Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([NH:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.Cl.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1>C1(C)C=CC=CC=1>[C:3]1([CH:2]([N:13]([CH2:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)[CH3:1])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Reactant: FC(F)(F)c1cccc(CCCBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(c1cccc2ccccc12)N(CCCc1cccc(C(F)(F)F)c1)CCCc1cccc(C(F)(F)F)c1
Temperature: 27.5 °C

Procedure:
To a stirred solution of Cinacalcet hydrochloride (1, 10 g, 0.028 mol) in toluene (150 mL) was added potassium carbonate (7.74 g, 0.056 mol) followed by 1-(3-bromopropyl)-3-(trifluoromethyl)benzene (5, 14.95 g, 0.056 mol) under stirring at 25-30° C. The reaction mass was heated and stirred at 110-111° C. for 48 h. Upon completion of the reaction (by TLC), the reaction mass was cooled and quenched with water (100 mL). The organic layer was separated, washed with water (100 mL), and concentrated under reduced pressure to obtain a thick oil. The crude oil was then purified by column chromatography on silica gel (70 mm×60 cm column) by eluting with chloroform to afford the title compound as a thick transparent oil. Yield: 10.50 g (69.03%); HPLC purity: 91.22%; IR (NaCl) cm−1: 3441, 3049, 2940, 2861, 1596, 1492, 1449, 1331, 900, 702, 661; MS: m/z=544.0 [M+H]+; 1H NMR (400 MHz, CDCl3): δ=1.35-1.37 (d, 3H), 1.57-1.63 (m, 4H), 2.42-2.46 (t, 4H), 2.52-2.55 (t, 4H), 4.60-4.62 (m, 1H), 7.23-7.25 (d, J=8.0 Hz, 1H), 7.32 (s, 2H), 7.37-7.41 (t, 3H), 7.47-7.51 (m, 6H), 7.76-7.78 (d, J=8.0 Hz, 1H), 7.87-7.89 (dd, 1H), 8.42-8.44 (d, J=8.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ=15.46 (CH3), 29.38 (CH2), 32.99 (CH2), 50.03 (CH2), 56.90 (CH), 122.68, 122.72, 122.76, 123.37, 124.78, 124.83, 124.86, 124.91, 125.58, 125.68, 125.72 (CF3), 128.88, 129.28, 129.33, 129.40, 129.49, 129.58, 129.60, 129.91, 132.06, 132.63, 134.04, 140.62, 144.01.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=O)[CH2:4][CH2:3]1.[CH2:13]([OH:16])[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOCC>[CH2:13]1[O:16][C:8]([CH:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)([O:10][CH2:11][CH3:12])[O:15][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCOC1(C2CCC(=O)CC2)OCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (15.01 g, 88.16 mmol) was combined with ethylene glycol (21 mL, 4.27 equiv.) and p-toluenesulfonic acid monohydrate (0.2 g, 0.012 equiv.) in anhydrous toluene (50 mL), and the mixture was stirred 14 h at room temperature. The reaction was diluted with ether (200 mL) and was washed with H2O (2×200 mL), saturated sodium bicarbonate (100 mL) and brine (80 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to yield 18.15 g ethyl 4-oxocyclohexanecarboxylate ethylene ketal (96% yield). LCMS (m/z): 214.8 (MH+), 0.74 min.
Reaction SMILES: [OH-].[K+].[O:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH2:5][CH2:4]1.[CH3:14][C:15]1[N:19]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:17][C:16]=1[CH:39]=O>CO>[CH3:14][C:15]1[N:19]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]=[N:17][C:16]=1/[CH:39]=[C:5]1\[CH2:4][O:3][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]\1=[O:13]
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCOc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(/C=C2\COc3ccccc3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of potassium hydroxide (0.5 g) in methanol (5 ml) was added to a solution of 4-chromanone (0.84 g) and 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (2 g) in methanol (25 ml) with warming, and the resulting solution was stirred at 50° for 3 h. The resultant precipitate was filtered off, washed with methanol (25 ml) and dried to give the title compound (2.6 g), m.p. 231°-233°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][CH:6]=1.Cl.[Br-:15].[K+].OO>C1(C)C=CC=CC=1>[Br:15][C:7]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)c1nc(C)cs1
Reactant: [Br-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(Br)c1nc(C)cs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
To a solution of Intermediate 104 (7.57 g, 38.0 mmol) in toluene (100 mL) was added hydrochloric acid (3.43 mL, 41.8 mmol). The mixture was kept at room temperature for 10 minutes. The mixture was cooled to 0° C. and potassium bromide (PANREAC, 4.97 g, 41.8 mmol) and hydrogen peroxide (4.59 mL, 49.4 mmol) were added. Reaction mixture was stirred at 0° C. for 3 hours and then was quenched with 1N Na2S2O3 (150 mL) and saturated NaHCO3 aqueous solution (150 mL). Organic phase was separated and the aqueous phase was extracted with EtOAc (2×150 mL). Combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound (10.22 g, 36.7 mmol, 97% yield) as oil. 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.43 (m, 1H), 4.21-4.28 (q, 2H), 2.30-2.35 (m, 6H), 1.19-1.24 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][S:11][C:12]2[NH:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=2)=[CH:5][C:4]=1[F:23])#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:22])[CH2:10][S:11][C:12]2[NH:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=2)=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: CCOC(=O)c1cnc(SCC(=O)c2ccc(C#N)c(F)c2)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cnc(SCC(O)c2ccc(C#N)c(F)c2)[nH]1

