Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([CH2:3][CH2:2][NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])[N:5]=1
Reactant: NCCc1cc2ccccc2cn1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To an ice-bath cooled solution of 3-(2-aminoethyl)isoquinoline (Description 113; 2.70 g, 15.7 mmol) and triethylarnine (2.84 ml, 20.41 mmol) in anhydrous dichloromethane (75 ml) was added slowly ethyl chloroformate (1.65 ml, 17.27 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water, sat NaCl, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica elution with a gradient rising from DCM to 2% MeOH in DCM+0.5% NH4OH to give the title compound (2.27 g, 59%).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[OH:9][CH2:10][C:11]1[N:16]=[CH:15][C:14]2[CH:17]=[C:18]([S:20](=[O:23])(=[O:22])[NH2:21])[O:19][C:13]=2[CH:12]=1>C(#N)C.C(Cl)(Cl)Cl>[CH3:6][N:4]([CH3:5])[CH:3]=[N:21][S:20]([C:18]1[O:19][C:13]2[CH:12]=[C:11]([CH2:10][OH:9])[N:16]=[CH:15][C:14]=2[CH:17]=1)(=[O:22])=[O:23]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1cc2cnc(CO)cc2o1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc2cnc(CO)cc2o1
Temperature: 25 °C
Reaction time: 40 h
Yield: 48.5 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (1.0 ml, 0.007 mole) was added dropwise (10 minutes) to a suspension of 6-hydroxymethyl-2-sulfamoylfuro[3,2-c]pyridine (1.33 g, 0.005% mole) in acetonitrile (25 ml). The mixture was stirred at room temperature under N2 for 40 hours. The reaction mixture was diluted with CHCl3 and washed with water. The organic phase was separated, dried (Na2SO4) and filtered through charcoal. The filtrate was concentrated to dryness and the residue recrystallized from ethyl acetate to give the product as a yellow solid 0.8 g (48% yield). Recrystallization from methanol/ethyl acetate gave an analytical sample, mp: 161°-163° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+]>CC(=O)CC.O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: Cc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(C)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]phenol (100 mg, 0.30 mmol, 1.0 eq) and Na2CO3 (58 mg, 0.60 mmol, 2.0 eq) in 2-butanone (10 mL) was added ethyl bromoacetate (75.1 mg, 0.45 mmol, 1.5 eq). The mixture was stirred at room temperature for 3 h. TLC showed the reaction to be incomplete so Cs2CO3 (50 mg, 0.15 mmol, 0.5 eq) was added and the reaction stirred a further 3 h. TLC showed the reaction was still not finished so ethyl bromoacetate (0.2 mL) was added and the reaction stirred for a further 1 h. The solution was then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as a solid (100 mg, 81%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:23]#[N:24].C(=O)(O)[O-].[Na+]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1cccc(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(I)c1
Yield: 82.9 %

