Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.CCCCCC.C([Li])CCC.[F:21][C:22]([F:30])([F:29])[C:23]([C:25]([F:28])([F:27])[F:26])=[O:24]>C(OCC)C>[F:21][C:22]([F:30])([F:29])[C:23]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)([OH:24])[C:25]([F:28])([F:27])[F:26]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1cc(Br)cc(Br)c1)(C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Under a nitrogen atmosphere, 30.0 g (95.0 mmol) of 1,3,5-tribromobenzene and 400 mL of diethyl ether were placed in a 500-mL glass flask and cooled to −78° C. Further, 60 ml (96.0 mmol) of 1.6M n-butyl lithium hexane solution was dropped into the glass flask at −78° C. over 1 hour. The resulting solution was subjected to aging at −78° C. for 1 hour. The lithiation of the raw material was confirmed by gas chromatography. After that, 16.6 g (100.0 mmol) of hexafluoroacetone was charged into the solution at −78° C. and stirred for 1 hour. After the completion of the stirring, the reacted solution was separated into an organic layer and an aqueous layer by the addition of 400 mL of 2N hydrochloric acid. The aqueous layer was extracted with 100 mL of isopropyl ether. The extracted organic layers were combined, dried with anhydrous magnesium sulfate, concentrated by an evaporator, and then, subjected to distillation. With this, 23 g of 1-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-3,5-dibromobenzene was obtained. The yield was 60%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.CS(C)=O.[H-].[Na+].Br[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>CC1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][C:35]3[S:36][CH:37]=[CH:38][N:39]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Fc1ccc(Cn2c(NC3CCN(CCOc4nccs4)CC3)nc3ccccc32)cc1
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a stirred and cooled (below 10° C.) mixture of 5.52 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidine ethanol, 100 parts of dimethyl sulfoxide and 90 parts of methylbenzene were added 0.75 parts of a sodium hydride dispersion 50%. After stirring for 30 minutes at a temperature below 10° C., 2.5 parts of 2-bromothiazole were added and stirring was continued overnight while the mixture was allowed to reach room temperature. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1 part (14.5%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-thiazolyloxy)ethyl]- 4-piperidinyl]-1H-benzimidazol-2-amine; mp. 156.5° C. (compound 72).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[CH:16]1([CH2:22][C:23](Cl)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[CH:16]1([CH2:22][C:23]([NH:15][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Solvent: c1ccncc1
Product: O=C(CC1CCCCC1)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 36.2 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.91 g, 4.5 mmol) and cyclohexylacetyl chloride (0.80 g, 5.0 mmol) in pyridine (10 mL) provided 2-cyclohexyl-N-[7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-yl]acetamide (0.53 g). Mp 188-189° C.; Anal. Calcd. for C21H27NO2: C, 77.50; H, 8.36; N, 4.30; Found: C, 77.51; H, 8.43; N, 4.32.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH2:11]([Mg]Br)[CH3:12]>C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[CH2:11][CH3:12]
Reactant: Nc1cccc(Cl)c1C=O
Reactant: CC[Mg]Br
Solvent: CCOC(C)=O
Product: CCC(O)c1c(N)cccc1Cl
Yield: 48 %

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from 2-amino-6-chlorobenzaldehyde (0.30 g, 1.9 mmol) and ethyl magnesium bromide (3 M in diethyl ether, 1.3 mL) to afford 0.17 g (48%) of (±)-1-(2-amino-6-chlorophenyl)propan-1-ol after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[C:11]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1

Procedure:
Commercially available trans-4-aminocyclohexanol hydrochloride (50 g, 0.33 mol) was treated with benzyl chloroformate (Cbz-Cl) (51.8 mL, 0.36 mol) under standard Schotten-Baumann conditions to provide N-Cbz-trans-4-aminocyclohexanol (62.33 g, 88% yield) as a white solid: m.p. 160°-162° C.; 1H NMR (300 MHz) δ 7.36 (m, 5H), 5.10 (s, 2H), 4.58 (br, 1H), 3.61 (m, 1H), 3.51 (m, 1H), 2.01 (br t, 4H, J=13.5 Hz), 1.40 (m, 2H), 1.20 (m, 2H); MS: (M+H)+ =250, (M+H+NH3)+ =267.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15].[OH-].[NH4+]>>[CH3:8][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([N+:14]([O-:16])=[O:15])[N:4]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ncccc1O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc([N+](=O)[O-])ccc1O
Yield: 9.7 %

