Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18].[N+:20]([O-])([OH:22])=[O:21]>C(OCC)(=O)C>[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([N+:20]([O-:22])=[O:21])[C:10]=1[Br:18]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Br
Temperature: 40 °C
Yield: 65 %

Procedure:
Concentrated sulfuric acid (20 mL) was slowly added to 2-bromo-5-nitro-benzoic acid methyl ester (20.52 g, 78.91 mmol) with stirring. After a few minutes, fuming nitric acid (20 mL) was added and the mixture was capped and heated at 40° C. for approximately 60 hours at which point the flask was cooled to ambient temperature, carefully opened, and the reaction was poured onto ice water and ethyl acetate. The product was extracted into ethyl acetate and washed twice with H2O, twice with saturated aqueous NaHCO3, brine, dried (Na2SO4), and filtered to afford Intermediate 6(a) (15.64 g, 51.26 mmol) as a cream solid in 65% yield.
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]([C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl:14]C1C([N+]([O-])=O)=CC=C(Cl)C=1C.[Br-].[K+]>>[Cl:14][C:2]1[C:3]([CH3:13])=[C:4]([C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1C#N
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [Br-]
Agent: [K+]
Product: Cc1c(Cl)ccc([N+](=O)[O-])c1C#N

Procedure:
The title compound was prepared using the method described above for preparing 3-bromo-2-methyl-6-nitrobenzonitrile, except that the reaction was carried out at 210° C. and employed 2,6-dichloro-3-nitrotoluene as the starting material. The infrared spectrum of a potassium bromide pellet of the product exhibited principal absorption peaks at 3121, 2231, 1602, 1560, 1530, and 1348 receiprocal centimeters.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][N:23]=[CH:24]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH:24]1[C:25]2[C:20](=[C:19]([C:2]#[C:1][N:3]3[C:11]4[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=4[C:5]4[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]3=4)[CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1cccc2cnccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2cccc3cnccc23)CCN(C)C1

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (194 mg, 0.866 mmol, 5-bromo-isoquinoline (150 mg, 0.721 mmol, TBAF.3H2O (680 mg, 2.15 mmol) and dichlorobis(triphenylphosphine) palladium(II) (25 mg, 0.035 mmol) was stirred at 85° C. for 5 min. The reaction mixture was diluted with water and extracted with EtOAc (3×40 mL). The organic layer was washed with water (5×30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography using silica (100:200) and 0.5% MeOH-DCM to yield 5-isoquinolin-5-ylethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 9.3 (s, 1H), 8.62 (d, 1H), 8.17 (d, 1H), 7.93 (dd, 2H), 7.6 (t, 1H), 7.57 (d, 1H), 7.23 (s, 1H), 7.17 (d, 1H), 3.65 (s, 2H), 3.07 (t, 2H), 2.93 (t, 2H), 2.6 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: Cl.[C:2]1([C:8]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+]>CO>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Reactant: N=C(N)CC1(c2ccccc2)CCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
To a stirred solution of 2-(1-phenyl-cyclopentyl)-acetamidine hydrochloride salt (281) (500 mg, 2.09 mmol) and (E)-3-benzyloxy-2-hydroxy-4-oxo-pent-2-enoic acid tert-butyl ester (4) (970 mg, 3.15 mmol) in methanol (10 mL) was added a sodium methoxide solution (25% in methanol) (1.4 mL, 6.29 mmol) at 0° C. and then the reaction mixture was allowed to warm slowly up to room temperature while stirring was continued for 16 h. After completion of the reaction, the reaction mixture was quenched with 1N HCl (5 mL) and the methanol was evaporated and water (20 mL) was added. The mixture was extracted with ethyl acetate (3×20 mL) and the phases separated. The organic part was dried and concentrated to get a crude product, which was purified by Combi-Flash column (eluted at 10-20% ethyl acetate in hexane) to obtain 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (282) (230 mg, 23.82%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18](=O)[C:17]([CH3:23])([CH3:22])[CH:16]2[C:24]([O-:26])=[O:25])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:27](OC(=O)C)(=O)C>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:20]=[CH:19][S:18][C:17]([CH3:23])([CH3:22])[C@@H:16]2[C:24]([O:26][CH3:27])=[O:25])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCS(=O)C(C)(C)C2C(=O)[O-])cc1
Product: CC#CCOc1ccc(S(=O)(=O)N2C=CSC(C)(C)[C@@H]2C(=O)OC)cc1

