solid (Yield 2.63 g, 92%).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][C:2]=1[NH2:10].[H-].[Na+].Cl[CH2:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:17]=2[N:16]=1>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:17]2[N:16]=[C:15]([CH2:14][N:5]3[CH:6]=[N:7][C:8]4[C:4]3=[N:3][C:2]([NH2:10])=[N:1][CH:9]=4)[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=2[CH:26]=1
Reactant: Nc1ncc2nc[nH]c2n1
Reactant: Fc1ccc2nc(CCl)n(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2ncn(Cc3nc4ccc(F)cc4n3-c3ccccc3)c2n1
Reaction time: 0.08 h
Yield: 46.5 %

Procedure:
To a stirred mixture of 9H-purin-2-ylamine (93 mg, 0.69 mmol) in DMF (1 mL) at RT and under a nitrogen atmosphere was added NaH (60% in mineral oil, 23 mg, 0.69 mmol). After 5 min, 2-chloromethyl-6-fluoro-1-phenyl-1H-benzoimidazole (150 mg, 0.575 mmol) in DMF (1 mL) was added. Stirring was continued for 18 h at RT. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 372 as a white solid (96 mg, 47%). LCMS (Method K): RT 3.17 min [M+H]+360.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.56 (1H, s), 8.00 (1H, s), 7.70-7.57 (6H, m), 7.16-7.07 (1H, m), 6.97 (1H, dd, J=8.93, 2.50 Hz), 6.43 (2H, s), 5.48 (2H, s)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:3])[CH3:2].ClC(Cl)C(OC(=O)C(Cl)Cl)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH3:38])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]>ClC(Cl)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH3:38])[C:33]([C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(C)cc1OC
Reactant: CC(=O)OCCCCCCCCCC(=O)O
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: COc1cc(C)c(C(=O)CCCCCCCCCOC(C)=O)cc1OC
Temperature: 75 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
In 50 ml of dichloroethane were dissolved 11.51 g (0.05 mole) of 10-acetyloxydecanoic acid and 14.39 g (0.06 mole) of dichloroacetic anhydride. To the resulting solution were added 9.89 g (0.065 mole) of 3,4-dimethoxytoluene and 0.71 g of boron trifluoridediethyl ether complex and the resulting mixture was then stirred at 75° C. for 5 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 15.3 g of 3,4-dimethoxy-6-(10-acetyloxydecanoyl)toluene.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.ClC1C=C2C(=CC=1)C(=O)CC2.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2=[O:27])=[CH:20][CH:19]=1>O1CCCC1.C(OCC)C>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2([CH:1]2[CH2:3][CH2:2]2)[OH:27])=[CH:20][CH:19]=1
Reactant: O=C1CCc2ccc(Cl)cc21
Reactant: Br[Mg]C1CC1
Agent: O=C1CCc2cc(Cl)ccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(C2CC2)CCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45 ml (22.5 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were added to 2.50 g (15.0 mmol) of a mixture of 5-chloro-2,3-dihydro-1H-inden-1-one and 6-chloro-2,3-dihydro-1H-inden-1-one in 56 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) and preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 152 mg (5% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Si:11]([Cl:13])([Cl:12])[Cl:10])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Clc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 70.2 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.22 g (0.75 mmol) of tetrabutylphosphonium chloride, 1.21 g (7.51 mmol) of 4-chlorobenzyl chloride, and 3.05 g (22.5 mmol) of trichlorosilane were reacted at 130° C. for 4 hrs. The resulting mixture was distilled to give 1.37 g of (4-chlorobenzyl)trichlorosilane (yield; 81%).