Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, benzyl alcohol and DBU in DME. ES-MS m/e (%): 313 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH:6]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:9])[C:5]([CH3:17])([CH3:16])[CH2:4][O:3]1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25]>>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:26][C:13](=[O:15])[CH2:12][CH2:11][NH:10][C:8]([CH:6]1[C:5]([CH3:17])([CH3:16])[CH2:4][O:3][C:2]([CH3:1])([CH3:18])[O:7]1)=[O:9]
Reactant: Nc1ccccc1N
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)Nc2ccccc2N)O1
Yield: 47.3 %

Procedure:
3-[N-(2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid (3.89 g) and 2.16 g of o-phenylenediamine were reacted in the same manner as in Reference Example 15 to obtain 2.48 g of the objective compound (yield: 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13](=[O:32])[O:14][C:15]2[C:20]([C:21]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)=[CH:19][CH:18]=[C:17]([O:30][CH3:31])[CH:16]=2.Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+].[2H]C(Cl)(Cl)Cl.O>CCO.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13](=[O:32])[O:14][C:15]2[C:20]([C:21]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:25][CH:24]=1)=[CH:19][CH:18]=[C:17]([O:30][CH3:31])[CH:16]=2
Reactant: COc1ccc2c(Cc3ccc(O)cc3)c(-c3ccc(C(F)(F)F)cc3Cl)c(=O)oc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [2H]C(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3Cl)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A mixture of 3-(2-chloro-4-trifluoromethylphenyl)-4-(4-hydroxybenzyl)-7-methoxychromen-2-one (460 mg, 1 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (254.7 mg, 1.5 mmol) and K2CO3 (413.9 mg, 2.99 mmol) in EtOH (5 mL) was stirred for 2 min prior to the addition of H2O (0.5 mL). The mixture was stirred at 55° C. for 2.5 h, after which time it was cooled to r.t. and poured into CHCl3—H2O. The layers were separated and the aqueous phase was extracted with CHCl3 (3×). The combined organic layers were washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The resultant brown foam was purified using flash chromatography (silica gel, 19:1 CH2Cl2:MeOH) to provide the title compound as a pale brown foam which displayed: 1H NMR (300 MHz, CD3OD) δ 7.83 (s, 1H), 7.65 (d, 1H, J=9.0 Hz), 7.63 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=2.5 Hz), 6.95 (d, 2H, J=8.5 Hz), 6.89 (dd, 1H, J=2.5, 9.0 Hz), 6.79 (d, 2H, J=8.5 Hz),), 4.07 (d, 1H, J=15.5 Hz), 4.05 (t, 2H, J=5.5 Hz), 3.90 (s, 3H), 3.83 (d, 1H, J=15.5 Hz), 2.89 (t, 2H, J=5.5 Hz), 2.72-2.60 (m, 4H), 1.90-1.75 (m, 4H). MS (ESI) m/z 558 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34](=[O:35])[CH2:33][NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=[C:7]2[CH2:6][C:5]2[CH:30]=[CH:31][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(4-nitro-benzyl)-1H-imidazole (2.6 g, 5 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH4+].[OH-].C(Cl)(Cl)Cl>FC(F)(F)C(O)=O.[Pt]=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])[N:14]3[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2c2c1nc1n2[C@@H](CCCNC(=O)N2CCOCC2)COC1
Agent: O=[Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(c3c1nc1n3[C@@H](CCCNC(=O)N3CCOCC3)COC1)CCCC2
Reaction time: 48 h
Yield: 56.1 %

Procedure:
N-{3-[(11S)-6-Amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propyl}morpholine-4-carboxamide (698 mg, 1.70 mmol) was dissolved in 5 mL of trifluoroacetic acid and the solution was placed in a pressure bottle. Platinum oxide (386 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 2 days, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with a mixture of methanol and CH2Cl2 and the combined filtrates were concentrated under reduced pressure to give a syrup. The syrup was portioned between 20 mL of concentrated NH4OH solution and 50 mL of CHCl3. The layers were separated and the aqueous portion was extracted with an additional 50 mL of CHCl3. The combined organic portions were washed successively with concentrated NH4OH, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 20% CMA/CHCl3) gave a fluffy, white solid. Crystallization from methanol/propyl acetate gave N-{3-[(11S)-6-amino-2,3,4,8,10,11-hexahydro-1H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propyl}morpholine-4-carboxamide (395 mg) as fluffy, white needles, mp 154-156° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[CH3:12][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COc1ccc(CCCO)cc1
Temperature: 65 °C
Yield: 95.1 %