Procedure:
A solution of 1.50 g (3.632 mmol) of methyl (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylate-1-oxide in 20 mL of acetic anhydride was heated to reflux for 4 h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.985 g of methyl(3S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3,4-dihydro-2H-1,4-thiazine-3-carboxylate as a colorless oil. Electrospray Mass Spec 396.1 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.Cl.[N:15]1([C:21]2[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[C:1]([N:18]1[CH2:17][CH2:16][N:15]([C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)[CH2:20][CH2:19]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)COc1ccc(N2CCNCC2)cc1
Reactant: CCCCCCC/C=C/C(=O)O
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccc(OCC(=O)OCC)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl 2-[4-(1-piperazinyl)phenoxy]acetate dihydrochloride as starting raw materials, to produce ethyl 2-[4-[4-((E)-2-decenoyl)piperazin-1-yl]phenoxy]acetate (ethyl ester of Compound 47).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].O[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2Cl)cc1C
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An oven-dried 1 L round-bottomed flask was charged with compound 10.5 (33.5 g, 91.3 mmol), 4-hydroxybenzotrifluoride (16.3 g, 101 mmol), triphenylphosphine (28.7 g, 109 mmol) and THF (335 mL). Next, diethyl azodicarboxylate (17.0 mL, 110 mmol) was added dropwise at 0° C., and the reaction was stirred at room temperature for 30 min. The reaction mixture was concentrated and purified by flash chromatography (SiO2 gel 60 N, eluted with 10% AcOEt/hexanes—15% AcOEt/hexane—20% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (43.4 g). 1H NMR (400 MHz) (CDCl3) δ 7.54 (2H, d, J=8.8 Hz); 7.42 (1H, d, J=1.6 Hz); 7.34-7.30 (2H, m); 7.09 (1H, dd, J=1.8, 8.2 Hz); 6.99 (2H, d, J=8.8 Hz); 6.76-6.72 (2H, m); 5.00 (2H, s); 4.68 (2H, s); 4.28 (2H, q, J=7.1 Hz); 2.29 (3H, s); 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7](Cl)(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1C=CC=CC=1>[C:7]([O:4][CH2:3][CH:2]([SH:1])[CH2:5][SH:6])(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OCC(S)CS
Agent: Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)OCC(S)CS
Yield: 38.8 %

Procedure:
2,3-Dimercaptopropanol (12.0 g) is dissolved in benzene (75 ml) and thereto is added dropwise lauroyl chloride (21.5 g) with stirring. The mixture is refluxed with stirring for about 3.5 hours until the generation of hydrogen chloride is ceased to evolve. The mixture is then distilled to remove benzene and the resulting residue is distilled to give 2,3-dimercaptopropyl laurate (11.5 g) as a yellow oily substance, b.p. 167° - 175° C/1 mmHg.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH:3]([NH:14]C(=O)O)[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:14][CH:3]([CH:2]([CH3:1])[CH2:18][CH3:19])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5]
Reactant: CCC(C)C(NC(=O)O)C(=O)NCc1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)C(N)C(=O)NCc1ccccn1

Procedure:
To 2.35 g of product from Example 1 in 10 ml of methylene chloride is added 2.8 ml of trifluoroacetic acid. The reaction is heated at 80°-90° C. for 41/2 hours and then concentrated in vacuo to give 3.6 g of the desired product as tris-trifluoroacetic acid salt.
Reaction SMILES: C(O/[C:4](=[C:6]1/C(=O)O[C:9](=[O:17])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]/1=2)/[CH3:5])C.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21].C(O)C>>[C:24]([O:23][C:19](=[O:22])[NH:20][N:21]1[C:4]([CH3:5])=[CH:6][C:11]2[C:10](=[C:15]([F:16])[CH:14]=[CH:13][CH:12]=2)[C:9]1=[O:17])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCO/C(C)=C1/C(=O)OC(=O)c2c(F)cccc21
Solvent: CCO
Product: Cc1cc2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 56 %

