Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:18].[C:19](=N)(OCC)[CH3:20]>C(O)C>[ClH:18].[ClH:18].[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]3[NH:16][C:19]([CH3:20])=[N:17][C:12]=3[CH:11]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(C)=N
Reactant: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]1
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of 6.2 parts of 4-[1-(1H-imidazol- 1-yl)-2-methylpropyl]-1,2-benzenediamine, 6.5 parts of ethyl ethanimidate hydrochloride and 80 parts of ethanol was stirred for 3 hours at reflux temperature. After evaporation to dry, the residue was taken up in water and sodium carbonate. The product was extracted three times with 120 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in a mixture of 2-propanone and ethanol. The salt was filtered off and crystallized from a mixture of ethanol and 2-propanone. The product was filtered off and dried, yielding 4 parts (44%) of 5-[1-(1H-imidazol-1yl)-2-methylpropyl]-2-methyl-1H-benzimidazole dihydrochloride.monohydrate; mp. 214.8° C. (comp. 22).
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[C:4](=[O:24])[CH2:3]1.C[Li].[CH2:27](OCC)C>C1COCC1>[OH:24][C:4]1([CH3:27])[C:5]2[N:6]=[CH:7][N:8]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:10]=2[C@H:2]([CH3:1])[CH2:3]1
Reactant: C[C@@H]1CC(=O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: C[C@@H]1CC(C)(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.120 mmol; see Example 3, Step 8) in THF (4 mL) was added to a 1.5M solution of methyllithium in diethyl ether (0.088 mL, 0.132 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour and quenched by saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2×). The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g) eluted by EtOAc to give tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as a solid (29 mg, 69%). LCMS (APCI+) [M-Boc+H]+ 349.1; Retention time: 2.49 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:4](=[O:13])[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>CC#N>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([NH:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:4](=[O:13])[N:3]=1)=[O:23]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1nc(=O)n(CC2CC2)cc1F
Solvent: CC#N
Product: O=C(Nc1ccccc1Cl)Nc1nc(=O)n(CC2CC2)cc1F
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirred solution of 4-amino-1-(cyclopropylmethyl)-5-fluoropyrimidin-2(1H)-one (150 mg, 0.819 mmol) in dry CH3CN (7.5 mL) at room temperature and under nitrogen was added 2-chlorophenylisocyanate (138.3 mg, 0.90 mmol). After stirring for 1 h, the crude reaction mixture was filtered, and the solids were rinsed with CH3CN (10 mL). The collected filtrate was then concentrated in vacuo and dried under high vacuum to afford 1-(2-chlorophenyl)-3-(1-(cyclopropylmethyl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)urea (160 mg, 58%) as an off-white solid: mp 197-199° C.; 1H NMR (400 MHz, methanol-d4) δ 8.26 (d, J=6.0 Hz, 1H), 8.21 (dd, J=8.3, 1.5 Hz, 1H), 7.47 (dd, J=8.0, 1.4 Hz, 1H), 7.35-7.28 (m, 1H), 7.13 (td, J=7.8, 1.5 Hz, 1H), 3.74 (d, J=7.3 Hz, 2H), 1.32 (m, 1H), 0.69-0.58 (m, 2H), 0.50-0.38 (m, 2H); ESIMS m/z 337 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:59][C:57]2[S:56][C:46]3[C:47]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a stirred solution of 44 mg (0.31 mmol) 4-fluoro-benzoic acid in 4 ml THF were added 130 mg (0.34 mmol) HATU and 0.068 ml (0.62 mmol) N-methylmorpholine and stirring continued at 50° C. for 16 h. 40 mg (0.16 mmol) 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 7 mg (12%) 4-fluoro-N-(7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-yl)-benzamide as a white crystalline solid. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])[N:8]=1.[CH3:14][N:15]1[CH:17](SC)[CH:16]1[N+:20]([O-:22])=[O:21]>O>[CH3:14][NH:15][C:17]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:7]1[N:8]=[C:4]([CH2:3][NH:2][CH3:1])[S:5][CH:6]=1)=[CH:16][N+:20]([O-:22])=[O:21]
Reactant: CNCc1nc(CSCCN)cs1
Reactant: CSC1C([N+](=O)[O-])N1C
Solvent: O
Product: CNCc1nc(CSCCNC(=C[N+](=O)[O-])NC)cs1

Procedure:
