Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21](C(Cl)(Cl)Cl)[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1.[CH3:28][O-:29].[Na+].CO>CN(C)C=O.O>[CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([O:29][CH3:28])[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1
Reactant: C[O-]
Reactant: Cc1cc(CCCOc2c(C)cc(-c3noc(C(Cl)(Cl)Cl)n3)cc2C)on1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1nc(-c2cc(C)c(OCCCc3cc(C)no3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
The product of Example 12 (627 mg, 1.46 mmol) was added to a freshly prepared solution of sodium methoxide in methanol (1.5 equivalents sodium in 5 mL methanol) in dry dimethylformamide (3-5 mL) and the mixture was stirred at room temperature for 15-30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (3x). The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue (0.64 g) was purified by chromatography (Silica Gel 60, first with 2% methanol in methylene chloride followed by 5% ethyl acetate in methylene chloride) to give pure title compound (308 rag) as a colorless oil which crystallized from methanol, mp 64.5°-65.5° C. (white solid).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Br:14][CH2:15][CH2:16]C>C1COCC1>[Br-:14].[CH2:15]([N:11]1[CH:12]=[CH:13][N+:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[CH:10]1)[CH3:16]
Reactant: Cc1ccc(-n2ccnc2)c(C)c1
Reactant: CCCBr
Solvent: C1CCOC1
Product: CCn1cc[n+](-c2ccc(C)cc2C)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 2.91 mmol (0.500 g) 1-(2,4-dimethylphenyl)imidazole and 3.20 mmol (0.392 g) 1-bromopropane are dissolved in 5 ml THF and heated for 6 h to 120° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([CH:16]([CH2:19][CH3:20])[CH2:17][NH2:18])[CH3:15].Cl[CH2:22][C:23](O)=[O:24]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:18]([CH2:17][CH:16]([CH2:19][CH3:20])[CH2:14][CH3:15])[C:23](=[O:24])[CH2:22][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: O=C(O)CCl
Reactant: CCC(CC)CN
Product: CCC(CC)CN1C(=O)CSC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-(2-ethyl-1-butyl)-1,3-thiazolidin4-one.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16])[CH3:3].[CH:17](=[O:19])[CH3:18].B(F)(F)F.CCOCC>ClCCCl>[CH3:3][C:2]1=[CH:4][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5](=[O:16])[O:19][CH:17]([CH3:18])[CH2:1]1
Reactant: CC=O
Reactant: C=C(C)C1CCCCCCCCCCC1=O
Agent: C/C1=C\CCCCCCCCCCC(=O)OC(C)C1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCCl
Product: CC1=CCCCCCCCCCCC(=O)OC(C)C1

Procedure:
Following the general procedure as described in Example 1, 2-(prop-1-en-2-yl)cyclododecanone (2.22 g, 10 mmol), acetaldehyde (0.53 g, 12 mmol) and boron trifluoride etherate (0.14 g, 1.0 mmol) in 1,2-dichloroethane (10 mL) were reacted to give the title product as a colorless liquid (2.34 g, 88% yield. Mixture of E/Z isomers in a ratio of 8:1.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[N:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].[CH3:18][N+:19]([CH3:21])=[CH2:20].[I-].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:17][N:2]([CH3:1])[C:3]([C:5]1[C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[C:14]([OH:16])[C:8]2[N:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Reactant: C=[N+](C)C
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2c(O)c(CN(C)C)c(C(=O)N(C)C)cc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 800.9 %

Procedure:
To a suspension of 2.0 g (8.6 mmol) 7-Hydroxy-2,3-dimethyl-3H-benzimidazole-5-carboxylic acid dimethylamide in dichloromethane (80 ml) was added dropwise a suspension of 1.7 g (9.4 mmol) Eschenmoser's salt in dichloromethane (50 ml). After stirring for 3 h at room temperature, the reaction mixture was poured into saturated sodium bicarbonate solution (100 ml) and extracted with dichloromethane (2×50 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo to give 20 g (82%) of the title compound as an orange foam. The compound was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([NH:21][CH:22]([CH3:24])[CH3:23])[N:20]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6].B(O)O.[C:28]([O-:31])([O-])=O.[Na+].[Na+].O1[CH2:39][CH2:38]OCC1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:14]1[CH:13]=[C:12]([CH3:16])[NH:11][C:10](=[O:17])[C:9]=1[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:18]=[C:19]([NH:21][CH:22]([CH3:24])[CH3:23])[N:20]=[C:2]([C:39]2[CH:38]=[CH:5][C:4]([CH:28]=[O:31])=[CH:3][CH:2]=2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc(NC(C)C)c2)c(=O)[nH]1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(NC(C)C)nc(-c3ccc(C=O)cc3)c2)c(=O)[nH]1
Temperature: 100 °C
Yield: 85.7 %

