Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([PH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]([O:9][C:10](=[O:13])[CH:11]=[CH2:12])[CH3:8]>>[CH2:1]([P:6]([CH2:12][CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:13])[CH2:12][CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:13])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: C=CC(=O)OCC
Reactant: CC(C)CCP
Product: CCOC(=O)CCP(CCC(=O)OCC)CCC(C)C

Procedure:
Using the procedure of Example 1, isopentyl phosphine is reacted at 70°-90° C. with ethylacrylate to give isopentylbis(carbethoxyethyl)phosphine. The latter is oxidized with hydrogen peroxide and hydrolyzed with aqueous dilute hydrochloric acid to give the corresponding acid, isopentylbis(β-carboxyethyl)phosphine oxide.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:41][CH:42]1[O:46][C:43]1([CH3:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:41][CH:42]2[O:46][C:43]2([CH3:45])[CH3:44])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OC1CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC1COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (51.6 mg, 0.0947 mmol), sodium hydride (95%, 21.1 mg, 0.879 mmol) and 1-bromo-2,3-epoxy-3-methylbutane (91.2 mg, 0.553 mmol) in tetrahydrofuran (1 ml) was stirred at room temperature for 20 min. and refluxed under heating for 20 min. The reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and the thus obtained residue was purified by preparative thin layer chromatography (1 sheet (0.5 mm thickness), hexane:ethyl acetate=10:1, developed twice) to give the titled compound (48.3 mg, 81%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24](O)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:30]=[C:31]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:32]=[CH:33][C:34]=1[F:35]>>[F:28][C:29]1[CH:30]=[C:31]([CH:36]2[CH2:41][CH2:40][N:39]([C:24]([C:13]3[CH:12]=[N:11][C:10]4[N:9]([N:8]=[CH:7][C:6]=4[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14]=3[NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[O:25])[CH2:38][CH2:37]2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Reactant: Fc1ccc(C2CCNCC2)cc1F
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc12
Yield: 27.9 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (150 mg, 0.42 mmol) obtained in step 2 and 4-(3,4-difluorophenyl)piperidine hydrochloride (WO2004/069798, 127 mg, 0.55 mmol), the title compound (63 mg, 28%) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].[Cl:8][C:9]1[C:14]([CH3:15])=[C:13](Cl)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:9]1[C:14]([CH3:15])=[C:13]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:12]=[CH:11][N:10]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(Cl)c1C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
0.32 g of sodium hydride (60% oil suspension) was suspended in 12 ml of tetrahydrofuran. 2 ml of tetrahydrofuran solution of 0.43 g of 2-butyn-1-ol was added dropwise at room temperature therein slowly, and the mixture was stirred for 20 minutes. Into the mixture was added dropwise 2 ml of tetrahydrofuran solution of 1 g of 4,6-dichloro-5-methylpyrimidine at 0° C. slowly, and stirred for 2 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.1 g of 4-chloro-6-(2-butynyloxy)-5-methylpyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:8]([NH:10][C:11](=[O:19])[CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=1)([O-])=O>CCO.O1CCOCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:8]([NH:10][C:11](=[O:19])[CH2:12][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1NC(=O)CN1CCCCC1
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)c1ccc(N)cc1NC(=O)CN1CCCCC1

Procedure:
N-(5-Nitro-2-tert-butylpheny)-2-piperidin-1-yl-acetamide (1.77 g, 5.5 mmol) was dissolved in EtOH (100 mL) and 1,4-dioxane (10 mL). The solution was degassed under vacuum with stirring. A catalytic amount of 5% Pd/C was added (as a slurry in EtOH). The mixture was degassed again, then the reaction vessel was charged with H2 gas (balloon) and stirred overnight at RT. The reaction was filtered through Celite® with MeOH and the filtrate was concentrated under reduced pressure. The recovered material was eluted through a column of silica gel with a 5 to 40% (90:10:1 CH2Cl2:MeOH:NH4OH(aq)) to CH2Cl2 linear gradient giving a brown foamy solid. MS: 290 (M+1). Calc'd. for C17H27N3O—289.42.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[C:19]([Cl:22])[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[C:19]([Cl:22])[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9a was dissolved in a 4 M solution of HCl in dioxane (60 mL). The solution was stirred at room temperature for 3 h and the solvent was removed. The residue was taken up in 200 mL of DCM and 40 mL of toluene and cooled to 0° C. Isopropyl chloroformate (60 mL of a 1 M solution in toluene, 1.2 eq) and diisopropylethylamine (24 mL) were added. The mixture was stirred for 36 h, washed with 1 M HCl (3×100 mL), 100 mL of water and 100 mL of brine. The solvent was evaporated and the residue taken up in 50 mL of hexane, cooled at 0° C. and stirred for 2 h to give a precipitate which was filtered and washed with hexane. 2.89 g of 9b were obtained. The filtrate was concentrated and recrystallized with IPA. Some light yellow crystals were obtained, filtered and washed with IPA to give 3.38 g of 9b. The filtrate was concentrated and purified on silica gel (eluent: 20% ethyl acetate in hexane) to give 2.2 g of 9b. Total yield of 9b: 8.47 g (54%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6](O)=[O:7])#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[BH4-].[Na+]>O1CCCC1>[F:12][C:11]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a solution of 3-cyano-4-fluorobenzoic acid (1.00 g, 6.06 mmol) in tetrahydrofuran (THF) (20 mL) was added dropwise CDI (1.47 g, 9.08 mmol) at 0° C. After at room temperature for 30 min, sodium borohydride (0.687 g, 18.2 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h, quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic part was separated, dried over Na2SO4, filtered and concentrated. Purification via flash column (petroleum ether/ethyl acetate=10/1) afforded the title product (350 mg).
