Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]4[C:16]([CH2:17][C:5]=3[C:4]=2[CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.C([Li])CCC.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl>>[CH3:23][Si:24]([CH3:27])([CH3:26])[N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:17][C:16]3[C:11]([C:6]1=2)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: Cc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Product: Cc1ccc2c(c1)c1c(n2[Si](C)(C)C)-c2ccccc2C1

Procedure:
The general procedure of Example A is followed. 8-Methyl-5, 10-dihydroindeno[1,2-b]indole reacts with n-butyllithium and the product then reacts with trimethylchlorosilane to form 5-trimethylsilyl-8-methyl-5, 10-dihydroindeno[1,2-b]indole. The later reacts with n-butyllithium to form a lithium salt, which reacts with zirconium tetrachloride to give Catalyst IV.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:18]([O:20][CH3:21])=[O:19])[C@@H:15]([CH3:17])[OH:16])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:15](=[O:16])[CH3:17])[C:18]([O:20][CH3:21])=[O:19])=[O:12])[CH3:10])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)[C@@H](C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)=O
Reaction time: 1.17 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-L-alanyl-L-threoninate (9.00 g, 29.6 mmol) in dichloromethane (90 mL) was added Dess-Martin periodinane (15.1 g, 35.5 mmol) at room temperature. After being stirred for 70 min, saturated aqueous sodium thiosulfate solution was added, then the reaction mixture was stirred for 15 min. The mixture was poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to give methyl (2S)-2-{[N-(tert-butoxycarbonyl)-L-alanyl]amino}-3-oxobutanoate. MS (APCI): m/z 303 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][C:5]=1[Cl:14])[CH:2]=[CH2:3]>CO.[Ni]>[Cl:14][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:10])[C:4]=1[CH2:1][CH2:2][CH3:3])[NH2:11]
Reactant: C=CCc1c(C)cc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CO
Product: CCCc1c(C)cc(N)cc1Cl
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A solution of 2-allyl-1-chloro-3-methyl-5-nitrobenzene (450 mg, 2.13 mmol) in 43 mL of MeOH was put on an H-cube with a Ra—Ni cartridge, the reaction was at room temperature and under 2 atm of H2 for 3 hr. The reaction was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, 100% Heptane-15% Ethyl Acetate/85% Heptane, to give 3-chloro-5-methyl-4-propylaniline (212 mg). LCMS retention time=1.34 minutes (LC method 1); MS (m+1)=184.1. 1H NMR (400 MHz, DMSO-d6) δ 0.92 (t, J=7.3 Hz, 3H), 1.34-1.48 (m, 2H), 2.16 (s, 3H), 2.48-2.52 (m, 2H), 5.03 (s, 2H), 6.32 (d, J=1.8 Hz, 1H), 6.43 (d, J=2.2 Hz, 1H).
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].C([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=O)C(C)C>>[C:1]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: CCCC(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 91 %

Procedure:
Butyric acid (37 mg, 0.418 mmol) was reacted with PTU (80 mg, 0.278 mmol) as the same manner as the synthesis of 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (91 mg, 0.255 mmol, 91% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.79 (s, 1H), 7.56 (s, 4H), 6.36 (d, J=7.8 Hz, 1H), 4.19 (d, J=12.9 Hz, 1H), 3.75 (d, J=14.4 Hz, 1H), 3.12 (t, J=11.4 Hz, 1H), 2.77 (m, J=12 Hz, 1H), 2.28 (t, J=7.5 Hz, 2H), 1.82 (t, J=13.2 Hz, 2H), 1.49 (m, 2H), 1.29 (m, 3H), 0.88 (t, J=7.5 Hz, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1.O[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>O1CCCC1>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([O:32][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH2:34][CH2:35]1
Reactant: CN1CCC(O)CC1
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.4 %