Procedure:
2.26 g (14.87 mmoles) of 3-(4-hydroxyphenyl)-1-propanol were dissolved in dry acetone (20 ml) and potassium carbonate (2.05 g, 14.87 mmoles) was added, followed by methyl iodide (MeI) (2.11 g, 14.87 mmoles). The mixture was kept at reflux in a water bath at 60-70° C. for 48 h. After that period of time, it was diluted with water and the acetone was removed at reduced pressure. Extraction was performed with diethyl ether, and the result was washed with water, dried over sodium sulphate, filtered and the solvent was evaporated in a vacuum to give an oil (2.35 g) (94.93% yield) of 3-(4-methoxyphenyl)-1-propanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.Cl[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C)C=O.FC(F)(F)C(O)=O.[Mn]>[F:13][C:4]1[CH:3]=[C:2]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:6][C:5]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCOC(=O)C(C)Cl
Reactant: CS(=O)(=O)Cc1ccc(Br)cc1F
Agent: [Mn]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(CS(C)(=O)=O)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-1-(methylsulfonylmethyl)benzene (2 g, 7.487 mmol) in dimethylformamide (11 mL) were added ethyl 2-chloropropionate (1.24 mL, 9.733 mmol), manganese (822 mg, 14.974 mmol) and (2,2′-bipyridine)nickel(II)-dibromide (196 mg, 0.524 mmol). Trifluoroacetic acid (4 drops) was added. The reaction mixture was stirred overnight at 60° C. After cooling down to room temperature, the mixture was hydrolyzed by 1N HCl (30 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent was removed in vacuo. The crude product was purified by CC (eluent: ethyl acetate/cyclohexane (1:1)) to give ethyl 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoate (966 mg, 45%).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[C:11](C)[C:10]([OH:14])=[C:9](C)[CH:8]=2)=[N:3]1.CC1C=C(C#N)C=C(C)C=1O>>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][CH:8]=2)=[N:3]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1O
Agent: Cc1cc(C#N)cc(C)c1O
Product: Cn1nnc(-c2ccc(O)cc2)n1

Procedure:
Preparation of 2-methyl-5-(3,5-dimethyl-4-hydroxyphenyl)tetrazole was prepared by the procedure described above for Intermediate 5 starting with 2,6-dimethyl-4-cyanophenol.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12]C)=[O:11])=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[CH:5]=1>CO.O1CCCC1>[Cl:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:18]=2)[CH:5]=1
Reactant: COC(=O)COc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2OCC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1M Sodium hydroxide solution (0.5 m) was added to a solution of the product from step (iii) (0.197 g) in methanol (1 ml) and tetrahydrofuran (3 ml) and stirred at RT for 16 h. The solvent was evaporated under reduced pressure and the residue partitioned between DCM/2M hydrochloric acid. The organics were dried, evaporated under reduced pressure and the residue recrystallised from DCM-isohexane, yield 0.108 g.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH2:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1.CCCCCC.C(Cl)Cl>C1(C)C=CC=CC=1.C(O)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH2:11])=[S:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)CCc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NC(=S)CCc1ccccc1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
To a solution of 3-phenylpropionamide (1.653 g, 6.827 mmol) in toluene (20 mL) was added Lawesson's reagent (0.716 g, 1.77 mmol). The reaction was refluxed overnight, cooled to room temperature and concentrated yielding an orange oil. Flash chromatography of this oil (1:1 hexane:methylene chloride with 1% acetic acid) yielded 3-phenylthiopropionamide (0.070 g) as a white solid: mp 82°-83° C.; 1HNMR (DMSO d6) 300 mHz 9.35 (br s, 1 H), 9.15 (br s, 1 H), 7.34-7.10 (m, 2 H), 2.95 (t, J=8.48 Hz, 2 H), 2.72 (t, J=8.48 Hz, 2 H).
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](Cl)=[O:7])=[N+:2]=[N-:3].[CH2:11]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].O>ClCCCl>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])=[N+:2]=[N-:3]
Reactant: CCCCNCCCC
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Solvent: ClCCCl
Solvent: O
Product: CCCCN(CCCC)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutanoyl chloride (10.0 g, 61.8 mmol) in anhydrous DCE (150 mL) was added dibutylamine (21.5 mL, 2 equiv, 0.123 mol) in one portion. A white solid formed immediately and the suspension was stirred vigorously for 3 h at room temperature. DCE (200 mL) and water (200 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with water (2×200 mL) and brine (200 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (15.7 g, quantitative). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 0.91-0.97 (dt, J=7.2, 7.4, 12H), 1.21-1.38 (m, 4H), 1.46 (s, 6H), 1.47-1.57 (m, 4H), 2.47 (s, 4H), 3.25-3.32 (m, 4H). LRMS (ESI+) for C13H26N4O (254.2); Found: 255 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[K+].I[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1>O.[Cu]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1
Reactant: CC(C(=O)O)c1ccc(I)cc1
Reactant: Oc1ccccc1F
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc(Oc2ccccc2F)cc1
Temperature: 180 °C