Reaction SMILES: C(OC(=O)[C@@H](OC)CC1C=CC(OCC(O)=O)=CC=1)C.C1(N)CCC1.[CH2:26]([O:28][C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C@@H:41]([C:43](=[O:60])[NH:44][CH2:45][CH2:46][C:47]2[CH:52]=CC(OC3C=CC=CC=3)=CC=2)C)=[CH:36][CH:35]=1)[C:30]([OH:32])=[O:31])C>>[CH:45]1([NH:44][C:43]([CH2:41][O:40][C:37]2[CH:36]=[CH:35][C:34]([CH2:33][C@H:29]([O:28][CH3:26])[C:30]([OH:32])=[O:31])=[CH:39][CH:38]=2)=[O:60])[CH2:46][CH2:47][CH2:52]1
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: NC1CCC1
Product: CO[C@@H](Cc1ccc(OCC(=O)NC2CCC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and cyclobutylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C16H21NO5 [M−H]−: 306.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8]1)=[O:6].CCN(C(C)C)C(C)C.[Br:34][CH2:35][C:36](Br)=[O:37]>C(Cl)Cl>[Br:34][CH2:35][C:36]([N:10]1[CH2:11][CH2:12][N:7]([C:5](=[O:6])[C:4]2[CH:21]=[C:22]([CH3:24])[CH:23]=[C:2]([CH3:1])[CH:3]=2)[CH2:8][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)=[O:37]
Reactant: Cc1cc(C)cc(C(=O)N2CCNC(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CBr)C(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a cooled solution of (+,-)-[3,5-dimethylbenzoyl]-3-(3,4-dichlorophenyl)piperazine (11.5 g, 31.65 mmol) in CH2Cl2 (200 mL) at 0° C. was added Hunig's base (4.5 g, 35 mmol) and bromoacetyl bromide (6.4 g, 31.65 mmol). The solution was stirred at 0° C. overnight under N2. After completion the reaction was diluted with CH2Cl2 (400 mL) and washed with brine (300 mL, 2×), dried over MgSO4, filtered and concentrated. The crude material was purified by flash grade silica gel chromatography, eluting with 2% [NH4OH/MeOH (1:9)]/98% CH2Cl2 to give the title compound as a light yellow solid (7.1 g, 47.3%), m.p. 77-79° C., FAB MS [M+1]+35Cl,79Br482.9, 484.9.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][NH:14][C:15](=[O:25])[CH2:16][NH:17]C(=O)OC(C)(C)C)=[C:11]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][N:30]=[CH:29]3)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1.C(OCC)C>[CH2:1]([N:8]1[C:12]([CH2:13][NH:14][C:15](=[O:25])[CH2:16][NH2:17])=[C:11]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][N:30]=[CH:29]3)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCC(=O)NCc1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Example 143C (66 mg, 0.217 mmol), N-(tert-butoxycarbonyl)-glycine (39 mg, 0.223 mmol), and HATU (85 mg, 0.224 mmol) were combined in methylene chloride (2.5 mL). Diisopropylethylamine (150 μL, 0.865 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-6% methanol in dichloromethane to afford tert-butyl 2-((1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl)methylamino)-2-oxoethylcarbamate. This carbamate was dissolved in tetrahydrofuran (2 mL) and 0.5 mL of a solution of 1 N hydrochloric acid in diethyl ether was added and the mixture was stirred for 20 minutes at room temperature. The solvents were removed under reduced pressure, and diethyl ether was added to the mixture and stirred at room temperature overnight. The solvent was decanted, and the resulting residue was dried under a stream of nitrogen to afford the title compound as a hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 13.21 (s, 1H) 9.02 (t, J=5.09 Hz, 1H) 8.11-8.16 (m, 2H) 8.06 (s, 2H) 7.75-7.82 (m, 1H) 7.64 (d, J=8.82 Hz, 1H) 7.30-7.45 (m, 3H) 7.23-7.31 (m, 2H) 5.72 (s, 2H) 4.57 (d, J=5.09 Hz, 2H) 3.41 (q, J=5.76 Hz, 2H). MS (ESI+) m/z 362.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:20])[C:11]=1[O:21]COC)=[O:9])([CH3:6])[CH3:5].B(Cl)(Cl)Cl>ClCCl.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:25])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:20])[C:11]=1[OH:21])=[O:9])([CH3:6])[CH3:5]
Reactant: COCOc1c(C(=O)NC(C)(C)C(=O)OC)ccc2c(F)cccc12
Agent: ClB(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)c1ccc2c(F)cccc2c1O
