Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:19]([NH:26][CH2:27][CH:28]=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:23][C:22]([O:21][C:19]([NH:26][CH2:27][CH2:28][N:4]1[CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:2][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:20])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1,1-dimethylethyl) 3-ethyl 1,3-piperazinedicarboxylate [EP1486498, 2004] (2.023 g, 8.28 mmol) in 10 mL of dichloroethane was added a solution of N-boc-2-aminoacetaldehyde (1.87 g, 12.42 mmol) in 20 mL of dichloroethane. The solution was stirred at room temperature and under nitrogen atmosphere for 30 min. Sodium triacetoxyborohydride (3.32 g, 16.56 mmol) was then added and the reaction kept at room temperature overnight. The product was isolated on a SCX cartridge. 2.492 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:24]=2[CH:25]=1)=[O:20]>CO>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:30][C:27]3[CH:28]=[CH:29][C:23]4[O:22][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:25][C:24]=4[CH:26]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Solvent: CO
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(N)c4)n3)ccc2o1
Temperature: 100 °C

Procedure:
A mixture of N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine (10 mg, 0.06 mmol) and 2-methoxycarbonyl-5-aminobenzofuran (36 mg, 0.18 mmol) in dry MeOH (0.5 ml) was refluxed for 2 days (100° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3:Acetone, 9:1) to give N4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.24 (s, 1H), 7.96 (dd, 1H, J=1.7, 3.5 Hz), 7.46-7.59 (m, 3H), 6.93-6.99 (m, 2H), 6.84 (d, 1H, J=8.2 Hz), 6.35 (m, 1H), 3.84 (s, 3H); LCMS purity: 97.8%; MS (ES) m/c 394.02 (M+, 70).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: NCCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(NCCCCO)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1.09 g (4.65 mmol) of 4-oxoazepane-1-carboxylic acid tert-butyl ester and 864 μl (9.30 mmol) of 4-aminobutan-1-ol were suspended in 40 ml of ethanol, stirred at room temperature for 40 minutes, 532 μl (9.30 mmol) of glacial acetic acid were added, and the mixture was stirred for a further 10 min. Sodium triacetoxyborohydride (1.97 g, 9.30 mmol) was added, and the mixture was stirred at room temperature overnight and evaporated to dryness in vacuo. The residue was taken up in water and extracted 4 times with EA. The organic phase was dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]1[CH:10]=[C:9]2[CH:11]([OH:19])[C:12]3[C:17]([O:18][C:8]2=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3>C(N(CC)CC)C>[CH3:1][NH:2][C:3]([O:19][CH:11]1[C:9]2[CH:10]=[CH:5][CH:6]=[CH:7][C:8]=2[O:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:4]
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reaction time: 0.67 h

Procedure:
Methyl isocyanate (20 g.) was added slowly, with stirring, to a filtered solution of 30 g. of xanthydrol in 100 ml. of anhydrous triethylamine. After standing for 40 minutes to a 20° C. water bath, the mixture was filtered. The collected solid was washed with anhydrous diethyl ether and dried in vacuo to give 9-(N-methylcarbamoyloxy)xanthene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:15]1[C:16]2[C:12](=[C:11]([CH3:18])[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(OCc2ccccc2)cc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc2c1ccn2CC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 1 c], 6-benzyloxy-4-methyl-1H-indole was reacted with bromo-acetic acid tert-butyl ester in the presence of cesium carbonate in DMF to obtain (6-benzyloxy-4-methyl-indol-1-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH:26](O)[CH3:27].CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3[N:60]=[CH:59][N:58](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:57]=3)=[CH:53][CH:54]=2)[C:49]([C:80]2[CH:81]=[C:82]([OH:86])[CH:83]=[CH:84][CH:85]=2)=[N:48]1.Cl>O1CCCC1>[NH:57]1[C:56]([C:52]2[CH:51]=[C:50]3[C:55](=[CH:54][CH:53]=2)[NH:47][N:48]=[C:49]3[C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([O:86][CH2:27][CH2:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][NH:20]3)[CH:81]=2)=[N:60][CH:59]=[N:58]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(O)C1CCCCN1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCC2CCCCN2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 48.2 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 2-piperidylethanol (0.352 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate elution followed by 0–20% methanol/ethyl acetate. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated which gave the title compound (0.124 g, 48% yield). 1H NMR (CD3OD) δ 8.72 (m, 1H), 8.34 (s, 1H), 8.10 (dd, 1H), 7.67 (dd, 1H), 7.62 (dt, 1H), 7.58 (m, 1H), 7.47 (t, 1H), 7.04 (m, 1H), 4.27 (t, 2H), 2.89 (t, 2H), 2.63 (m, 4H), 1.68 (m, 4H), 1.51 (m, 2H). ES-MS (m/z) 389 [M+1]+
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][N:13]=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[H][H]>CO.[Pt]=O>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][NH:13][CH2:14]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3ccncc3c2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: c1ccc(-c2ccc3c(c2)CNCC3)cc1

