Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.[OH2:33]>CC(C)=O>[C:12]([O:11][C:10]([NH:9][C@H:7]1[CH2:8][C@@:4]([CH2:3][C:2]([OH:33])=[O:1])([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH:5]=[CH:6]1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC(=O)O)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 2 h

Procedure:
To a solution of the product of Example 1, Step D (508 mg, 1.12 mmol, 1 eq) in acetone (10 mL) at 0° C. was added Jones oxidation solution (0.46 mL, 1.23 mmol, 1.1 eq). After 2 hr, water was added, the aqueous was extracted with ethyl acetate, the organics combined, dried over MgSO4 and concentrated to afford the product of Step A that was used unpurified in the next step. Calculated for C22H26F3N3O5: 492.2 (M+23). found: 492.1.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][C:15](=[O:29])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH:7]([CH2:14][C:15]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)=[O:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ccccc1)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl)phenylcarbamate (1.30 g) was dissolved in 50% trifluoroacetic acid in dichloromethane (26 mL) and the mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated in vacuo and the residue was crystallized from n-hexane-ethyl acetate (1:1, 15 mL). The crystals were collected by filtration and washed with n-hexane/ethyl acetate (1:1, 5 mL) to afford 2-anilino-N-[4-(4-pyridinyl)phenyl]acetamide bis(trifluoroacetate) (1.46 g) as yellow crystals.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH3:23].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH3:23]
Reactant: CC=O
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CC=C1OC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.527 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 0.311 ml (5.0 mmol) of acetaldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 17 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=3/1) to yield 77 mg (4.65%, yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]3[N:23]([N:27]=[C:28]([NH2:30])[N:29]=3)[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]3[N:23]([N:27]=[C:28]([NH:30][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:29]=3)[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1nc2c(-c3ccc(F)cc3)cccn2n1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(F)cc5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting with 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (example 1f). The title compound was obtained as a white solid (yield=28%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([Sn](C)(C)C)[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][N:4]=1.[C:18]1([CH2:24][CH2:25][C:26](Cl)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:26](=[O:27])[CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][N:4]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCOC(=O)c1cnc(SC)nc1[Sn](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(SC)nc1C(=O)CCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of Example 6A (600 mg, 1.74 mmol) in toluene (20 ml) was added palladium tetrakis(triphenylphosphine) (96 mg, 0.08 mmol) and 3-phenylpropanoyl chloride (0.37 ml, 2.5 mmol). The reaction mixture was purged with nitrogen and heated at 100° C. for 12 hours. After cooling, the reaction mixture was directly separated by flash chromatography which was eluted with 15% ethyl acetate in hexane to provide the title compound. MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:12])[C@@H:11]2[C@@H:9]([O:10]2)[CH2:8][CH2:7][CH2:6]1)=[O:4].CO.[NH4+].[Cl-].[N-:17]=[N+:18]=[N-:19].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1([CH3:12])[CH2:6][CH2:7][CH2:8][CH:9]([N:17]=[N+:18]=[N-:19])[CH:11]1[OH:10])=[O:4]
Reactant: COC(=O)C1(C)CCC[C@@H]2O[C@@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1(C)CCCC(N=[N+]=[N-])C1O

Procedure:
Racemic cis-methyl-5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate, 66b, (2.2 g, 12.93 mmol) was added to a flask containing MeOH (90 mL) and H2O (10 mL) under nitrogen atmosphere. NH4Cl (1.38 g, 0.90 mL, 25.86 mmol) and NaN3 (2.52 g, 38.79 mmol) were then added to the reaction mixture. The mixture was heated to reflux for 16 hours. The solvent was evaporated under reduced pressure and the oil was taken up in H2O and extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. The crude product was purified by silica gel chromatography to afford 900 mg of racemic methyl-3-azido-2-hydroxy-1-methyl-cyclohexanecarboxylate.
Reaction SMILES: [O:1]1[CH:6]2[CH2:7][N:8](C(OCC3C=CC=CC=3)=O)[CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1>CO.C(O)=O.[OH-].[OH-].[Pd+2]>[O:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CC2OCCOC2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: C1COC2CNCC2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of benzyl tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6(3H)-carboxylate (0.46 g, 1.94 mmol) in MeOH (20 mL) was added two drops of HCO2H followed by 20% Pd(OH)2 (50 mg). The reaction mixture was stirred under H2 for 4 h at rt and was filtered. The filtrate was concentrated in vacuo to give the crude product, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C@@H:23]([OH:26])[CH2:24][OH:25])[CH:16]=1.[CH3:28][C:29]([CH3:31])=O>[Cl-].[Zn+2].[Cl-]>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C@@H:23]2[O:26][C:29]([CH3:31])([CH3:28])[O:25][CH2:24]2)[CH:16]=1
Reactant: CC(C)=O
Reactant: Nc1c(C(=O)c2cccc(OC[C@@H](O)CO)c2)cnn1-c1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1(C)OC[C@H](COc2cccc(C(=O)c3cnn(-c4ccc(F)cc4)c3N)c2)O1
Reaction time: 13 h

