Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 4-hydroxybenzaldehyde, Compound 63 (10.00 g, 81.89 mmol) and imidazole (16.72 g, 245.59 mmol) in dry DMF (30 mL) cooled in an ice-water bath (0° C.) was added a solution of t-butyldimethylsilyl chloride (18.55 g, 123.07 mmol) in dry DMF (50 mL) followed by stirring at room temperature for 1 hour. The reaction mixture was then quenched with brine (60 mL) and extracted with Et2O (60 mL×3). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 5 percent EtOAc in hexane) to give Compound 64 (19.02 g, 98 percent): pale yellow oil; Rf=0.44 (10 percent EtOAc in hexane); IR (neat) 2956, 2931, 1698, 1598, 1273, 1156 cm−1; 1H NMR (300 MHz, CDCl3) δ9.89 (s, 1H), 7.81-7.77 (AA′BB′, 2H), 6.96-6.92 (AA′BB′, 2H), 0.98 (s, 9H), 0.25 (s, 6H); 13C NMR (75 MHz, CDCl3) δ190.9, 161.5, 131.9, 130.4, 120.5, 25.5, 18.2, −4.4; MS (+CI) m/z (relative intensity) 237 (M+H+, 100).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[CH:19][CH:18]=2)[CH2:8][CH2:7][CH2:6]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[CH:19][CH:18]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CN=[N+]=[N-])c3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CN)c3ccccc32)cc1
Reaction time: 6 h
Yield: 47.2 %

Procedure:
5-Azidomethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.27 g) is suspended in ethanol (50 ml) and the mixture is subjected to catalytic hydrogenation at room temperature under 3 kg/cm2 for 6 hours by using 10% Pd-C (27 mg). The catalyst is removed by filtration with celite and the filtrate is distilled off and the resulting residue is recrystallized from ethanol to give 5-aminomethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.12 g) as colorless needles, m.p. 233-235° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)([OH:20])[C:14]2[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=2)=[CH:9][C:8]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:29].CCOC(C)=O.[OH-].[Na+]>C(O)(=O)C>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)([OH:20])[C:14]2[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=2)=[CH:9][C:8]=1[C:28](=[O:29])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(N)c(C(=O)c2cccc(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(NC(=O)CBr)c(C(=O)c2cccc(Cl)c2)c1
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
Bromo-acetyl bromide (0.0138 mol) was added slowly at 5° C. to a mixture of (±)-[2-amino-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone (prepared as described in WO 97/21701) (0.0137 mol) in acetic acid (60 ml). The mixture was stirred for 15 min and poured out into EtOAc and NaOH 0.5N. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 7.3 g (93%) of 2-bromo-N-[2-(3-chlorobenzoyl)-4-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-acetamide (intermediate 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:11]([CH2:26][OH:27])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:11]([CH2:26][O:27][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: COc1ccc(CN2CCN(c3cc(Cl)cc(Cl)c3)CC2CO)cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN2CCN(c3cc(Cl)cc(Cl)c3)CC2COCc2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
In a manner similar to Preparation 19, react 4-(3,5-dichlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-2-piperazinemethanol with sodium hydride and 1-(chloromethyl)-4-nitrobenzene to give the titlecompound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[N:10][OH:11])[CH3:9])[C:5]([C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[CH:4][N:3]=1>C(Cl)(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[N+:10]([O-:11])=[C:8]2[CH3:9])=[CH:4][N:3]=1
Reactant: CC(=NO)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(F)cc1-c1cc2cnc(Cl)cc2c(C)[n+]1[O-]
Temperature: 60 °C
Yield: 57.8 %

Procedure:
A mixture of 1-(2-chloro-5-((5-fluoro-2-methylphenyl)ethynyl)pyridin-4-yl)ethanone oxime (700 mg, 2.0 mmol) and silver nitrate (˜10 wt. % on silica gel, +230 mesh, 825 mg, 0.5 mmol) in chloroform (12 mL) was heated at 60° C. for 1 hour. The cooled reaction mixture was treated with silica gel (2 g), concentrated in vacuo, and purified by flash chromatography (silica, 12 g, ISCO, 0-90% ethyl acetate in heptane) to afford the title compound as pale yellow solid (350 mg, 50% over two steps), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: OCc1c(-c2ccc(Cl)cc2)ccnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a solution of 2-chloro-4-(4-chlorophenyl)nicotinic acid (2.4 g) in tetrahydrofuran (60 ml) was added thionyl chloride (3.2 g), and the mixture was heated under reflux for 3 hrs. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (60 ml). Sodium borohydride (1.5 g) was added by small portions at 0° C., and the mixture was allowed to warm gradually and stirred at room temperature for 2 hrs. Water was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.9 g) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C=C>CS(O)(=O)=O>[C:5]([O:4][CH2:1][CH2:2][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH2:8])(=[O:7])[CH3:6]
Reactant: C=CCCCCCCCCO
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Product: C=CCCCCCCCCOC(C)=O
Temperature: 30 °C
Reaction time: 18 h