Procedure:
To a solution of 7-phenylisoquinoline (1.25 g, 6.1 mmol)in methanol (50 ml) was added conc HCl (2 ml) and platinum oxide (100 mg). The reaction mixture was hydrogenated at 50 psi until no further uptake of hydrogen was observed. The catalyst was filtered off, washed with methanol. The filtrate was evaporated under reduced pressure to give a solid. The solid was partitioned between ethyl acetate and sodium carbonate solution. The aqueous solution was extracted with ethyl acetate (2×100 ml). The ethyl acetate extracts were combined, washed with brine (2×100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil, which crystallised on standing. The solid was a mixture of the title compound and 7-phenyl-decahydroisoquinoline; Rf 0.66 (EtOAc/MeOH/NH3 5:1:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[CH:17](=[O:20])[CH2:18][CH3:19]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:17]([OH:20])[CH2:18][CH3:19])=[CH:4][N:3]=1
Reactant: CCC=O
Reactant: Clc1ccnc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)c1cnc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (1.10 mL; 7.85 mmol) (Aldrich) was dissolved in freshly distilled tetrahydrofuran (15 mL) and cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 3.10 mL; 7.75 mmol) (Aldrich) was added dropwise and stirring continued for 30 minutes to give a LDA solution. A solution of 2,4-dichloropyrimidine (0.50 g; 3.36 mmol) (Aldrich) in tetrahydrofuran (3 mL) was added to this freshly prepared LDA solution over 12 minutes. After 30 minutes stirring at −78° C., propionaldehyde (0.48 mL; 6.65 mmol) (Aldrich) was added over 6 minutes and stirring continued for another 35 minutes. The reaction was quenched with the addition of 25% aqueous ammonium chloride solution (15 mL) and was then diluted with ethyl acetate and water. The organic phase was washed with a second portion of ammonium chloride solution and then brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage; 40M; 15:85 to 25:75 ethyl acetate-hexanes gradient) to give (±)-1-(2,4-dichloro-pyrimidin-5-yl)-propan-1-ol. (Yield 0.260 g; 37%).
Reaction SMILES: [CH2:1]([NH2:5])[C@@H:2]([NH2:4])[CH3:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>ClCCl>[NH2:4][C@@H:2]([CH3:3])[CH2:1][NH:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](N)CN
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC[C@H](C)N)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To 62.9 parts of (S)-1,2-propanediamine under a nitrogen atmosphere (temp. 0°-5° C.) was added dropwise over 7 hours a solution of 80.84 parts of 4-methylbenzenesulfonyl chloride in 1689 parts of dichloromethane. After stirring overnight at 20° C., the reaction mixture was washed with 250 parts of water (3x). The organic layer was separated dried, filtered and evaporated. About 1 gram of the thus obtained product was dissolved in 4-methyl-2-pentanol by heating just below the reflux temperature. The mixture was allowed to cool slowly and at about 30° C. was seeded with the previously obtained crystals. After further cooling to 0° C., the precipitate was filtered off and triturated with 2,2'-oxybispropane. The crystals were filtered off, dried in vacuo, yielding 50.75 parts (52.4%) of (S)-N-2-aminopropyl-4-methylbenzenesulfonamide; mp. 82°-86° C.; [α]D20 =-1.10° (c=1% in methanol) (interm.1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]=O>C(O)=O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH3:31])[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Solvent: O=CO
Product: CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Yield: 95 %