Procedure:
Under a nitrogen atmosphere, a solution of diethyl azodicarboxylate (6.80 g. 39.0 mmol) in tetrahydrofuran (THF) (25 mL) was added drop-wise at ambient temperature to a stirring solution of triphenylphosphine (10.23 g, 390 mmol) in THF (100 mL). The resulting solution was allowed to stir at ambient temperature for 30 min. 4-Hydroxy-1-methylpiperidine (3.05 g, 26.5 mmol) and 3-hydroxypyridine (3.71 g, 39.0 mmol) were added, and the reaction mixture was stirred at ambient temperature for 18 h. The solution was concentrated by rotary evaporation, and the resulting residue was dissolved in CHCl3 (100 mL). The suspension was cooled in an ice-water bath, and a solution of 1 M HCl (75 mL) was added with stirring. The aqueous phase was separated. The organic phase was extracted with water (3×75 mL). The combined aqueous extracts were cooled in an ice-water bath, basified with 1 M NaOH solution (125 mL) to pH ˜11 and extracted with CHCl3 (6×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude product was dissolved in CHCl3 (75 mL), and the CHCl3 solution was extracted with 1 M NaOH solution (4×25 mL) to remove residual 3-hydroxypyridine. The CHCl3 phase was separated, and the combined NaOH layers were back extracted with CHCl3 (3×50 mL). All CHCl3 extracts were combined, dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was purified by vacuum distillation using a test-tube distillation apparatus, collecting the fraction with bp 83-93° C. at 0.10-0.075 mm Hg. Further purification by a second vacuum distillation yielded 120 mg (2.4%) of a colorless oil, bp 72-75° C. at 0.75 mm Hg. The compound exhibits a Ki of 4897 nM.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12]Br)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH3:14]>CO>[NH2:14][CH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Br:1])[CH:11]=1
Reactant: N
Reactant: COC(=O)c1ccc(CBr)cc1Br
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1Br
Reaction time: 3 h

Procedure:
A solution of methyl 2-bromo-4-(bromomethyl)benzoate (4.57 g; 14.84 mmol) in 50 mL of methanol is added dropwise to a well-stirred solution of ammonia in methanol (7M; 315 mL) at ambient temperature, and the solution is then stirred for 3 hours. All the solvents are evaporated off and the residue is purified by chromatography over silica gel using dichloromethane-methanol as eluants to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH:13]1[CH:14]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:11]=[CH:12]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2c[nH]cn2)cc1
Reaction time: 1 h
Yield: 102.6 %

Procedure:
A suspension of 4-(4-nitro-phenyl)-1H-imidazole (50 g, 0.2646 mol), 5% Pd/C (6 g) in 600 mL of methanol is hydrogenated at 7 psi of hydrogen at room temperature. After 1 h, the pressure of hydrogen remained unchanged, the mixture is filtered through a Celite cake. The filtrate is evaporated to give a red residue. After drying at high vacuum overnight, 43.2 g of a beige foam is isolated. It is hydroscopic, and sensitive to light and air.
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[S-]C#N.[K+].C(=O)([O-])O.[Na+].[NH2:20][C:21]1[CH:45]=[CH:44][C:24]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:43])[N:34]([CH3:42])[CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH:27]=2)=[C:23]([F:46])[CH:22]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:62]1([CH2:68][C:69]([N:71]=[C:72]=[S:73])=[O:70])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(#N)C.C(O)C.C1(C)C(CCO)=CC=CC=1.CCCCCC.C(OCC)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:46][C:23]1[CH:22]=[C:21]([NH:20][C:72]([NH:71][C:69](=[O:70])[CH2:68][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[S:73])[CH:45]=[CH:44][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:43])[N:34]([CH3:42])[CH:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)[CH:27]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cc1ccccc1CCO
Agent: N#C[S-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
2-Phenylacetyl chloride (0.032 ml) was dissolved in acetonitrile (3 ml) under a nitrogen atmosphere, and then potassium thiocyanate (46.6 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added thereto, followed by stirring for 30 min. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added toluene (1 ml)-ethanol (1 ml) to prepare a solution. 3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.0 mg) was dissolved in ethanol (1 ml) under a nitrogen atmosphere, and then D-10-camphorsulfonic acid (24.9 mg) was added thereto, followed by stirring for 5 min. To the reaction mixture was added the solution of 2-phenylacetyl isothiocyanate in toluene-ethanol (2 ml) synthesized above, followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (0.5 ml)-hexane (1.0 ml) was then added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (10.3 mg, 17.5%) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][CH2:9][C:10]([N:12]([CH2:14][CH:15](OC)OC)[CH3:13])=[O:11])[CH2:4][CH2:3]1.O.CS(O)(=O)=O.[OH-].[Na+]>[Pt].CO>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:15][CH2:14][N:12]([CH3:13])[C:10](=[O:11])[CH2:9]2)[CH2:6][CH2:7]1
Reactant: COC(CN(C)C(=O)CN[C@H]1CC[C@H](O)CC1)OC
Agent: [Pt]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCN([C@H]2CC[C@H](O)CC2)CC1=O