Procedure:
To a stirred solution of 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(isopropylamino)isonicotinamide (0.58 g, 1.67 mmol), boronic acid (0.277 g, 1.84 mmol) in dioxane/water mixture (7 mL+3 mL), Na2CO3 (0.64 g, 6.037 mmol) was added and reaction mass purged for 15 min with argon. Then Pd(PPh3)4 (0.194 g, 0.168 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 100° C. for 3 h. On completion, reaction mass filtered through celite and celite bed washed with ethyl acetate. Combined filtrates were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column over silica gel to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-formylphenyl)-6-(isopropylamino)isonicotinamide (0.6 g, 85.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH2:15][CH2:16]O)[C:12]3[C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=3[N:10]=2)=[C:4]([Cl:27])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][C:11]4[C:12](=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:19]=[CH:20][C:21]=4[Cl:22])[N:13]3[CH2:14][CH2:15][CH2:16]2)=[C:4]([Cl:27])[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(Br)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87 %

Procedure:
To a solution of methyl 2-[(4-bromo-2-chlorophenyl)amino]-4-chloro-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (9.08 g, 19.20 mmol) in tetrahydrofuran (90.0 mL) were added triethylamine (13.4 mL, 96.00 mmol) and methanesulfonyl chloride (5.94 mL, 76.80 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3.5 hrs. The mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting mesylate was dissolved into N,N-dimethylformamide (50.0 mL) and to the solution was added potassium carbonate (5.31 g, 38.40 mmol). The mixture was stirred at 60° C. for 17 hrs. After cooling, the mixture was diluted with water. The generated precipitate was collected by filtration and washed with diisopropyl ether/ethyl acetate to give the title compound as a colorless solid (7.60 g, 16.70 mmol, 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:21]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24]O)[CH3:22]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:13][CH:6]([CH2:7][CH3:8])[CH2:5][CH2:4][CH2:12][CH3:11])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([O:10][CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CCCCC(CC)CO
Agent: O=S(=O)(O)O
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OCC(CC)CCCC
Temperature: 120 °C
Yield: 65.5 %

Procedure:
4-Nitrophthalic acid (2.0 g, 9.5 mmol) was dissolved in 30 ml of 2-ethylhexanol, and then 0.3 ml of sulfuric acid was added. The mixture was heated at 120° C. for 24 hours, and the solvent was evaporated under reduced pressure. Excess 2-ethyihexanol was removed from the oily residue by distillation. The oily residue was dissolved in diethyl ether and washed three times with water and once with 10%Na2CO3 solution. The ether solution was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (n-hexane: acetic acid =30:1) to give 2.3 g (65.5%) of bis(2-ethylhexyl) 4-nitrophthalate (compound 411.)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[N:3]=[CH:2]1.OS(O)(=O)=O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[CH2:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1c[nH]cn1
Yield: 90 %

Procedure:
A solution of 3-(1H-imidazol-4-yl)-propionic acid (1.95 g, 13.9 mmol) and H2SO4 (catalytic) in MeOH (30 mL) was heated at reflux for 15 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (40 mL) and washed with saturated NaHCO3(aq) (30 mL). The aqueous phase was saturated with sodium chloride and extracted with EtOAc (4×25 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give a yellow oil (1.93 g, 90%). 1H NMR (CDCl3) δ 2.68 (t, 2H, J=7.2 Hz), 2.93 (t, 2H, J=7.2 Hz), 3.69 (s, 3H), 6.81 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CCCCO>[ClH:1].[ClH:1].[I:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncccc1I
Reactant: C1CNCCN1
Solvent: CCCCO
Product: Cl
Product: Ic1cccnc1N1CCNCC1

