Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br.O>C(COC)OC>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:15]=1[F:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cccc(CBr)c1F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(C)c1F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a suspension of sodium hydride (215 mg, 4.92 mmol) in dimethoxyethane (3 ml) was added dropwise a solution of diethyl malonate (868 mg, 5.42 mmol) in dimethoxyethane (2 ml) in an inert atmosphere at rt. Stirring was continued for 1 h followed by the addition of a solution of 2-fluoro-3-methyl-benzylbromide (1 g, 4.92 mmol) in dimethoxyethane (15 ml). The reaction mixture was refluxed for 90 minutes, cooled again to rt and water (5 ml) was carefully added. The diemthoxyethane was removed under reduced pressure, DCM (100 ml) was added and the organic layer was washed with water (100 ml), dried over magenisum sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silicagel, DCM/heptane=4/1) to give 973 mg (70%) of 2-(2-fluoro-3-methyl-benzyl)-malonic acid diethyl ester. LC-MS: tR=1.03 min; [M+H]+=283.22.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37]([O:39]C(C)(C)C)=[O:38])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[C:10]([C:37]([OH:39])=[O:38])=[N:11][C:12]([CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)O)c1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 5-(benzyloxy)-2-{(1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylate (0.81 g, 1.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), and an aqueous sodium hydroxide solution (5 M, 10 mL, 50 mmol) was added, followed by stirring at 50° C. for 15 minutes. The reaction solution was cooled to room temperature, and hydrochloric acid (5 M, 10 mL, 50 mmol) was added, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to afford 5-(benzyloxy)-2-{(1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:50])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16](CC=O)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].C[Mg]Br.[CH2:54]1[CH2:58][O:57]CC1>S([O-])(O)(=O)=O.[K+]>[CH2:1]([O:3][C@H:4]([CH3:50])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:16]([CH2:25][C@H:26]([NH:27][C:58](=[O:57])[CH3:54])[CH3:36])[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@@H](CC=O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@@H](C[C@@H](C)NC(C)=O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.0 mmol [(2S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetaldehyde in 10 ml of THF are added 2.0 mmol of methyl magnesium bromide (3M in THF) at 0° C. The reaction mixture is allowed to warm to RT and stirred for 1 h, diluted with an aqueous solution of 1N potassium hydrogen sulfate and extracted with TBME. The organic phases are combined and dried over Na2SO4. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound, which is identified based on its Rf value.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.[CH2:20]([N:22](CC)CC)C>ClCCl>[CH3:20][NH:22][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid (120 g, 519 mmol) in dichloromethane (800 mL) is added 1,1-carbonyldiimidazole (88.4 g, 545 mmol). The resulting solution is stirred at 25° C. for 1 h and methylamine hydrochloride (52.5 g, 779 mmol) and triethylamine (157.3 g, 1557 mmol) are added and the reaction is stirred for an additional 18 h. The mixture is diluted with dichloromethane (600 mL) and washed with 1 M hydrochloric acid and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid methylamide as a white solid (126 g, 100% yield).
Reaction SMILES: [C:1]([C:4]1[CH:20]=[C:19](Br)[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:22])(=[O:3])[CH3:2].C([O-])=O.[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Br)c2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Yield: 67.6 %

Procedure:
Mix 7-acetyl-9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (833 mg, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol) and sodium formate (224 mg, 3.3 mmol) in anhydrous DMF (15 mL). Degas twice then flush with argon. Keep the flask under argon and heat the reaction at 95° C. for 16 h. Dilute with EtOAc then wash with 1 N HCl. Separate the organic layer, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:100 to 20:80 EtOAc:hexanes) to give the title compound (448 mg, 68%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C1COCC1.[C:14]([O:18][C:19]([NH:21][C@H:22]([C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[C:39]([F:45])[CH:38]=1)[C@H:23]([O:25]C(=O)C1C=CC([N+]([O-])=O)=CC=1)[CH3:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>O.C(OCC)(=O)C>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]([C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[C:39]([F:45])[CH:38]=1)[C@H:23]([OH:25])[CH3:24])([CH3:15])([CH3:16])[CH3:17]
Reactant: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A potassium carbonate powder (6.43 g) was added to a solution mixture of methanol (90 mL) and THF (10 mL) of 4-nitrobenzoic acid (1R,2R)-2-tert-butoxycarbonylamino-1-methyl-2-(3,4,5-trifluorophenyl)ethyl ester (7.03 g). This reaction solution was stirred at room temperature for 1 hr. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The obtained organic layer was washed with saturated saline twice, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue, diethylether was added. The insoluble matter was removed by filtration and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (toluene ethyl acetate=6:1) to give 4.49 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: CC(C)(OC([CH2:7][NH:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([O:25]CC)=[O:24])=[CH:10]1)=O)C.C(O)(=O)C.Cl>O>[F:21][C:15]1[CH:14]=[C:13]2[C:18](=[C:17]([F:19])[C:16]=1[F:20])[N:9]([NH:8][CH3:7])[CH:10]=[C:11]([C:23]([OH:25])=[O:24])[C:12]2=[O:22]
Reactant: CCOC(=O)c1cn(NCC(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
To 2.00 g (5.0 mmol) of 1-[[(1,1-dimethylethoxy)carbonyl]methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester was added 35 ml of acetic acid and 15 ml of 2N hydrochloric acid. The mixture was placed on a steam bath for 2.5 hours, was diluted with 15 ml of water, and was cooled. The solids were filtered to give 1.09 g of 6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3quinolinecarboxylic acid, mp 237°-238° C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(F)cc1
Reactant: NCc1cccc2ccccc12
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(F)cc1
Yield: 21.9 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-fluorophenyl)-3-oxopropionate (10.0 g) and 1-aminomethylnaphthalene (8.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-fluorophenyl)-2-(1-naphthyl)imidazole-4-carboxylate (3.3 g). 3.0 g therefrom was dissolved in ethyl alcohol (100 ml) and 1 M sodium hydroxide solution (20 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-fluorophenyl)-2-(1-naphthyl)imidazole-4-carboxyic acid (2.4 g), melting point 175° C. (decomposition).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)(O)[O-].[Na+].[I-].[K+].[ClH:27]>CN(C)C=O.CCOCC>[ClH:27].[CH2:18]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:5][CH2:6]1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCN1CCC(c2noc3ccccc23)CC1
Reaction time: 20 h

