Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([OH:13])=O)[C:7](=[O:21])[CH:6]=1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:13])[C:7](=[O:21])[CH:6]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (154 mg, 0.40 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 75 mg, 0.48 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (424 mg, 0.96 mmol) and N,N-diisopropylethylamine (129 mg, 1.0 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (85 mg, 41%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.75-1.32 (m, 6H) 1.04 (s, 3H) 1.06 (s, 3H) 1.51-1.84 (m, 7H) 3.89 (s, 2H) 4.24 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.91 (dd, J=10.7, 5.0 Hz, 1H) 4.96 (s, 1H) 6.44 (d, J=2.1 Hz, 1H) 7.36-7.53 (m, 3H) 7.54 (d, J=2.1 Hz, 1H) 10.81 (s, 1H). HR-ES-MS m/z calculated for C26H32ClFN4O4 [M+H]+ 519.2169, observed 519.2169.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8](O)[CH:9]=1)=[O:3].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-:31].[K+].[K+]>CN(C=O)C>[CH3:12][CH2:13][CH:14]([O:31][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(CC)OCC(=O)c1ccccc1
Yield: 58.6 %

Procedure:
A mixture of 2.0 g (14.7 mmol) of 3-hydroxyacetophenone, 5.9 g (17.6 mmol) of 1-bromooctadecane and 4.1 g (29.4 mmol) of anhydrous potassium carbonate in 35 ml of anhydrous DMF was stirred and heated at 80° for 45 hours. The solvent was removed under high vacuum, the residue was treated with 50 ml of 0.5 N HCl and the resultant solid was filtered and recrystallized from methanol to give 3.35 g (59% yield, mp 50°-52°) of 3-octadecyloxyacetophenone.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1)C.O.[OH-].[Li+]>C1COCC1>[F:19][C:16]([F:17])([F:18])[C:14]1[O:13][N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:20])=[O:3])=[CH:6][CH:7]=2)[CH:15]=1
Reactant: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution of 4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid ethyl ester (Preparative Example 9, 2.25 g, 7.86 mmol) in THF (20 mL) was treated with an aqueous solution (5 mL) of lithium hydroxide monohydrate (660 mg, 15.72 mmol) and allowed to stir for 16 hr. The reaction was then evaporated to a small volume and treated with a 1 N aqueous hydrochloric acid solution (25 mL) and the resulting solids filtered, washed with water and air dried to afford product as a colorless solid (1.48 g, 73%). 1H NMR (DMSO-d6) 8.06 (s, 4 H), 8.13 (s, 1 H). 13C NMR 106.5, 118.0 (q, J=270), 127.9, 130.8, 131.2, 132.4, ˜150 quartet not resolved from baseline noise, 133.8, 162.8, 167.3. 19F NMR −63.6. LC/MS 6.04 min, [M+1]+ 258.
Reaction SMILES: [C:1]([NH:9][C:10](=[N:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:16][CH:15]=1)SC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][NH2:36]>CCO>[CH3:34][NH:33][C:29]1[N:28]=[C:27]([C:26]2[C:21]([O:20][C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:10]4[NH:9][C:1]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:36][N:35]=4)=[CH:15][CH:16]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:32]=[CH:31][N:30]=1
Reactant: NN
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N=C(NC(=O)c3ccccc3)SC)cc2)n1
Solvent: CCO
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)[nH]3)cc2)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A slurry of 1-benzoyl-2-methyl-3-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)isothiourea (0.174 g, 0.37 mmol) and anhydrous hydrazine (0.35 ml, 11 mmol) in EtOH was sealed and heated to 80° C. After 16 h, a yellow precipitate formed. The reaction was cooled to ambient temperature, filtered, rinsing with 2×1 mL EtOH, and the solid was dried in vacuo to give N-methyl-4-(2-(4-(5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=437 [M+H]+. Calc'd for C24H20N8O: 436.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:16])[CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.[Ag]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:16])[CH2:14][O:15][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CO)C1
Agent: O=[Ag]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)COCc2ccccc2)C1
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of (S)-3-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (294.0 mg, 1.3 mmol) in DCM (6.3 mL) at room temperature, was added benzyl bromide (181.4 μL, 1525 μmol) followed by silver(II) oxide (472.4 mg, 3.8 mmol). The resulting mixture was stirred overnight. The mixture was filtered and the filtrate was subjected to same amount of silver (II) oxide and benzyl bromide and stirred overnight. The mixture was concentrated and the residue was purified by flash chromatography (12 g silica gel, 0-50% EtOAc/Hexanes). Desired fractions were combined and concentrated to yield the title compound as a colorless oil (165.6 mg).