Procedure:
The product from Step H (3.00 g, 9.00 mmol) was suspended in methanol (20 mL). Sodium borohydride (340 mg, 9.00 mmol) was added in portions at 0° C., and the suspension was stirred until it became homogeneous (1 hour). The reaction was quenched by the addition of saturated aqueous ammonium chloride until hydrogen evolution ceased. The resulting suspension was concentrated in vacuo and then partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title product as an off-white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [NH2:1][CH:2]([CH:5]([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:7][C:6]([F:9])([F:8])[CH:5]([CH:2]1[CH2:3][O:4][C:19](=[O:21])[NH:1]1)[CH3:10]
Reactant: CC(C(N)CO)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C1COC(=O)N1)C(F)(F)F

Procedure:
To a solution of 2-amino-4,4,4-trifluoro-3-methylbutan-1-ol (580 mg, 3.69 mmol) in DCM (13 ml) was added triethylamine (1.132 ml, 8.12 mmol) and added dropwise a solution of triphosgene (329 mg, 1.107 mmol) in 1 mL in DCM (3 ml) over 10 min. The reaction mixture was washed with sat. NH4Cl solution (13 ml) dry, and concentrated in vacuo. Afforded 450 mg (It yellow solid). Used crude in the next step. 1H NMR (400 MHz, CDCl3) b 5.91 (d, J=13.3 Hz, 1H), 4.61-4.34 (m, 1H), 4.22-4.00 (m, 2H), 3.05 (q, J=7.3 Hz, 1H), 2.54-2.14 (m, 1H), 1.34 (t, J=7.3 Hz, 1H), 1.17 (d, J=7.1 Hz, 2H), 1.09 (d, J=7.1 Hz, 1H). MS 183.0507 m/z.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH2:28])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:26])(=[O:27])[NH2:28])[CH:10]=1
Reactant: NCc1cc(F)ccc1S(N)(=O)=O
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(N)(=O)=O
Yield: 8.1 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g), 2-(aminomethyl)-4-fluorobenzenesulfonamide hydrochloride obtained in Step 3 (1.23 g) and potassium carbonate (1.76 g) were stirred in ethanol (20 ml) overnight at 70° C. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→4:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (68 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[C:14]([N+:24]([O-:26])=[O:25])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH3:23][CH:20]1[CH2:19][CH2:18][N:17]([C:15]2[C:14]([N+:24]([O-:26])=[O:25])=[CH:13][CH:12]=[C:11]([N:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:10][CH2:9]3)[N:16]=2)[CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: CC1CCN(c2nc(N3CCN(C(=O)CCl)CC3)ccc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCN(c2nc(N3CCN(C(=O)CN4CCOCC4)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 76 %