Procedure:
A suspension of 4.0 g of 3-(4-piperidyl)-1,2-benzisoxazole, 2.6 g of allyl bromide, 5.0 g of sodium bicarbonate, and 3.0 g of potassium iodide in 90 ml of dimethylformamide was stirred at 80° for 20 hrs. The reaction was cooled, filtered and poured into 1 l of water. The mixture was extracted with ether (three times) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give an oil. The oil was dissolved in a small amount of ether into which hydrochloric acid was bubbled. The precipitate was recrystallized from ethanol-ether (three times) to give 2.4 g of product, mp, 174°-176°.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:16](=O)[NH:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:16]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(OCc3ccccc3)nc2n1-c1ccccc1Cl
Product: Oc1ccc2nc(Cl)n(-c3ccccc3Cl)c2n1
Reaction time: 0.25 h
Yield: 0.7 %

Procedure:
5-(Benzyloxy)-3-(2-chlorophenyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (905 mg, 2.58 mmol) and POCl3 (1965 μl, 21.08 mmol) was heated in microwave at 100° C. for 1 h. The mixture was concentrated. The residue was dissolved in EtOAc and saturated NaHCO3. The organics were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in DCM (2.5 mL) and H2SO4 (6 drops) was added. The mixture was stirred vigorously for 15 minutes. DCM was removed by gentle heating. The residue was dissolved in MeOH and purified by preparative HPLC to give the title compound (5.0 mg). LCMS m/z=280.2, [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.63 (d, J=8.6 Hz, 1H), 7.63 (dd, J1=7.6, J2=1.6 Hz, 1H), 7.66 (td, J1=7.6, J2=1.8 Hz, 1H), 7.79 (m, 2H), 7.98 (d, J=8.6 Hz, 1H), 11.10 (broad s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[CH:5][C:3]=1[OH:4].[C:11](O)(=[O:13])[CH3:12]>>[CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[C:5]([C:11](=[O:13])[CH3:12])[C:3]=1[OH:4]
Reactant: Cc1c(O)ccc(O)c1C
Reactant: CC(=O)O
Product: CC(=O)c1cc(O)c(C)c(C)c1O
Temperature: 80 °C

Procedure:
276 g (2 mole) of 2,3-dimethyl-hydroquinone were suspended in 300 ml of acetic acid and heated to 80° C. with stirring. Through the obtained solution boron trifluoride was bubbled whereby care was taken that the temperature did not exceed 100° C. The reaction mixture was stirred at 120° C. for 3.5 h and then poured into 4 l of ice-water containing 500 g of dissolved sodium acetate. This mixture was stirred for 12 h till the precipitate could be separated by suction. This precipitate was then treated with 3 l of water whereto enough sodium hydrogen carbonate was added to reach a final pH of 7.5. The precipitate was suction filtered again, washed with water till neutral and recrystallized from toluene. Yield: 230 g. Melting point: 151° C. (structure confirmed by NMR).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:15])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH:26][CH3:27]>CN(C)C=O.CCOC(C)=O>[CH2:24]([N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:15])[C:3](=[O:4])[C:2]([F:16])([F:1])[F:17])[CH:25]=[CH:26][CH3:27]
Reactant: CC=CCBr
Reactant: O=C(NCCc1ccc(Cl)cc1I)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC=CCN(CCc1ccc(Cl)cc1I)C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 36.7 %

