Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([NH:8][CH:9]2[C:18]3[CH2:17][S:16][N:15]=[C:14]([N:19](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:13]4=[N:34][N:35]([CH2:37][C:38]5[C:43]([CH3:44])=[C:42]([O:45][CH3:46])[C:41]([CH3:47])=[CH:40][N:39]=5)[N:36]=[C:11]([C:12]=34)[CH2:10]2)[CH2:7][CH2:6]1.ClCCl.C(N(CC)CC)C>C(OCC)(=O)C>[NH2:19][C:14]1[C:13]2[C:12]3[C:11](=[N:36][N:35]([CH2:37][C:38]4[C:43]([CH3:44])=[C:42]([O:45][CH3:46])[C:41]([CH3:47])=[CH:40][N:39]=4)[N:34]=2)[CH2:10][CH:9]([N:8]([CH:5]2[CH2:7][CH2:6]2)[C:1](=[O:3])[CH3:2])[C:18]=3[CH2:17][S:16][N:15]=1
Reactant: COc1c(C)cnc(CN2N=C3CC(NC4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(C)cnc(CN2N=C3CC(N(C(C)=O)C4CC4)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
Acetyl chloride (14 μL) was added to a mixture composed of the above di-tert-butyl {8-(cyclopropylamino)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate (100 mg), dichloromethane (2 mL) and triethylamine (42 μL) under cooling in an ice bath, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (4 mL) and trifluoroacetic acid (1 mL) were added to the resulting residue, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue under ice-cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (55 mg, 75%) as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:30][S:29]1.[C:43]([O:47][C:48]([NH:50][C:51]1([CH:54]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[C:55](O)=[O:56])[CH2:53][CH2:52]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl>[Cl:64][C:61]1[CH:62]=[CH:63][C:58]([CH:54]([C:51]2([NH:50][C:48](=[O:49])[O:47][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:52][CH2:53]2)[C:55]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[S:29][CH2:30][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:56])=[CH:59][CH:60]=1
Reactant: CC(C)(C)OC(=O)NC1(C(C(=O)O)c2ccc(Cl)cc2)CC1
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1SCc2ncnc(N3CCN(C(=O)C(c4ccc(Cl)cc4)C4(NC(=O)OC(C)(C)C)CC4)CC3)c21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
HBTU (0.097 mmol, 47 mg) was added to a solution of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (30 mg, 0.097 mmol) and 2-(1-(tert-butoxycarbonylamino)cyclopropyl)-2-(4-chlorophenyl)acetic acid (0.097 mmol) in DCM (5 mL) and TEA (5 mL). The mixture was stirred at room temperature for 6 hours. The solvent was removed, and the residue was subject to column chromatography, eluted by DCM/MeOH (50:1) to give tert-butyl 1-(1-(4-chlorophenyl)-2-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)cyclopropylcarbamate LCMS: 544.0 [M-Boc+H+] (APCI+); Rf: 3.49 min. The tert-butyl 1-(1-(4-chlorophenyl)-2-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)cyclopropylcarbamate was deprotected using procedures described previously to give 2-(1-aminocyclopropyl)-2-(4-chlorophenyl)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethanone. Rf: 2.24 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C@H:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@@H:30]([OH:43])[CH2:29]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:14]([C@@H:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:15]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[CH2:29][C@H:30]([OH:43])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:17])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4COCCN4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
(S)-2-((R)-4-(tert-Butoxycarbonyl)morpholin-3-yl)-2-(4-chlorophenyl)acetic acid (0.051 g, 0.143 mmol) was combined with (5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0440 g, 0.143 mmol), and then slurried in methylene chloride (1.4 mL). The suspension was treated with diisopropylethylamine (0.0749 mL, 0.430 mmol) and then with HBTU (0.0544 g, 0.143 mmol). The mixture was then stirred at ambient temperature for 60 hours. The reaction was quenched with 10% Na2CO3 and separated. The reaction mixture was washed with methylene chloride (3×), and the combined organics were then dried with Na2SO4 and concentrated in vacuo. The resulting residue was subjected to chromatography on SiO2 (Biotage 12M) eluting with methylene chloride (96 mL) then 0% to 5% MeOH/methylene chloride (500 mL) and 5% MeOH/methylene chloride (96 mL). The desired material eluted cleanly in approximately 1% MeOH/methylene chloride to yield (R)-tert-butyl 3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)morpholine-4-carboxylate as an oil. (81.2 mg, 99%).