Temperature: -67.5 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a stirred solution of 0.107 g of 2-{[5-fluoro-1-(methoxymethoxyl)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 3 ml of dichloromethane at −65 to −70° C. was added by syringe 0.344 ml of 1M BCl3 in dichloromethane. The mixture was stirred for 10 minutes at −65 to −70° C. after which it was allowed to warm to RT and stirred at RT for 0.5 h. The mixture was poured into brine, extracted twice with ethyl acetate, dried, filtered and concentrated to an oil, which was chromatographed on silica gel eluting with ethyl acetate/dichloromethane/heptane to provide 0.088 g of 2-{[5-fluoro-1-(hydroxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][CH2:9][C:10]1[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1.ClC1[CH:26]=[N:27]C=C(Cl)C=1CC(C1C2CC(C)(C)OC=2C(OC)=CC=1)O.C[Si](C#N)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:26]([CH:9]([C:10]1[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1)[CH2:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])#[N:27]
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Reactant: COc1ccc(CCc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C#N)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
A solution (70 ml) obtained in Step A of Example 45 of Compound 45a (2.5 g) in methylene chloride was cooled to 0° C. and then trimethylsilylcyanide (5.4 ml) and boron trifluoride ether complex (2.5 ml) were successively added thereto, followed by stirring at 0° C. for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 63 (0.61 g, 23.8%) as pale-yellow crystals.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C1(C)C=CC=CC=1>[CH3:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccccc1
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: CC=Cc1ccccc1
Yield: 90 %

Procedure:
Compounds of Formula 1 readily catalyse the dehydration of olefins. Standard conditions were used to conduct these reactions. For example heating cyclohexanol in the presence of compounds of Formula 1 where R and R1 are hydrogen or R is hydrogen and R1 is a C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, aryl or C1-8 alkylaryl fragment gave the desired cyclohexene. In a similar fashion treatment of 1-phenyl-1-propanol in toluene with catalysts of Formula 1 where R and R1 are hydrogen or R is hydrogen and R1 is a C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, aryl or C1-18 alkylaryl fragment in toluene at 75° C. gave β-methyl styrene in greater than 90% yield. An advantage of this procedure is that the catalyst can simply be filtered off and reused without any apparent reduction in activity.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:6][C:7](=[O:26])[N:8]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[CH3:2]>O1CCOCC1.O.Cl>[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:6][C:7](=[O:26])[N:8]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCc1cc2c(c(Sc3ccccc3)cc(=O)n2Cc2ccc(C(=O)OC)cc2)c(CC)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc2c(c(Sc3ccccc3)cc(=O)n2Cc2ccc(C(=O)O)cc2)c(CC)n1
Yield: 61.9 %

Procedure:
Methyl 4-[(5,7-diethyl-2-oxo-4-phenylthio-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]benzoate (200 mg) was dissolved in a mixture of dioxan (4 ml), water (1 ml) and concentrated hydrochloric acid (1 ml) and the mixture was heated at reflux for 4 hours. Volatile material was then removed by evaporation and toluene was added to the residue. Volatile material was again removed by evaporation. The solid residue was recrystallised from ethanol/ether to give 4-[(5,7-diethyl-2-oxo-4-phenylthio-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]benzoic acid (120 mg) m.p. 260°-262° C.; NMR (d6 -DMSO): 1.19(t, 3H), 1.51(t, 3H), 2.98(q, 2H), 3.72(q, 2H), 5.56(s, 2H), 5.91(s, 1H), 7.35(d, 2H), 7.47(s, 1H), 7.6-7.8(complex m, 5H), 7.88(d, 2H), mass spectrum (CI, ammonia): 445(M+H)+ ; microanalysis, found: C, 64.5; H, 5.4; N, 5.9%; C26H24N2O3S requires: C, 64.9; H, 5.2; N, 5.8%.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:11](=[O:46])[CH2:12][N:13]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[C:1]([NH:9][CH:10]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:11]([OH:46])[CH2:12][N:13]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCN(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(NCCCCN(CC(O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