Procedure:
2-Fluorophenol (2.35 g.) was fused with potassium hydroxide (1.7 g.) and a few drops of water by heating to 180° C. 2-(4-Iodophenyl)propionic acid (2.76 g.) and copper powder (0.1 g.) were then added and the melt ws heated at 160°-170° C. for 1 hour. The cooled solid was partitioned with methylene chloride (50 ml.) and 2.5N sodium hydroxide (50 ml.). The aqueous layer was acidified with hydrochloric acid, the resulting gum was extracted into ether, and the ether extract was extracted with saturated potassium carbonate solution. This aqueous extract was acidified with hydrochloric acid and the product isolated in ether. After evaporation the resulting solid was purified by preparative layer chromatography using 5% acetic acid/petroleum ether b.p. 62°-68° C. and eluting with ethyl acetate. Recrystallization from petroleum ether b.p. 62°-68° C. gave 2-[4-(2-fluorophenoxy)phenyl]propionic acid, m.p. 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH:16]([CH3:18])[CH3:17])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]2[N:6]([CH:16]([CH3:18])[CH3:17])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)ccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.7 %

Procedure:
5-Chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole (24.1 g) was dissolved in concentrated sulfuric acid (160 ml). To the solution were added dropwise concentrated nitric acid (7.8 g) and concentrated sulfuric acid (20.2 g) at 0° C. and the mixture was stirred at 0° C. for 5 minutes. The reaction mixture was poured into water and the mixture was made basic with an aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to give 5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-6-nitrobenzimidazole (25.5 g). A part of the obtained product was recrystallized from acetonitrile, which showed the physical properties consistent with those in Preparation 8.
Reaction SMILES: [CH3:1][S-:2].[Na+].C[O-].[Na+].[F:7][C:8]([F:25])([F:24])[C:9]1[CH:10]=[C:11]([N:15]2[CH2:19][CH:18]([CH2:20][Cl:21])[CH:17](Cl)[C:16]2=[O:23])[CH:12]=[CH:13][CH:14]=1.N1CCCC1=O>CN(C)C=O.CO>[F:7][C:8]([F:25])([F:24])[C:9]1[CH:10]=[C:11]([N:15]2[CH2:19][CH:18]([CH2:20][Cl:21])[CH:17]([S:2][CH3:1])[C:16]2=[O:23])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1C(Cl)C(CCl)CN1c1cccc(C(F)(F)F)c1
Reactant: C[S-]
Agent: C[O-]
Agent: O=C1CCCN1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CSC1C(=O)N(c2cccc(C(F)(F)F)c2)CC1CCl
Yield: 85 %

Procedure:
In the same manner as descried above for Example 1, sodium methyl mercaptide prepared from 6.5 g of a 25% methanol solution of sodium methoxide in 50 ml of dimethylformamide was added to 9.4 g (0.034 mole) of N-(m-trifluoromethylphenyl)-3-chloro-4-chloromethyl-2-pyrrolidone (prepared according to the procedure described in U.S. Pat. No. 4,069,038). The product weighed 9.3 g, representing 85% yield based on the pyrrolidone, structure confirmed by NMR analysis, with refractive index nD30 =1.5028. This compound is shown in Table I as Compound No. 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[Cl:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[CH:45]=[C:44]([S:49]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)(=[O:51])=[O:50])[CH:43]=[CH:42]2>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][C:19]([N:55]3[CH2:54][CH2:53][N:52]([S:49]([C:44]4[CH:43]=[CH:42][C:41]5[C:46](=[CH:47][CH:48]=[C:39]([Cl:38])[CH:40]=5)[CH:45]=4)(=[O:51])=[O:50])[CH2:57][CH2:56]3)=[O:21])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CCC(=O)O)cc2C1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2sc(CCC(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
In tetrahydrofuran (10 ml), 3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin -2-yl)propionic acid (445 mg) was dissolved, followed by the dropwise addition of N-methylmorpholine (170 μl) and isobutyl chloroformate (210 μl) successively at −20° C. After stirring at −20° C. for 10 minutes, 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (607 mg) dissolved in advance in dichloromethane (10 ml) was added to the reaction mixture. The reaction mixture was stirred at −20° C. for 10 minutes and then heated to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloroethane. The resulting solution was washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturate saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1˜2:1), whereby the title compound (625 mg, 72%) was obtained.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[P:13](=[O:22])([O:18][CH:19]([CH3:21])[CH3:20])[O:14][CH:15]([CH3:17])[CH3:16])(C(C)(C)C)(C)C>C(O)(=O)C.O>[OH:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[P:13](=[O:22])([O:14][CH:15]([CH3:17])[CH3:16])[O:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)OP(=O)(/C=C/CCO[Si](C)(C)C(C)(C)C)OC(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(C)OP(=O)(/C=C/CCO)OC(C)C
Yield: 75.8 %

