Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7](O)=[O:8])C(C)C.C(OC(=O)C)(=O)C.[NH4+:21].[OH-]>>[C:7]([NH2:21])(=[O:8])[CH2:6][CH2:5][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CC(C)CC(CC(=O)O)CC(=O)O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: NC(=O)CCCC(=O)O

Procedure:
In Scheme 1, 3-isobutyl glutaric acid, compound 2, is converted into the corresponding anhydride, compound 3, by treatment with refluxing acetic anhydride. The reaction of the anhydride with NH4OH produces the glutaric acid mono-amide, compound 4, which is resolved with (R)-1-phenylethylamine, yielding the (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, compound 5. Combining the salt with an acid liberates the R enantiomer, compound 6. Finally, a Hoffinann degradation with Br2/NaOH provides (S)-Pregabalin. A disadvantage of this method is that it requires separating the two enantiomers, thereby resulting in the loss of half the product, such that the process cost is high.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[N:6][CH:5]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:7]=[N:6][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(C#C[Si](C)(C)C)c1
Yield: 13.6 %

Procedure:
Under the conditions of example 21 B, 5 g of 5-bromonicotinic acid methyl ester is reacted with 2.43 g of trimethylsilylacetylene, worked up, and the crude product is chromatographed on silica gel with hexane/0-5% ethyl acetate. 734 mg of 5-(2-trimethlsilylethinyl)-nicotinic acid methyl ester is obtained as oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[CH2:10]1[CH:17]2[NH:18][CH:12]([CH2:13][C:14]([CH2:16]2)=O)[CH2:11]1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:14]1[CH2:13][CH:12]3[NH:18][CH:17]([C:16]2=1)[CH2:10][CH2:11]3
Reactant: NNc1ccc(F)cc1
Reactant: O=C1CC2CCC(C1)N2
Solvent: CCO
Product: Fc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Yield: 75 %

Procedure:
This compound was prepared from 4-fluorophenylhydrazine and nortropinone by the procedures described in Example 1, Method A (75% yield) or Method B (60% yield). A hydrogen fumarate hemihydrate was prepared in ethanol, mp 145° C. dec; NMR (DMSO-D6) d 1.71-1.78. (1H, m), 1.95-1.98 (1H, m), 2.19-2.22 (2H, m), 2.79 (1H, d, J=16.8 Hz), 3.36 (1H, dd, J-16.9, 4.4 Hz), 4.33 (1H, bs), 5.00 (1H, d, J=4.2 Hz), 6.43 (2H, s), 6.84-6.91 (1H, m), 7.28=7.36 (2H, m), 11.30 (1H, s). Anal. (C13H13N2F.C4H4O4.0.5H2O).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:26](=[O:28])[O:27][C:23]=2[CH:22]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(Cl)ccc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 6-chloro-3H-benzooxazol-2-one (105 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (3): HPLC retention time, 2.62 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 436.3, found, 436.4.
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24](=[O:25])[NH:23][N:22]=[N:21]2)[CH:17]=[CH:18][CH:19]=1>CC(O)=O>[CH3:1][C:2]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[C:24](=[O:25])[NH:23][N:22]=[N:21]3)[CH:15]=2)[C:4](=[O:12])[C:5]2[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:7]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: Nc1cccc(-n2nn[nH]c2=O)c1
Solvent: CC(=O)O
Product: Cc1nc2ccccc2c(=O)n1-c1cccc(-n2nn[nH]c2=O)c1
Reaction time: 8 h

Procedure:
A mixture of 2-methyl-4H-benzo[d][1,3]oxazin-4-one (101 mg, 0.63 mmol) and 1-(3-aminophenyl)-1,4-dihydro-5H-tetrazol-5-one (111 mg, 0.63 mmol) in AcOH (10 mL) was heated to reflux and stirred overnight. Analysis indicated the formation of product. The mixture was allowed to cool and dry-loaded onto silica gel. The mixture was purified by column chromatography on silica gel using CH2Cl2/MeOH (1:0 to 9:1) as eluent to give the product (32 mg, 16% ca. 94% purity by LC/MS). The product was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:24][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])(=O)=O)=CC=1>CCO.O>[OH:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:24][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])[CH:3]=1)[CH2:9][C:10]#[N:11]
Reactant: CCCC(CCC)COS(=O)(=O)c1ccc(C)cc1
Reactant: N#CCC(O)c1cccc(N)c1
Solvent: O
Solvent: CCO
Product: CCCC(CCC)CNc1cccc(C(O)CC#N)c1