Following the above procedure, 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine and N-methyl-1-methylthio-2-nitroethyleneamine were reacted in water solution. The reaction was worked up and the product isolated by the above procedure to yield N-methyl-N'-2-(2-methylaminomethyl-4-thiazolylmethylthio)ethyl 2-nitro-1,1-ethenediamine melting at 105°-107° C. after recrystallization from acetonitrile followed by recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[C@@H:17]([CH3:28])[CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:28])[CH2:16]1
Reactant: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2Cl)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2Cl)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl (2S)-4-[[2-chloro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate (1.20 g, 2.93 mmol, 1.00 equiv), trifluoroacetic acid (4 mL), dichloromethane (20 mL). The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure to yield 0.910 g (crude) of 4-(3-chloro-4-[[(3S)-3-methylpiperazin-1-yl]methyl]phenyl)morpholine as light yellow oil. LCMS (ESI, m/z): 310 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([NH:20][C:21]3[CH2:29][C@H:28]4[C@H:23]([CH2:24][CH2:25][C:26]5[CH:33]=[C:32]([O:34]C)[CH:31]=[CH:30][C:27]=54)[N:22]=3)=[O:19])[CH2:14][CH2:13]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.Cl>ClCCl.CO>[C:1]1([S:7]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([NH:20][C:21]3[CH2:29][C@H:28]4[C@H:23]([CH2:24][CH2:25][C:26]5[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:27]=54)[N:22]=3)=[O:19])[CH2:14][CH2:13]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1N=C(NC(=O)[C@H]3CC[C@H](CNS(=O)(=O)c4ccccc4)CC3)C[C@H]21
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1=N[C@H]2CCc3cc(O)ccc3[C@H]2C1)[C@H]1CC[C@H](CNS(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of trans-4-[[(phenylsulfonyl)amino]methyl]-N-(cis-3a,4,5,9b-tetrahydro-7-methoxy-1H-benz[e]indol-2-yl)cyclohexanecarboxamide (7) (0.200 g, 0.403 mmol) in dichloromethane (2 mL) was added dropwise with stirring, to a solution of boron tribromide (1.6 mmol) in dichloromethane (12 mL) at 0° C. The resultant suspension was stirred at 0° C. for 30 min. Methanol (˜1 mL) was added at which point the mixture became a clear yellow solution. The solution was stirred for 30 min at 0° C. The solvents were evaporated in vacuo, and the residue was purified by preparative HPLC on C18 reverse phase column, using water/acetonitrile/trifluoroacetic acid (50:50:0.1) as the eluent. The product obtained was dissolved in a minimum amount of methanol and converted to the hydrochloride salt by treatment with ethanolic hydrogen chloride. The solvents were evaporated in vacuo and the residue was triturated with diethyl ether to give trans-4-[[(phenylsulfonyl)amino]methyl]-N-(cis-3a,4,5,9b-tetrahydro-7-hydroxy-1H-benz[e]indol-2-yl)cyclohexanecarboxamide (9) as a beige solid (0.093 g, 45%). NMR (DMSO-d6): δ 0.77-0.95 (m, 2 H), 1.20-1.37 (m, 3 H), 1.64-1.80 (m, 2 H), 1.83-1.98 (m, 3 H), 2.43-2.64 (m, 5 H), 2.91 (d of d, 1 H), 3.48-3.74 (m, 4 H), 4.37-4.47 (m, 1 H), 6.54 (d, 1 H), 6.65 (d of d, 1 H), 7.03 (d, 1 H), 7.53-7.83 (m, 6 H), 9.37 (br s, 1 H), 11.56 (br s, 1 H), 13.22 (br s, 1 H); MS 482 (M+H)+ (FIG. 3).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH2:19][N:20]3[CH2:25][CH2:24][C:23]([OH:35])([CH2:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21]3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>C(Cl)Cl>[C:36]([N:7]([CH:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([CH2:19][N:20]2[CH2:25][CH2:24][C:23]([OH:35])([CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:22][CH2:21]2)[CH2:9]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: OC1(CCCc2ccccc2)CCN(CC2CC(NC3CCCCC3)CC2c2ccccc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(C1CCCCC1)C1CC(CN2CCC(O)(CCCc3ccccc3)CC2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(RS and SR)-(cyclohexylamino)-3-(SR)-((4-hydroxy-4-(3-phenylprop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane (prepared as in Example 43A) in methylene chloride (2 mL) was added acetic anhydride (0.17 mL, 1.67 mmol) and pyridine (0.17 mL, 2 mmol). The reaction was stirred at rt for 16 h. It was then diluted with methylene chloride and quenched with 1N NaOH. The mixture was washed with 1N NaOH and brine, dried over sodium sulfate and evaporated to dryness. The sample was purified by HPLC and the fractions containing the title compound by HPLC/MS were combined and evaporated.