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-dihydroxypropoxy} benzoyl]pyrazole (0.6 g, 1.6 mmol) in 30 ml acetone was added zinc chloride (0.34 g, 2.6 mmol). The reaction mixture was stirred and heated at reflux. After 13 hours, the reaction mixture was concentrated to dryness and the product was purified by flash column chromatography on silica gel using 40% EtOAc/Hexane as elutent. The product was stirred with 1:1 ether/hexane and 125 mg of 5-amino-1-(4-fluorophenyl) 4-{3-[(2,2-dimethyl-1,3-dioxolan-5(S)-yl)methoxy]benzoyl}pyrazole was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:19])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCC(C(=O)c2ccc(Br)cc2)C1
Reactant: Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCC(C(=O)c2ccc(-c3ccc(N)cc3)cc2)C1
Temperature: 80 °C

Procedure:
To a solution of 3-(4-bromo-benzoyl)-cyclohexanecarboxylic acid methyl ester (500 mg, 1.54 mmol) and 4-aminophenyl boronic acid (252 mg, 1.85 mmol) in toluene (40 mL) and dioxane (10 mL), 2 N aqueous Na2CO3 (10 mL) was added, and the mixture was degassed by bubbling with a flow of argon for 45 minutes. (1,1-Bis(diphenylphosphino)ferrocene)-dichloropalladium (63 mg, 0.08 mmol) was added to the mixture, which was then heated at 80° C. overnight. The reaction mixture was cooled to rt, and then filtered through a pad of Celite®, rinsing with ethyl acetate. The organic layer was separated, washed with water and brine, and dried (Na2SO4). The solvent was removed by rotary evaporation, and the solid residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 3:1 hexane/EtOAc). The product 3-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid methyl ester was obtained as a brown solid (200 mg, yield 38.5%). 1H NMR (300 MHz, DMSO) δ 7.90 (d, 2H), 7.60 (d, 2H), 7.45 (d, 2 H), 6.80 (d, 2H), 3.70 (s, 3H), 3.25 (m, 1H), 2.50 (m, 1H), 2.20-1.90 (m, 4 H), 1.70-1.50 (m, 4H); LC-MS ret. time 3.80 min (method 2), m/z 338.17 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([Cl:28])=[O:8]
Reactant: CCCCCCc1ccc(SC)c(C=CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(SC)c(C=CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 25 ml of methylene chloride is added 2-methylthio-5-n-hexylcinnamic acid (1.4 g, 0.005 mmol) with cooling in an ice bath. To this mixture is added DMF (0.365 g, 0.005 mmol) and then oxalyl chloride (0.9 ml, 0.01 mmol) dropwise. The bath is removed and the reaction mixture stirred at room temperature for 2 hours to afford 2-methylthio-5-n-hexylcinnamic acid chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:10](OS(C)(=O)=O)/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@@H]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@@H](OS(C)(=O)=O)/C=C/C(OC)=O)=O)(C)(C)C.CCCCCC>C(OCC)(=O)C>[CH2:50]([C@@H:12](/[CH:11]=[CH:10]/[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]([O:15][CH3:16])=[O:14])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: COC(=O)/C=C/[C@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@H](/C=C/[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1
Yield: 90 %