Procedure:
To a stirred solution of aniline 12 (1.0 g, 6.1 mmol) in EtOH:H2O (9:1) was added 2-propylpentyl 4-methylbenzenesulfonate (0.87 g, 3.08 mmol). The reaction mixture was heated under reflux for 4 days, concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc three times. Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by flash chromatography (25% EtOAc—hexanes) gave 3-hydroxy-3-(3-(2-propylpentylamino)phenyl)propanenitrile as a colorless semi-solid. Yield (0.3 g, 18%); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=7.6 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 6.57 (dd, J=2.0, 8.0 Hz, 1H), 4.95 (dt, J=3.2, 6.0 Hz, 1H), 3.72 (bs, 1H), 3.02 (d, J=6.0 Hz, 2H), 2.80 (d, J=6.8 Hz, 2H), 2.89 (d, J=3.2 Hz, 1H), 1.64-1.57 (m, 1H), 1.37-1.20 (m, 8H), 0.84 (t, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[NH:13][C:12](=[O:14])[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH:16]([CH3:19])[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:15][CH:16]([CH3:19])[CH2:17][N:13]1[C:12](=[O:14])[O:11][N:10]=[C:9]1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)CO
Reactant: O=c1[nH]c(OCc2ccccc2)no1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Cn1c(OCc2ccccc2)noc1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A 50 mL round bottom flask equipped with a thermometer, a stirrer, addition funnel and nitrogen inlet was charged with 3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (1 g, 5.2 mmol), 2-methyl propanol (0.45 g, 6 mmol), triphenylphosphine (1.57 g, 6 mmol) and tetrahydrofuran (5 mL). The mixture was cooled to 0° C. and a solution of diethyl azodicarboxylate (1.04 g, 6 mmol) in tetrahydrofuran (2 mL) was added dropwise over a period of 10 min. The reaction mixture was allowed to warm to room temperature, and stirred for 18 h. The entire mixture was flash chromatographed (silica gel, 8:2 hexane-ethyl acetate) to provide 1.1 g (84%) of the title compound as a white solid melting at 53-60° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6].[Na].Cl([F:23])(=O)(=O)=O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([CH2:3][CH:4]([F:23])[CH2:5][CH3:6])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:12]
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(F)CC)C(=O)OCC

Procedure:
To a suspension of sodium hydride (1.08 mol) in 1200 ml of toluene was added dropwise 235 g (1.08 mol) of diethyl n-butylmalonate. To the resulting clear solution of the sodium salt was then bubbled perchloryl fluoride while the the temperature was maintained below 10° C. When the calculated amount of perchloryl fluoride had been added a stream of argon was bubbled through the solution for a short period of time. The mixture was filtered and the toluene removed under reduced pressure. The remaining oil was distilled to give 223 g, b.p. 78° (0.1 mmHg) of diethyl-2-fluoro-n-butylmalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:40]1[CH2:45][CH2:44][NH:43][C@H:42]([CH3:46])[CH2:41]1)=O)(C)(C)C>CC#N.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[N:20]=[C:19]([CH2:21][N:43]5[CH2:44][CH2:45][NH:40][CH2:41][CH:42]5[CH3:46])[O:18][N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1cc(-c2noc(CCl)n2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2noc(CN3CCNCC3C)n2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 70 °C
Yield: 39.5 %

Procedure:
To a solution of 2-(4-chlorobenzyl)-5-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-7-methyl-2,3-dihydroisoindol-1-one (37 mg, 0.0952 mmol) in MeCN (4 mL) was added K2CO3 (39 mg, 0.286 mmol) and (3R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (38 mg, 0.190 mmol). The mixture was heated at 70° C. overnight, then diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to a yellow oil. This residue was dissolved in 1:1 TFA/CH2Cl2 for 30 minutes, then the reaction mixture was concentrated and basified with NaHCO3 to pH 9-10. The product was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica (1% 2M NH3 in MeOH/CH2Cl2) to provide 2-(4-chlorobenzyl)-7-methyl-5-[5-(2-methylpiperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one as a yellow oil (17 mg). 1H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H), 7.93 (s, 1H), 7.33 (d, 2H), 7.26 (d, 2H), 4.77 (s, 2H), 4.29 (s, 2H), 4.17 (d, 1H), 4.06 (d, 1H), 2.83-3.04 (m, 4H), 2.83 (s, 3H), 2.50-2.61 (m, 3H), 1.19 (d, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[C:7](OC(C)=C)(=[O:9])[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:7]([O:5][CH:4]=[CH:3][C:2]([CH3:6])=[CH2:1])(=[O:9])[CH3:8]
Reactant: CC(C)=CC=O
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=C(C)C=COC(C)=O