Procedure:
A solution of N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (6.2 g, 15.8 mmol) in dimethylformamide (350 mL) was treated with K2CO3 (15.8 g, 114 mmol) and crotyl bromide (6.0 g, 44 mmol) sequentially, the mixture was stirred at 60 C for 16 hours and then cooled to 20 C. The mixture was diluted with EtOAc (350 mL), washed with water (3×300 mL), dried with Na2SO4 and concentrated. Flash chromatography (5-15% EtOAc in hexane) resulted in 2.5 g of a clear oil. MS calculated for C14H14ClF3INO+H: 432, observed: 432.
Reaction SMILES: FC(F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:36])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:16][C:15]([CH3:36])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[CH:3][N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)c(F)cc1F
Yield: 55 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (31.7 mg, 0.166 mmol, from Example 1, Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 57 mg, 0.166 mmol), HOBT (26.9 mg, 0.199) mmol, and EDC (47.8 mg, 0.249 mmol) in 4 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol in dichloromethane) gave 40 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 3.00 (m, 2H), 3.30 (m, 2H), 3.93 (m, 1H) 4.04-4.24 (m, 2H), 4.23 (s, 1H), 4.35 (m, 1H) 4.97-5.48 (m, 2H) 7.22 (m, 1H), 7.44 (m, 1H), 8.04 (m, 1H). ESI-MS 507 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[O:20]1CCOCC1.[OH-].[Na+:27]>O>[NH2:3][C:4]1[C:5]([S:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:27]
Reactant: C1COCCO1
Reactant: O=C1Cc2cccc(S(=O)c3ccc(Cl)cc3)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1S(=O)c1ccc(Cl)cc1
Reaction time: 15 h

Procedure:
A mixture of 2-oxo-7-(4-chlorophenylsulfinyl)indoline (4.7 g) and dioxane (30 ml) was added to a solution of sodium hydroxide (2.5 g) in water (30 ml), and the mixture was refluxed with stirring for 15 hrs. Dioxane was distilled off from the reaction mixture in vacuo, and the residue was dissolved in water and washed with diethyl ether. The aqueous solution was adjusted to pH 7 with 5% sulfuric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with saline, dried over magnesium sulfate and then evaporated in vacuo. The residue was dissolved in 1N-sodium hydroxide (12.2 ml) under heating and the solution was concentrated in vacuo. The residue was recrystallized from ethanol twice to give powdery sodium 2-[2-amino-3-(4-chlorophenylsulfinyl)phenyl]acetate (1.5 g). mp 242°-245° C. (dec.).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15](F)=[C:14](C)[C:13]=1[C:20]([F:23])([F:22])[F:21]>CCCCCC.CN(C)C=O>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)=[CH:14][C:13]=1[C:20]([F:21])([F:23])[F:22]
Reactant: Cc1cc[nH]n1
Reactant: COC(=O)c1ccc(F)c(C)c1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1C(F)(F)F
Yield: 59.7 %

Procedure:
Sodium hydride (60% suspension in oil, 3.85 g, 96.3 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (150 mL). A solution of 3-methylpyrazole (7.75 mL, 96.3 mmol) in dimethylformamide (50 mL) was added dropwise at ambient temperature. Stirring was continued until the gas evolution subsided, and then a solution of methyl 4-fluoro-2-trifluoromethylbenzoic acid methyl ester of Step A (17.8 g, 80.1 mmol) in dimethylformamide (50 mL) was added dropwise to the clear solution. After stirring for 30 min at room temperature, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was dissolved in 1:1 mixture of dichloromethane and hexane and absorbed onto a silica Merck-60 flash column. Elution with a dichloromethane-hexane gradient (from 1:1 to 4:1) provided the title compound (13.6 g) as a white solid, m.p. 59-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7](Br)[C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.O.O.O.O.C1(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=O)C=2C=CC=1>C(#N)C.CC(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]([N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)[C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 58.5 %

Procedure:
21.6 g (0.05 mol) of crude 1,4-bis-(4-chlorophenoxy)-1-bromo-3,3-dimethyl-butan-2-one were stirred under reflux with 14 g (0.2 mol) of 1,2,4-triazole in 100 ml of acetonitrile for 17 hours. The mixture was then concentrated by distilling off the solvent under reduced pressure. The residue was taken up in 400 ml of methylene chloride and the mixture was extracted by shaking three times with 800 ml of water each time, dried over sodium sulphate and concentrated. The residue was taken up in 100 ml of acetone, and 9 g (0.05 mol) of 1,5-naphthalenedisulphonic acid tetrahydrate in 50 ml of acetone were added dropwise. The precipitate formed was filtered off and suspended in 200 ml of methylene chloride. 400 ml of saturated sodium bicarbonate solution were added, the mixture was stirred for 30 minutes and the organic phase was separated off, dried over sodium sulphate and concentrated by distilling off the solvent. 12.3 g (58.6% of theory) of 1,4-bis-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one were obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH2:23]OS(C)(=O)=O)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.O>ClCCl>[Cl:1][C:2]1[CH:22]=[C:21]([CH2:23][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(COS(C)(=O)=O)cc3Cl)c2n1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(Cn4ccnc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of methyl 3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in dichloromethane (6.0 ml) was added imidazole (193 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was washed with diethyl ether, and collected by filtration to give the objective compound (213 mg) as a pale-yellow powder.