Procedure:
While maintaining a temperature of 0-5° C. with external ice cooling, 3-hydroxy-2-methyl pyridine (10.00 g, 91.63 mmol) was added gradually to concentrated sulfuric acid (65.00 ml). A mixture of concentrated sulfuric acid (8.50 ml) and nitric acid (6.50 g, 103.16 mmol) was added over 2 h. The resulting mixture was poured onto ice. Addition of a few milliliters of saturated ammonium hydroxide caused precipitation of crude 2-methyl-6-nitro-pyridin-3-ol. This was collected by filtration and recrystallized from methanol/water to yield pure 2-methyl-6-nitro-pyridin-3-ol (1.37 g, 10%). Basification of the mother liquors to pH 3-4 triggered precipitation of the isomeric 2-methyl-4-nitro-pyridin-3-ol (major component), which was discarded.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.C([Li])CCC.CCCCCC.Cl>C1COCC1>[C:5]([C:4]1[CH:3]=[C:2]([B:10]([OH:15])[OH:11])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
3-Bromobenzonitrile (3.6 g, 20 mmol) in anhydrous THF (100 ml) is treated with triisopropyl borate (13 ml, 56 mmol) followed by 1.6 M butyllithium in hexane (14 ml, 22 mmol) over 15 min. at −78° C. The reaction is stirred at −78° C. for 45 min . then warmed to room temperature over 60 min. The reaction mixture is poured into 40 ml 2 N HCl and the precipitated solid is collected . The filter cake is washed with water (3×) and methylene chloride (3×) to yield 3-cyanophenyl boronic acid (2.3 g, 15.6 mmol). 1H NMR (CDCl3, 300 MHz) δ 8.4 (br, 2H), 8.13 (s, 1H), 8.07 (d, 1H), 7.85 (d, 1H), 7.55 (t, 1H). EI MS M+ 147.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[K+].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:6]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:17])([O-:9])=[O:7]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccccc1[N+](=O)[O-]

Procedure:
The toluene derivative (h) is charged with concentrated sulfuric acid and potassium nitrate to obtain the 2-nitrotoluene derivative (i) (reaction 7), which is subsequently reduced (reaction 8) with hydrogen over Raney-nickel to the amine (j). In a Sandmeyer reaction (reaction 9) with amylnitrate and the halogenide (R7 -Hal) in the presence of copper, the toluene derivative (k) is obtained. The reaction with chromium(VI)oxide in acetic acid leads to the aldehyde (a).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=4)=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=[C:7]([F:30])[C:3]=1[C:4]([NH2:6])=[O:5].B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=4)=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=[C:7]([F:30])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cccc(-c2ccc3sc(COc4ccc(F)c(C(N)=O)c4F)nc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(-c4cccc(O)c4)ccc3s2)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
To a suspension of 2,6-difluoro-3-[5-(3-methoxy-phenyl)-benzothiazol-2-ylmethoxy]-benzamide (0.14 g, 0.3 mmol) in 15 ml of anhydrous DCM was added drop wise boron tribromide (0.493 g, 1.9 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 3 h under nitrogen atmosphere. To the reaction mixture 5 ml of water was added at 0° C. The compound was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using ethyl acetate (40:60) as the eluent to provide the title compound as yellow solid (0.020 g, 14%). 1H NMR (DMSO-d6, 400 MHz): δ 5.71 (s, 2H), 6.80 (dd, 1H, J=9.6 Hz (o-coupling), 7.11 (dt, 1H, J=8.0 Hz (o-coupling), 7.17 (dt, 1H, J=8.0 Hz (o-coupling), 7.29 (t, 1H, J=8.0 Hz (o-coupling), 7.39-7.43 (m, 1H), 7.71 (dd, 1H, J=9.6 Hz) 7.89 (broad s, 1H), 8.18-8.22 (m, 2H). MS ES+ (413.01), HPLC (method 5) Rt=14.95 min
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][O:17]C1CCCCO1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:5][CH:4]=1)[CH2:15][CH2:16][OH:17]
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCO)c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
A mixture of N-methyl-(4-trifluoromethoxyphenyl)amine (4.83 g, 24.24 mmol), 2-(2-bromoethoxy)-tetrahydropyran (6.1 g, 29.03 mmol), and potassium carbonate (3.84 g, 27.76 mmol) in DMF (20 ml) was stirred at 100° C. for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford 2-[N-methyl-(4-trifluoromethoxyphenyl)-amino]ethanol (3.1 g, yield 53%) as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:23]([CH3:25])[CH3:24])=[C:11]([CH:14]=1)[CH2:12][OH:13]>C(#N)C.C(N(CC)CC)C>[C:1]([O:13][CH2:12][C:11]1[CH:14]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][N:23]([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: CN(C)Cc1ccccc1Sc1ccc(Cl)cc1CO
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cc(Cl)ccc1Sc1ccccc1CN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
A solution of acetyl chloride (2.5 g) in 50 mL of acetonitrile was added dropwise to a solution of 9.8 g of 5-chloro-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol (Example 2) in 25 mL of triethylamine and 200 mL of acetonitrile. The reaction mixture was stirred for 3 hr at room temperature, filtered and concentrated in vacuo to give a yellow oil. This oil was chromatographed on silica gel with EtOAc as the eluent. Concentration of solvents afforded 3.8 g (34% yield) of 5-chloro-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl acetate as a light yellow oil. Upon standing, oil crystallized to a beige solid, m.p. 41°-44° C.
Reaction SMILES: N1C=CC=CC=1.[C:7]12([C:17](Cl)=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.[C:20]1([NH:26][C:27](=[S:30])[NH:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:7]12([C:17]([NH:29][NH:28][C:27]([NH:26][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[S:30])=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NNC(=S)Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NNC(=S)Nc1ccccc1)C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h