Reaction SMILES: [CH3:1][Al](C)C.[C:5]([C:8]1[N:9]=[C:10]([Cl:17])[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:7])[CH3:6]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:17][C:10]1[S:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:5]([OH:7])([CH3:1])[CH3:6])[N:9]=1
Reactant: C[Al](C)C
Reactant: COC(=O)c1sc(Cl)nc1C(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(Cl)nc1C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
A solution of 5.6 ml (11.2 mmol) 2N AlMe3 in toluene was added to a dry ice-acetone bath of 1.14 g (5.2 mol) of methyl 4-acetyl-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 212) in 20 ml dry CH2Cl2. The mixture was allowed to warm to room temperature slowly before being quenched with MeOH. After stirring at room temperature overnight, the mixture was diluted with 1N HCl and stirred 15 min before being diluted with water and extracted twice with EtOAc. The EtOAc was washed with brine, dried (MgSO4) and concentrated to give an oil that was purified by chromatography (50% hexanes in CH2Cl2 with gradient elution to 100% CH2Cl2) affording 720 mg of product as an oil. NMR (CDCl3): 1.5 (s, 6H), 3.8 (s, 3H), 5.7 (s, broad, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]2[CH:17]=[CH:16][N:15]([C@@H:18]3[O:38][C@H:37]([CH2:39][O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C@@H:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:19]3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1)[CH:2]=[CH2:3].[NH3:48]>>[NH2:48][C:9]1[N:10]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:6]2[CH:17]=[CH:16][N:15]([C@@H:18]3[O:38][C@H:37]([CH2:39][O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C@@H:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:19]3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[N:8]=1
Reactant: C=CCOc1nc(S(C)(=O)=O)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: N
Product: C=CCOc1nc(N)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 13.5 g of 4-allyloxy-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine and 250 ml of liquid ammonia is heated at 100° C. for 2 hours and allowed to evaporate in a stream of nitrogen. The residue is dissolved in ethyl acetate and chromatographed over silica gel with ethyl acetate to provide 9.3 g of pure 2-amino-4-allyloxy-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[NH:18][C:17](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:16][N:15]=2)=[CH:9][CH:8]=1.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:35](=[O:38])[CH2:36][CH2:37][N:15]3[N:16]=[C:17](/[CH:19]=[CH:20]/[C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[N:18]=[C:14]23)=[CH:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/c2nc3n(n2)CCC(=O)N3c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (3 mL) and TEA (0.06 mL) were added to (4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}amine synthesized in Example 162 (44 mg), and the reaction solution was stirred at room temperature for 10 minutes. Acrylic acid chloride (0.01 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for one hour and at 60° C. for two hours. TEA (0.03 mL) and acrylic acid chloride (0.01 mL) were added to the reaction solution at 60° C., and the reaction solution was stirred at 60° C. for four hours. The reaction solution was left to cool to room temperature and then diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) and further purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 6 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23]Br>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:6]=2[N:5]=[C:4]1[CH:1]1[CH2:3][CH2:2]1
Reactant: COc1cccc2nc(C3CC3)[nH]c12
Reactant: Fc1cccc(F)c1CBr
Product: COc1cccc2c1nc(C1CC1)n2Cc1c(F)cccc1F
Yield: 92.1 %

Procedure:
2-(Cyclopropyl)-4-methoxylbenzimidazole (1.00 g, 5.32 mmol) (5014) was reacted with 2,6-difluoro-a-bromo-toluene (1.30 g, 6.28 mmol, 130 M %). The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-(2,6-Difluorobenzyl)-2-(cyclopropyl)-4-methoxylbenzimidazole (5016) (1.54 g, 4.90 mmol, 92% yield). M.p. 136-139° C. 1H-NMR (200 MHz, CD2Cl2) δ 7.31 (m, 1H, H4′), 7.07 (dd, J=8.0, 7.8 Hz, 1H, H6), 6.94 (m, 3H, H3′,5′,5), 6.61 (dd, J=7.8, 1.0 Hz, H7), 5.46 (s, 2H, CH2PhF2), 3.95 (s, 3H, OCH3), 2.20×2.03 (m, 1H), 1.18-0.97 (m, 4H).
