Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:16][CH:15]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:37]>ClCCl>[ClH:37].[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:18][CH:19]=1)=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(COC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(COC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.5 %

Procedure:
To a suspension of 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl tert-butyl hydrazine-1,2-dicarboxylate (203.0 mg, 0.467 mmol) in anhydrous dichloromethane (2.3 ml) was added 4M hydrogen chloride dioxane solution (2.3 ml, 9.2 mmol). After stirring at room temperature for 2.5 hr, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. This operation was performed 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in ethyl acetate and filtered. The filtered product was washed with ethyl acetate and dried under reduced pressure to give the title compound (179.3 mg, quantitative) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[N:4]([C:5](=[S:11])[NH:6][CH2:7][CH2:8]2)[N:3]=1.I[CH3:13]>[OH-].[Na+]>[CH3:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([S:11][CH3:13])=[N:6][CH2:7][CH2:8]2)[N:3]=1
Reactant: Cc1nc2n(n1)C(=S)NCC2
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSC1=NCCc2nc(C)nn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 505 mg (3 mmol) of 2-methyl-7,8-dihydro[1,2,4]triazolo[1,5-c]pyrimidine-5(6H)-thione in 12 mL of 50% sodium hydroxide (aqueous) was treated with 0.187 mL (426 mg, 3.3 mmol) of iodomethane. The mixture was stirred vigorously at room temperature in a stoppered flask. After 2 h, the mixture was partitioned between 25 mL of dichloromethane and 12 mL of water (CAUTION: exotherm upon addition of water). The organic phase was separated, and the aqueous phase was re-extracted with an additional 5 mL of dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was flash chromatographed on silica gel (99:1 dichloromethane:methanol) to yield the title compound as white crystals, mp 75.5-76.5° C. LC-MS 183 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C1COCC1>[C:39]([N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[CH:15]2[CH2:14][C:13](=[O:29])[NH:12][CH:11]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:38])[CH2:24][CH2:25]1)(=[O:41])[CH3:40]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reaction time: 1 h
Yield: 31.1 %

Procedure:
At room temperature, to a solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(piperazin-1-yl)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.054 mmol) in THF was added acetic anhydride (6 mg, 0.06 mmol). After stirred for 1 h, the mixture was concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (10 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1>CC(C)=O>[CH3:10][C:4]1[N:3]=[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13]2)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=1
Reactant: CC1CCCNC1
Reactant: CNc1nc(C)nc(Cl)n1
Solvent: CC(C)=O
Product: CNc1nc(C)nc(N2CCCC(C)C2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.1 %

Procedure:
A mixture of 4-chloro-2-methyl-6-methylamino-1,3,5-triazine (1.06 g; 6.7 mM; described in J. Pharm. Soc. (Japan) 1975, 95, p.512) and 3-methylpiperidine (1.32 g, 13.3 mM) in acetone (10 ml) was stirred at ambient temperature for 6 hours. The mixture was filtered and the solid was partitioned between 3N aqueous ammonia solution (50 ml) and dichloromethane (50 ml). The organic solution was separated and dried (MgSO4) and the solvent was removed, and the residue was crystallised from elthanol. There was thus obtained 2-methyl-6-methylamino-4-(3-methylpiperidino)-1,3,5-triazine (608 mg, 41.3% yield) m.p. 155°-155.50° C.; microanalysis found: C,59.9; H,8.7; N,31.6%; C11H19N5 requires C,59.7; H,8.6; N,31.7%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6](=O)[CH3:7])[CH3:2].[CH:11]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[CH:6]([NH:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:7])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)C(C)NC1CCCC1
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a solution of 2.1 g (0.014 mole) of 2-methyl-3-oxo-butanoic acid ethyl ester and 40 mL of dichloroethane was added 1.37 g (0.016 mole) of cyclopentylamine. The mixture was stirred for 1.5 hours, then 4.63 g (0.020 mole) of sodium triacetoxyborohydride and 0.84 g (0.014 mole) of acetic acid were added. The mixture was stirred at room temperature for 24 hours and then quenched by the addition of 50 mL of saturated aqueous sodium bicarbonate. After 20 minutes, the organic layer was separated and the aqueous layer was extracted twice with 30 mL of dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the crude product as yellow oil. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (30:70) gave 1.5 g of (rac)-3-cyclopentylamino-2-methyl-butanoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[C:27]1([CH:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:35][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CC(N)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CC(NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)c1ccccc1