Procedure:
A mixture of (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.5 g, 1.24 mmol), formic acid (10 ml) and 37% formaldehyde (7.5 ml) was heated for 3 hours at reflux temperature and evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate (25 ml) and 1N sodium hydroxide (25 ml). The organic phase was isolated, washed once with water, dried over magnesium sulphate and evaporated in vacuo to give (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-methylpyrrolidine (0.49 g, yield: 95%) as a golden oil.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)[CH3:3].C(O)C.C([O-])([O-])=O.[K+].[K+].[I-].C[N+]1(C)[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>O>[N:6]1[CH:5]=[C:4]([CH:2]([N:1]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH3:3])[CH:9]=[N:8][CH:7]=1
Reactant: C[N+]1(C)CCC(=O)CC1
Reactant: CC(N)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(c1cncnc1)N1CCC(=O)CC1
Yield: 26.2 %

Procedure:
To a stirred mixture of 1.1 g of 5-(1-aminoethyl)pyrimidine (O. Cervinska and P. Malon, Coll. Czechoslov. Chem. Commun. 1977, 42, 3464-72.), 17 mL of ethanol and 1.36 g of K2CO3 heated to reflux was added dropwise over 30 min, a solution of 4 g of 1,1-dimethyl-4 -oxopiperidinium iodide in 70 mL of water. When the addition was complete, the mixture was heated under reflux for an additional 2 h, cooled, basified to pH 9 with K2CO3 and extracted with 5 times with 50 mL portions of methylene chloride. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel, eluting with 90:10 CH3CN:MeOH gave 0.48 g of 1-(1-(5-pyrimidinyl)-ethyl)-4-oxopiperidine as an oil: 1H NMR (400 MHz, CDCl3) 9.14 (s, 1H), 8.78 (s, 2H), 3.8 (q, J=7 Hz, 1H), 2.7-2.9 (m, 4H), 2.45 (m, 4H), 1.5 (d, J=7 Hz, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1.Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([C:14]2([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:12][CH:13]=1
Reactant: ClCCOCCCl
Reactant: N#CCc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 165.3 %

Procedure:
Potassium tert-butoxide (5.48 g, 48.8 mmol) was added to a stirred solution of 2-(3-fluorophenyl)acetonitrile (2.58 mL, 22.2 mmol) in DMF (30 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0° C. before 1-chloro-2-(2-chloroethoxy)ethane (2.86 mL, 24.4 mmol) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was then cooled to 0° C. and quenched with 10% HCl. The aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give the product as an orange oil (7.53 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[C:6]([OH:10])=[CH:7][C:8]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([O:10][CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[C:5]([CH3:11])[CH:4]=1
Reactant: COc1cc(C)c(O)cc1C
Reactant: COC(=O)C(C)(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(OC)cc1C

Procedure:
A 500 mL, 3 neck round bottom flask is charged with 7.6 g (50 mmol) of 4-methoxy-2,5-xylenol, 8.3 g (60 mmol) of anhydrous potassium carbonate 13.4 g (60 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) and 150 mL of acetonitrile. The mixture is stirred mechanically at reflux for 24 hours. The reaction flask and inorganic solids are washed with fresh acetonitrile and the filtrate evaporated. The residue is taken up in diethyl ether and the solution washed with 50 mL of 2N potassium hydroxide solution, brine, dried (magnesium sulfate) and evaporated. The crude product amounts to 16.6 g. Distillation through a short path apparatus first at aspirator pressure and then at 0.5 mm affords 12.9 g of the title compound; infrared spectrum (IR) (C=0) 1732 cm-1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32](O)=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[N:37](CC)CC>C(Cl)Cl.CC#N>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32]([NH2:37])=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: NC(=O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1.25 h

Procedure:
To a solution of the title acid of Example 2 (200 mg) in CH2Cl2 (3 mL) and CH3CN (1 mL) at 0° C. was added Et3N (120 μL) followed by 2-chlorol-methylpyridinium iodide (220 mg). After stirring for 75 mins. at 0° C., an excess of NH3 was slowly bubbled into the mixture and the reaction was allowed to stir at RT for 12 h. It was then diluted with ethyl acetate and washed successively with aq. NH4OAc (x2) and brine. After drying, the organic solution was concentrated and the residue was purified on a column of silica to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.O[C@@H:36]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22]3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C@H:36]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O)cc3)cc2)CC1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O[C@H](Cc4ccccc4)C(=O)OCC)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 48.7 %