Procedure:
A mixture of 3.10 ml (25.7 mmol) 3-iodoaniline, 200 ml ethanol, and 5.00 g (21.4 mmol) 4-chloro-6-nitro-quinoline-3-carbonitrile was heated to reflux under N2 for 3½ hours. Cooled and made basic with a saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected. Air dried, washed solids with water, and dried in vacuo. Dissolved solids in 400 ml ethyl acetate, stirred with Darco, filtered and removed solvent. Dried solids in vacuo to give 7.38 g of yellow solid: mass spectrum (electrospray m/e): M+H=417.0.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:40])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:39])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:39][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
Lithium hydroxide monohydrate (0.021 g, 0.50 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.07 g, 0.13 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-3-methyl-4-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.048 g, 70%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s., 1 H) 8.23 (d, J=8.80 Hz, 2 H) 8.17 (d, J=7.82 Hz, 2 H) 7.97 (d, J=8.80 Hz, 1 H) 7.91 (s, 1 H) 7.68 (d, J=7.82 Hz, 2 H) 7.55 (d, J=8.80 Hz, 2 H) 7.48 (d, J=7.82 Hz, 1 H) 6.94 (s, 1 H) 3.85 (s, 2 H) 2.02 (s, 3 H). MS calcd. for C26H17ClF3O5S [(M−H)−] 533, obsd. 533.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:13](=[O:16])[CH2:14][CH3:15])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:17]([O:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH2:35][O:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:30]Br)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:18]1([C:17]([O:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=2[CH2:35][O:36][C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:44])[CH2:30][O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]([C:13](=[O:16])[CH2:14][CH3:15])[S:11][CH:12]=3)[CH:5]=[CH:6][CH:7]=2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(=O)c1cc(-c2cccc(O)c2)cs1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(=O)c1cc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)cs1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 3.8 g (16.3 mmol) of 1-[4-(3-hydroxyphenyl)-2-thiophenyl]-1-propanone with 16.9 g (18 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 2.36 g (17 mmol) of potassium carbonate, the desired product is obtained in the form of white crystals (m.p.=117° C.; m=9.1 g; Y=95%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][O:12][C:11](=[O:15])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.O.[NH2:19][NH2:20]>C(O)C>[OH:12][CH2:13][CH2:14][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=1)[CH2:10][C:11]([NH:19][NH2:20])=[O:15]
Reactant: NN
Reactant: O=C1CC(c2cccc(C(F)(F)F)c2)CCO1
Solvent: O
Solvent: CCO
Product: NNC(=O)CC(CCO)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
4-(3-Trifluoromethylphenyl)tetrahydropyran-2-one (2.5 g) was dissolved in ethanol (10 mL), and hydrazine monohydrate (4.96 mL) was added at room temperature. The mixture was stirred at 80° C. for 4.5 hours and then concentrated under reduced pressure. The resulting oil was partitioned with methylene chloride and water. The aqueous layer was extracted with methylene chloride five times. After drying over magnesium sulfate, concentration under reduced pressure and purification by silica gel column chromatography (amino silica gel, mobile phase:ethyl acetate/heptane=0 to 50%→methanol/ethyl acetate=10%) gave the title compound (1.55 g).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([OH:16])(=O)=[O:14])[CH:8]=1.P(Cl)(Cl)([Cl:19])=O>>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([Cl:19])(=[O:16])=[O:14])[CH:8]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 130 °C
Yield: 35.9 %

Procedure:
Phosphorus pentachloride (3.0 g, 14.6 mmol) was added to a solution of 3-pyridinesulfonic acid (1.5 g, 9.42 mmol) dissolved in phosphoryl trichloride (2.45 g, 16.0 mmol) and the mixture heated to 130° C. for 3 h under argon. The mixture was concentrated in vacuo, the residue was quenched over ice and extracted with ether. The organic phase was washed with a saturated sodium bicarbonate solution and concentrated in vacuo to give the crude title compound (0.6 g, 36%) which was used immediately without purification.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([O:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CN(C)C=O.O>[CH2:40]([O:3][CH2:4][CH:5]([O:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: C=CCCCCC(CO)OC
Reactant: CCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCCC(COCCCCCCCCCCCCCCCC)OC
Reaction time: 18 h