Procedure:
62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-phenylethanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-phenylethyl)terephthalamide. MS (Q1) 490.1 (M)+.
Reaction SMILES: [Cl-].[F:2][C:3]([F:31])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]=O.[OH-].[Na+]>O>[F:31][C:3]([F:2])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH:6]=[CH2:32]
Reactant: FC(F)(F)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccccc1C(F)(F)F

Procedure:
457 g (1 mol) of o-trifluoromethylbenzyltriphenyl-phosphonium chloride and 150 g (5 mols) of paraformaldehyde are initially introduced into 1,200 ml of water. 150 ml of 50% strength by weight sodium hydroxide solution are added at about 20° C. The mixture is allowed to after-react at 40° to 50° C. for 1 hour and the o-trifluoromethylstyrene formed is then distilled out of the reaction mixture with steam. The organic phase of the distillate contains 170 g (about 98% of the theoretical yield) of o-trifluoromethylstyrene with a purity, according to analysis by gas chromatography, of 99%. nD20 :1.4663. Boiling point: 61° C. under 53 mbars.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc[nH]n2)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2cc[nH]n2)cc1
Yield: 95.7 %

Procedure:
To a refluxing suspension of 3-(4-nitrophenyl)-pyrazole (18 g) and Raney nickel (3.3 g) in methanol (190 ml) was added dropwise a solution of 85% hydrazine hydrate (22 g) in methanol (50 ml). The solution was refluxed for 30 minutes more, filtered and evaporated to dryness. The oily residue, after crystallization from water, furnished 14.5 g of 3-(4-aminophenyl)-pyrazole; M.p. 104° C. 3-(3-Aminophenyl)-pyrazole, M.p. 144°-145° C., was prepared in a similar manner starting from 3-nitroacetophenone.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:9]([NH2:15])[CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[N:18]=1>CC(O)C.Cl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([NH:15][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[N:20]=2)[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(N)c1S(N)(=O)=O
Reactant: COc1ccc(Nc2nccc(Cl)n2)cc1OC
Agent: Cl
Solvent: CC(C)O
Product: C=CCOc1cccc(Nc2ccnc(Nc3ccc(OC)c(OC)c3)n2)c1S(N)(=O)=O

Procedure:
A solution of 6-Allyloxy-2-aminophenyl-sulfonamide (38 mg, 0.166 mmol) and 4-chloro-2-(3,4-dimethoxy-phenylamino)pyrimidine (44.2 mg, 0.166 mmol) in 2-propanol (5 ml) and 1 N HCl (333 μl) is refluxed for 105 min. The reaction mixture is partitioned between ammonia (pH 10-11) and EtOAc. The organic layer is dried (Na2SO4) and concentrated. Precipitation with ether/hexanes gives the desired 2-Allyloxy-6-[2-(3,4-dimethoxy-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](Cl)=[O:9]>O1CCCC1.[Cl-].[Na+].O>[Br:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:1])=[O:9])[CH:6]=[N:5][CH:4]=1
Reactant: N
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In an amount of 555 mg of 5-bromonicotinoyl chloride was dissolved in 5.5 ml of tetrahydrofuran, added with 768 μl of 28% aqueous ammonia under ice cooling, stirred for 40 minutes, then warmed to room temperature, and further stirred at room temperature for 20 minutes. The reaction system was added with 15% brine, and extracted with tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure until about half amount of crystals were deposited, and added with ethyl acetate until the deposition of crystals was terminated, and the crystals were taken by filtration to obtain 374 mg of the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9](#[N:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: NO
Reactant: CCCCCCCCC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCCCCCC(=N)NO
Reaction time: 0.21 h