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1([F:12])[F:11].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][C:7]2([F:11])[F:12])[C:3]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COC(=O)C(CC1CCCC1(F)F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1(F)F)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 11.4 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(2,2-difluoro-cyclopentyl)-propionic acid methyl ester (265 mg, 0.73 mmol) and 2-aminothiazole (18 mg, 0.18 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. %, 0.28 mL, 0.19 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(2,2-difluoro-cyclopentyl)-N-thiazol-2-yl-propionamide (8.3 mg, 23%) as a yellow oil: EI-HRMS m/e calcd for C17H16F2Cl2N2OS (M+H)+ 405.0402, found 405.0407.
Reaction SMILES: CC(C)([O-:4])C.[K+].[I:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=1.O.Cl>ClCCl.C(COC)OC>[I:7][C:8]1[CH:9]=[CH:10][C:18]([C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]([OH:21])=[O:4])=[CH:19][CH:20]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1c2ccccc2-c2ccc(I)cc21
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1ccc(I)cc1
Temperature: 25 °C
Yield: 772 %

Procedure:
Add potassium tert-butoxide (5.61 g, 0.05 moles) and dimethoxyethane (67 mL) to a 250 mL 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, and a nitrogen inlet. Stir the mixture at ambient temperature until the solid dissolves. Add 2-iodofluoren-9-one (1.5 grams, 0.005 moles, preparation 54) and stir until the solid dissolves. Add water (0.27 grams, 0.015 moles) and stir the reaction mixture at 23° C. for 1 hour. Add dichloromethane (70 mL) and concentrated hydrochloric acid to pH 1.0. Add water (50 mL) and separate the phases. Concentrate the organic phase under reduced pressure (15-25 mm) to a solid, and suspend the solid in a mixture of hexane (5 mL) and methyl-tert-butyl ether (5 mL) at ambient temperature for 3 hours. Isolate the solid by filtration and rinse the filter cake with pentane. Vacuum dry the solids to provide the title compound (1.25 grams, 0.0386 moles, 77.1% yield). 1H NMR (acetone-d6, 500.0 MHz): δ 7.94 (dd, 1H, J=1, 7.5); 7.82 (app. d, 2H, J=8); 7.66 (td, 1H, J=1, 7.5); 7.55 (td, 1H, J=1, 8); 7.44 (dd, 1H, J=1, 7.5); 7.22 (app. d, 2H, J=8).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1.[CH3:14][CH:15]([C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[O:20])[C:16](O)=[O:17].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:14][CH:15]([C:19]([NH:21][CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:27])[F:26])=[O:20])[C:16]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1)=[O:17]
Reactant: N[C@H]1COc2ccccc2NC1=O
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1COc2ccccc2NC1=O
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a solution of 0.07 g (0.37 mmol) (S)-7-amino-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in 7 ml tetrahydrofurane were added 0.15 g (0.59 mmol) 2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, 0.09 g (0.59 mmol) 1-hydroxybenzotriazole hydrate, 0.12 g (0.59 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride and 1.0 ml (5.9 mmol) diisopropylethylamine. After stirring at room temperature over night the solvent was removed by distillation and the residue was purified by chromatography on silicagel with ethylacetate/heptane (gradient 0–80/100–20) to yield 0.06 g (23%) 2-methyl-N-((S)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as light yellow solid, MS m/e (%): 410.3 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:29])[CH2:27][CH3:28])[CH:23]=[CH:24][CH:25]=1>CN(C)C=O>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:29])[CH2:27][CH3:28])[CH:23]=[CH:24][CH:25]=1)[CH3:9]
Reactant: CNCC=CC#CC(C)(C)C
Reactant: CCC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 26.7 %

Procedure:
N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine (trans:cis=about 3:1) (0.80 g; 5.29 mmol) and sodium carbonate (0.80 g; 7.56 mmol) were added to N,N-dimethylformamide (20 ml). While the mixture was stirred at room temperature, 3′-bromomethylpropiophenone (1.14 g; 5.04 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. The mixture was stirred for 2.5 hours at room temperature, and poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.40 g of the target compound as orange oily matter (yield: 26.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24](Cl)(=[O:26])=[O:25])([O:17][CH3:18])=[O:16]>C1COCC1>[CH3:18][O:17][C:15]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24](=[O:26])(=[O:25])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of an aniline (1.02 g, 10.9 mmol, 11.1 equivalents) dissolved in dry THF (35 mL) and triethylamine (1.53 mL, 1.1 equivalents) at room temperature, sealed with a septum and a nitrogen inlet, was added 2-carbomethoxythiophene-3-sulfonyl chloride (2.5 g, 9.9 mmol, 95% purity). The reaction mixture was stirred at room temperature over night. Upon completion, the reaction will be extracted by diluting with ethyl acetate and washing with aqueous HCl (2N), water and saturated, aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The solution will be decanted and evaporated under reduced pressure to give the desired 3-phenylsulfamoylthiophene-2-carboxylic acid methyl ester (2.6 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[NH:19]([C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[C:20]([NH2:22])=[NH:21].[OH-].[Na+]>CO.O>[N:27]1[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][C:23]=1[N:19]=[C:20]1[NH:22][C:8]2([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:22][C:20](=[N:19][C:23]3[NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[NH:21][C:10]2([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[NH:21]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Brc1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccc(Br)cc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 4,4'-dibromobenzil (4.42 g, 12 mmol) and 2-guanidinobenzimidazole (1.75 g, 10 mmol) in methanol (100 mL) was treated with a solution of sodium hydroxide (400 mg, 10 mmol) in 10 mL of water. The title compound was isolated as pale yellow crystals (800 mg, 24% yield). mp: 274-278 ° C. (dec); MS (ESI) m/z 683 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:13](OCC)(OCC)(OCC)[CH3:14]>C(O)C.CN(C)C(=O)C>[CH3:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]3[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]3)=[CH:10][C:11]=2[N:12]=1
Reactant: Nc1cc2ccccc2cc1N
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: Cc1nc2cc3ccccc3cc2[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 4.74 g of 2,3-diaminonaphthalene in 150 ml of ethanol and 30 ml of N,N-dimethylacetamide was added 4.86 g of triethyl orthoacetate, and the mixture heated at 60° C. for 2 hours. An additional 5.5 ml of triethyl orthoacetate was added and stirring continued at 60° C. overnight. The solvent was removed and the residue treated with chloroform. The solids were filtered and the filtrate concentrated to a small volume, treated with ether and filtered. The solids were combined to give 4.07 g of the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C:14]([CH2:16][OH:17])=[CH:13][CH2:12]2)=[C:4]([Cl:18])[N:3]=1.C[N+]1([O-])CC[O:23]CC1.C(O)(C)(C)C.[OH2:32]>[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:12][C@H:13]([OH:32])[C@:14]([CH2:16][OH:17])([OH:23])[CH2:15]2)=[C:4]([Cl:18])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3CC=C(CO)C3)c2n1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Product: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](O)[C@@](O)(CO)C3)c2n1

Procedure:
(4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-1-cyclopentene-1-methanol (Part b, 501 mg, 1.89 mmol), N-methylmorpholine N-oxide (60% aqueous solution, Aldrich, 0.33 mL, 1.89 mmol), osmium tetroxide (2.5% in t-butyl alcohol, Aldrich, 0.47 mL), and t-butyl alcohol (12 mL) were heated at 60° C. for 1.5 hours. Volatiles were evaporated and the residual solids were chromatographed on silica gel. Title compound was eluted with 10% methanol-chloroform as tan solid (210 mg) and resolidified from absolute ethanol to give white powder, m.p. 217-219° C.; mass spectrum (Cl/CH4): 302, 300 (M+1), 172, 170 (B+H); 1H-NMR (DMSO-d6) δ: 8.29 (s, 1, purine CH), 6.9 (br s, 2, NH2), 5.15-4.90 (m, 1, NCH), 4.80 (d, J=3.9 Hz) overlapping 4.78 (t, J=3.5 Hz, total 2, 2 OH), 4.30 (s) overlapping 4.3-4.2 (m, total 2, OH and OCH), 3.45-3.35 (m, overlapping water, CH2OH), 2.25-2.05 (m, 4, 2 CH2).