Procedure:
Using the procedure of Example 8 but replacing the resultant compound of Example 7 with the resultant compound of Example 14 provided, after silica gel chromatography using 6:1 hexane:ethyl acetate, the desired compound (m.p. 84°-85° C., R 0.73, 2:1 hexane:ethyl acetate) in 90% yield. 1H NMR (CDCl3) 1.41 s, 9 H), 2.7-2.8 (m, 3 H), 3.01 (dd, J=14, 8 Hz, 1 H), 3.26 (q, J=7 Hz, 1 H), 3.61 (s, 3 H), 4.37 (m, 2 H), 5.42 (br d, 1 H), 5.56 (dd, J=15, 8 Hz, 1 H), 7.03-7.12 (m, 4 H), 7.2-7.3 (m, 6 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([CH:10]([CH3:12])[CH3:11])[OH:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 9.0 g (0.048 mol) of 4-Bromobenzaldehyde in 150 mL of ether at 0° C. under argon, 2.0 M solution of isopropyl magnesium chloride in ether (29.2 mL) was added and stirred for 30 minutes. The solution was slowly warmed up to room temperature and stirred for an additional 4 hours. The mixture was then added to 150 mL of aqueous saturated sodium bicarbonate and extracted with 200 mL of ether. The organic extract was washed once with water, dried and evaporated to afford 9.8 g (95%) of the product as a gum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[C:6]([CH3:20])[CH:5]=1)([O-])=O.CO.Cl>CCOCC>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])=[C:6]([CH3:20])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCNC(=O)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1cc(N)ccc1NCCNC(=O)C(F)(F)F
Yield: 108.2 %

Procedure:
1.7 g of nitro derivative (1) prepared above and about 80 ml of methanol were introduced into a 200 ml autoclave (hydrogenator) equipped with a magnetic stirrer. The solution obtained was degassed with nitrogen. 0.2 g of palladium-on-charcoal (5% humidity, comprising 50% water) was added thereto. The reaction mixture was stirred, while flushing once with hydrogen, and hydrogen was then introduced therein at a pressure of about 5 bar. After reaction for 4 hours, the reactor was purged with nitrogen. The reaction mixture was filtered quickly through Celite under a gentle pressure of nitrogen. The filtrate: was recovered in a pre-cooled solution of methanol comprising about 3 equivalents of hydrogen chloride gas. The resulting mixture was rinsed several times with methanol under a stream of nitrogen. The concentrated solution thus obtained was then treated with ether. The product obtained, in the form of a pale pink paste, was stirred and then rinsed several times with acetonitrile and ether under nitrogen. 1.65 g of expected product (2) were isolated in the form of a slightly pink white powder. The proton and 13C NMR spectra and the microanalyses were in accordance with the expected structure of the product.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(Cl)Cl>[CH2:17]([NH:20][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH3:19]
Reactant: CCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzoyl chloride (116 μL, 1 mmol) in 1 mL of dry CH2Cl2 was treated successively at 0° C. with triethylamine (167 μL, 1.2 mmol) and n-propylamine (124 μL, 1.5 mmol). The reaction was stirred at room temperature for two hours. The resulting reaction mixture was diluted with CH2Cl2 washed with 2M HCl, followed by saturated NaHCO3, then brine. The resulting solution was then dried over MgSO4. The residue was purified using SiO2 with CH2Cl2/Petroluem ether 95:5 to CH2Cl2 100%. A white solid was obtained (166 mg, quantitative yield). NMR 1H (ppm, CDCl3): 7.74 (d, J3=8.1 Hz, 2H), 7.41 (t. t., J3=7.2 Hz, J4=1.3 Hz, 1H), 7.33 (t. t., J3=7.6 Hz, J4=1.6 Hz, 2H), 5.23 (br. s., 1H), 3.36-3.30 (m, 2H), 1.57 (sext., J3=7.2 Hz, 2H), 0.90 (t, J3=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][C:42]1([CH3:50])[CH2:48][C:47](=[O:49])[O:46][C:44](=[O:45])[CH2:43]1.C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:47](=[O:49])[CH2:48][C:42]([CH3:50])([CH3:41])[CH2:43][C:44]([OH:46])=[O:45])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CC(C)(C)CC(=O)O)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.4 %

Procedure:
To a mixture of 181 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 0.114 mL of triethylamine, and 3.0 mL of THF was added 64 mg of 3,3-dimethylglutaric anhydride at room temperature, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by stirring, extracting with chloroform, and drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 266 mg of 5-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,3-dimethyl-5-oxopentanoic acid as a crude product. ESI+: 587
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]CC3C=CC=CC=3)[CH:14]=2)=[CH:8][C:7]=1[CH3:27]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[CH:8][C:7]=1[CH3:27]
Reactant: COC(=O)CCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Oc2cccc(O)c2)cc1C
Yield: 102 %