Procedure:
Pyridine (0.808 mL, 10 mmol) was added dropwise at room temperature to a stirred solution of 1-adamantanecarbonyl choride (A) (1 g, 5 mmol) and 4-phenyl-3-thiosemicarbazide (B) (0.845 g, 5.05 mmol) in CH2Cl2 (10 mL). After stirring for 4 h, the solvent was removed in vacuo, and the residue washed with water and dried to give 1-(1-adamantylcarbonyl)-4-phenyl thiosemicarbazide (C).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>ClCCl>[C:20]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: C#CCCCCCCCCCCC
Reactant: CCOC(=O)C(=Cc1ccccc1Br)C(=O)OCC
Solvent: ClCCl
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(C(=O)OCC)C(=O)OCC
Yield: 62.9 %

Procedure:
Reaction of diethyl 2-(2-bromophenyl)methylenepropan-1,3-dioate (6.54 g, 20 mmole, from example 1) with 1-tridecyne (6.1 g, 34 mmole) as described in example 3 gave 5.37 g (63%) of the title compound after chromatography on silica gel eluting with dichloromethane: petroleum ether [bp 60°-80° C.] (1:1). It had, νmax (film) 1730, 2850, 2920 cm-1, δ(CDCl3) 0.84 (3H, distorted t, terminal CH3), 1.13-1.68 (24H, m, ester CH3 +alkylene chain), 2.42 (2H, t, J 6.3 Hz, ≡--CH2), 4.23 (2H, q, J 7.5 Hz, ester CH2), 4.26 (2H, q, J 7.5 Hz, ester CH2), 7.31 (4H, m, aromatics), 8.20 (1H, s, CHO), M+ 426.2780 (C27H38O 4 requires; 426.2770).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C@H:10]1[NH:18][C:17]2[C:12](=[N:13][C:14]([NH:19][CH:20]3[CH2:29][CH2:28][C:23]4(OCC[O:24]4)[CH2:22][CH2:21]3)=[N:15][CH:16]=2)[N:11]1[CH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C@H:10]1[NH:18][C:17]2[C:12](=[N:13][C:14]([NH:19][CH:20]3[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]3)=[N:15][CH:16]=2)[N:11]1[CH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1
Reactant: OC1CCC(N2c3nc(NC4CCC5(CC4)OCCO5)ncc3N[C@@H]2Nc2ccc(F)cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC(Nc2ncc3c(n2)N(C2CCC(O)CC2)[C@@H](Nc2ccc(F)cc2F)N3)CC1
Reaction time: 24 h
Yield: 1.9 %