Procedure:
A solution of 2-chloro-3-iodopyridine (2.39 g, 10 mmol) and piperazine (8.61 g, 100 mmol) in n-BuOH, 100 mL, was stirred at reflux under N2 for 18 h. After removing most of the n-BuOH under reduced pressure, the residue was partitioned between toluene and 10% NaOH. The toluene layer was washed further with water, dried (Na2SO4), filtered and concentrated to an oil. The pyridinylpiperazine was purified by recrystallization of the dihydrochloride salt from methanol-ethanol-ethylacetate, m.p. 185°-189° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[C:16](=[O:18])=[O:17]>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]([OH:18])=[O:17])=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: O=C=O
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-3-methyl-benzonitrile (10.008 g, 51.05 mmol) (commercially available) in tetrahydrofuran (“THF”) (350 ml) was added n-butyl lithium (1.6M in THF) (35 ml, 56.16 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 hour. Then carbon dioxide (24.933 g, 566.66 mmol) was added. The reaction mixture was allowed to warm to ambient temperature. The reaction mixture was quenched by addition of water (300 ml), and extracted with diethyl ether (3×300 ml). The phases were separated. The aqueous phase was acidified by addition of aqueous hydrochloric acid (concentrated) and extracted with chloroform (3×200 ml). The combined organic phases were concentrated and used without further purification.
Reaction SMILES: OC(CC(O)/C=C/[C:11]1[C:21]([CH3:23])([CH3:22])[CH2:20][C:14]2(SCCCS2)[CH2:13][C:12]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH3:31])[CH:25]=1)CC(O)=O.C(N(CC)CC)C.Cl[C:41]([O:43][CH2:44]C)=[O:42]>C(Cl)Cl.CCOCC>[CH3:23][C:21]1([CH3:22])[CH2:20][CH2:14][CH:13]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH3:31])[CH:25]=2)[CH:11]1[C:41]([O:43][CH3:44])=[O:42]
Reactant: Cc1cc(C2=C(/C=C/C(O)CC(O)CC(=O)O)C(C)(C)CC3(C2)SCCCS3)ccc1F
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Reaction time: 0.5 h
Yield: 118 %

Procedure:
To a 0°-5° C. solution of 12 (0.90 gm, 1.87 mmol) and triethylamine (315 μL, 2.25 mmol) in 10 mL CH2Cl2 was added dropwise ethyl chloroformate (185 μL, 1.87 mmol). The mixture was stirred for 30 min, diluted with ether, washed with H2O, saturated NaHCO3 and brine and dried (MgSO4). Removal of the volatiles in vacuo and purification of the residue by SiO2 using 3:2 hexanes:EtOAc as eluent provided 0.61 g of the product. mp 136°-8° C. Anal. C25H31FO3S2 : Theory C: 64.91; H: 6.75. Found C: 65.3I; H: 6.82.
Reaction SMILES: CC1(C)[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14]([CH2:17][CH3:18])=[CH:15][CH3:16])[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO>[CH2:17]([C:14](=[CH:15][CH3:16])[C@H:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:4][OH:3])[CH3:18]
Reactant: CC=C(CC)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC=C(CC)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A solution of (S)-tert-butyl 2,2-dimethyl-4-(pent-2-en-3-yl)oxazolidine-3-carboxylate (Intermediate 201, 15.815 g, 58.71 mmol) and p-toluenesulfonic acid monohydrate (3.35 g, 17.61 mmol) in methanol (100 mL) was heated to 85° C. for 3 h. The reaction mixture was cooled to room temperature and triethylamine (8.18 mL, 58.71 mmol) and di-tert-butyl dicarbonate (6.82 mL, 29.35 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a yellow oil. Purification by flash column chromatography (0-100% ethyl acetate/hexanes) afforded the title compound (10.12 g, 75%) as a white solid.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:27])[CH:12]=[C:13]([C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:6][O:5]C(=O)[NH:3]1.O1CCCC1.CO.[OH-].[K+]>O>[NH2:3][C@:2]([CH3:1])([CH2:8][CH2:9][C:10]1[N:11]([CH3:27])[CH:12]=[C:13]([C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=1)[CH2:6][OH:5]
Reactant: Cn1cc(C(=O)CCCCc2ccccc2)cc1CC[C@]1(C)COC(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CCCCc2ccccc2)cc1CC[C@@](C)(N)CO
Yield: 87.6 %

Procedure:
To a solution of (4R)-4-methyl-4-{2-[1-methyl-4-(5-phenylpentanoyl)pyrrol-2-yl]ethyl}-1,3-oxazolidin-2-one (11 mg, 0.03 mmol) obtained in Example (38a) in a mixed solvent of tetrahydrofuran (1 ml) and methanol (1 ml) was added a 5N aqueous potassium hydroxide solution (1 ml), and the resulting mixture was refluxed for 2 days. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to afford the crude product of (2R)-2-amino-2-methyl-4-[1-methyl-4-(5-phenylpentanoyl)pyrrol-2-yl]butan-1-ol (9 mg).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C1CCN2C(=NCCC2)CC1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][N:33]=1>C(#N)C>[Br:31][C:32]1[N:33]=[C:34]2[CH:5]=[CH:4][C:2]([CH3:3])([CH3:1])[O:6][C:35]2=[CH:36][CH:37]=1
Reactant: Oc1ccc(Br)nc1
Reactant: C#CC(C)(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CC1(C)C=Cc2nc(Br)ccc2O1
Reaction time: 0.5 h