Reaction SMILES: [C:1](Cl)(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH2:27]([OH:31])[CH2:28][CH2:29][OH:30].C(N(CC)CC)C>C(Cl)Cl>[OH:30][CH2:29][CH2:28][CH2:27][O:31][C:1](=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: OCCCO
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)OCCCO
Temperature: 0 °C

Procedure:
A solution of z-15-tetracosenoyl chloride, prepared according to Description 1, (0.129 mol, 49.7 g) in methylene chloride (500 mL) was added dropwise (over a period of 2.5-3 h) to a mixture of propane-1,3-diol (0.780 mol, 58.9 g) and triethylamine (0.323 mol, 32.6 g) in methylene chloride (1200 mL) at 0° C. under nitrogen. The mixture was left stirring in the ice bath for another 2 h, until TLC (80:18:2 petroleum ether-ethyl ether-acetic acid) showed that the by-product of the reaction started to form (Rf product: 0.16; by-product: 0.63). The solution was washed with 2M sulphuric acid (2×150 mL), saturated sodium bicarbonate (3×300 mL) and saturated sodium chloride (2×300 mL). It was finally dried over anhydrous sodium sulphate, concentrated and purified by flash chromatography on silica gel (7:3 petroleum ether-ethyl ether) to yield 1-hydroxy-3-(z-15-tetracosenoyloxy)propane as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:15][C:14](=O)[C:6]2=[CH:7][C:8]3[C:13]([N:5]2[N:4]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.P(Cl)(Cl)([Cl:19])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:19][C:14]1[C:6]2=[CH:7][C:8]3[C:13]([N:5]2[N:4]=[C:3]([S:2][CH3:1])[N:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nn2c(cc3ccccc32)c(=O)[nH]1
Solvent: CCN(CC)c1ccccc1
Product: CSc1nc(Cl)c2cc3ccccc3n2n1
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A mixture of 2-methylsulfanyl-3H-[1,2,4]triazino[1,6-a]indol-4-one (3.00 g, 13.0 mmol), phosphoryl chloride (6.04 mL, 64.8 mmol), and N,N-diethylaniline (4.0 mL, 25.0 mmol) was allowed to sit for 30 min at room temperature and then refluxed for 1 hour. The mixture was then concentrated and the residue was azeotroped with toluene, cooled, and poured over ice. The resulting mixture was transferred to a separation funnel and the product was extracted in ether with 10-20% dichloromethane. The combined organic extracts were washed with dilute and cold aqueous HCl. then with dilute cold NaHCO3, and finally with cold water, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (ISCO, Silicagel, EtOAc/Hexanes 10-15%) to provide 4-chloro-2-methylsulfanyl-[1,2,4]triazino[1,6-a]indole (2.30 g, 71%). 1H-NMR (CDCl3) δ 8.11 (d, J=8.5 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.49 (m, 1H), 7.41 (m, 1H), 7.14 (s, 1H), 2.68 (s, 3H); LC/MS (ESI+): 250.5 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:18]([Cl:19])=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][C:10]=1[Cl:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C:9]1[C:10]([Cl:20])=[CH:11][C:12]([CH2:13][OH:14])=[CH:17][C:18]=1[Cl:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(Cl)cc(CO)cc1Cl
Temperature: 25 °C
Yield: 25.9 %

Procedure:
To a stirred and cooled (0° C.) solution of 7.70 g (23.0 mmol) of the product of Step A dissolved in 50 mL of anhydrous THF was added 23.0 mL (23.0 mmol) of a 1M solution of lithium aluminum hydride in THF. After the addition was complete the reaction mixture was allowed to warm to room temperature and stirred 3.5 hours. The stirred reaction was then quenched by dropwise addition of 0.88 mL water, then 0.88 mL of 15% NaOH, and finally 2.62 mL water. The reaction mixture was then filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1N HCl, saturated NaHCO3, dried (MgSO4), and evaporated in vacuo to afford 1.83 g (26%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9](N)=[CH:8][C:7]=1[Cl:14])(=[O:3])[CH3:2].[N:15]([O-])=O.[Na+].[O-:19][S:20]([O-:22])=O.[Na+].[Na+]>CN(C=O)C.Cl>[C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([S:20](=[O:22])(=[O:19])[NH2:15])=[CH:8][C:7]=1[Cl:14])(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: O=S([O-])[O-]
Reactant: CC(=O)OCc1c(F)cc(N)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(F)cc(S(N)(=O)=O)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
