Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[O:36])=[CH:31][C:30]=1[F:43]>ClCCl>[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:38][CH2:39][N:40]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[CH2:41][CH2:42]2)=[O:36])=[CH:31][C:30]=1[F:43]
Reactant: Nc1ccc(C(=O)N2CCNCC2)cc1F
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 6 h

Procedure:
tert-Butyl 4-(4-amino-3-fluorobenzoyl)piperazine-1-carboxylate (0.649 mmol, 210 mg) was stirred with dichloromethane (˜2 mL) and trifluoroacetic acid (˜0.5 mL) overnight. The mixture was purified by SCX chromatography to give the intermediate (4-amino-3-fluorophenyl)(piperazin-1-yl)methanone. 2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.649 mmol, 219 mg), potassium carbonate (0.649 mmol, 90 mg) and acetonitrile (5 mL) were added to the intermediate (4-amino-3-fluorophenyl)(piperazin-1-yl)methanone and the mixture was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was stirred in dichloromethane, filtered and the filtrate was purified by silica chromatography (eluting with dichloromethane increasing to ethyl acetate) to afford the title compound (46 mg).
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+].O>CO>[OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]/[C:4](/[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[N:25]\[OH:26]
Reactant: O=C(CC(O)(c1ccccc1)c1ccccc1)c1ccncc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O/N=C(\CC(O)(c1ccccc1)c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
To a solution of 3-hydroxy-3,3-diphenyl-1-pyridin-4-yl-propan-1-one (115 mg) in methanol (4 ml) were added hydroxylamine hydrochloride (63 mg) and sodium acetate (75 mg). The mixture was stirred at room temperature for 6 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:1 to 1:3) to give the title compound (60 mg) as a colorless solid, MS (ESI+): m/z=319.1 [M+H]+.
Reaction SMILES: C[Si](C)(C)[NH:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:5].[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>C(Cl)Cl>[O:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]([NH:3][C:13](=[O:17])[C:14]([Cl:16])=[O:15])=[O:5]
Reactant: C[Si](C)(C)NC(=O)c1ccco1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)C(=O)NC(=O)c1ccco1
Reaction time: 1 h

Procedure:
3.6 g. of N-(trimethylsilyl)-2-furancarboxamide are dissolved in 50 ml. of absolute methylene chloride and the solution is added dropwise at -10° to a solution of 1.8 g. of oxalyl chloride in 100 ml. of methylene chloride. The mixture is stirred for one hour at 0°. After evaporating the solvent, [(2-Furanylcarbonyl)amino]oxoacetyl chloride remains as a yellowish oil which is used for the next reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>>[CH2:18]([O:17][C:15]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1

Procedure:
trans-4-(Aminomethyl)cyclohexanecarboxylic acid (10.00 g, 0.06361 mol), in a 10% aq solution of NaOH (5.60 g in 55 mL) was cooled to 0° C. and treated over 15 min with vigorous stirring, with benzyl chloroformate (11 mL, 0.076 mol).
Reaction SMILES: Cl[C:2](=[CH2:12])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].C[O-].[Na+].Cl>NCCCN>[C:6]1([CH:4]([CH2:3][C:2]#[CH:12])[OH:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C(Cl)CC(O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: NCCCN
Product: C#CCC(O)c1ccccc1

Procedure:
19.5 Grams of 2-chloroallylphenylcarbinol were dissolved in 100.0 g of 1,3-diaminopropane, and 9.2 g of sodium methylate were added. The mixture was allowed to react at 30° C. for 16 hours. Then, the reaction mixture was neutralized with concentrated hydrochloric acid, and insolubles were filtered off. The filtrate was concentrated under reduced pressure, and the resultant oily substance was purified by silica gel column chromatography to give 12.6 g of phenylpropargylcarbinol, nD20 =1.546, FI-MS m/e 146(M+), propargyl compound/ allene compound=93.0/7.0.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:8](=O)[C:9]1[CH:23]=[CH:22][C:12]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1)[CH2:4][C:5](O)=[O:6].CN(C(O[N:33]1[N:41]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.NN>C1COCC1>[CH3:1][O:2][C@H:3]1[C:8]([C:9]2[CH:23]=[CH:22][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:41][NH:33][C:5](=[O:6])[CH2:4]1
Reactant: CO[C@H](CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CO[C@@H]1CC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1
Reaction time: 0.17 h