Procedure:
A solution of 2-chloro-1-[4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-ethanone (as prepared in the previous step, 0.18 g, 0.48 mmol) in CH2Cl2 (10 mL) was treated with Et3N (0.10 mL, 0.72 mmol) and morpholine (46 μL, 0.53 mmol). The reaction was stirred at room temperature for 18.5 h. The reaction was diluted with CH2Cl2 and washed with water. The aqueous layer was extracted further with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.16 g, 76%) as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.21 (d, 1H, J=9.2 Hz), 6.03 (d, 1H, J=9.2 Hz), 3.85-3.63 (m, 12H), 3.32-3.22 (m, 2H), 3.05-2.93 (m, 2H), 2.66-2.50 (m, 2H), 1.75-1.66 (m, 2H), 1.66-1.60 (m, 2H, partially obscured by water peak), 1.44-1.38 (m, 1H), 1.37-1.16 (m, 4H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C21H32N6O4, 433.2 (M+H), found 432.9.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([NH2:23])=[O:22])[CH:16]=[N:15][C:14]=2[C:26]#[N:27])=[CH:8][CH:7]=1.[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]([C:26]([NH2:27])=[O:34])=[N:15][CH:16]=[C:17]([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([NH2:23])=[O:22])[N:18]=2)=[CH:8][CH:7]=1
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3nnco3)cc2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc(-c3nnco3)cc2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(6-(4-(1,3,4-oxadiazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)butanamide (57 mg, 0.156 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (3 mg). MS 383.3 (M+H); UV 204.7, 275.5, 329.8 nm; t 0.449 min.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:29]([CH:33]1[CH2:35][O:34]1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:35][CH:33]([OH:34])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC(C)(C)C1CO1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 80 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2-tert-butyloxirane (0.78 g), potassium carbonate (1.1 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.63 g, 50%).
Reaction SMILES: [CH2:1]([O:4]/[N:5]=[C:6](/[C:37]1[N:38]=[C:39]([NH:42]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:40][CH:41]=1)\[C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:20])=[C:14]([CH2:17]I)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3].[NH2:62][C:63]1[S:64][C:65]2[CH:70]=[CH:69][N:68]=[CH:67][C:66]=2[N:71]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>CS(C)=O.C(OCC)(=O)C>[NH2:42][C:39]1[S:40][CH:41]=[C:37](/[C:6](=[N:5]/[O:4][CH2:1][C:2]#[CH:3])/[C:7]([NH:9][CH:10]2[C:35](=[O:36])[N:12]3[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N+:68]4[CH:69]=[CH:70][C:65]5[S:64][C:63]([NH2:62])=[N:71][C:66]=5[CH:67]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:38]=1
Reactant: C#CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Nc1nc2cnccc2s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C#CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4sc(N)nc4c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(propargyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIf] (580 mg, 0.61 mmole), and 2-aminothiazolo[4,5-c]pyridine (94 mg, 0.62 mmole) in 2.5 ml of dry DMSO was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (50 ml), and the resulting precipitate was collected by filtration and dissolved in CHCl3 --CH3OH (4:1, 50 ml). The solution was filtered and evaporated, and the residue was triturated with iso-propyl ether. The precipitate was collected by filtration to give 404 mg of crude quaternary salt [XIIIf], which was mixed with anisole (0.4 ml) and treated with 95% TFA (5 ml) under ice cooling. The solution was stirred at room temperature for an hour and then evaporated. The residue was triturated with iso-propyl ether and the resulting precipitate was collected by filtration to afford 282 mg of crude product If, which was purified on an HP-20 column (50 ml). Elution with water (150 ml), 30% aqueous CH3OH (200 ml) and 50% aqueous CH3OH (200 ml) gave 39 mg (5%) of If as pale yellow powder. Mp. 138°~150° C. (dec.). Estimated purity by HPLC: 45%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=2)[NH:3]1.[C:28]1([CH:34]2[CH2:36][O:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl([O-])(=O)(=O)=O.[Li+].[NH4+].[Cl-]>C(#N)C.CCOCC>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:26][CH3:27])([C:12]([F:15])([F:14])[F:13])[C:16]([F:17])([F:18])[F:19])[CH:8]=2)[N:3]1[CH:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:36][OH:35]
Reactant: c1ccc(C2CO2)cc1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC#N
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2C(CO)c1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
To a solution of 114 mg (0.275 mmol) of 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole (example 51.2) in 1 mL of acetonitrile were added 0.063 mL (0.55 mmol) of racemic phenyloxirane and 58 mg (55 mmol) of lithiumperchlorate. After stirring at 80° C. for 18 hrs, the mixture was distributed between Et2O and a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 yielded 77 mg (52%) of 2-[2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-yl]-2-phenyl-ethanol, MS: 534 (MH+).
Reaction SMILES: B(Br)(Br)Br.[I:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[O:19]C)[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[I:5][C:6]1[CH:7]=[C:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:16]=[CH:17][C:18]=1[OH:19]
Reactant: COc1ccc(Cc2cccnc2)cc1I
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cc2cccnc2)cc1I
Reaction time: 1 h

