Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][O:6][N:7]=[C:8]([O:10][CH2:11][CH3:12])[CH3:9].[CH3:14][NH2:15]>CO>[CH2:11]([O:10][C:8](=[N:7][O:6][CH2:5][CH2:4][C:3](=[O:2])[NH:15][CH3:14])[CH3:9])[CH3:12]
Reactant: CCOC(C)=NOCCC(=O)OC
Reactant: CN
Solvent: CO
Product: CCOC(C)=NOCCC(=O)NC
Temperature: 60 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of a known compound, 3-(1-ethoxyethylideneaminooxy)-propanoic acid methyl ester (CAS No. 97164-30-2, 41.3 g, 0.218 mol) in methanol (150 ml) was added methylamine (40% solution in methanol, 200 ml) at room temperature, and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give N-(2-methylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (41.0 g, 100%).
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl(O)(=O)(=O)=[O:22].FC(F)(F)C(O)=O>ClCCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:22])[CH2:17][OH:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)c1ccc(OCC(O)CO)cc1
Temperature: 70 °C
Yield: 66 %

Procedure:
2-(4-benzoylphenoxymethyl)oxirane (10.0 g; 39.3 mmol) was dissolved in 1,2-dichloroethane (100 mL). To the solution was charged water (100 mL), 1 M aqueous perchloric acid (25 mL), trifluoroacetic acid (5 mL) and tetrabutylammonium hydrogensulfate (1.336 g; 3.93 mmol). The biphasic reaction mixture was stirred vigorously and heated to 70° C. for 6 h. The reaction was cooled to ambient temperature, diluted with dichloromethane (100 mL) and the organic phase was separated. The aqueous phase was further extracted with dichloromethane (50 mL). The solvent were evaporated to give a white solid. Recrystallisation from 1,2-dimethoxyethane/isopropylalcohol provided the desired 3-(4-benzoylphenoxyl)propane-1,2-diol as a white solid (7.05 g; 66% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=2[CH:16]=[C:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[N:11]1([C:14]2[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=2[CH2:16][CH:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=C1NCCC1=Cc1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1NCCC1Cc1ccccc1N1CCNCC1
Yield: 80.8 %

Procedure:
A mixture of 25 g of benzylpiperazine (1) and 10 g of 2-fluorobenzaldehyde (2) were allowed to react in refluxing dioxane/water (1:2, 90 mL total volume) for 24 hours in the presence of 17 g K2CO3. The resultant reaction mixture was allowed to cool to room temperature, was extracted with methylene chloride and the organic layer was then washed with water, 5% hydrochloric acid, brine, and was then dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (5:1 hexanes-ethyl acetate) afforded 20 g of the benzaldehyde 3 in 89% yield; MS (AP/CI) observed: 281.1 (M+H)+ (100%). The benzaldehyde 3 (8 g) was subsequently allowed to react with 7.3 g of 1-acetyl-pyrrolidin-2-one (4) in the presence of 4.6 g of NaH (60% in mineral oil) at 0° C. for 1 hour followed by warming to room temperature and stirring for 2 hours. After quenching carefully with methanol at 0° C., the solvent was removed in vacuo, the residue was diluted with water, was extracted with methylene chloride and the organic extracts were washed with brine and were dried over magnesium sulfate and were filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40:1 chloroform-methanol) to provide 7.9 g of 3-[2-(4-benzyl -piperazin-1-yl)-benzylidene]-pyrrolidin-2-one (5) in 80% yield; MS (AP/CI) observed: 348.1 (M+H)+, 100%. Hydrogenation of 6.3 g of 5 with 1.5 g of Pd/C in 100 mL of methanol under 50 p.s.i. of pressure at 60° C. provided 3.8 g (82% yield) of 3-(2-piperazin-1-yl-benzyl)-pyrrolidin-2-one (6) following filtration, removal of solvent in vacuo, and purification by silica gel chromatography (30:1:0.3 chloroform-methanol-ammonium hydroxide); MS (AP/CI) observed: 260.1 (M+H)+, 100%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[C:12]1([S:18]([N:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(COC)OC.CN(C)C=O>[CH3:9][O:8][C:6]1[N:5]=[C:4]([S:10][CH3:11])[N:3]=[C:2]([C:23]2[C:24]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:21]([S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)(=[O:20])=[O:19])[CH:22]=2)[CH:7]=1
Reactant: COc1cc(Cl)nc(SC)n1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(SC)n1
Temperature: 85 °C