Procedure:
A solution of diisopropyl (E)-4-(t-butyldimethylsilyloxy)but-1-enylphosphonate (0.84 g, 2.40 mmol) in acetic acid-water (2:1) (10 ml) was stirred at 70° C. for 2 hr. The solvent was removed and the residue purified by column chromatography on silica gel eluting with acetone-hexane (1:1) to give diisopropyl (E)-4-hydroxybut-1-enylphosphonate as a gum (0.43 g, 76%); νmax (film) 3380, 2970, 1625, 1460, 1380, 1370, 1220 and 980 cm-1 ; δH (CDCl3) 1.32 (12H, dd, J 9 Hz and 6 Hz, CH(CH3)2), 1.85 (1H, br.s, OH), 2.50 (2H, m, CH2), 3.76 (2H, t, J 6 Hz, CH2O ), 4.69 (2H, m, CH(CH3)2), 5.80 (1H, dd, J 16 Hz and 18 Hz, PCH=CH) 6.75 (1H, ddt, J 7 Hz, 17 Hz and 22 Hz, PCH=CH); CIMS (isobutane) 237 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH:12]1([C:15](O)=O)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[N:11]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)C1CC1
Product: O=[N+]([O-])c1ccc2[nH]c(C3CC3)nc2c1
Yield: 98 %

Procedure:
By analogy with a described method (WO 96/04270), a solution of 5 g (32.65 mmol) of 4-nitro-1,2-phenylenediamine in 77 ml (0.979 mol) of cyclopropanecarboxylic acid is stirred at reflux for 14 hours. The reaction mixture is then concentrated under reduced pressure and taken up in 150 ml of ethyl acetate and 100 ml of sodium hydrogen carbonate. The organic phase is washed with 100 ml of water and then with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. 6.5 g of a brown oil are obtained, and are used without further purification in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19]>>[CH3:12][C:10]1([CH3:11])[C:13]([CH3:15])([CH3:14])[O:16][B:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])[O:9]1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: CC1(C)OB(c2ccccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)OC1(C)C

Procedure:
The title compound was prepared by coupling 2-aminobenzeneboronic acid pinacol ester and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (prepared in Example 11, step (d)) according to the procedure in Example 32, step (c). Mass spectrum (ESI, m/z): Calcd. for C23H33BN4O4Si, 469.2 (M+H), found 468.9.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH3:30][O:31][CH2:32]Cl>CN(C)C=O.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:30][O:31][CH3:32])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: COCCl
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(O)cc1C2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC12CCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 75.4 %

Procedure:
A solution of 9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (5.30 g, 21 mmol) in anhydrous dimethylformamide (50 mL) was cooled in an ice bath, stirred under a nitrogen atmosphere, and treated successively with N,N-diisopropyl-ethylamine (10.5 mL, 60 mmol) and chloromethyl methyl ether (3.45 mL, 41 mmol). The resulting mixture was stirred while gradually warming to room temperature over 5 hours. After 5.5 hours, additional N,N-diisopropyl-ethylamine (3 mL) and chloromethyl methyl ether (1 mL) were added. After stirring an additional 25 minutes at room temperature, the reaction mixture was diluted with EtOAc (1 L) and washed with 1.3N HCl (1 L). The aqueous phase was separated and extracted with EtOAc (200 mL). The combined organics were washed with 5% NaHCO3 (500 ml) and brine, dried over MgSO4, filtered, and concentrated under vacuum to an orange oil (6.5 g). This material was divided into three portions and each purified by flash chromatography on silica gel using Biotage FLASH 40M columns and 10:1 hexanes-EtOAc as eluting solvent. The product containing fractions were combined and evaporated under vacuum to afford 9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (4.98 g) as an oil.