Procedure:
Prenal (0.332 mol) was run gradually into isopropenyl acetate (0.532 mol) in which paratoluenesulphonic acid (1% by weight) had been dissolved. The acetone was distilled off as it was formed. The temperature of the mixture was 93°-94° C. at the beginning and 118° C. after heating for 1 hour 50 minutes. The 1-acetoxy-3-methylbutadiene was then purified by distillation. The boiling point of the product was 48°-52° C./13 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=O)=[CH:7][N:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1cnc(C=O)cn1
Product: COC(=O)c1cnc(CN2CCOCC2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 23, Step C, using 5-formyl-pyrazine-2-carboxylic acid methyl ester (0.78 g, 4.7 mmol) and morpholine (0.44 g, 5.2 mmol).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].C(N(CC)CC)C.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>COCCOC>[CH3:18][N:19]([CH3:23])[C:20]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)=[O:21]
Reactant: CN(C)C(=O)Cl
Reactant: CC1=NC(=NO)SC1(C)C
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC1=NC(=NOC(=O)N(C)C)SC1(C)C

Procedure:
15.8 g. (0.1 mol) of 2-oxo-4,5,5-trimethyl-3-thiazoline-oxime and 15.2 g. (0.15 mol) of triethylamine were dissolved in 100 ml. of anhydrous 1,2-dimethoxy-ethane. 16.1 g. (0.15 mol) of dimethylcarbamoyl chloride were added dropwise. The mixture was refluxed for 3 hours and the solvent was distilled off under vacuum. The residue was dissolved in 100 ml. of dichloromethane and washed with water. After the organic phase was dried over sodium sulfate, the solvent was distilled off. The residue was purified chromatographically on silica gel using ether/dichloromethane (9:1) for the elution to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(dimethylcarbamoyl)-oxime, m.p. 108°-110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccon2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccon2)cc1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
To a solution of 3-(4-methylphenyl)isoxazole (prepared using literature methods) (1.95 g, 12.25 mmol) in carbon tetrachloride (60 mL), N-bromosuccinimide (2.18 g, 12.25 mmol) and benzoyl peroxide (0.059 g, 0.245 mmol) were added and the mixture refluxed for 1 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with hexanes/EtOAc to give the title compound, 3-(4-(bromomethyl)phenyl)isoxazole, (0.6 g) as a white solid. 1H NMR (CDCl3): δ 8.48 (d, J=1.6 Hz, 1H), 7.83 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 6.67 (d, J=1.6 Hz, 1H), 4.53 (s, 2H).
Reaction SMILES: [CH:1]1([CH:6]2[C:31](=[O:32])[N:30]3[CH2:33][CH:27]([CH2:28][CH:29]3[C:34]([O-:36])=[O:35])[O:26][C:25]3[N:20]([C:21](=[O:37])[CH:22]=[CH:23][CH:24]=3)[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15][CH:14]3[CH:10]([CH2:11][CH2:12][CH2:13]3)[O:9][C:8](=[O:38])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:39](O)C>>[CH:1]1([C@H:6]2[C:31](=[O:32])[N:30]3[CH2:33][C@@H:27]([CH2:28][C@H:29]3[C:34]([O:36][CH3:39])=[O:35])[O:26][C:25]3[N:20]([C:21](=[O:37])[CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[O:9][C:8](=[O:38])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1NC(C2CCCC2)C(=O)N2CC(CC2C(=O)[O-])Oc2cccc(=O)n2CC=CCCC2CCCC2O1
Reactant: CCO
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCCn1c(cccc1=O)O2
Yield: 94 %