Procedure:
To a suspension of 7.4 g of 60% sodium hydride in 100 ml of dimethylformamide was added a solution of 8-hydroxy-7-methoxy-1-octene in 150 ml of dimethylformamide over 1.5 hours. A 63.4 g portion of the tosylate of 1-hexadecanol was added and the mixture was stirred for 18 hours, poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was purified by chromatography giving 41.5 g of the title compound as a oil.
Reaction SMILES: O1[CH2:6][CH2:5][O:4][CH2:3]C1.CC(C)([O-])C.[K+].[Br:13][C:14]1C=C[C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][C:15]=1F>CO>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:22])=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: C1COCCO1
Reactant: CC(C)S(=O)(=O)c1ccc(Br)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(S(=O)(=O)C(C)C)ccc1Br
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To dioxane (5 mL) and MeOH (0.216 mL) was added a solution of potassium tert-butoxide (1M in THF, 5.16 mL) and the mixture stirred for 15 minutes. To the mixture was added 1-bromo-2-fluoro-4-(isopropylsulfonyl)benzene (Preparation 34, 500 mg, 1.78 mmol) and the reaction mixture stirred for 16 hours at 60° C. The cooled reaction mixture was quenched with water (15 mL), and extracted with EtOAc (3×15 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc/heptanes 33/67-100/0 to afford title compound as a colourless solid in 75% yield.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[O:5]=[C:6]([CH3:19])[CH2:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9].N1CCCCC1.Cl>O>[C:6]([C:7](=[CH:1][CH2:2][CH3:3])[C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9])(=[O:5])[CH3:19]
Reactant: CCC=O
Reactant: C=C(C)C(=O)OCCOC(=O)CC(C)=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Product: C=C(C)C(=O)OCCOC(=O)C(=CCC)C(C)=O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a magnetically stirred, 1000 mL, round bottom flask were added 200 mL of propionaldehyde and 587 mL 2-(methacryloyloxy)ethyl 3-oxobutanoate. The reaction mixture was cooled to 0° C., in an ice bath, and then 3 to 5 mL of piperidine was added dropwise over one minute. The mixture was stirred at 0° C., for 2 hours, and then allowed to warm to room temperature over the course of 2-2.5 hours. To the reaction mixture was slowly added 30 mL of 3N HCl, over about one minute, to neutralize the piperdine. The mixture was poured into a separatory funnel, and then 150 mL of deionized water was added. The mixture was shaken, and then the aqueous layer was separated and disposed of. The reaction mixture was washed three more times with 150 mL of deionized water, each time, and then dried over MgSO4. The reaction mixture was filtered, and then stabilized with 10 mass ppm of 4-hydroxy-TEMPO. The dried reaction mixture was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C2CCCCCC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(C2CCCCCC2)cc1

Procedure:
6.81 g (36.0 mmol) of 4-aminophenyl-cycloheptane were dissolved in 60 ml of methylene chloride and treated with 3.13 g (39.6 mmol) of pyridine. The reaction mixture was treated dropwise at room temperature while stirring with a solution of 4.3 g (39.6 mmol) of ethyl chloroformate in 15 ml of methylene chloride. After 2 hours the mixture was washed with water and the organic phase was dried over sodium sulfate, filtered and evaporated. The ethyl 4-cycloheptylphenyl-carbamate distilled at 165°-170° and 0.3 mbar.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: ICc1ccccc1
Product: c1ccc(CN2CCN3c4c(cccc42)[C@@H]2CNCC[C@@H]23)cc1

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using benzyl iodide as the alkyl halide and following the procedure of Step B–D of Example 255, as a viscous liquid. 1H NMR(CDCl3, 300 MHz) δ 1.60–2.0 (m, 2H), 2.55–2.95(m, 4H), 2.95–3.15 (m, 2H), 3.20–3.45 (m, 3H), 4.40 (q, J=16.1 Hz, 2H), 6.41 (d, J=7.1 Hz, 1H), 6.51 (d, J=7.1 Hz, 1H), 6.62 (t, J=7.1 Hz, 1H), 7.20–7.40 (m, 5H) ppm. MS (CI): 306 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][N:10]=1)=[O:5])C.[CH2:20]([NH2:22])[CH3:21]>CO.O1CCCC1>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:8]1[O:7][C:6]([C:4](=[O:5])[NH:22][CH2:20][CH3:21])=[N:10][N:9]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CCN
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Reaction time: 1.5 h

