Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:36]COC)=[C:7]([C@:9]([NH:29][S@](C(C)(C)C)=O)([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([F:27])[C:16]=2[Cl:28])[CH2:10][O:11][CH2:12][C:13]#[N:14])[CH:8]=1.C[Al](C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.CCOC(C)=O>[NH2:14][C:13]1[CH2:12][O:11][CH2:10][C@:9]([C:7]2[CH:8]=[C:3]([Br:2])[CH:4]=[CH:5][C:6]=2[OH:36])([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([F:27])[C:16]=2[Cl:28])[N:29]=1
Reactant: COCOc1ccc(Br)cc1[C@](COCC#N)(N[S@@](=O)C(C)(C)C)c1cc(N2CCOCC2)nc(F)c1Cl
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC1=N[C@@](c2cc(Br)ccc2O)(c2cc(N3CCOCC3)nc(F)c2Cl)COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A solution of hydrogen chloride (5-6N in iPrOH; 1.025 mL, 5.12 mmol) was added to a solution of (S)—N—((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-(cyanomethoxy)ethyl)-2-methylpropane-2-sulfinamide (1083 mg, 1.708 mmol) in THF (4 mL) under nitrogen atmosphere. The reaction mixture was stirred for 10 min at RT. The solvent was removed under reduced pressure and the residue was dissolved in DCE (2 mL). A solution of AlMe3 (2M in toluene; 2.56 mL, 5.12 mmol) was added drop wise and the reaction mixture was allowed to stir at 70 C for 3 h. The reaction mixture was cooled to RT and a solution of aqueous saturated solution of potassium sodium tartrate was added, followed by EtOAc. The reaction mixture was allowed to stir vigorously for 1 h. The organic phase was separated, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (100% EtOAc) to afford 390 mg of (S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-bromophenol.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH2:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:36]>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][N:37]([CH2:35][CH3:36])[CH2:38][CH2:39]4)[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Reactant: CCN1CCNCC1
Product: CCN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5cccc(F)c5)c(C)c4)c23)CC1
Yield: 57 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 21) and N-ethylpiperazine to give the title compound in 57% yield; NMR Spectrum: 0.95 (t, 3H), 2.26 (s, 3H), 2.26-2.55 (m, 10H), 2.77 (t, 2H), 4.41 (t, 2H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.30 (m, 2H), 7.43 (m, 3H), 8.17 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 506 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6]1[N:7]=[C:8]2[N:12]([CH:13]=1)[N:11]=[C:10]([CH3:14])[S:9]2)C.[OH-].[Na+]>CCO>[CH3:14][C:10]1[S:9][C:8]2=[N:7][C:6]([CH2:5][C:4]([OH:15])=[O:3])=[CH:13][N:12]2[N:11]=1
Reactant: CCOC(=O)Cc1cn2nc(C)sc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn2cc(CC(=O)O)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To (2-methyl-imidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetic acid ethyl ester (4.0 g, 17.76 mmol) in 30 mL EtOH was added aqueous NaOH (1M, 19.5 mL) and the mixture was stirred at room temperature for 1 hour or until LC-MS showed complete consumption of starting material. To the mixture was added Amberlyst 15 (wet) ion-exchange resin (Aldrich) until the pH reached 5. The resin was removed by filtration and the filtrate was concentrated to obtain 1.7 g (50%) of the title compound (SM-1ae). Further purification was performed by trituration with water and ethyl ester to obtain a white solid. MS (ES+) 198.1 (M+H)+ 1H NMR (DMSO-d6) δ 2.66 (s, 3H), 3.53 (s, 2H), 7.86 (s, 1H), 12.31 (br s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:53])([S:51][CH3:52])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:49]([CH3:50])([S:51][CH3:52])[CH3:53])[C:46](=[O:47])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28](=[O:31])[O:29][CH3:30]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)SC