Procedure:
The title compound was prepared in a similar manner as Example 13 Step 1, utilizing methyl (1R,10E, and 10Z,14S,18R,22S,25S)-22-cyclopentyl-7,20,23-trioxo-2,19-dioxa-8,21,24-triazatetracyclo[22.2.1.03,8.014,18]heptacosa-3,5,10-triene-25-carboxylate and replacing THF with ethanol as the solvent to give a 94% yield. LCMS (ES+) m/z 544.3 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:7]([C:11]1[CH:16]=[C:15]([NH:17][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C(C)C(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)methacrylamide was prepared by adding a solution of 11.5 grams of methacryloyl chloride in 50 milliliters of benzene to the solution of 2,6-di tert.butyl-4-aminophenol to which had been added 6 grams of sodium carbonate. The addition was accomplished in 30 minutes at 24° C. to 37° C. The mixture was stirred for 1 hour and the solid product was filtered off, washed thoroughly with 2% hydrochloric acid and dried. The yield was 10.0 grams of product which melted at 222° C. to 225° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.Cl[CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:1]5[CH2:28][CH2:29][CH2:30][S:31]5(=[O:33])=[O:32])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O=S(=O)(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(N2CCCS2(=O)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a 2 ml pyridine solution of 100 mg (0.280 mmol) of the compound obtained in Example 44, 85.2 μl (0.700 mmol) of 3-chloropropanesulfonyl chloride was added, and the mixture was stirred at room temperature for 8 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. To the residue, 2 ml of ethanol and a 1M aqueous solution of sodium hydroxide were added, and the mixture was stirred at room temperature for 48 hours. Then, the reaction mixture was neutralized with a 1M aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 68 mg (53%) of the captioned compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][CH:48]([CH3:52])[C@H:49]([NH2:51])[CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][C@H:49]([CH3:50])[CH:48]([CH3:52])[CH3:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@@H](C)N
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@H](C)C(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(−)-3-methyl-2-butylamine (Fluka) to give the title product. LC-MS (ES+) 734 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].[CH3:15][O-:16].[Na+]>CO>[F:1][C:2]1[C:3]([F:14])=[C:4]([O:16][CH3:15])[C:5]([F:12])=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(F)c(F)c([N+](=O)[O-])c(F)c1F
Yield: 71.9 %

Procedure:
50 g of pentafluoronitrobenzene was dissolved in 400 ml of dry methanol. Thereto was dropwise added, with ice-cooling, a solution of 13.95 g of sodium methoxide dissolved in 50 ml of dry methanol. A reaction was allowed to take place at room temperature for 2 hours. The reaction mixture was concentrated to a volume of about ⅓ under vacuum. The residue was poured into 500 ml of water. The organic layer was extracted with 300 ml of ether. The ether layer was washed with an aqueous sodium chloride solution and dried over MgSO4. The resulting solution was subjected to vacuum distillation to remove the solvent. The residue was subjected to vacuum distillation (96 to 97° C./0.35 mmHg (47 Pa)) to obtain 38 g of 2,3,5,6-tetrafluoro-4-methoxynitrobenzene (yield: 72%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21])=[O:11]>Cl.C(O)(=O)C.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:4]3[C:3]([C:8](=[O:23])[CH:9]=2)=[CH:2][CH:7]=[CH:6][CH:5]=3)=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1
Reactant: COc1ccc(C(=O)CC(=O)c2ccccc2O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(=O)c3ccccc3o2)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
1-(2-Hydroxyphenyl)-3-(4-methoxy-2-nitrophenyl)propane-1,3-dione (5.92 g, 18.77 mmol) was dissolved in a mixture of 48% HCl (2 mL) and acetic acid (35 mL) and heated at 100° C. for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated to give the crude compound, which was purified by column chromatography using 5% ethyl acetate in CH2Cl2 to give 2-(4-methoxy-2-nitrophenyl)-4H-chromen-4-one (3.92 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]([O:16]C)=O)[N:9]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][C@@H:25]([CH2:29][NH2:30])[CH2:24]1>CN1CCCC1=O.CO>[Cl:18][C:19]1[CH:20]=[C:21]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][C@@H:25]([CH2:29][NH:30][C:14](=[O:16])[CH2:13][C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:12][N:11]=2)[CH2:24]1
Reactant: COC(=O)Cc1noc(-c2ccc(F)cc2)n1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=C(Cc1noc(-c2ccc(F)cc2)n1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 57.4 %

Procedure:
A mixture of Intermediate 38 (0.024 g), Intermediate 9 (0.025 g), and 1-methyl-2-pyrrolidinone (1 drop) was subjected was subjected to irradiation in a 600 W microwave oven on full power for 4 mins. The reaction mixture was dissolved in methanol and applied to an ion exchange cartridge (2 g Isolute SCX, pre-conditioned with methanol). Elution with methanol (3 column volumes) followed 10% 0.880 ammonia in methanol (2 column volumes) and evaporation of the first basic fraction in vacuo gave the crude product. Purification by Biotage flash column chromatography on silica gel (8 g cartridge), eluting with 100:8:1 dichloromethane/ethanol/0.880 ammonia, gave the title compound as a white solid (0.025 g). LCMS (System A) Rf 2.85 min Mass Spectrum m/z 479, 481 [MH+]