Procedure:
A mixture of 4-chloro-6-methoxy-2-(methylthio)pyrimidine (10.2 g, 53.7 mmol), 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (18.8 g, 48.8 mmol), potassium carbonate (48.8 g, 98 mmol), and tetrakis(triphenylphosphine) palladium (2.26 g, 1.95 mmol) in 9/1 dimethoxyethane/N,N-dimethylformamide (200 mL) was evacuated under vacuum and refilled with nitrogen and heated at 85° C. for 20 minutes. The cooled mixture was filtered to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.C(Br)(Br)(Br)[Br:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(Br)ccc1CO
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1CBr
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
(4-Bromo-2-methylphenyl)methanol (10.4 g, 51.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (18.8 g, 56.8 mmol) added. The reaction mixture is cooled to 0-5° C. and PPh3 (14.9 g, 56.8 mmol) is added. The reaction mixture is stirred overnight then hexane/EtOAc (9:1) (250 mL) is added with vigorous stirring. The triphenylphosphine oxide that forms during the reaction is filtered off and the filtrates are concentrated in vacuo. The resulting oil is purified on a silica gel pad with hexane/EtOAc (8:2). The solvent are removed on a rotary evaporator and the bromoform is removed by vacuum distillation (15 mm Hg, bp: 40-50° C.) to provide the expected product 1-Bromo-4-(bromomethyl)-3-methylbenzene (13.23 g, 97%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.37-7.27 (2H, m), 7.17 (1H, d, J=8.1 Hz), 4.45 (2H, s), 2.39 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:14])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.6 %

Procedure:
To a solution of 2,4-difluorocinnamic acid (20 g, 135 mmol) in N,N-dimethylformamide (500 mL) at room temperature under dry nitrogen was added potassium carbonate (90 g, 675 mmol) then iodomethane (21 mL, 337.5 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 7 hours before being quenched by the addition of water (1 L) and extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco) using a pre-packed column (Redisep™ Disposable Columns for Flash Chromatography by Isco, 120 g column) eluting with 2% ethyl acetate in pentane increasing polarity in a linear gradient to 10% ethyl acetate in pentane over 1 hour to afford the title compound as a white solid (20.5 g, 77%). 1H NMR (400 MHz, CDCl3) δH 3.80 (3H, s), 6.50 (1H, d), 6.85 (1H, m), 7.50 (1H, m), 7.75 (1H, d); LRMS (APCI) 216 [MNH4+], 199 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:16][CH2:15][C:14](=O)[CH2:13]1.N1CCCC1.Cl>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:14]1([CH2:15][CH2:16][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=C1CCOC1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC2(CCOC2)Oc2ccc(Br)cc21
Yield: 25.8 %

Procedure:
A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (4.97 g, 23.23 mmol), dihydrofuran-3(2H)-one (3 g, 34.87 mmol) and pyrrolidine (2.48 g, 34.87 mmol) in toluene (60 mL) was refluxed overnight. After cooling, the mixture was treated with water and acidified with concentrated HCl to pH around 1. The resulting solution was extracted with ethyl acetate and washed with brine. The combined organic layers were concentrated and the residue was purified by column to give 6-bromo-4′,5′-dihydro-2′H-spiro[chroman-2,3′-furan]-4-one (1.7 g, 30%). 1H-NMR (CDCl3): 1.9 (m, 1H), 2.3 (m, 1H), 2.8 (m, 2H), 3.65 (m, 1H), 3.9 (m, 1H), 4.0 (m, 2H), 6.8 (m, 1H), 7.5 (m, 1H), 7.9 (m, 1H).
Reaction SMILES: [OH:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C[CH:16]1[CH2:20][CH2:19]C[O:17]1.C(N(CC)CC)C.C(Cl)(=O)C=C>>[CH:13]1[C:14]2[CH:2]([O:1][C:16](=[O:17])[CH:20]=[CH2:19])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CC1CCCO1
Reactant: OC1c2ccccc2-c2ccccc21
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1c2ccccc2-c2ccccc21