Procedure:
A suspension of 4-[1-Ethoxy-eth-(E)-ylidene]-8-fluoro-2-benzopyran-1,3-dione (5.25 g, 21.0 mmol), tert-butyl carbazate (3.43 g, 26.0 mmol) in ethanol (25.0 mL, 428 mmol) was heated under reflux for 30 min with intensive gas formation. The obtained clear purple solution was allowed to cool to r.t. with formation of white precipitate, cooled on dry ice—ethanol bath, filtered, washed with cold ethanol (3×10 ml) to give 3.436 g of the pure title product. Supernatant was quenched with water (200 ml), sat. aq. NaHCO3 (50 ml) and diisopropyl ether (ca 20 ml), shaked, then quenched with heptane (100 ml) and sonicated. White precipitated was separated from this bilayer system by filtration to give 470 mg more of the title product; total yield 63.7%. LC-MS (m/z) 293.0 (traces, MH+), fragments: 237.3, 193.2 (major, M-Boc), 176.3. 1H NMR (500 MHz, DMSO-d6), 88:12 mixture of rotamers A and B: 1.29 (s, 1.1H, tBu of B), 1.47 (s, 7.9H, tBu of A), 2.21 (s, 2.6H, Me of A), 2.21 (s, 0.4H, Me of B), 6.52 (s, 1H, C4-H), 7.17 (dd, J=8.3 Hz, J (H—F)=11.6 Hz, 1H, C7-H), 7.36 (d, J=7.9 Hz, 1H, C5-H), 7.68 (dt, J=7.8 Hz, J (H—F)=4.9 Hz, 1H, C6-H), 9.33 (s, 0.12H, NH of B), 9.8 (s, 0.88H, NH of A). 13C APT NMR (125.76 MHz, dmso-d6=39.89 ppm): 18.96 (Me), 27.99 (tBu of B), 28.31 (tBu of A), 80.98 (C of tBu), 103.59 (C4-H), 112.81 (d, J=20.9 Hz, C7-H), 113.25 (d, J=5 Hz, C9), 122.03 (d, J=3.5 Hz, C5-H), 134.62 (d, J=9.9 Hz, C6-H), 139.64 (C10), 143.96 (C3), 155.39 (NHCO2), 157.88 (d, J=4.5 Hz, C1=O), 161.77 (d, J=262 Hz, C8-F). 19F NMR (470.59 MHz): −111.47 (unres. dd, J=11 Hz, J<4 Hz, rotamer A), −111.35 (unres. dd, J=10.5 Hz, rotamer B). VT 1H NMR (T=353 K, 250 MHz): all doubled signals corresponding to rotamers A and B have coalesced.
Reaction SMILES: OO.[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([OH:31])[C:25]([CH3:33])([CH3:32])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)=[O:8].S([O-])([O-])=O.[Na+].[Na+].[C:40]([OH:44])([CH3:43])([CH3:42])[CH3:41]>>[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:41][C:40]([OH:44])([CH3:43])[CH3:42])[C:25]([CH3:33])([CH3:32])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH2:41][C:40]([OH:44])([CH3:43])[CH3:42])[C:12]([CH3:20])([CH3:19])[CH2:11]1)=[O:8]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(OC(=O)CCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethyl-pieridin-4-yl) glutarate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqeuous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=1)(=[O:8])=[O:7].B(Br)(Br)[Br:18]>C(Cl)Cl>[Br:18][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)(=[O:8])=[O:7]
Reactant: COc1cccc(S(=O)(=O)NCCCO)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(NCCCBr)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Hydroxy-propyl)-3-methoxy-benzenesulfonamide (0.478 g, 1.95 mmol) in CH2Cl2(10 mL) at 0° C. was treated with BBr3 (9.74 mL of a 1M solution in CH2Cl2, 9.74 mmol) then left to warm to room temperature. After 1 h, the reaction mixture was concentrated in vacuo, neutralized to pH 6 with aqueous saturated NaHCO3 solution, and extracted with CH2Cl2 (3×20 mL), dried (MgSO4), filtered and concentrated to give the title compound. MS (M+1) 294.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]23[CH2:14][CH2:13][CH2:12][N:11]2[C:10](=[O:15])[N:9]([C:16]2[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([Cl:23])[CH:17]=2)[C:8]3=[O:24])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[N:52]1[CH:53]=[CH:54][C:49]([CH2:48][CH2:47][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]34[CH2:14][CH2:13][CH2:12][N:11]3[C:10](=[O:15])[N:9]([C:16]3[CH:17]=[C:18]([Cl:23])[N:19]=[C:20]([Cl:22])[CH:21]=3)[C:8]4=[O:24])=[CH:25][CH:26]=2)=[CH:50][CH:51]=1
Reactant: OCCc1ccncc1
Reactant: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)C2(Cc3ccc(O)cc3)CCCN12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)C2(Cc3ccc(OCCc4ccncc4)cc3)CCCN12

Procedure:
To a mixture of the compound from Example 196 (0.15 g), Ph3P (0.22 g) and 4-hydroxyethylpyridine ((0.070 mL) in anhydrous CH2Cl2 (3 mL) was added DEAD (0.15 mL) under N2. After 30 minutes the reaction mixture was concentrated and the residue was purified via HPLC to give the desired compound (97 mg). MS m/z 498(MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:45])[F:47])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A solution of triphenylphosphine (312 mg, 1.19 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (212 mg, 1.19 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 70, 300 mg, 0.99 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (205 mg, 2.18 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide (171 mg, 45%) as a pale yellow foam: mp 40–44° C. (foam to gel); EI-HRMS m/e calcd for C20H20F4N2O (M+) 380.1512, found 380.1519.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1)=O)(C)(C)C>O1CCOCC1.CO>[CH3:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH2:9])=[CH:16][CH:15]=1
Reactant: CC(C)(C)CCc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)CCc1ccc(CN)cc1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
Add 4N hydrogen chloride in dioxane (15 mL) to a stirred solution of N-(tert-butoxycarbonyl)-4-(3,3-dimethyl-butyl)-benzylamine (1.25 g, 4.29 mmol) in methanol (20 mL) and stir at room overnight. Concentrate in vacuo and wash the solid with diethyl ether. Suspend the solid in dichloromethane and saturated aqueous NaHCO3 and stir until both phases are clear (15 min). Extract the aqueous phase twice with dichloromethane. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to give the title compound as an oil (0.654 g, 80%) that was used without any further purification. MS (ES+) m/z: 192 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Ca+2]>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of ethyl 3-(4-hydroxyphenyl)lactate (22.4 g) in N,N-dimethylformamide (220 ml) were added benzyl bromide (21.9 g) and calcium carbonate (35.3 g), and the reaction mixture was stirred at 50° C. for 2 hours. The reaction solution was partitioned between ethyl acetate and water, and then the separated ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate=7/3) to give the target compound (31.0 g) as a pale yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].I[CH3:18]>O1CCCC1.C(OCC)(=O)C>[CH3:18][O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.42 h
Yield: 72.2 %