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)SC)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution containing the product from Example 2C (0.10 g, 0.18 mmol) in THF (2 mL) was treated with the product from Example 30A (0.05 g, 0.226 mmol), DEPBT (0.085 g, 0.28 mmol), and N,N-diisopropylethylamine (0.165 mL, 0.947 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.052 g, 38% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 1.10 (s, 3 H), 1.21 (s, 3 H), 1.54 (m, 2 H), 1.98 (s, 3 H), 2.57 (m, 1 H), 2.75 (m, 3 H), 3.49 (s, 3 H), 3.56 (s, 3 H), 3.64 (m, 1 H), 3.82 (d, J=9.56 Hz, 1 H), 4.17 (m, 3 H), 4.83 (d, J=5.88 Hz, 1 H), 6.61 (d, J=9.56 Hz, 1 H), 6.90 (d, J=9.56 Hz, 1 H), 7.15 (m, 7 H), 7.31 (m, 1 H), 7.84 (m, 6 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][C@@H:18]2[CH2:20][C@H:15]1[CH2:16][NH:17]2.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][C@@H:18]2[CH2:20][C@H:15]1[CH2:16][N:17]2[C:31]([C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([C:25]2[N:24]=[C:23]([C:22]([F:37])([F:21])[F:38])[O:27][N:26]=2)[CH:29]=1)=[O:32]
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1ccc(N2C[C@@H]3C[C@H]2CN3)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1C[C@@H]2C[C@H]1CN2c1ccccn1
Yield: 27 %

Procedure:
This compound was synthesized from (1S,4S)-2-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (30 mg, yield 27%). 1H NMR (400 MHz, CDCl3) δ8.28-8.07 (m, 3H), 7.74-7.71 (m, 1H), 7.65-7.43 (m, 2H), 6.66-6.55 (m, 1H), 6.45-6.33 (m, 1H), 5.16-4.94 (m, 2H), 3.82-3.49 (m, 4H), 2.10-2.05 (m, 2H). MS (ESI) m/z: Calculated for C20H16F3N5O2: 415.13. found: 416.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:22](/[CH:25]=[N:26]\O)=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+].Cl[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:35](=[O:36])[O:37][CH3:38])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccnc1)c1cc(/C=N\O)ccc1OCc1ccc(F)cc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)NCc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-{[(4-fluorophenyl)methyl]oxy}-5-[(Z)-(hydroxyimino)methyl]-N-3-pyridinylbenzamide (may be prepared by Example 83; 215 mg, 0.57 mmol) in tetrahydrofuran (5 ml) was added 2M aqueous hydrochloric acid (1.72 ml, 56.7 mmol) followed by zinc (371 mg, 5.67 mmol) at room temperature. After stirring at room temperature for 30 min the mixture was heated to 60° C. for 30 min. On cooling, the mixture was treated with saturated sodium hydrogen carbonate (excess). A small amount of the solution was put aside to generate the amine. Methyl chloroformate (0.53 ml, 6.80 mmol) was added to the remainder and the pH was adjusted with further NaHCO3 to pH 9-10. The mixture was then stirred at room temperature for 1 hour. The tetrahydrofuran was evaporated under reduced pressure, and the resulting aqueous layer was extracted with ethyl acetate (2×30 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified twice using MDAP to yield the title compound. 12 mg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C=O)c3)c2F)[nH]1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(CO)c3)c2F)[nH]1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.178 g, 0.398 mmol) in methanol (5 ml) at 0° C. was added sodium borohydride (0.015 g, 0.398 mmol) and the reaction mixture was allowed to warm to rt over 30 minutes. The reaction mixture was neutralized with saturated sodium bicarbonate, diluted with EtOAc, and the organic layer was separated. The solvent was evaporated and the crude material was purifed via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(hydroxymethyl)phenyl]oxy}-2-fluorophenyl)methyl]-2-methyl-1H-imidazole-5-carboxamide (0.135 g, 0.300 mmol, 76% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.39 (s, 1H), 7.27-7.38 (m, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 4.60 (s, 2 H), 4.58 (s, 2H), 2.32 (s, 3H). LC-MS (ES+) m/z 448.94, [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].C(O)C.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:19][C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]([F:25])([F:23])[F:24])[CH:4]=2)=[O:10])[CH:17]=[CH:16][C:15]=1[CH3:18]