Reaction SMILES: C(OC(=O)NC1CC(=O)OC1OCC)C=C.NC1C=CC(C(NC(C)C(N2CCCC2C(O)=O)=O)=O)=CC=1Cl.[O:40]=[C:41]1[O:45][CH:44]([O:46][CH2:47][CH2:48]C2C=CC=CC=2)[CH:43]([NH:55][C:56]([CH:58]2[CH2:62][CH2:61][CH2:60][N:59]2[C:63](=[O:77])[CH:64]([NH:66][C:67](=[O:76])[C:68]2[CH:73]=[CH:72][C:71]([NH2:74])=[C:70]([Cl:75])[CH:69]=2)[CH3:65])=[O:57])[CH2:42]1>>[CH2:47]([O:46][CH:44]1[CH:43]([NH:55][C:56]([CH:58]2[CH2:62][CH2:61][CH2:60][N:59]2[C:63](=[O:77])[CH:64]([NH:66][C:67](=[O:76])[C:68]2[CH:73]=[CH:72][C:71]([NH2:74])=[C:70]([Cl:75])[CH:69]=2)[CH3:65])=[O:57])[CH2:42][C:41](=[O:40])[O:45]1)[CH3:48]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OCC
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(N)c(Cl)c1

Procedure:
Prepared from (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a. The title compound was isolated as a white solid (175 mg, 77% yield). 1H-NMR (500 MHz, CD3OD) δ 1.13 (t, 0.5H), 1.23 (t, 2.5H), 1.36 (d, 0.5H), 1.44 (d, 2.5H), 1.75-2.38 (m, 4H), 2.56 (dd, 1H), 2.76 (dd, 1H), 3.45-3.97 (m, 5H), 4.47 (dd, 1H), 4.59-4.67 (m, 1H), 4.7-4 (q, 1H), 5.55 (d, 0.2H), 5.56 (d, 0.8H), 6.75-6.82 (m, 1H), 7.56 (dd, 1H), 7.77 (d, 1H), 8.39 (d, 1H). Analytical HPLC 8.17 min. LC-MS (ES+) m/e=467.4 (MH+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Reactant: C1CCNC1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(N3CCCC3)cc2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=547.2 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, pyrrolidine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([CH3:23])[C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:29].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([CH3:23])[C:14]([CH:21]=[O:29])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.40 g) in a mixed solvent of acetone (8.00 mL)-acetonitrile (8.00 mL)-water (8.00 mL) were added osmium oxide (fixed catalyst I) (0.15 g) and sodium periodate (1.24 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1.N([O-])=[O:25].[Na+].N>C(O)(=O)C.O>[OH:25][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(N)cc2[nH]1
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(O)cc2[nH]1
Reaction time: 1 h

Procedure:
An amount of 3.2 (9.6 mmol) of 5-amino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole was dissolved in 509 ml of glacial acetic acid, and then a solution of 1.38 gm (20 mmol) of sodium nitrite in 5.0 ml of water was added dropwise, under stirring. After one hour, the mixture was diluted with 100 ml of water, and the solution was refluxed for 1.5 hours. Subsequent to cooling, the solution was adjusted to a pH of 5 with concentrated ammonia and extracted three times, each time with 40 ml of methyl ethyl ketone, and the extracts are dried and concentrated by evaporation in vacuo. The oily residue was chromatographed over 500 gm of aluminium oxide (neutral) (eluant: methylene chloride with 8% ethanol).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([CH2:18]O)[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH3:20]>>[ClH:3].[Cl:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([CH2:18][Cl:3])[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc2ccc(CO)cc2n1Cc1ccccc1Cl
Product: Cc1nc2ccc(CCl)cc2n1Cc1ccccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Five milliliters of thionyl chloride were added to 3.56 g of 1-(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole, and the mixture was stirred at room temperature for 20 minutes and then at 80° C. for 20 minutes. After excess thionyl chloride was distilled off under reduced pressure, the residue was dissolved in 10 ml of chloroform, and the solution was crystallized from hexane. The crystals were separated through filtration, washed with hexane, and dried to give 4.07 g of 1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole hydrochloride.