To a solution of 4-amino-2-chloro-6-fluorobenzyl acetate (5.2 g, 0.024 mol) in DMF (10 mL) at 0° C. was added slowly 3M HCl (100 mL) followed by NaNO2 (2 g, 0.029 mol). After stirring at the same temperature for 20 min, the mixture was added dropwise to a solution of Na2SO3 (12 g, 0.096 mol) and CuSO45H2O in 3N HCl (100 mL). After stirring for 30 min, the reaction mixture was then poured into ice-water and extracted with EtOAc. The combined extracts were concentrated, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was dissolved in THF and added dropwise to a stirred solution of NH4OH (17 mL) in THF (17 mL) at 5° C. After stirring 30 min, the mixture was concentrated under reduced pressure and extracted with EtOAc. The combined extracts were washed with H2O, dried over anhyd MgSO4, concentrated and purified by column chromatography (Hex/EtOAc=5:1) to afford 2-chloro-6-fluoro-4-sulfamoylbenzyl acetate (1.02 g, 15%, 3 steps) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (t, 1H), 7.59 (dd, 1H), 5.28 (d, 2H), 5.16 (s, 2H), 2.10 (d, 3H); MS (EI) m/z 303 (M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][C:21](=O)[CH3:22])=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:34][CH2:35][C@H:36]([OH:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][CH:21]([NH:34][CH2:35][C@H:36]([OH:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:22])=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc2c(c1)cc(C(=O)OCc1ccccc1)n2Cc1ccc([N+](=O)[O-])cc1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(Cc1ccc2c(c1)cc(C(=O)OCc1ccccc1)n2Cc1ccc([N+](=O)[O-])cc1)NC[C@H](O)COc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 1-(4-nitro-benzyl)-5-(2-oxo-propyl)-1H-indole-2-carboxylic acid benzyl ester (540 mg, 1.22 mmol) and 1-amino-3-phenoxypropan-2(S)-ol (245 mg, 1.46 mmol) in dichloroethane (20 ml) was added powdered sodium sulfate (1.73 g, 12.2 mmol), and the mixture was stirred for about one hour at room temperature under nitrogen. Acetic acid (87.9 mg, 0.084 ml, 1.46 mmol) and sodium triacetoxyborohydride (388 mg, 1.83 mmol) were added. After about 6 hours, additional sodium triacetoxyborohydride (194 mg, 0.915 mmol), acetic acid (0.2 ml, 3.5 mmol) and 1-amino-3-phenoxypropan-2(S)-ol (122 mg, 0.73 mmol) were added, and the mixture was stirred for about two days at room temperature under nitrogen. The reaction was then diluted with methylene chloride, washed with dilute sodium bicarbonate and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was flash chromatographed on silica (55 g), eluting with 5% methanol/methylene chloride, to give the title compound (500 mg) as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)#[N:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:45]2[CH:46]=[CH:47][C:42]([C:40]#[N:41])=[CH:43][CH:44]=2)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(C#N)cc2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
To a solution of N-carbobenzyloxy-trans-4-hydroxy-L-proline methyl ester (10.0 g, 35.8 mmol) in 200 mL of anhydrous THF under N2 was added triphenylphosphine (10.6 g, 3 9.4 mmol) and 4-cyanophenol (4.7 g, 39.4 mmol) . This solution was cooled to 0° C. and then treated with diethylazodicarboxylate (6.3 mL, 39.4 mmol), added dropwise over 30 minutes The reaction was warmed to room temperature and stirred for 2 days. The solvent was removed in vacuo and the residue chromatographed (SiO2, 30% ethyl acetate/hexanes) to provide 12.1 g (89%) of N-carbobenzyloxy-4-(cis)-(4-cyanophenoxy)-L-proline methyl ester as a colorless oil. MS.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([O:28][CH3:29])[C:16]=2[C:17](O)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:21]=[C:20]([O:28][CH3:29])[C:16]=2[C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])[CH2:14][CH2:13]1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: COc1cc(C(F)(F)F)cc(C2CC2)c1C(=O)O
Product: COc1cc(C(F)(F)F)cc(C2CC2)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, light yellow solid, MS: m/e=397.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclopropyl-6-methoxy-4-trifluoromethyl-benzoic acid (intermediate AS).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH:32]([C:40]([O:42]C)=[O:41])[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[C:23]([CH3:30])[C:22]=3[CH3:31])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[C:40]([CH:32]([N:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[S:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[C:23]([CH3:30])[C:22]=1[CH3:31])(=[O:20])=[O:19])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([OH:42])=[O:41]