Procedure:
To a 250 ml 3 neck round bottom was added 9-Hydroxyfluorene (5 g, 0.027 mole, 1.0 equivalent), 2-methyltetrahydrofuran (50 g), triethylamine (3.3 g, 0.03 mole, 1.2 equivalents) and cooled in an ice bath. The cooled solution was treated with acryloyl chloride (2.7 g, 0.03 mole, 1.1 equivalents) dropwise over 1 hour. Analysis by gas chromatography indicated 60/40 mixture. The reaction was washed two times with sodium chloride brine (25 ml, 20% aqueous solution), concentrated invacuo to recover a solid. The material was dissolved in chloroform (50 ml) and added to a silica gel column containing 500 g silica gel and eluted with hexane/ethyl acetate at varying concentrations of 1-2.5% (ethyl acetate). The product was eluted first and was recovered by concentrating invacuo. Recovered 2.5 g of a pale yellow oil, which quickly solidified, having a melting point of 64-65 C. Polymerizable Resin Composition 1: 40 parts of FA-1 (with a refractive index of 1.613), 50 parts CN120 (epoxy acrylate available from Sartomer Company, Exton, Pa., reported by Sartomer to have a viscosity of 2150 cps at 65° C., a refractive index of 1.5556 and a Tg of 60° C.), 10 parts SR339(2-phenoxyethyl acrylate available form Sartomer), and 0.3 parts Darocur 4265 (available from Ciba Specialty Chemicals, Tarrytown, N.Y.) were mixed together thoroughly in an amber jar. Optical Film Sample Preparation: Brightness enhancing films samples were made using Polymerizable Resin Composition 1. About 3 grams of warm resin was applied to a 2 mil primed PET (polyester) film, available from DuPont under the trade designation “Melinex 623” and placed against a microstructured tool with a 90/24 pattern similar to the commercially available Vikuiti TBEF-90/24. The PET, resin and tool were passed through a heated laminator set at approximately 150° F. to create a uniformly thick sample. The tool containing the film and coated resin sample was passed at 50 fpm through a Fusion UV processor containing two 600 W/in D-bulbs. The PET and cured resin were removed from the tool and cut into samples. Gain Test Method
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(C(C)C)CC)(C)C.[O:43]1[C:45]([CH3:47])([CH3:46])[CH2:44]1>CO>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:44][C:45]([CH3:47])([OH:43])[CH3:46])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CC1(C)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(C)(C)O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
To a mixture of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (250 mg, 0.52 mmol) in MeOH (3 mL) was added diisopropylethylamine (110 μL, 0.62 mmol) followed by 1,2-epoxy-2-methylpropane (230 μL, 2.6 mmol) and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-7.5% MeOH in DCM) to give a solid that was recrystallised from heptane to give 421 (87 mg, 38%). LCMS: RT=7.41 min, [M+H]+=440. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1H, d, J=8.17 Hz), 8.06 (1H, d, J=0.59 Hz), 7.16 (1H, dd, J=8.23, 1.81 Hz), 7.00 (1H, d, J=1.76 Hz), 5.83-5.75 (1H, m), 4.32 (2H, t, J=5.03 Hz), 4.00 (1H, s), 3.65 (2H, t, J=6.98 Hz), 3.61-3.51 (1H, m), 3.39 (2H, t, J=5.08 Hz), 3.14 (2H, t, J=6.52 Hz), 2.32 (2H, s), 1.51 (6H, d, J=6.59 Hz), 1.03 (6H, s)
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH3:3].Cl[CH2:17][C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:17][C:18]3[O:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:21][N:22]=3)[CH:11]=2)[CH2:6]1)[CH3:1]
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Reactant: ClCc1nnc(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC1CCc2cc(OCc3nnc(-c4ccccc4)o3)ccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(N,N-dimethylamino)methyl-6-hydroxytetralin (206 mg, a free form of Reference Example 16) and 2-chloromethyl-5-phenyl-1,3,4-oxadiazole (231 mg) in DMF (5 ml) was added potassium carbonate (215 mg) and the reaction mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate: hexane=1:2) to obtain the titled compound (307 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([CH3:18])[CH:12]=[CH:11][N:10]=1.[CH2:19]([OH:21])[CH3:20].Cl.C(OC(=O)C)(=O)C>[Fe].C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([NH:15][C:19](=[O:21])[CH3:20])=[C:13]([CH3:18])[CH:12]=[CH:11][N:10]=1
Reactant: CCO
Reactant: Cc1ccnc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Nc1c(C)ccnc1-c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 68 %