Reactant: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1N
Temperature: 80 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-methyl-3-nitrophenyl)urea (7 g, 18.7 mmol) obtained in Step (1) above was stirred in a solvent of ethanol (100 mL). The reaction solution was added with tin chloride (II) dihydrate (12.68 g, 56.2 mmol), followed by stirring for about 4 hours at 80° C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated solid was added with a mixed solution of ethyl acetate/hexane (1/1), and stirred for 2 hours or more. The resulting solid was filtered under reduced pressure, washed with diethyl ether, and the filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (3.9 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:9]([CH3:22])=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:9]([CH3:22])=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([Cl:27])=[O:20])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Product: Cc1c(CCCCCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
Using the procedure of Example 2, 3-(4-chlorobenzoyl)-2-methylbenzene hexanoic acid was reacted with thionyl chloride to form 3-(4-chlorobenzoyl)-2-methyl-benzenehexanoic acid chloride which was then reacted with 4-(3-trifluoromethylphenyl)-1-piperazinyl-ethanol followed by hydrochloric acid to obtain 2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-ethyl 3-(4-chlorobenzoyl)-2-methyl-benzenehexanoate hydrochloride melting at 108° C.
Reaction SMILES: [Na].C(O)C.[CH:5]1[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][C:6]=1[CH:18]=O.[N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N+:21]=[N-:22]>O1CCCC1>[N:20]([C:23](=[CH:18][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:16][C:17]=2[CH:5]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N+:21]=[N-:22]
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc2c(c1)Cc1ccccc1-2)N=[N+]=[N-]
Temperature: 25 °C
Yield: 37 %

Procedure:
Sodium (1.7 eq) was added to absolute ethanol stirred under nitrogen at room temperature. When dissolution was complete the reaction was cooled to -10° C. and fluorene-2-carboxaldehyde (1 eq) and ethyl azidoacetate (3 eq) dissolved together in the minimum of tetrahydrofuran were added dropwise. The mixture was stirred at -10° C. for 20 h and then quenched by the addition of water and dichloromethane. The combined organic extracts were dried (MgSO4) and evaporated in vacuo. Flash chromatography yielded the pure product (37%) νmax (CHCl3)cm-1 2120 and 1765.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:17][CH2:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)CCn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
A mixture of 4-(4-nitrophenyl)-1H-imidazole (for a preparation see Intermediate 120) (3.5 g, 18.5 mmol), 1,1-dimethylethyl 2-propenoate (2.37 g, 2.71 mL, 18.5 mmol) and DBU (2.82 g, 2.79 mL, 18.5 mmol) in DMF (50 mL) was stirred at 50° C. for 16 h then was cooled to room temperature and partitioned between AcOEt (100 mL) and water (100 mL). The layers were separated and the organic phase was washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 25 to 50% AcOEt in hexanes) gave 1,1-dimethylethyl 3-[4-(4-nitrophenyl)-1H-imidazol-1-yl]propanoate (2.6 g, 8.19 mmol, 44%) as an orange solid. LCMS (method G): Retention time 0.90 min, [M+H]+=318.0
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[N:22]=1>>[CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[N:22]=3)[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)n1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1ccccc1)CO2
Product: O[C@@H]1c2cc(OCc3cccc(Cl)n3)ccc2OC[C@H]1Cc1ccccc1

Procedure:
By the method of Example 5, 0.50 g (1.96 mmol) of trans-3-benzyl-4,6-chromandiol and 445 mg (2.16 mmol) of 2-chloro-6-(bromomethyl)pyridine were converted to present title product purified by recrystallization from CH2Cl2 /hexane, to yield 0.50 g (67%) of present title compound, m.p. 117°-119° C.