Reactant: COC(=O)c1ccc(-c2ccc(CN(C(Cc3ccccc3)C(=O)OC)S(=O)(=O)c3c(C)cc(OC)c(C)c3C)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc(-c3ccc(C(=O)O)o3)cc2)C(Cc2ccccc2)C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-(4-{[(1-Methoxycarbonyl-2-phenyl-ethyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-methyl}-phenyl)-furan-2-carboxylic acid methyl ester (16 mg, 0.026 mmol.) in THF:H2O:MeOH (3:1:2) (1 ml.), was added LiOH in water (1N) (0.2 ml. 0.26 mmol.). The reaction mixture was stirred at room temperature during 1 hr. TLC monitored the progress of the reaction. When the reaction was completed, the mixture was concentrated under reduced pressure on a rotary evaporator. The residue was treated with a solution 20% of KHSO4 and extracted in EtOAc. The EtOAc layer was dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by silica chromatography using 90% EtOAc, 10% MeOH and 1 drop of AcOH, afforded 5-(4-{[(1-Carboxy-2-phenyl-ethyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-methyl}-phenyl)-furan-2-carboxylic acid. 1HNMR (Varian 400 MHz, DMSO) δ7.37 (d, 2H, J=8.5 Hz, HPh), 7.27 (d, 2H, J=8.3 Hz, HPh), 7.13 (m, 6H, HPh), 6.69 (d, 1H, J=3.2 Hz, furanH), 6.58 (d, 1H, J=3.2 Hz, furanH), 6.50 (s, 1H, MTRH), 4.81 (d, 1H, J=15.5 Hz, NCH2Ph), 4.41 (d, 1H, J=15.9 Hz, NCH2Ph), 4.06 (dd, 1H, J=3.5 and 9.5 Hz, CHCH2), 3.64 (s, 3H, OCH3), 3.10 (dd, 1H, J=9.5 and 12.6 Hz, CHCH2), 2.65 (dd, 1H, J=3.8 and 12.6 Hz, CHCH2), 2.49 (s, 3H, ArCH3), 2.38 (s, 3H, ArCH3), 1.92 (s, 3H, ArCH3) ppm. MS 576.5 (M−).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([Cl:34])=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:43])=[O:42]>>[ClH:34].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:51][CH2:50]3)=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)Cl)cc1
Agent: Cl
Product: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)cc1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12c) and 1-(2-methanesulfonylethyl)-piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 665.5 [(M+H)+]
Reaction SMILES: [CH2:1]([N:16]=[C:17]=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C=C(CO)CO.[C:25](=[C:28]([CH2:31]O)[CH2:29][OH:30])([CH3:27])[CH3:26]>>[CH2:1]([NH:16][C:17]([CH2:31][C:28](=[C:25]([CH3:27])[CH3:26])[CH2:29][OH:30])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCN=C=O
Reactant: CC(C)=C(CO)CO
Agent: C=C(CO)CO
Product: CCCCCCCCCCCCCCCNC(=O)CC(CO)=C(C)C

Procedure:
Following the procedure described in Preparation 3, but replacing octadecyl isocyanate with pentadecyl isocyanate and 2-methylenepropane-1,3-diol with 2-isopropylidenepropan-1,3-diol, the desired product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:36].IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C@@H:10]([CH3:36])[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of (S)-1-t-butoxycarbonyl-5-t-butyldiphenylsiloxymethyl-pyrrolidine-2-one (15 g, 33 mmol) in THF (250 mL) at -78° C. a 1M solution of LiN(SiMe3)2 (35 mL, 35 mmol) was slowly added. After stirring for 1 hr, iodomethane (6.2 mL, 100 mmol) was added. The reaction mixture was allowed to stir for another 2 hr at -78° C. and then quenched with acetic acid. The mixture was concentrated into half volume, diluted with water (200 mL) and extracted with ethyl acetate (EtOAc). The combined extracts were washed with water, brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue purified by flash column chromatography on silica gel, eluted with EtOAc:Hexane (1:2.5). The desired (2S,5R) isomer was eluted first from the column and crystallized in hexanes to give 7.3 g (47%) of product as white crystals. mp=84°-85° C. 1H NMR (200 MHz, CDCl3): δ 7.62 (m, 5H), 7.40 (m, 5H), 4.12 (m, 1H), 3.85 (dd, J=10.3, 4.7 Hz, 1H), 3.72 (dd, J=10.3, 2.8 Hz, 1H), 2.82 (m, 1H), 2.31 (dd, J=12.7, 8.9 Hz, 1H), 1.75 (m, 1H), 1.42 (s, 9H), 1.20 (d, J=7.0 Hz, 3H), 1.02 (s, 9H).