Procedure:
To a mixture of 2-(2,4-dichloro-phenyl)4-methyl-3-nitro-pyridine (29; 1.15 g, 4.05 mmol), 10 mL of ethanol, 2.5 mL of water, and 0.5 mL of a concentrated HCl solution at 85° C. was added iron powder (1.37 g, 24.6 mmol). The grey suspension was stirred for 1 h, allowed to cool, and filtered through CELITE® 521 and the residual pad was washed well with methanol. The filtrate was concentrated, and the reddish-orange residue was partitioned between 50 mL of ethyl acetate and 50 mL of a saturated aqueous NaHCO3 solution. The organic layer was washed with 50 ML of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a yellow oil. To the oil was added 10 mL of toluene and acetic anhydride (0.41 mL, 4.35 mmol), and the yellow solution was stirred at 100° C. for 23 h then concentrated to a dark yellow residue. Column chromatography (50→66% EtOAc/hexanes) afforded of N-[2-(2,4-dichloro-phenyl)-4-methyl-pyridin-3-yl]-acetamide (30; 0.815 g; 68%) as an off-white solid.
Reaction SMILES: C(OCCOCCOCCO)C.[BH4-].[Na+].[O:15](C)[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:16]([OH:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC(=O)OC
Agent: CCOCCOCCOCCO
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCO
Temperature: 25 °C
Yield: 99 %

Procedure:
14.8 g (0.083 mole) of triethylene glycol monoethyl ether was added dropwise to a mixture consisting of 1.6 g (0.042 mole) of sodium borohydride, 10 ml of xylene and 5 g (0.027 mole) of methyl caprate at 95° C. over two hours while agitating the mixture. Subsequently, the mixture was agitated at the same temperature for 1.5 hours. After cooling to room temperature, the mixture was neutralized with dilute sulfuric acid. As a result, n-decanol was obtained in 99% yield.
Reaction SMILES: [CH3:1][C:2](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](Cl)=[O:5].CC1CCC([OH:42])C/C/1=C/C=C1\CCCC2(C)C(C(/C=C/C(C(C)C)C)C)CCC\12.C(CN)O>C1C=CC=CC=1>[CH3:1][C:2](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:42])=[O:5]
Reactant: CC(=Cc1ccccc1)CC(=O)Cl
Reactant: CC1CCC(O)C/C1=C/C=C1\CCCC2(C)C1CCC2C(C)/C=C/C(C)C(C)C
Solvent: NCCO
Solvent: c1ccccc1
Product: CC(=Cc1ccccc1)CC(=O)O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
194 g of 3-methyl-4-phenyl-3-butenoic acid chloride (1 mole), dissolved into 500 ml benzene, are treated at-10° C with 183 g of monoethanolamine (3 moles). The mixture is stirred at 20° C for 3 hours.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([CH3:9])=[N:3]1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(CO)n(C)n1
Reactant: O=S(Cl)Cl
Product: Cc1cc(CCl)n(C)n1