Reaction SMILES: [Br-:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:42])[C@:16]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:32])[CH:25]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)#[N:3].[C:43]([N:50]1[CH2:57][CH2:56][CH2:55][C@H:51]1[C:52](O)=[O:53])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].Cl.CN(C)CCCN=C=NCC>ClCCl>[Br-:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:42])[C@:16]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([O:31][C:52]([C@@H:51]5[CH2:55][CH2:56][CH2:57][N:50]5[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:53])=[C:26]([CH3:32])[CH:25]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To a solution of 3 g of 3,5-dimethyl-4-hydroxybenzyl bromide in CH3CN(30 mL) was added 1.2 g of (1R,2R)-4-[2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]thiazol-4-yl]benzonitrile and stirring was continued for 2 h at room temperature. The precipitate was filtered and washed with ether to give 1.37 g(81% y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxy)benzyl-1H-[1,2,4]triazol-4-ium bromide(Ro09-3846) as a white solid. To a mixture of 30 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-diflouro-phenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxybenzyl)-1H-[1,2,4]triazol-4-ium bromide, 10.9 g of Boc-(L)-proline and 2.8 g of N,N-dimethylaminopyridine in 1.2 L of dichloromethane was added 17.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture was stirred for 1.5 h at room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2 /MeOH=14/1) to give 30.9 g(79% y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide as a white solid. 30.9 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide was stirred in 600 mL of 10% TFA -dichloromethane for 5 h at room temperature and the solvent was removed in vacuo. The residue was diluted with ether and the precipitate was washed with ether to give 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5dimethyl-4-(pyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide trifluoroacetic acid salt as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:47][C:48]([F:62])([F:61])[C:49]([N:51]1[CH2:60][CH2:59][C:54]2([CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][CH2:52]1)=[O:50]>C1COCC1>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:57]3[CH2:56][CH2:55][C:54]4([CH2:53][CH2:52][N:51]([C:49](=[O:50])[C:48]([F:61])([F:62])[F:47])[CH2:60][CH2:59]4)[CH2:58]3)=[O:18])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(N1CCC2(CCNC2)CC1)C(F)(F)F
Reactant: O=C(O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: O=C(NC1CCc2ccc(C(=O)N3CCC4(CCN(C(=O)C(F)(F)F)CC4)C3)cc21)c1ccccc1Cl
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a suspension of 3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid (E-01) (789 mg, 2.49 mmol, 1.0 eq.) in THF (20 ml) was added HATU (1.04 g, 2.76 mmol, 1.1 equiv.) and DI PEA (2.1 ml, 12.4 mmol, 5 eq.) at 0° C. and the reaction mixture was allowed to stir for 15 min. A solution of 2,2,2-trifluoro-1-(2,8-diazaspiro[4.5]decan-8-yl)ethanone (587 mg, 2.49 mmol, 1.0 equiv.) in THF (5 ml) was then added and the reaction mixture was stirred at 25° C. for 15 h. The mixture was diluted with MC (300 ml) and washed successively with sodium bicarbonate solution (40 ml), ammonium chloride solution (50 ml), water (50 ml) and brine (50 ml). The organic layer was dried over sodium sulfate and the solvent evaporated under reduced pressure to obtain the crude material which was purified by column chromatography (silica gel; 0-3% methanol/MC) to yield the pure final product as a white solid. Yield: 72% (1 g, 1.8 mmol).
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.O(C1C=CC(N)=CC=1)C1C=CC=CC=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)[NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:60][CH:59]=2)C)=CC=1)C(O)=O)C>>[CH3:21][O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([CH3:15])([C:17](=[O:19])[NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:60][CH:59]=2)[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: Nc1ccc(Oc2ccccc2)cc1
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 4-phenoxy-phenylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C28H31NO6 [M+H]+: 478.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([CH:21]1[CH2:26][NH:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)[CH3:20]>>[CH2:19]([CH:21]1[CH2:26][N:25]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH:24]([CH3:27])[CH2:23][CH2:22]1)[CH3:20]
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: CCC1CCC(C)NC1
Product: CCC1CCC(C)N(C(=O)c2cnoc2-c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 5-ethyl-2-methylpiperidine (7.6 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.3 mg). Calcd for C19H21F3N2O2: 366.1555, found 366.1552.