Procedure:
Acetic anhydride, 54.0 grams (0.52 mole), was stirred, and one drop (catalyst) of methanesulfonic acid was added. To this was cautiously added dropwise 50.0 grams (0.32 mole) of 9-decen-1-ol. The addition caused an exothermic reaction which warmed the reaction mixture to 30° C. Upon completion of addition, the reaction mixture was warmed to 60° C. where it stirred for 18 hours. The reaction mixture was cooled and poured into 600 ml of ice/water. The mixture was stirred until the ice melted, and then the layers were separated. The aqueous layer was washed with one 300 ml portion of diethyl ether. The wash was combined with the organic layer, and the combination was washed repeatedly with aqueous 1N sodium hydroxide until the organic layer was basic. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure, yielding 57 grams of 9-decenyl acetate; b.p. 93°-95° C./1.5 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH3:1].[CH2:2]([N:4]([CH2:22][CH3:23])[C:5](=[O:21])[C:6]1([S:13][C:14](=[O:20])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=[CH:10][CH:9]=[N:8][CH:7]1F)[CH3:3]>CO>[CH2:2]([N:4]([CH2:22][CH3:23])[C:5](=[O:21])[C:6]1([S:13][C:14](=[O:20])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=[CH:10][CH:9]=[N:8][CH:7]1[NH2:1])[CH3:3]
Reactant: N
Reactant: CCN(CC)C(=O)SC1(C(=O)N(CC)CC)C=CC=NC1F
Solvent: CO
Product: CCN(CC)C(=O)SC1(C(=O)N(CC)CC)C=CC=NC1N
Temperature: 100 °C
Yield: 47 %

Procedure:
43 g of ammonia are injected into an autoclave with a solution of 40.2 g (122 mmol) of N,N-diethyl-3-(diethylcarbamoylthio)-2-fluoronicotinamide in 350 g of methanol, and the mixture is heated at 100° C. for 10 hours. It is then concentrated in vacuo and chromatographed on silica gel using ethyl acetate. Subsequent recrystallization from Et2O/hexane gives 18.7 g (47%) of yellowish crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=[CH:6]2.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[C:4]([C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=[CH:6]2
Reactant: COC(=O)c1cccc2c(C(F)(F)C(F)(F)F)c(OC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(C(=O)O)cccc2c1C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 79.2 %