Procedure:
To a solution of 5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-1,3,4-oxadiazole-2-carboxylic acid ethyl ester (prepared as described in JOC (1995), 60(10), 3112-20) (0.150 g) in methanol (5 ml) was added a solution of 2.0M ethylamine in tetrahydrofuran (3 ml). The solution was left standing at 20° C. for 1.5 h. The solvent was removed by evaporation using a stream of nitrogen to give the title compound as a yellow gum (0.139 g).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]=2[CH:27]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+:28]([O-:33])([N+]([O-])=O)=[O:29].[OH-].[Na+].Cl>ClCCl.C(OCC)C>[N+:28]([C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:27][C:17]=2[C:18]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:33])=[O:29]
Reactant: CCCCCCCCCCC(O)c1ccc2occ(-c3ccccc3)c2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCC(O)c1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reaction time: 16 h

Procedure:
To the solution of product from step A is added 2 g. of dinitrogen tetraoxide dissolved in dichloromethane, and the mixture is stirred for about 16 hours. Evaporation provides a residue which is mixed with ice and 10 percent sodium hydroxide solution. The mixture is stirred for 15 minutes, then cold 6N hydrochloric acid and diethyl ether are added. The ether layer is separated, then washed with saturated sodium chloride solution and dried. The solution is chromatographed on silica gel, eluting first with carbon tetrachloride, then dichloromethane. The later fractions are evaporated to provide 1-(2-nitro-3-phenyl-5-benzofuranyl)undecan-1-ol as a yellow solid, m.p. 84°-85° C. after recrystallization from hexane.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH:27](C)[CH3:28]>CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)CCCCCO
Agent: CC(C)[O-]
Agent: [Al+3]
Product: CCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate (256 g, 0.88 mole) and isooctanol (133 g, 0.91 mole) are added to a laboratory reactor equipped with the necessary auxiliary equipment. The mixture is heated to 85 C under a vacuum of 30 mmHg. After fifteen minutes, the vacuum is released and aluminum isopropoxide (1.77 g, 0.0087 mole, Rhone-Poulenc, Manalox 130) is added. The reaction mass is heated to 130 C while under a vacuum of 75 mmHg. After two hours, the reaction mass is heated to 165 C while under a vacuum of 30 mmHg for one hour. The excess isooctanol is removed by vacuum distillation at 165 C. The title compound (331 g, 97% yield) is obtained as a light yellow oil whose assay is 97% as judged by calibrated gas chromatography.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([NH:34][C:31]2[CH:32]=[CH:33][N:29]([CH2:28][CH2:27][O:26][CH3:25])[N:30]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: COCCn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 71 mg, 0.21 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 32 mg, 0.23 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.11 g, 0.25 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.62 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium bicarbonate solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50-80% ethyl acetate/hexanes) to give (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (42 mg, 43%) as an off white solid: HR-ES(+) m/e calcd for C23H27N4O3F3 [M+H]+ 465.2108, observed 465.2107; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-2.18 (m, 10H), 3.20 (s, 3H), 3.51-4.28 (m, 4H), 4.60-5.34 (m, 3H), 6.40 (d, J=1.81 Hz, 1H), 7.41-8.28 (m, 5H), 10.93 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].C(OCC)(=O)C>Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[N:5]=[C:12]([CH3:13])[CH:11]=[CH:10]2)[CH3:2]
Reactant: CCc1ccccc1N
Reactant: C/C=C/C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1cccc2ccc(C)nc12
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A solution of 2-ethylaniline (4.00 g, 33.0 mmol) in 6 N HCl (40 mL) was added (E)-but-2-enal (6.20 ml, 75.9 mmol) dropwise at reflux. The reaction was heated at reflux for 3 hours. After cooling to ambient temperature, ethyl acetate (40 mL) was added. The aqueous layer was separated, basified with ammonium hydroxide to about pH 9, and extracted with DCM (2×50 mL). The combined organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/DCM) to give 8-ethyl-2-methylquinoline (3.34 g, 59.1%) as a solid.