Procedure:
To a solution of 0.74 g (10.7 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 1.327 g (17.8 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 1.0 g (7.1 mmol) of nonanenitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After the reaction period, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue with chased with 5 mL of toluene below 45° C., under vacuum, to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[CH:9]=1)([O-])=O.[H][H]>[Pd].COCCO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)[CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(Oc2cc(Oc3cccc([N+](=O)[O-])c3)cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: COCCO
Product: Nc1cccc(Oc2cc(Oc3cccc(N)c3)cc(C(F)(F)F)c2)c1
Temperature: 90 °C

Procedure:
Into a reducing device equipped with a thermometer, a reflux condenser and an agitator were charged 55 g of 1,3-bis(3-nitrophenoxy)-5-trifluoromethylbenzene (0.131 mol), 150 g of methyl cellosolve and 5 g of 5%-Pd/C (50% of water content), and the mixture was reacted at 70 to 80° C. for 4 hours in an atmosphere of hydrogen. At the end of the reaction, the catalyst was filtered out and the filtrate was heated to 90° C., to which 140 g of water was added. The mixture was cooled to room temperature to crystallize the desired product, which was filtered and dried under a reduced pressure to give 1,3-bis(3-aminophenoxy)-5-trifluoromethylbenzene as a white solid; Melting point: 98.0 to 98.6° C., Yield: 41 g (87%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][CH3:23])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:22]([C@H:2]1[NH:1][C:32](=[O:34])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:20])[CH3:21])[CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:23]
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc(C(C)C)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(2R)-2-amino-N-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)butanamide (Intermediate 70, 930 mg) was dissolved in dry dichloromethane (100 mL). The reaction mixture, under argon, was cooled down in an ice bath. Triethylamine (2.482 mL, 17.81 mmol) was added. Then a solution of triphosgene in dry dichloromethane (352 mg, 1.187 mmol dissolved in 40 mL of dichloromethane) was added dropwise. The reaction mixture was stirred at 0° C., under argon, during 10 min. A saturated aqueous solution of NaHCO3 was added (100 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×80 mL). After drying over sodium sulphate, the solvent was removed under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, 120 g silica cartridge), with a gradient cyclohexane/ethyl acetate 100/0 to 55/45. The title compound (5R)-5-ethyl-3-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione was obtained as a beige powder (768 mg).
Reaction SMILES: [H][H].[Si:3]([O:10][CH2:11][CH:12]([NH:14]C(=O)OCC1C=CC=CC=1)[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>[Pd].C(O)C>[Si:3]([O:10][CH2:11][CH:12]([NH2:14])[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(N)CO[Si](C)(C)C(C)(C)C
Yield: 80.3 %