Procedure:
The 6-methoxy-5-(pentafluoroethyl)-1-naphthalenecarboxylic acid, methyl ester (2.82 g, 8.44 mmol), methanol (50 ml) and 2N aqueous sodium hydroxide (8.43 ml) were stirred at room temperature overnight. The mixture was cooled to 0° C., neutralized with 1N aqueous hydrochloric acid to pH 8 and the methanol evaporated off. Water was added to the residue and neutral impurities were removed by extraction with ethyl acetate. The aqueous layer was cooled to 0°, acidified to pH 1-3 with 1N aqueous hydrochloric acid, the product extracted with ethylacetate, the extract washed with brine and dried over anhydrous MgSO4. Evaporation gave 2.14 g of crude 6-methoxy-5-(pentafluoroethyl)-1-naphthalene carboxylic acid which was used, without further purification, in the next step. nmr (DMSO): δ4.05 (s, 3H, OCH3); δ8.0 (m, 4H, Har); δ9.1 (d, 1H, J=9, Har) ms: m/e 320 (M+), 303, 251, 203.
Reaction SMILES: [OH:1][C@H:2]1[C:12]2[C@@H:6]([C@H:7]3[N:10]([C:11]=2[C:13]([O-:15])=[O:14])[C:9](=[O:16])[C@@H:8]3[C@H:17]([OH:19])[CH3:18])[O:5][CH2:4][CH2:3]1.[Na+].O[C@@H:22]([C@@H:24]1[C@@H]2N(C(C([O-])=O)=C3[C@@H]2CCC[C@@H]3CCOC(=O)C2C=CC=NC=2)C1=O)[CH3:23].[Na+]>C1(C)C=CC=CC=1>[OH:1][C@H:2]1[C:12]2[C@@H:6]([C@H:7]3[N:10]([C:11]=2[C:13]([O:15][CH2:24][CH:22]=[CH2:23])=[O:14])[C:9](=[O:16])[C@@H:8]3[C@H:17]([OH:19])[CH3:18])[O:5][CH2:4][CH2:3]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C3[C@@H](CCOC(=O)c4cccnc4)CCC[C@@H]3[C@H]12
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C3[C@H](O)CCO[C@@H]3[C@H]12
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C2[C@H](O)CCO[C@@H]2[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Sodium (5S,6S, 7S, 11R)-11-hydroxy-5-[(R)-1-hydroxyethyl]-4-oxo-8-oxa-3-azatricyclo[5.4.0.03,6 ]undec-1-ene -2-carboxylate ##STR54## (1) A solution of the compound obtained in Reference Example 29 (220 mg) in toluene (5 ml) was stirred at 50° C. for 4 hours and, then, at 80° C. for 8 hours. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (70-230 mesh, 20 g; ethyl acetate-hexane =1:2) to give allyl (5S,6S,7S,11R)-11-hydroxy-5-[(R) -1-hydroxyethyl]-4-oxo-8-oxa-3azatricyclo[5.4.0.03,6 ]undec-1-ene-2-carboxylate (R2 =CH2CH=CH2) (93 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][CH2:14][C@H:15]([OH:26])[C:16]([NH:18][C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)=[O:17])[CH3:12].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:34]1[C:30]2[N:31]=[CH:32][N:33]=[C:28]([O:26][C@@H:15]([CH2:14][O:13][CH2:11][CH3:12])[C:16]([NH:18][C:19]3[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[O:17])[C:29]=2[CH:36]=[N:35]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)Nc1cnc(C)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1.398 mL, 1.40 mmol) was added dropwise to a stirred solution of (S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate H1) (315 mg, 1.40 mmol) in anhydrous THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (371 mg, 1.40 mmol) in dry THF (3 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 3 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography with EtOAc to afford (2S)-2-[1-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyrazin-2-yl)propanamide (460 mg, 72%).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)oxy)methyl)phenyl)propanoate (253 mg) in THF (4.0 mL) and methanol (2.0 mL) was added 1N aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was neutralized with 1N hydrochloric acid (4.0 mL) at room temperature, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (220 mg) as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH:3]=1
Reactant: NCCCO
Reactant: Clc1cc(-c2ccc3ccccc3c2)nc2ccccc12
Product: OCCCNc1cc(-c2ccc3ccccc3c2)nc2ccccc12

Procedure:
A solution of 4-chloro-(2-napthyl) quinoline (420 mg, 1.4 mmol) in 3-aminopropanol (1.0 mL) was heated to 130° C. for 1.5 h under a nitrogen atmosphere. Treatment with water (2 mL) was followed by extraction of the mixture with AcOEt, drying of the extract with MgSO4, and concentration to give a residue of crude N-(3-hydroxypropyl)-2-(2-naphthyl)quinolin-4-amine. This compound was purified by silica gel chromatography eluting with CH2Cl2/MeOH (5:1) followed by crystallization of its hydrobromide salt; yield 82% of C22H20N2O.HBr.H2O; mp 230-235° C. Anal. Calcd for C22H20N2O.HBr.H2O: C, 61.82: H, 5.43; N, 6.55. Found: C, 61.98; H, 5.28; N, 6.49.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18][O:19][C:20]=3[CH3:21])[N:13]=[CH:12]2)=[CH:7][CH:6]=1)C.O.[OH-].[Li+]>C1COCC1.O>[CH3:21][C:20]1[O:19][N:18]=[C:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]=1[C:14]1[N:13]=[CH:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=2)[CH:15]=1
Reactant: CCOC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Yield: 99.9 %