Procedure:
To a solution 2-methyl-3-butyn-2-ol (21) in acetonitrile (6 mL) was added DBU (0.80 mL, 6.61 mmol) at 0° C., then TFAA was added dropwise, also at 0° C. The reaction was stirred for 30 min. In another round bottom flask, DBU (0.80 mL, 6.61 mmol) was added to a solution of 2-bromo-5-hydroxy pyridine (1 g, 5.75 mmol) in 6 mL of acetonitrile at 0° C. Then 2-methyl-3-butyn-2-ol was added dropwise into this reaction, which was stirred for 30 additional min. The solvent was removed by rotary evaporation, and the residue was diluted with DCM. After separation, the organic layer was washed with 1M HCl, 1M NaOH, sat NaHCO3 and brine, was dried over MgSO4 and concentrated in vacuum. The crude product was dissolved in 2 ml of xylene and subjected to microwave irradiation (130° C., 220 W) for 30 min. The solvent was removed by rotary evaporation and the product concentrated in vacuum. The crude product was purified by column chromatography (silica gel) (10:1 Hx/EtOAc) to give 300 mg of a yellow solid (23% over the two steps). 1H NMR (CDCl3): 1.45 (s, 6H), 5.86 (d, 1H, J=10.4), 6.44 (d, 1H, J=10), 6.90 (d, 1H, J=8.8), 7.14 ppm (s, 1H, J=8.4). HRMS (ESI) m/z calcd for C10H11NOBr [(M+H)+] 240.0024. found: 240.0026.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](N(OC)C)=[O:20]>C1COCC1>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9])=[O:20]
Reactant: CON(C)C(=O)CCCCl
Reactant: Fc1ccc(F)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(CCCCl)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF) (133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid.
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=1[CH:8]=[O:9])[CH2:2][CH2:3][CH3:4].CC(=CC)C.O.O.P([O-])(O)(O)=[O:28].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[CH2:1]([N:5]([CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:7]=1[C:8]([OH:28])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1C=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1C(=O)O
Reaction time: 2 h
Yield: 0.1 %

Procedure:
2-(Butyl-ethyl-amino)-5-trifluoromethyl-benzaldehyde (1.72 g) is dissolved in a mixed solvent of tert-butanol (8 ml) and water (2 ml), and thereto are added 2-methyl-2-butene (4 ml), sodium dihydrogenphosphate dihydrate (1.37 g) and sodium chlorite (1.82 g) under ice-cooling, and the mixture is stirred for 2 hours. Thereto are added ethyl acetate and a 1N-hydrochloric acid and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 2-(butyl-ethyl-amino)-5-trifluoromethyl-benzoic acid (1.29 mg). MS (m/z): 290 [M+H]+
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C=O)C.[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].CO[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[N:27][C:28]2[N:32]([CH3:33])[CH:31]=[CH:30][N+:29]=2[CH3:34])=[CH:22][CH:21]=1>C(OCC)(=O)C>[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].[N:1]1([C:20]2[CH:25]=[CH:24][C:23]([N:26]=[N:27][C:28]3[N:29]([CH3:34])[CH:30]=[CH:31][N+:32]=3[CH3:33])=[CH:22][CH:21]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNC1
Reactant: COc1ccc(N=Nc2n(C)cc[n+]2C)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc[n+](C)c1N=Nc1ccc(N2CCCNCC2)cc1
Temperature: 100 °C

Procedure:
5 g of homopiperazine (0.05 mol) and 6 ml of dry DMF are charged to a fully equipped round-bottomed flask. The mixture is brought to 100° C. 1.65 g of 2-(4-methoxyphenylazo)-1,3-dimethyl-3H-imidazol-1-ium perchlorate are added over 20 min. The reaction mixture is maintained for 1 hour at 100° C. with stirring and then it is allowed to cool. The reaction mixture is then poured, with stirring, into 150 ml of ethyl acetate. A precipitate forms and it is separated from a gum. This precipitate is recovered by filtration and it is washed 3 times with ethyl acetate.
Reaction SMILES: C([C@H:3]1[CH2:10][CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:11])[O:7]2)=O.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC.O.C(O)C>[CH2:20]([O:19][CH:12]([O:16][CH2:17][CH3:18])[C@H:3]1[CH2:10][CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:11])[O:7]2)[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: O=C[C@H]1CC[C@@H]2OC(=O)C[C@@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(OCC)[C@H]1CC[C@@H]2OC(=O)C[C@@H]21

Procedure:
4.3 g. of (1S,5R,6S)-6-formyl-2-oxabicyclo-[3,3,0]octan-3-one [see Example 9(a)], 15 ml. of triethyl orthoformate, and 40 mg. of p-toluenesulfonic acid in 15 ml. of absolute ethyl alcohol are agitated for 16 hours at 20° under argon. The mixture is then diluted with ether, shaken in succession with sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated under vacuum, thus obtaining 4.8 g. of the title compound as an oil which is completely uniform as determined by thin-layer chromatography.