Procedure:
To a solution of 4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenol (830 mg, 1.81 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (526 mg, 2.71 mmol) and triphenylphosphine (711 mg, 2.71 mmol) in toluene (1 ml) was added 1,1′-(azodicarbonyl)dipiperidine (684 mg, 2.71 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 560 mg (yield: 48.7%)
Reaction SMILES: [C:1](Cl)(=O)C.[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](=[O:26])[C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)[CH3:6]>CO>[CH3:1][O:24][C:23](=[O:25])[C:22](=[O:26])[CH:21]=[CH:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:5][CH3:6])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: CCOc1cccc(-c2ccc(C=CC(=O)C(=O)O)cc2)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: CCOc1cccc(-c2ccc(C=CC(=O)C(=O)OC)cc2)c1
Yield: 38.4 %

Procedure:
Acetyl chloride (2.0 mL, 28.7 mmol) was slowly added to methanol (10.0 mL) at 0° C. under stirring. A solution of 4-(3′-ethoxy-biphenyl-4-yl)-2-oxo-3-butenoic acid (2.5 g, 8.4 mmol) prepared in Step 2 in methanol (10.0 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 1 hour, additionally at 80° C. for 16 hours, and then filtered at room temperature to give 1.0 g of the titled compound as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[N:12][C:13]([Br:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cccnc2)CC1
Reactant: O=C1CCC(=O)N1Br
Product: CC(=O)N1CCN(c2ccc(Br)nc2)CC1

Procedure:
1-Acetyl-4-(6-bromopyridin-3-yl)piperazine was synthesized from above-mentioned 1-acetyl-4-pyridin-3-ylpiperazine by brominating with N-bromosuccinimide by a method similar to Production Example 86, step 2,
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:31])/[CH:12]=[CH:13]/[CH:14]=[C:15](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)\[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH:33]=1>O1CCCC1>[F:30][C:26]1[CH:25]=[C:24](/[C:15](/[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:29]=[CH:28][CH:27]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1cccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: COc1cccc(/C(=C\C=C\C(=O)NCCCCc2cccnc2)c2cccc(F)c2)c1
Yield: 86.6 %

Procedure:
As in Example 134, a solution of (2E,4E)-5-(3-fluorophenyl)-5-(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.8 g) and 3-pyridinebutanamine (0.650 g) in tetrahydrofuran (20 mL) was stirred for 17 hours at room temperature. The crude amide, isolated in the usual fashion, was purified by HPLC (ethyl acetate) and then crystallized from ether-hexane to furnish 1.6 g of (2E,4E)-5-(3-fluorophenyl)-5-(3-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 55°-60° C. A sample was recrystallized from ethyl acetate-hexane to yield the analytical specimen, mp 58°-60° C. Anal. Calculated for C27H27FN2O2 : C, 75.33; H, 6.32; F, 4.41; N, 6.51 Found: C, 75.31; H, 6.34; F, 4.38; N, 6.47.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:16]([C:18]2[CH:23]=[C:22]([C:24]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[O:28][CH2:27][CH2:26][O:25]3)[CH:21]=[CH:20][C:19]=2[NH2:36])=[O:17])[CH:13]=[CH:14][CH:15]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:16]([C:18]1[CH:23]=[C:22]([C:24]2([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[O:28][CH2:27][CH2:26][O:25]2)[CH:21]=[CH:20][C:19]=1[NH:36][C:1](=[O:3])[CH3:2])=[O:17]
Reactant: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2N)c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2NC(C)=O)c1
Yield: 100 %

Procedure:
Acetic anhydride (13.9 ml) was added to a solution of interm. (5-c) (31.2 g) in toluene (300 ml) and the mixture was stirred and refluxed for 2 hours. The mixture was evaporated till dryness and the product was used without further purification, yielding 36.4 g (100%) of N-[2-(3-methoxybenzoyl)-4-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl]acetamide (interm. 5-d).