Procedure:
4-[(R)-8-(2,4-Difluoro-phenylamino)-2-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-7H-purin-9-yl]-cyclohexanol (0.62 g, 1.7 mmol) was dissolved in 25 mL of methylene chloride under an N2 atmosphere. Trifluoroacetic acid (5 mL) was then added dropwise via addition funnel. After stirring for 24 h the resulting reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate was added to the resulting residue until pH 12. The basic aqueous layer was then extracted using chloroform (2×75 mL). The combined organic layers were dried with MgSO4. The crude product was then purified on the preparatory HPLC using a 5-70% CH3CN/H2O over 39 minutes method. Fractions of greater then 98% purity via analytical HPLC were combined and concentrated. Excess trifluoroacetic acid was removed by washing the product with 1.75 M potassium carbonate (3×100 mL). The organic layers were then concentrated to dryness under vacuum to give the ketone (0.015 g 0.033 mmol, 12%) as a fine white powder: LC-MS (m/z) 457.1 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[Cl:56][C:57]1[CH:67]=[CH:66][C:60]([O:61][CH:62]2[CH2:65][NH:64][CH2:63]2)=[CH:59][CH:58]=1>ClCCl>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([N:64]1[CH2:65][CH:62]([O:61][C:60]2[CH:59]=[CH:58][C:57]([Cl:56])=[CH:67][CH:66]=2)[CH2:63]1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: Clc1ccc(OC2CNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CC(Oc2ccc(Cl)cc2)C1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-succinic acid 1-benzyl ester (5.0 g, 13.99 mmol) in dichloromethane (50 ml) is treated with diisopropylethylamine (7.51 ml, 41.97 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (4.49 g, 13.99 mmol). To the reaction mixture is added 3-(4-chloro-phenoxy)-azetidine hydrochloride (3.06 g, 13.99 mmol) and stirring continued for 3 hours. The dichloromethane is evaporated and residue partitioned between ethylacetate and saturated NaHCO3 solution. The ethylacetate phase is washed with 1M HCl solution and brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 1:1 ethylacetate/hexane) to afford (S)-2-tert-butoxycarbonylamino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]4-oxo-butyric acid benzyl ester. [M-BOC] 389.0.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:3].C([O:21][C@@H:22]1[C@H:26]([O:27]C(=O)C2C=CC=CC=2)[C@@H:25]([CH2:36][O:37]C(=O)C2C=CC=CC=2)[O:24][C@H:23]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([Cl:56])=[N:50][C:51]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C.N>O1CCOCC1>[Cl:56][C:49]1[N:50]=[C:51]([NH:3][N:2]([CH3:1])[CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:52]2[N:53]=[CH:54][N:46]([C:47]=2[N:48]=1)[C@@H:23]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:27])[C@H:22]1[OH:21]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CN(N)CCOc1ccccc1
Agent: N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CCOc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 47 %

Procedure:
The title compound was prepared according to method A by reacting 1-methyl-1-(2-phenoxyethyl)hydrazine (prepared by the general method described in example 1) (0.80 g, 4 mmol) and 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.53 g, 4 mmol) and triethylamine (1.11 ml, 8 mmol) in dioxan (25 ml), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro-N-(N-methyl-N-(2-phenoxyethyl)amino)adenosine (0.84 g, 47%) (after column chromatography) obtained as a solid, mp 166°-8° C., 1H NMR (DMSO-d6)γ 2.70 (3H, s, --CH3), 3.22 (2H, br t, --CH2 --), 3.51-3.58 (1H, m, H-5'a), 3.62-3.69 (1H, m, H-5'a), 3.95 (1H, q, H-4'), 4.05-4.15 (3H, m, --CH2 -- and H-3' ), 4.50 (1H, q, H-2'), 5.06 (1H, t, 5'-OH), 5.21, 5.49 (2H, 2d, 2'- and 3--OH), 5.81 (1H, H-1'), 6.79-7.25 (5H, m, Ar-H), 8.41 (1H, s, H-8), 9.41 (1H, br s, N-H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:35]([O:37][CH3:38])=[O:36].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([O:32][C:35]([O:37][CH3:38])=[O:36])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)OC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a stirred solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (500 mg) in tetrahydrofuran (20 ml) are added dropwise methyl chloroformate (200 mg) and triethylamine (216 mg) under ice cooling. After 1 hour, the reaction mixture is poured into ice water, and is extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated to give p-nitrobenzyl α-[3-penoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methoxycarbonyloxyethylidene)acetate (546 mg). Foam. Yield: 97%.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][S:27]([CH2:30][C:31](O)=[O:32])(=[O:29])=[O:28]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (25.3 mg, 68.7%), MS (ISP) m/z=451.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-(methylsulfonyl)acetic acid.
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:27]C1C=CC(C(=O)C)=CC=1>C1COCC1.CCCCCC>[Br:27][C:5]1[CH:6]=[CH:7][C:2]([C:8]([CH3:15])=[CH2:9])=[CH:3][CH:4]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a slurry of triphenylmethylphosphonium bromide (71.4 g, 200 mmole), in 500 ml dry THF at 0° C., were slowly added dropwise 135 ml (200 mmole) 1.44 M n-butyllithium in hexane. The mixture was stirred 30 minutes at 0° C., and a solution of 39.8 g (200 mmole) p-bromoacetophenone, in 100 ml dry THF, was slowly added dropwise. The mixture was allowed to warm slowly to ambient temperature, whereafter stirring was continued overnight. The stirred mixture was next filtered and the solvent removed by careful distillation at atmospheric pressure, the resulting residue was diluted with hexane, filtered, and the hexane removed by distillation. The remaining material was distilled, using a water aspirator vacuum, to produce 23.2 g (58.3% yield) of p-bromo-α-methylstyrene, bp 95°-98° C.