Procedure:
To a solution of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid ethyl ester (1.50 g, 4.0 mmol) in THF (20 mL) was added a solution of lithium hydroxide monohydrate (0.5 g, 12 mmol) in water (10 mL). The resulting mixture was concentrated, acidified and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and evaporated to afford the title compound (1.38 g, 99%) which was obtained as a light yellow solid. MS m/e=346.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([CH:6]1[CH2:15][C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:7]1)=[O:5])[CH3:2].Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[CH:24][CH:23]=1.S(=O)(=O)(O)O>C(O)C>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([CH:6]1[C:15]2[C:26]3[C:25](=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=3)[NH:28][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(NN)cc1
Reactant: CCN(CC)C(=O)C1CC(=O)c2ccccc2S1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCN(CC)C(=O)C1Sc2ccccc2-c2[nH]c3ccc(OC)cc3c21
Yield: 57.3 %

Procedure:
To a solution of (+−)-4-Oxo-thiochroman-2-carboxylic acid diethyl amide (50) (1.32 g, 5.0 mmol) and 4-methoxyphenyl hydrazine hydrochloride (0.87 g, 5.0 mmol) in ethanol (10 ml) was added concentrated sulphuric acid (0.73 ml, 1.35 g, 13.8 mmol) under nitrogen. The reaction mixture was heated under reflux for 24 h. After cooling, the reaction mixture was filtered, the solid washed with ethanol, dried in vacuo (45° C.) to give the title compound (51) (1.05 g, 57%) as a pale yellow solid. The structure was confirmed by 13C NMR (75 MHz, DMSO-d6) δ 10.5, 12.7, 32.7, 37.9, 39.5, 53.0, 97.6, 103.3, 109.87, 109.92, 120.3, 123.5, 123.8, 124.3, 124.7, 124.9, 127.8, 129.4, 131.8, 151.3, 166.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23](Br)=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.[CH2:31]([Sn](CCCC)(CCCC)C#CC)[CH2:32][CH2:33]C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:31]#[C:32][CH3:33])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2ccc(Br)c(C(F)(F)F)c2)cn1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC#Cc1ccc(NC(=O)c2cccnc2NCc2ccc(OC)nc2)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A stirred solution of 2-[(6-Methoxypyrid-3-yl)methylamino]-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (Example 24; 0.96 g, 2.0 mmol) in dry toluene (50 mL) is purged with argon for 20 minutes at 40° C. Tributyl-l-propynylstannane (1.0 g, 2.4 mmol) and tetrakis-(triphenylphosphine)palladium (0) (60 mg) are then added and the resulting mixture is heated at 100° C. for 30 hours under an argon atmosphere. The mixture is then cooled, treated with an aqueous solution of sodium hydroxide (20 mL of 0.1 M) and purged with air for 2 hours. The resulting mixture is then diluted with ethylacetate (200 mL). The orgainic phase is then sequentially washed with water (2×40 mL) and saturated aqueous sodium chloride (1×40 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 50% ethyl acetate in hexane and recrystallised from ether-hexane to give the tite compound as a pale-yellow crystalline solid, m.p. 109-111° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:2][O:1][C:27](=[O:28])[NH:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CO
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1COC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R,5S)-4-hydroxymethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (108 mg) in pyridine (0.5 ml) was added phenyl isocyanate (0.1 ml) and the mixture was stirred at room temperature for 30 minutes. Water (1 ml) was added and extracted with ether and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the crude product was purified with preparative TLC (hexane:ether=1:1) to give (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-phenylcarbamoyloxymethyl-1,3-dioxane (140 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]#[N:20])([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.O1CCC[CH2:22]1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:8]([C:19]#[N:20])([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:14][CH2:15][C:16]1=[O:18])([O:13][CH3:22])=[O:12]
Reactant: C1CCOC1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(F)cc2)CCC1=O
Yield: 93 %

Procedure:
To a solution consisting of 42.71 gm. (0.139 mole) of the dimethyl ester of 4-(p-fluorophenyl)-4-cyanopimelic acid (prepared in Part A, above) and 900 ml. tetrahydrofuran is added 31.3 gm. (0.28 mole) potassium tert-butoxide. This reaction mixture is heated at the reflux temperature for four and one half (41/2) hours. It is allowed to cool. It is then chilled in ice and 225 ml. of 2.5 N aqueous acetic acid is added. The organic layer that forms is recovered and diluted with 750 ml. benzene. The benzene:tetrahydrofuran solution is washed successively with sodium bicarbonate, with water, and finally with brine. The solvents are then removed by evaporation under reduced pressure to give 35.6 gm. (93% yield) of 2-carbomethoxy-4-cyano-4-(p-fluorophenyl)cyclohexanone as a gum.