Procedure:
140 mg (430 μmol) (R)-3-methoxy-4-oxo-4-(2-phenyl-benzoxazol-6-yl)-butyric acid are combined at RT with 190 mg (500 μmol) HATU, 200 μl (1424 μmol) TEA and 2 ml DMF. The mixture is stirred for 10 min, then 431 μl (431 μmol) hydrazine 1M in THF are added. The mixture is stirred for a further 2 h at RT, then extracted with DCM and phosphate buffer (pH7). The org. phase is dried and evaporated down. The residue is purified by RP-HPLC.
Reaction SMILES: C(O)(=O)C.CS[C:7]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:27])=[CH:14][CH:13]=1)([CH3:11])[C:8]([OH:10])=[O:9].Cl.O>S([O-])([O-])(=O)=O.[Cu+2].[Zn].C(Cl)Cl>[O:27]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][N:18]1[C:15]1[CH:16]=[CH:17][C:12]([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=1
Reactant: CSC(C)(C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 97.5 %

Procedure:
Acetic acid (2 ml), 8 mg of anhydrous copper sulfate and 120 mg of zinc powder were added to 148 mg of α-methylthio-α-[p-(1-oxo-2-isoindolinyl)phenyl]propionic acid, and the mixture was heated under reflux for 5 hours. Conc. hydrochloric acid was added to adjust the pH of the mixture to 1. Water (20 ml) and 20 ml of methylene chloride were added, and the insoluble matter was separated by filtration. The filtrate was extracted four times with 20 ml of methylene chloride. The organic layer was washed with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 124 mg of α-[p-(1-oxo-2-isoindolinyl)phenyl]propionic acid as colorless crystals in a yield of 99.8%. Recrystallization of the resulting product from ethanol afforded crystals having a melting point of 205° to 208° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([OH:17])[CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[H][H]>C(O)C.[Pd]>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH:9]([OH:17])[CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCCCC(CC)C(O)C=CC1CCC(O)C1CCCCCCC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCC(CC)C(O)CCC1CCC(O)C1CCCCCCC(=O)O
Yield: 77.9 %

Procedure:
A stirred solution of 7-[2-hydroxy-5-(4-ethyl-3-hydroxyoct-1-enyl)-cyclopentyl]heptanoic acid [0.6 g; prepared as described in Example 4(iii)] in ethanol (25 ml.) was reduced with hydrogen at a hydrogen pressure of 6.3 kg./cm2 and in the presence of a 5% palladium on charcoal catalyst (0.68 g.). The catalyst was then filtered off and the filtrate evaporated to give 7-[2-hydroxy-5-(4-ethyl-3-hydroxyoctyl)cyclopentyl]heptanoic acid (0.47 g.), νmax 1700 cm-1 (Found: C, 71.2; H,11.7%; C22H42O4 requires C, 71.4; H, 11.4%). N.M.R. (approximately 10% solution in deuterochloroform) 0.65-1.05δ (2 overlapping triplets, terminal CH3 groups), 1.05-2.2δ (overlapping multiplets, cyclic and chain CH2 groups), 2.30δ (triplet CH2C=O),3.60-3.88δ, 4.2δ (multiplets, methylidene groups attached to hydroxy groups), 5.6-6.6δ broad singlet, OH and COOH groups).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH:9]1[CH3:20])([CH3:7])[CH3:6].[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>[N+](C)([O-])=O>[C:21]([C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:19])([CH3:18])[CH:9]([CH3:20])[CH:8]2[CH:5]([CH3:7])[CH3:6])=[CH:12][C:13]=1[CH3:17])(=[O:24])[CH2:22][CH3:23]
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCC(=O)c1cc2c(cc1C)C(C)(C)C(C)C2C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
At 0°-5° C. a solution of 4 g AlCl3 in 50 ml nitromethane is added to a mixture of 6 g 1-isopropyl-2,3,3,5-tetramethyl indan (obtained according to example I or II) and 25 g propionyl chloride. Then the reaction mixture is stirred at room temperature during one hour and poured out into ice and extracted three times with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure to obtain 6-propionyl-1-isopropyl-2,3,3,5-tetramethyl indan in a yield of 80%. B.p. 145° C./1 mm Hg.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[N:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.2 g, 0.806 mmol) in toluene (1.60 mL) was added 2-methyl-6-(tributylstannyl)pyridine (0.34 g, 0.89 mmol), and palladium tetrakistriphenylphosphine (0.093 g, 0.081 mmol). The reaction was stirred at 100° C. and stirring continued for 18 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with (0-50% EtOAc in hexanes) to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-methylpyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[NH2:10][C@@H:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:10][C@@H:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:32])[F:33])[CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[O:9])[CH:3]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1coc(Br)c1
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 5-bromo-3-furancarboxylic acid (0.30 g, 1.57 mmol) [prepared according to J. Org. Chem. 1976, 41, 2350.], 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.60 g, 1.73 mmol) [from Preparation 5] and diisopropylethyl amine (0.82 mL, 4.7 mmol) in DCM (50 mL) at 25° C. was added PyBrOP (1.09 g, 2.36 mmol) in one portion. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, hexanes/EtOAc, 1:1) affording the title compound (0.45 g, 55%) as a white solid: LC-MS (ES) m/z=521 (WH)+.
Reaction SMILES: C([N:8]([C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])[C@H:9]([C:38]([OH:40])=[O:39])[CH2:10][O:11][C:12](=[O:37])[CH:13]([NH:26]C(OCC1C=CC=CC=1)=O)[CH:14]([O:19]C1CCCCO1)[C:15]([F:18])([F:17])[F:16])C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:26][CH:13]([CH:14]([OH:19])[C:15]([F:16])([F:17])[F:18])[C:12]([O:11][CH2:10][C@@H:9]([C:38]([OH:40])=[O:39])[NH:8][C:41](=[O:46])[C:42]([F:44])([F:43])[F:45])=[O:37]
Reactant: O=C(NC(C(=O)OC[C@@H](C(=O)O)N(Cc1ccccc1)C(=O)C(F)(F)F)C(OC1CCCCO1)C(F)(F)F)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: NC(C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O)C(O)C(F)(F)F
Yield: 94 %