The ester product from part (f) is treated with sodium borohydride according to the procedure of Example 1(f) to yield 1-[[[3-(benzoylamino)-2-hydroxy-4-phenylbutyl][[[(phenylmethoxy)carbonyl]amino]butyl]amino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>CCOC(C)=O>[Cl:20][CH2:21][C:22]([N:6]([CH2:5][C:4]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)=[O:23]
Reactant: COc1ccc(CNc2cccc(O)c2)c(OC)c1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C(=O)CCl)c2cccc(O)c2)c(OC)c1

Procedure:
To a solution of the product from Step I (1 equiv) in 1:1 EtOAc-saturated NaHCO3 solution at 0° C. is added chloroacetyl chloride (3 equiv) dropwise. After completion, the layers a separated, and the organic solution is washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH2:11]([C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nc(Cc2ccccc2)no1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-Benzyl-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (360 mg, 1.6 mmol) and lithiumhydroxide-hydrate (65 mg, 1.6 mmol) in 10 mL MeOH and 5 mL water was stirred at room temperature for 1 h. The mixture was evaporated in vacuo to yield the crude product which was used in the next step without further purification.
Reaction SMILES: C[C@H]([O:10][C:11](=[O:31])[C@@H:12]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)C(=O)N1CCCC1.O.Cl>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[C:11]([OH:31])=[O:10])=[CH:29][CH:28]=1
Reactant: C[C@H](OC(=O)[C@H](Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1)C(=O)N1CCCC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To the residue prepared in STEP C above was added water (10 g) and a 36-38% HCl solution (60 g). The resulting biphasic mixture was stirred at 80° C. for between about 4 and about 8 hours (till completion of the hydrolysis as determined by HPLC) The resulting mixture was then cooled to 60° C. and toluene (125 mL) added. The aqueous phase was discarded and the organic phase washed with water (50 mL). Toluene (about 80 g) was removed by distillation to dry the organic phase. The resulting solution was then cooled to 70° C. and petrol ether 60/90 (250 mL) was added. The resulting solution was further cooled to 37° C. and seeded. The resulting mixture was stirred for 30 minutes at 37° C., the resulting suspension then cooled to 0° C. over about 2.5 hours. The precipitated crystals were filtered off and washed with a mixture of toluene (5 mL 0 and petrol ether 60/90 (9 mL) to yield wet product. The wet product was dried in a vacuum at 30° C. to yield the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][S:10][CH3:11])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].N1([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C=CN=C1>CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([S:10][CH3:11])[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)n1ccnc1
Reactant: CSCC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COC(C)(C)C
Product: CCOC(=O)C(=O)C(SC)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 15 g of 1-(4-chlorophenyl)-2-(methylthio)ethanone (2) in 70 mL of MTBE is added a solution of 86 mL of lithium hexamethyldisilazide (LiHMDS) under nitrogen gas, while keeping the temperature at −40° C. After stirring for 1.5 hours at this temperature, 14.4 g of ethyl 2-(1H-imidazol-1-yl)-2-oxoacetate (3) in 50 mL MTBE are added at 0° C., and the mixture is left stirring overnight at room temperature. The reaction solution was filtered off and the filtrate was suspended in 80 mL of MTBE. 50 mL of 6N HCl are added to the suspension. After separation of the phase by settling, the ether phase is washed 4 times with water and then concentrated under reduced pressure to obtain 22 g (73 mmol) of the title compound.