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-hydroxypiperidine-1-carboxylate (Preparation 127, 1.8 g, 9.2 mmol) in anhydrous tetrahydrofuran (40 ml) was added sodium hydride (60% dispersion in oil, 0.39 g, 9.2 mmol) in portions. The resulting mixture was stirred for 25 min then iodomethane (2.83 g, 20 mmol) was added dropwise and the reaction mixture was stirred for 17 h. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with brine (5% solution, 200 ml). The aqueous layer, was extracted with ethyl acetate (2×50 ml) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography on silica gel (100 g) eluting with dichloromethane:methanol (100:1 and then 50:1) to give a yellow oil. The trace of iodine was removed by dissolving the product in diethyl ether (60 ml) and washing with aqueous sodium metabisulphite (5% solution, 1×40 ml), water (2×40 ml) and aqueous sodium hydrogen carbonate (5% solution, 40 ml). The organic extracts were dried (MgSO4) and concentrated in vacuo to give the desired product as a colourless oil (1.43 g).
Reaction SMILES: [C:1]([CH:8]([CH2:12][CH3:13])[C@@H:9](N)[OH:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC1(C)[N:20]([O])C(C)(C)CCC1.[Br-].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O>[C:4]([O:3][C:1]([C@:8]([NH2:20])([CH2:12][CH3:13])[CH:9]=[O:10])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: CCC(C(=O)OC(C)(C)C)[C@@H](N)O
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC[C@](N)(C=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 77 %

Procedure:
To a solution of (S)-2-Boc-aminobutanol (50 g; 264 mmol) in dichloromethane (500 mL) and water (350 mL) were added at 20° C. TEMPO (0.01 eq), sodium bromide (1 eq) and sodium hydrogencarbonate (3 eq). The reaction mixture was stirred at 0° C. and diluted bleach (1.3 eq, 450 mL) was added over 40 min. The reaction mixture was stirred for 30 min. at 0° C. and then quenched with aq. thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacuo to dryness, giving (S)-2-(tert-butoxycarbonyl)-amino-butyraldehyde as a low-melting solid (38.1 g; yield: 77%). C9H17NO3; MW=187.2; Tmelt=44° C.; NMR (CDCl3, ppm): 0.97 (t, J=7 Hz, 3H), 1.45 (s, 9H), 1.68 (m, 1H), 1.91 (m, 1H), 4.20 (lq, J=6.5 Hz, 1H), 5.09 (1s, 1H (mobile)) and 9.59 (s, 1H); SM (EI; m/z): 158 (M+—CHO), 102, 57.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][C:25]([F:28])([F:27])[F:26])[C:17]([O:19]C)=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1>CO>[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][C:25]([F:26])([F:27])[F:28])[C:17]([OH:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(OC(F)(F)F)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OC(F)(F)F)c(OC2CCCC2)c1
Yield: 71.2 %

Procedure:
Potassium carbonate (0.43 g) and water (2 mL) are added to a solution of methyl 3-cyclopentyloxy-4-trifluoromethoxybenzoate (0.78 g) in methanol (10 mL) and the mixture is heated under reflux for 2 hours. Methanol is evaporated off under reduced pressure, and the crude material is partitioned between water (75 mL) and ethyl acetate (75 mL). The organic layer is separated, and the aqueous layer is acidified with hydrochloric acid (2 N) and extracted with ethyl acetate (2×75 mL). The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure, to give 3-cyclopentyloxy-4-trifluoromethoxybenzoic acid (0.53 g), in the form of a white solid, m.p. 116°-118° C. [NMR (CDCl3): 7.72(d,1H,J=2Hz); 7.7(dd,1H,J=8Hz, 2Hz); 7.3(d,1H,J=8Hz);4.9(m,1H,);2.0-1.6(m,8H)].