Procedure:
A mixture of 3-[4-(3-benzyloxy-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (10.54 g, 28.0 mmol) and 10% Pd/C (5 g) in ethyl acetate (150 mL) is purged with N2, and then purged with H2, which is stirred under a hydrogen balloon. Upon reaction completion, the mixture is filtered through Hyflo, and the solvent is removed in vacuo to afford about 8.18 g (100%) of the titled compound. Rf=0.59 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C17H18O4 286, found 287 (M+1, 100%).
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[O:13]>O1CCCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:2]([Cl:4])([Cl:3])[Cl:1])=[O:13]
Reactant: C=CCCCCOC(=O)/C=C/c1ccc(OC)c(OC)c1
Reactant: Cl[SiH](Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)OCCCCCC[Si](Cl)(Cl)Cl)cc1OC
Reaction time: 5 h

Procedure:
5 ml of trichlorosilane are added to a solution of 0.1 g of H2PtCl6 in 20 ml of dry tetrahydrofuran while stirring. A solution of 14.8 g of hex-5-enyl (E)-3,4-dimethoxycinnamate, dissolved in 20 ml of dry tetrahydrofuran, is carefully added dropwise to this. Thereafter, stirring is carried out for 5 hours at room temperature and then for 16 hours at 50° C. The reaction mixture is concentrated in a vacuum produced by a water-jet pump and is completely freed from the remaining solvent and trichlorosilane by means of an oil pump with a cold trap under reduced pressure. This gives crude 6-trichlorosilanylhexyl (E)-3,4-dimethoxycinnamate, which is dissolved in dry tetrahydrofuran for storage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:17])[C:13](=O)[CH2:14][CH3:15].B.CSC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:17])[CH2:13][CH2:14][CH3:15]
Reactant: CCC(=O)N(C)c1cc([N+](=O)[O-])ccc1OC
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCCN(C)c1cc([N+](=O)[O-])ccc1OC
Yield: 96.6 %

Procedure:
N-(2-Methoxy-5-nitro-phenyl)-N-methyl-propionamide (3) (10.0 g 42 mmol) and borane-methyl sulfide complex (21 mL of 2.0M solution in tetrahydrofurane) in 50 mL THF were heated unter reflux for 30 min, cooled and quenched by ice-water (slowly). Extraction with EtOAc and the organic layer washed with brine dried (Na2SO4), filtered and evaporated in vacuo to give (9.1 g, 96%) (2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:15][CH3:16])=[O:9])=[CH:4][N:3]=1
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(N)nc1
Yield: 88 %

Procedure:
To a solution of 2-amino-5-pyridinecarboxylic acid 113 (150 g, 1.09 mol) in ethanol (2 L) was added thionyl chloride (259 g, 2.18 mol) at 0° C. The mixture was heated at reflux for 12 h. The solvent was removed under reduced pressure. Saturated aq Na2CO3 was added to adjust the pH to 9 and the resulting solid was collected by filtration, rinsed with H2O, and dried to give 114 (160 g, 88% yield).
Reaction SMILES: O.[OH:2][C:3]([C:6]1[N:7]=[C:8]([CH2:54][CH2:55][CH3:56])[N:9]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48](=[O:53])[C:49]([O:51][CH3:52])=[O:50])=[CH:38][CH:37]=2)[C:10]=1[C:11]1[N:12]=[N:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:15]=1)([CH3:5])[CH3:4]>C(O)(=O)C>[OH:2][C:3]([C:6]1[N:7]=[C:8]([CH2:54][CH2:55][CH3:56])[N:9]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48](=[O:53])[C:49]([O:51][CH3:52])=[O:50])=[CH:40][CH:41]=2)[C:10]=1[C:11]1[NH:15][N:14]=[N:13][N:12]=1)([CH3:5])[CH3:4]
Reactant: CCCc1nc(C(C)(C)O)c(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(-c2nnn[nH]2)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
1.5 ml of water were added to a solution of 527 mg of methyl {4'-[4-(1-hydroxy-1-methylethyl)-2-propyl-5-(2-trityltetrazol-5-yl)imidazol-1-ylmethyl]biphenyl-2-yl}glyoxylate [prepared as described in step (a) above] dissolved in 3.5 ml of acetic acid, and the resulting mixture was stirred at 70° C. for 1.5 hours. At the end of this time, 2 ml of water were added to the mixture. The resulting mixture was ice-cooled, and then the precipitate was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the residual acetic acid was removed by azeotropic distillation with toluene, to give 206 mg of the title compound, as crystals melting at 131°-132° C. (after crystallization from a mixture of diethyl ether and ethyl acetate).