Procedure:
A solution of benzyl N-trifluoroacetyl-O-[2-benzyloxycarbonylamino-3-(2-tetrahydropyranyloxy)-4,4,4-trifluoro-1-oxobutyl]-L-serine (1.36 g) and p-toluenesulfonic acid monohydrate (39 mg) in methanol (14 ml) was stirred overnight. The solvent was distilled off and the residue was diluted with ethyl acetate and washed successively with 10% aqueous sodium hydrogen carbonate and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was dissolved in acetic acid (50 ml) and 10% palladium on activated carbon (500 mg) was added. The mixture was hydrogenated under hydrogen at 40 psi at room temperature for an hour. The solvent was distilled off and the residue was lyophilized to give O-(2-amino-3-hydroxy-4,4,4-trifluoro-1-oxobutyl)-N-trifluoroacetyl-L-serine (685 mg).
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[I:19]I.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH:1]1([S:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([I:19])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: Brc1cccc(SC2CCCC2)c1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Ic1cccc(SC2CCCC2)c1
Yield: 42.3 %

Procedure:
To a solution of 1-(cyclopentylthio)-3-bromobenzene (3.6 g) in dry THF (40 ml) at −60° under nitrogen was added n-butyl lithium (10 ml, 1.6M in hexanes). After stirring for 15 min a solution of iodine (4.3 g) in dry THF (30 ml) was added dropwise and the solution was allowed to warm to 0°. Wet THF was added to the brown solution, followed by aqueous sodium sulphite. The resulting colourless solution was extracted with diethyl ether and the combined organic extracts were washed with water, brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by column chromatography on silica using cydohexane as eluant. This gave the title compound (1.8 g). LCMS RT=4. 1 min
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH3:30])[CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=1)[NH:7][C:8](=[O:17])[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(=O)C.C[O-].[Na+]>CO>[OH:4][CH2:5][C@H:6]([NH:7][C:8](=[O:17])[C@H:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]([CH3:30])[CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=1
Reactant: CCCC(C)COc1ccc([C@H](COC(C)=O)NC(=O)[C@@H](C)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C)COc1ccc([C@H](CO)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
To a solution of (2R)-2-(4-(2-methylpentyloxy)phenyl)-2-((S)-2-phenylpropanamido)ethyl acetate (358 mg, 0.870 mmol) in methanol (5 mL) at 0° C. was added sodium methoxide (14.0 mL, 7.00 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 20 min. Saturated aqueous NH4Cl (5 mL) was added and the methanol was removed on the rotovapor. The mixture was transferred to a separatory funnel containing saturated aqueous NH4Cl solution (20 mL). The aqueous layer was extracted with ethyl acetate (4×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (40%→75% ethyl acetate in hexanes; 25 g column) to afford (2S)-N-((1R)-2-hydroxy-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (269 mg, 84% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 7.29-7.36 (m, 2H), 7.22-7.29 (m, 3H), 6.94 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 6.01 (d, J=6.8 Hz, 1H), 4.89-4.97 (m, 1H), 3.76 (d, J=4.8 Hz, 2H), 3.71-3.75 (m, 1H), 3.59-3.68 (m, 2H), 2.46 (br. s., 1H), 1.84-1.95 (m, 1H), 1.50 (d, J=7.1 Hz, 3H), 1.25-1.48 (m, 3H), 1.13-1.22 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 370.2 [(M+H)+, calcd for C23H32NO3 370.2].