Reaction SMILES: Br[CH:2]([C:7](=[O:18])[C:8]([CH2:14][CH2:15][CH2:16][CH3:17])([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[K+]>CS(C)=O.O>[CH2:9]([C:8]1([CH2:14][CH2:15][CH2:16][CH3:17])[C:7](=[O:18])[CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[O:13]1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(O)(CCCC)C(=O)C(Br)CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC1(CCCC)OC(CC(C)C)C1=O
Temperature: 0 °C
Yield: 95 %

Procedure:
To the solution of allene (48. mg, 0.230 mmol) in 1:1 solution of t-BuOH and pH 7.4 buffer (3.0 ml) at rt was added NMO (60. mg, 0.460 mmol) and 4 wt % OsO4 in water (0.300 ml, 0.046 mmol). NBS (77. mg, 0.460 mmol) was dissolved in 1:1:1 solution of t-BuOH, water and acetone (3.00 ml) and added to the reaction mixture via syringe pump over 5 h at rt. After the complete consumption of allene as judged by TLC (5 h), the reaction was quenched by a saturated solution of sodium sulfite (3.00 ml). The reaction was diluted by water and the organic layer was extracted in EtOAc (3×10.0 ml), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (4% EtOAc/Hexane) to obtain 4-bromo-6-butyl-6-hydroxy-2-methyldecan-5-one (63. mg, 85% yield) as colorless oil. The 4-bromo-6-butyl-6-hydroxy-2-methyldecan-5-one (63. mg, 0.196 mmol) was dissolved in DMSO (3.92 ml) and cooled to 0° C. To the reaction at 0° C. was added KOH (0.180 ml, 0.216 mmol) dropwise. Upon the completion of reaction as judged by TLC (10 min), the reaction was diluted with water and the organic layer was extracted in EtOAc (3×5.00 ml), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (2% EtOAc/Hexane) to obtain 2,2-dibutyl-4-isobutyloxetan-3-one (45. mg, 95% yield) as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23]C3CCCCO3)[CH:17]=2)=[C:11]([CH3:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)=[C:11]([CH3:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(COC2CCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(CO)c1
Yield: 83.5 %

Procedure:
A solution of 2-{[4′-(benzyloxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}tetrahydro-2H-pyran (1.71 g, 4.25 mmol) and p-toluenesulfonic acid monohydrate (80.8 mg, 0.425 mmol) in methanol (15 mL) was stirred at room temperature for 20 hrs. The reaction solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-50% ethyl acetate/hexane) to give the title compound (1.13 g, yield 84%) as a colorless oil.
Reaction SMILES: O[CH:2]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:3][N:4]1[CH:8]=[N:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.O1CCOCC1.CCN(S(F)(F)[F:30])CC>O>[F:30][CH:2]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:3][N:4]1[CH:8]=[N:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COCCOCC(O)Cn1cnc([N+](=O)[O-])n1
Solvent: O
Solvent: C1COCCO1
Product: COCCOCC(F)Cn1cnc([N+](=O)[O-])n1
Yield: 44.8 %

Procedure:
To 1.1 g (4.5 mmol) of 1-[2'-hydroxy-3'-(2"-methoxyethoxy)-propyl]-3-nitro-1,2,4-triazole, 10 ml of 1,4-dioxane was added and then 1.0 g (6.2 mmol) of DAST was dropwise added. Then, the mixture was reacted for a day at room temperature with stirring. After the reaction, to the reaction solution, 2 ml of water was added to decompose excess DAST. The solution was concentrated and partitioned between chloroform and water. The chloroform phase was washed with water, dried on magnesium sulfate and filtered. The filtrate was concentrated and subjected to isolation and purification by silica gel column chromatography to give 500 mg of 1-[2'-fluoro-3'-(2"-methoxyethoxy)-propyl]-3-nitro-1,2,4-triazole.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:26])([CH3:25])[C:21]([O:23]C)=O)[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[CH:27]=1)(=[O:3])[NH2:2].Cl.[NH:29]1[CH2:32][CH:31]([C:33]#[N:34])[CH2:30]1.C(N(CC)CC)C>CO>[C:33]([CH:31]1[CH2:32][N:29]([C:21](=[O:23])[C:20]([OH:26])([CH3:25])[C:19]#[C:18][C:14]2[C:15]([F:17])=[CH:16][C:11]3[O:10][CH2:9][CH2:8][N:7]4[CH:27]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=[C:6]4[C:12]=3[CH:13]=2)[CH2:30]1)#[N:34]
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Reactant: N#CC1CNC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(=O)N1CC(C#N)C1
Yield: 5.2 %

Procedure:
A solution methyl 4-(2-carbamoyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)-2-hydroxy-2-methylbut-3-ynoate (150 mg, 0.40 mmol, 1.00 equiv), azetidine-3-carbonitrile hydrochloride (237 mg, 2.00 mmol, 5.00 equiv), triethylamine (203 mg, 2.01 mmol, 5.00 equiv) in methanol (5 mL) was stirred for 12 h at 40° C. The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with dichloromethane/methanol (30:1) to give 8.8 mg (5%) the titled compound as an off-white solid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]([O-:9])=[O:8].[Na+].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: O=C([O-])C1CCC=CO1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCC=CO1
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of sodium 3,4-dihydro-2H-pyran-2-carboxylate (150.0 g, 10 mol), ethyl iodide (192.3 g, 1.2 mol), sodium carbonate (10 g), and dimethylformamide (500 ml) was heated at 105°-110° C. for 5 hours. The reaction mixture was cooled to room temperature and water (450 ml) was added to dissolve inorganic sales. The mixture was extracted with four 200 ml portions of benzene. The combined organic layers were washed with four 200 ml portions of water and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed by rotary evaporation. The oily residue was distilled under reduced pressure giving a yield of 87% of product having a bp of 75°-80° C.