Procedure:
Boron tribromide (11.1 mL, 11.1 mmol, 1M in DCM) was added to a solution of 3-(3-iodo-4-methoxybenzyl)pyridine (720 mg, 2.21 mmol) in DCM (3 mL) at 0° C., and the mixture was stirred for 1 h. The mixture was quenched by the careful addition of water, the layers were separated, and the organic layer was washed with water three times. The combined organic extracts were dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give 2-iodo-4-(pyridin-3-ylmethyl)phenol as a yellow oil. MS (ESI) m/z: Calculated: 311.0; Observed: 312.3 (M++1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19].C1C(O)=CC=CC=1C>>[F:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:18]([N:17]([CH3:20])[CH3:16])=[NH:19])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=1
Reactant: Nc1ccc(F)cc1-c1ccccc1
Reactant: CN(C)C#N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: CN(C)C(=N)Nc1ccc(F)cc1-c1ccccc1

Procedure:
A mixture of 2-amino-5-fluorobiphenyl hydrochloride (3.6 g), N,N-dimethylcyanamide (1.68 g) and m-cresol (25 ml) was heated at 90°-95° C. for 8 hours to give N-(5-fluoro-2-biphenylyl)-N',N'-dimethylguanidine (m.p. 160°-161° C.) which was recrystallised from hexane.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>O>[C:14]([NH:5][CH2:4][CH2:3][Br:2])([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15]
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(NCCBr)OCc1ccccc1
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
Twenty point five g (0.10 mole) of 2-bromoethylamine hydrobromide was dissolved in 140 ml of water. At 0° C., 15.3 g (0.089 mole) of benzylchloroformate was added, followed by 18.5 g (0.1 moles) of sodium bicarbonate, and the mixture was stirred for 15 minutes at 0°. The mixture was then stirred overnight at room temperature. The mixture was extracted with diethylether (3×250 ml), the combined portions of which were washed thrice with 150 ml portions of saturated sodium bicarbonate, dried with magnesium sulfate and evaporated to yield 20.98 g of the crude N-carbobenzyloxy-2-bromoethylamine (NCBA).
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([C:34]([O:36]C(C)(C)C)=[O:35])[NH:18][C:19]([C:21]3[CH:22]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH:24]=[CH:25][CH:26]=3)=[O:20])=[CH:12][C:11]=2[F:41])[N:6]=1)=[O:4].C(OC(=O)[CH:48]([NH:61][C:62]([C:64]1[CH:65]=[C:66](C2C=CC(C)=CC=2)C=CC=1)=O)[CH2:49]C1C=CC(C(O)=NO)=C(F)C=1)(C)(C)C.COC(C(Cl)=O)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:41][C:11]1[CH:12]=[C:13]([CH2:16][CH:17]([NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH:24]=[CH:25][CH:26]=2)=[O:20])[C:34]([OH:36])=[O:35])[CH:14]=[CH:15][C:10]=1[C:7]1[N:6]=[C:5]([C:3]([N:61]2[CH2:48][CH2:49][CH:65]([CH3:66])[CH2:64][CH2:62]2)=[O:4])[O:9][N:8]=1
Reactant: COC(=O)c1nc(-c2ccc(CC(NC(=O)c3cccc(-c4ccc(C)cc4)c3)C(=O)OC(C)(C)C)cc2F)no1
Reactant: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(C(O)=NO)c(F)c3)C(=O)OC(C)(C)C)c2)cc1
Agent: COC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(-c4noc(C(=O)N5CCC(C)CC5)n4)c(F)c3)C(=O)O)c2)cc1
Yield: 64 %

Procedure:
3-(4-{2-tert-Butoxycarbonyl-2-[(4′-methyl-biphenyl-3-carbonyl)-amino]-ethyl}-2-fluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acid methyl ester. A mixture of 3-[3-fluoro-4-(hydroxy-hydroxyimino-methyl)-phenyl]-2-[(4′-methyl-biphenyl-3-carbonyl)-amino]-propionic acid tert-butyl ester (10 g, 0.02 mol) and methyl(chlorocarbonyl)formate (5 g, 0.04 mol), and pyridine (1 mL) in toluene (150 mL) was refluxed overnight. TLC showed the reaction was completed. An aqueous NaHCO3 solution (80 mL) was added to the reaction mixture, the layers were separated, and the aqueous portion was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by chromatography and recrystallization to give the title compound (7 g, 64% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH3:23][C:24]1[N:25]([C:2]2[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:6]=2)[CH:26]=[CH:27][N:28]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-chloro-4-(4-trifluoromethylphenyl)-5-oxazolepropionate (1.33 g), 2-methylimidazole (1.33 g), potassium carbonate (2.00 g) and N-methylpyrrolidone (10 mL) was stirred at 110° C. for 2 h. The reaction mixture was poured into iced water (100 mL), and the precipitated crystals were collected by filtration, washed with water and air-dried to give the title compound as crystals. Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals (1.07 g, 71%). melting point: 94-95° C.