Procedure:
Hydrogen was introduced into a mixture of 4.0 g of benzyl N-(2-t-butyldimethylsilyloxy-1-methylethyl)-carbamate (prepared as described in Preparation 8), 0.80 g of 10% w/w palladium-on-carbon and 40 ml of ethanol for 1 hour. At the end of this time, the atmosphere was replaced by nitrogen, the palladium-on-carbon was removed by filtration from the reaction mixture, and the filtrate was concentrated by evaporation under reduced pressure, to give 1.88 g of the title compound having an Rf value of 0.27 (on silica gel thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)c1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example A.42) (0.65 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.2 mmol) according to the general procedure IVb. Obtained as a white solid (0.43 g, 48%). MS (EI) 448.0 [(M)+]; mp 102.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[S:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:35]3[CH2:36][CH2:37][S:33][CH2:34]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Reactant: C1CSCN1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCSC3)cc2F)CC1
Yield: 23 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.48 g, 3.3 mmol) by using thiazolidine (2.5 ml) as an amine to yield the titled compound (314 mg, 23%).
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:20])=O)[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH2:37])[CH3:36].CCN(CC)CC>C(Cl)Cl>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([NH:37][CH2:35][CH3:36])=[O:20])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCN
Reactant: O=C(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of 0.037 g (0.08 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidine and 0.06 mL (0.12 mmol) of ethylamine in 2 mL of CH2Cl2 at rt was added 0.031 g (0.12 mmol) of BOPCl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride, Aldrich) and 0.045 mL Et3N and the reaction mixture was stirred for 18 h. The reAction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:2) to give the title compound. 1H NMR (CDCl3) δ (key peaks) 7.85-7.90 (m, 3H), 7.45-7.56 (m, 4H), 7.09-7.19 (m, 2H), 6.96-7.03 (m, 2H), 3.94-4.49 (m, 4H); Mass Spectrum (ESI) m/e=488 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH2:2]1.Cl.O1CCOCC1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:41][CH:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[N:54]=[C:53]([C:55]3[C:59]([CH2:60][CH2:61][CH3:62])=[C:58]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[O:57][N:56]=3)[O:52][N:51]=2)=[CH:46][CH:45]=1)[OH:43]>>[OH:43][CH:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[N:54]=[C:53]([C:55]3[C:59]([CH2:60][CH2:61][CH3:62])=[C:58]([C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)[O:57][N:56]=3)[O:52][N:51]=2)=[CH:46][CH:45]=1)[CH2:41][N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1CCCNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC[C@H](CC(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
(R)-tert-Butyl 2-(piperidin-3-yl)acetate (66 mg, 0.331 mmol) was treated with 4N HCl/dioxane for 30 minutes. The reaction mixture was concentrated in vacuo and dried. The solid material was dissolved in DMSO (2 mL) and tetrabutylammonium hydroxide (0.352 mL, 0.352 mmol) was added. After stirring 15 minutes, 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (40 mg, 0.088 mmol) was added. The reaction mixture was heated at 80° C. for 2 hours, and then filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 20 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 9 mg of 2-((3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.11 (2H, m), 7.68-7.75 (2H, m), 7.59 (2H, m, J=8.35 Hz), 7.43-7.55 (3H, m), 5.16 (1H, dd, J=9.01, 4.61 Hz), 3.71-3.89 (1H, m), 3.50-3.67 (2H, m), 3.24 (1H, d, J=2.42 Hz), 2.96 (2H, dd, J=8.90, 6.92 Hz), 2.83-2.93 (1H, m), 2.72 (1H, td, J=11.86, 5.27 Hz), 2.16-2.39 (3H, m), 1.77-2.00 (3H, m), 1.59-1.75 (2H, m, J=7.61, 7.61, 7.61, 7.61, 7.36 Hz), 1.13-1.32 (1H, m), 0.95 (3H, t, J=7.25 Hz). MS (m+1)=517. HPLC Peak RT=3.32 minutes (Analytical Method A). Purity=95%.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.S(Cl)(Cl)=O.[CH2:25](Cl)Cl>>[CH3:25][O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(OC)c1ccccc1CO2
Reaction time: 2 h

Procedure:
In 300 ml of methylene chloride was dissolved 30.0 g of Compound b obtained in Reference Example 2. Under ice cooling, 10 ml of thionyl chloride was dropwise added to the solution. After stirring for further 2 hours under ice cooling, the reaction mixture was concentrated under reduced pressure. To the resulting residue, 500 ml of methanol and 20 ml of triethylamine were added and the mixture was stirred at room temperature for an hour. The solvent was distilled off under reduced pressure and the residue was extracted with 1 liter of ethyl acetate. The extract was washed in sequence with saturated aqueous sodium bicarbonate solution and then saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from isopropyl ether to give 19.0 g of white crystalline methyl 11-methoxy6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.