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1)[C:22](O)=[O:23]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH3:17])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[C:19]([F:18])[CH:20]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Reactant: Cc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.10 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([CH3:25])[C:17]=1[OH:26].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]O>C(OCC)(=O)C>[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([CH3:25])[C:17]=1[O:26][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27]
Reactant: CN(C)CCO
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1OCCN(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.4 mL of diisopropyl azodicarboxylate was added to 1.9 g of 2,6-dimethyl-4-nitrophenol and 1.71 mL of 2-dimethylaminoethanol, and stirred at room temperature for 16 hours. The reaction liquid was diluted with ethyl acetate, and the organic layer was extracted with 2 N hydrochloric acid. The aqueous layer was made basic with aqueous 2 N sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure to obtain 667 mg of the entitled compound.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30]Br)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:10][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=Cc1cc(I)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(I)cc2C=O)CC1
Temperature: 60 °C
Yield: 63 %

Procedure:
To a solution of 5-iodosalicylaldehyde (2 g, 8.2 mmol) (Aldrich) in N,N-dimethylformamide (20 mL) was added anhydrous K2CO3 (1.15 g, 8.2 mmol), and 4-bromomethyl-piperidine -1-carboxylic acid tert-butyl ester (2.3 g, 8.2 mmol, Pharmacore). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated to give 4-(2-formyl-4-iodo-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (Yield 2.3 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([CH3:20])([CH3:19])[CH:8](O)[CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.ClC1C=CC(OC(C)(C)C=O)=CC=1.[BH4-].[Na+].[OH-].[K+].Cl>C(O)C.CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH:8]2[O:14][C:12](=[O:13])[CH2:11][CH:10]([OH:17])[CH2:9]2)([CH3:19])[CH3:20])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(=O)CC(O)C(C)(C)Oc1ccc(Cl)cc1
Agent: CC(C)(C=O)Oc1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)(Oc1ccc(Cl)cc1)C1CC(O)CC(=O)O1
Yield: 25.8 %

Procedure:
10 g (0.0354 mole) of ethyl 6-(p-chlorophenoxy)-6-methyl-5-hydroxy-3-oxoheptanoate [prepared from 2-(p-chlorophenoxy)-2-methylpropanal according to the procedure of step (a) of Example 1] were reduced with 0.8 g (0.021 mole) of sodium borohydride in 100 ml of ethanol, with ice-cooling and stirring. The residue obtained from the reaction mixture by the procedure described in Example 1 was dissolved, without purification, in 50 ml of acetone, and then 100 ml of a 15% w/w aqueous solution of potassium hydroxide was added. The mixture was then stirred at room temperature for 20 hours, after which it was acidified with hydrochloric acid and extracted three times, each time with 100 ml of ethyl acetate. The combined extracts were dried over anhydrous sodium sulphate and then the solvent was evaporated off under reduced pressure. The residue was adsorbed on a silica gel chromatography column and fractions eluted with a 1:5 by volume mixture of benzene and ethyl acetate were evaporated to dryness to give 2.6 g (yield 30%) of the desired Compound No. 4. This was recrystallized to give colourless crystals melting at 72°-76° C.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:23][NH2:24]>C(O)C>[CH3:23][NH:24][CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:12]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC(C)C/C=C/c2cccnc2)cc1
Solvent: CCO
Product: CNC(C)C/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
A mixture of (4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (5.60 g, 17.66 mmol), methylamine (100 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 1.60 g (51.6%) of a colorless oil, bp 110-120° C. at 0.1 mm Hg.