Procedure:
10.0 g (trans)-1-hydroxy-4-{[N-(2,2-dimethoxy-ethyl)-N-methyl-amino]-carbonylmethylamino}-cyclohexane are hydrogenated in a solution of 60 ml of water, 140 ml of methanol and 10.5 g methanesulphonic acid with 3.25 g platinum on charcoal (5% Pt) for 24 hours at 50° C. The solution is made alkaline with 50% sodium hydroxide solution and evaporated down. The residue is extracted with dichloromethane. The organic phase is dried on magnesium sulphate and evaporated down.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])[O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:43][CH:44]=3)[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C(Cl)OCc1ccc(C(F)(F)F)cc1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
4-(Trifluoromethyl)benzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (52 mg, 0.17 mmol) and 4-(trifluoromethyl)benzyl carbonochloridate (71.3 mg, 0.21 mmol) according to General Procedure H to give 27.4 mg (32.2%) of white solid. Anal. Calcd. for C22H31F3N4O2 m/z 500.2, found: 501.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.60 (d, J=8.1 Hz, 2H), 7.48 (m, 4H), 6.98 (d, J=9 Hz, 2H), 5.08 (s, 2H), 3.66 (m, 4H), 3.58 (m, 1H), 3.0 (m, 1H), 2.75 (m, 2H), 2.5 (m, 1H), 2.1 (d, 1H), 2.04 (s, 1H), 1.93 (s, 2H), 1.8 (m, 3H), 1.76 (s, 3H), 1.6 (m, 1H), 1.34 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.[Li]CCCC.CON(C)[C:18](=[O:33])[CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:18](=[O:33])[CH2:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CC(c1ccccc1)c1ccccc1)c1cc(Cl)nc(Cl)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 175.8 %

Procedure:
At −70° C. to a solution of 2,6-dichloro-4-iodopyridine (1.02 g) in THF (20 mL) was added n-BuLi (1.6 M in hexane, 2.3 mL) dropwise. The mixture was stirred for additional 15 min at which timepoint a solution of N-methoxy-N-methyl-3,3-diphenyl-propionamide (200 mg) in THF (10 mL) was added. The reaction mixture was stirred for 1 hour at −70° C. A saturated aqueous solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:10) to yield 1-(2,6-dichloro-pyridin-4-yl)-3,3-diphenyl-propan-1-one (465 mg, 88%) as a yellow oil, which was directly subjected to the next step.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:30]=2[N:31]=[CH:32][N:33]=1)[C@@H:15]1[O:29][C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35]([CH3:37])=O.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:30]=2[N:31]=[CH:32][N:33]=1)[C@@H:15]1[O:29][C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23])[C@@H:17]([O:18][CH2:34][S:35][CH3:37])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
3.0 g N6-Benzoyl-5′-O-tert-butyldimethylsilyl-2′-deoxyadenosine (5a) (6.38 mmol) was dissolved in a mixture consisting of 11.96 mL DMSO, 5.46 mL acetic acid, and 17.55 mL acetic anhydride and stirred at room temperature for 48 h. The reaction mixture was then neutralized treating with a sufficient amount of saturated NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extract was then washed with a saturated NaHCO3 solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The resultant yellowish oil was then purified on silica gel column (Hex: EtOAc/1:1 to 1:4) to obtain the product N6-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxyadenosine (6a) as white powder in 71% yield (2.4 g, Rf 0.6, EtOAc: hex/7:3). HR-MS: obs. m/z 530.2273, calcd. for C25H36O4N5SiS 530.2257 [M+H]+. 1H-NMR (CDCl3): δH 9.00 (s, 1H), 8.83 (s, 1H), 8.35 (s, 1H), 8.05 (d, J=7.6 Hz, 2H), 7.62 (m, 1H), 7.55 (m, 2H), 6.55 (t, J=7.19 Hz, 1H), 4.73 (m, 2H), 4.68 (m, 1H), 4.24 (m, 1H), 3.88 (dd, J=11.19, 3.19 Hz, 1H), 2.74-2.66 (m, 2H), 2.35 (s, 3H), 0.94 (s, 9H) and 0.13 (s, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C@@:8]2([CH3:11])[CH2:10][O:9]2)[CH:7]=1.[N-:13]=[N+:14]=[N-:15].[Na+].[NH4+].[Cl-].C1OCCOCCOCCOCCOCCOC1>CCO>[N:13]([CH2:10][C@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:12])([OH:9])[CH3:11])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]1(c2cc(Br)ccc2F)CO1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: C[C@@](O)(CN=[N+]=[N-])c1cc(Br)ccc1F