Procedure:
The title compound was prepared analogously to example 48b starting from (2,5-dimethyl-2H-pyrazol-3-yl)-methanol (778 mg) and thionyl chloride (2.35 ml). Yield: 900 mg.
Reaction SMILES: BrC(C(=O)C1C=CC=CC=1F)C(C)C(N1CCC[C@H]1C(O)=O)=O.Br[CH:25]([C:38](=[O:46])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1)[CH:26]([CH3:37])[C:27]([N:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32])=[O:28].[C:47]([O-:50])(=[S:49])[CH3:48].[K+].C(OCC)(=O)C.CCCCCC.C(O)(=O)C>C(O)C>[C:47]([S:49][CH:25]([C:38](=[O:46])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1)[CH:26]([CH3:37])[C:27]([N:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32])=[O:28])(=[O:50])[CH3:48]
Reactant: CC(C(=O)N1CCC[C@H]1C(=O)O)C(Br)C(=O)c1cccc(F)c1
Reactant: CC([O-])=S
Agent: CC(C(=O)N1CCC[C@H]1C(=O)O)C(Br)C(=O)c1ccccc1F
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)SC(C(=O)c1cccc(F)c1)C(C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
As described in Example 55, 4.0 g. of (S)-1-[3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline (isomer A); m.p. 182°-185° C. is brominated to give the bromo derivative of isomer A [mixture of [S-(R*,S*)]-1-[3-bromo-3-(fluorobenzoyl)-2-methylpropionyl]-L-proline and [S-(R*,R*)]-1-[3-bromo-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline]. Separation of the mixture by chromatography on a prep LC/500 column with hexane-ethyl acetate-acetic acid (75:25:2) as solvent gives 1.68 g. of pure diastereomer labelled X and 0.74 g. of pure diastereomer labelled Y. Reaction of diastereomer labelled X with potassium thioacetate in ethanol for 4 days gives the products of the Example (mixture of diastereomers). Reaction of diastereomer labelled Y with potassium thioacetate in ethanol for 4 days gives the products of the Example (mixture of diastereomers). Chromatography of the mixture on a silica gel column with ethyl acetate-hexane-acetic acid (5:5:0.2) separates the diastereomers to give [S-(R*,S*)]-1-[3-acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl] -L-proline, m.p. 158°-159° C.; [α]D +252°±3(c, 0.318 ethanol) and [S-(R*,R*)]-1-[3 -acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline as a white glass, [α]D -147°±1(c, 0.834 ethanol).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:13][O:14][CH2:15][CH2:16][CH3:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:18]1([CH2:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)O)[CH:22]=[CH:21][N:20]=[CH:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[N:18]1([CH2:23][C@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:1][C:2]2[C:3]([CH2:13][O:14][CH2:15][CH2:16][CH3:17])=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CCCOCc1c(O)ccc2c1CCCC2=O
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 73.7 %

Procedure:
According to step 2 in the method of example 19a, 6-Hydroxy-5-propoxymethyl-3,4-dihydro-2H-naphthalen-1-one (0.123 g, 0.53 mmol), (R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.131 g, 0.7 mmol), triphenylphosphine resin (0.620 g, loading 1.24 mmol/g, Argonaut Technologies), diethyl diazodicarboxylate (0.121 ml, 0.77 mmol, Aldrich Chemical) and freshly distilled tetrahydrofuran (5 ml, Aldrich Chemical) were combined in a 2 dram screw topped vial with a teflon lined cap. After mixing on an inverting mixer at 25° C. for 16 hrs., the resin was removed by gravity filtration and mixture concentrated in vacuo to a yellow-brown syrup. The residue was dissolved in methanol (5 ml) and macroporous polystyrene sulfonic acid resin (0.583 g, loading 1.5 mmol/g, Argonaut Technologies) added. After mixing for 2 hrs. at 25° C., the resin was collected by gravity filtration, washed with methanol (2×5 ml). Elution of product from the resin with 2.0 M ammonia in methanol (5 ml, Aldrich) and concentration in vacuo yielded 158 mg yellow glass compound. Low resolution mass spectroscopy m/z (APCI) 405 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.N#N>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:11]=[C:7]1[NH:6][C:5]2[N:12]=[CH:13][C:2](/[CH:16]=[CH:15]/[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:3][C:4]=2[CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCCc2cc(Br)cnc2N1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CCCC(=O)N2
Yield: 58.5 %

Procedure:
A solution of 3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (1.00 g, 4.15 mmole), tert-butyl acrylate (0.67 mL, 4.60 mmole), DIEA (1.45 mL, 8.30 mmole), Pd(OAc)2 (0.09 g, 0.42 mmole) and P(o-tol)3 (0.25 g, 0.85 mmole) in propionitrile (25 mL) was purged with N2 and then heated at reflux overnight. The dark mixture was filtered through a pad of Celite®, and the filter pad was rinsed with acetonitrile (250 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (ethyl acetate). The title compound (0.70 g, 58%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 289 (M+H)+.