Procedure:
To a solution of (S)-2-(5-bromo-2-fluoro-phenyl)-2-methyl-oxirane (51.85 g, 224 mmol) in EtOH (800 ml) was added NaN3 (36.8 g, 531 mmol), NH4Cl (60.6 g, 1122 mmol) and 18-crown-6 (59.8 g, 224 mmol) and the reaction mixture was heated at reflux for 6 h. The reaction mixture was filtered and concentrated to half of its volume. The residual oil was extracted with EtOAc. Combined extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound as a light yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.70; HPLC RtH3=1.115 min; 1H NMR (360 MHz, CDCl3): δ 7.72 (dd, 1H), 7.32 (m, 1H), 6.85 (dd, 1H), 3.73 (d, 1H), 3.51 (d, 1H), 2.44 (s, 1H), 1.50 (s, 3H).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=3[F:24])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2([C:39](O)=[O:40])[CH2:38][CH2:37]2)=[O:35])=[CH:29][CH:28]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:39]([C:36]4([C:34](=[O:35])[NH:33][C:30]5[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=5)[CH2:37][CH2:38]4)=[O:40])=[CH:19][C:18]=3[F:24])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)Oc3ccccc3)ncn2)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)Oc1ccccc1
Reaction time: 5 h
Yield: 20.7 %

Procedure:
A crude product of [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]carbamic acid phenyl ester (303 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (497 mg), triethylamine (0.310 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (984 mg) were added in this order under a nitrogen atmosphere at room temperature, followed by stirring for 5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture. The resultant organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give residue, which was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:1). Fractions containing the target compound were concentrated under reduced pressure, the resultant residue was purified again by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:1). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as white powder (100.4 mg).
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH2+:5][CH:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:7].[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:5]([CH:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH3:7])[CH2:4][CH2:3][S:26]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC([NH2+]CCCl)C1CCCCC1
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1C(C)C1CCCCC1

Procedure:
1-Cyclohexyl-1-ethylamine was converted to N-(2-hydroxyethyl)-N-(1-cyclohexyl-1-ethyl)amine according to Method B5a. The alcohol was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(1-cyclohexyl -1-ethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pd]>[C:5]1([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=3[N:10]=[CH:9]2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc2c(ncn2-c2ccc(Br)cc2)[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(ncn2-c2ccccc2)[nH]1
Reaction time: 16 h

Procedure:
A suspension of ethyl 1-(4-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (EXAMPLE 1) (50 mg) and 10% Pd—C (100 mg) in ethanol (10 mL) and ethyl acetate (10 mL), was hydrogenated at atmospheric pressure for 16 h. The catalyst was removed by filtration through Celite and the filtrate concentrated in vacuo to yield ethyl 1-phenyl-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate EXAMPLE 2. LC-MS (ES+): m/z 256 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ=1.46 (t, J=7.1 Hz, 3H), 4.42 (q, J=7.1 Hz, 2H), 7.22 (d, J=1.0 Hz, 1H), 7.48 (m, 1H), 7.69 (m, 2H), 7.94 (m, 2H), 8.73 (s, 1H), 12.28 (br s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1.[CH2:13](B(CC)CC)C.CI.[OH-].[Na+].OO>C1COCC1.O>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]1[CH3:13]
Reactant: CC1(C)CC(=O)c2ccccc21
Reactant: CCB(CC)CC
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CC1C(=O)c2ccccc2C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
KH (32 g at 35% in mineral oil, 280 mmol, 1.4 equiv.) was suspended in THF (160 ml) and 3,3-dimethyl-1-indanone (as prepared as described above, 32 g, 200 mmol) in THF (150 mmol) was added. The green suspension was stirred for 1.5 h at RT, then triethylborane (1M solution in THF, 280 ml, 280 mmol, 1.4 equiv.) was added slowly. After 1 h stirring at RT methyl iodide (40 g, 280 mmol, 1.4 equiv.) was added and the suspension stirred for 48 h at RT. Treatment with H2O (240 ml), 10% aq. NaOH (240 ml) and 30% aq. H2O2-solution (240 ml) under occasional cooling was followed by extraction with MTBE. The organic layer was washed with brine, dried over MgSO4 and concentrated in a rotary evaporator. Bulb-to-bulb distillation (0.05 mbar/100° C.) yielded 24.8 g (71%) of product.