Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (686 mg) was dissolved in DMF (5 mL), and tert-butyl bromoacetate (473 mg) was added. Potassium carbonate (352 mg) was further added, and the mixture was stirred at room temperature overnight. After water was added carefully to the reaction solution, ethyl acetate (200 mL) was added, followed by extraction. The resulting organic layer was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded white crystals. The resulting fraction was recrystallized from IPE to obtain 679 mg of white powders.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][NH:11][C:10]=1[CH3:21])C1C=CC=CC=1.[CH2:22](OC1C(=O)C(C(OC)C(F)(F)F)=CNC=1C)C1C=CC=CC=1>>[OH:8][C:9]1[C:14](=[O:15])[C:13]([CH2:16][C:17]([F:18])([F:19])[F:20])=[CH:12][N:11]([CH3:22])[C:10]=1[CH3:21]
Reactant: Cc1[nH]cc(CC(F)(F)F)c(=O)c1OCc1ccccc1
Reactant: COC(c1c[nH]c(C)c(OCc2ccccc2)c1=O)C(F)(F)F
Product: Cc1c(O)c(=O)c(CC(F)(F)F)cn1C

Procedure:
To a clear solution of 3-benzyloxy-5-(1-chloro-2,2,2-trifluoro-ethyl)-2-methyl-1H-pyridin-4-one hydrochloric acid salt (2.03 g, 5.50 mmol) in methanol (70 mL) was added sodium borohydride (1.25 g, 33.0 mmol) in several portions. The reaction was completed within 20 min. The reaction mixture was quenched with deionized water (80 mL). The volume of the resulting clear solution was reduced to about 10 mL by evaporation under reduced pressure to give a solid/liquid mixture. Another 50 mL of deionized water was added. The aqueous solution was extracted with dichloromethane (3×50 mL). The combined organic fractions was dried over Na2SO4, filtered, then concentrated in vacuo to give an oil (1.3 g), which solidified upon standing. HPLC analysis (HPLC Method 1, Example 24) of the crude solid material indicated presence of a mixture of the desired compound 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (RT=14.7 min, peak percent area=80.6%) and 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-methoxy-ethyl)-1H-pyridin-4-one (RT=15.7 min, peak percent area=16.2%) in about 5/1 ratio. Purification of the solid by column chromatography on silica gel (methanol/dichloromethane 2/100 to 3/100 v/v as eluant) afforded the title compound (0.9 g, 56% yield, HPLC purity (peak percent area): 98% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 11.47 (br s, 1H), 7.60 (s, 1H), 7.37 (m, 5H), 5.06 (s, 2H), 3.41 (q, J=11.5 Hz, 2H), 2.06 (s, 3H); MS-ESI (m/z) 298.2 [M+1]+, 91.1 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12](C(OC)=O)[C:11](=[O:19])[C:10]3([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:9]2)=[CH:5][CH:4]=1.O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH2:12][C:11](=[O:19])[C:10]3([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[CH2:9]2)=[CH:32][CH:33]=1
Reactant: COC(=O)C1C(=O)N(Cc2ccc(OC)cc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)CC2=O)cc1

Procedure:
Crude product A3 was dissolved in acetonitrile (50 mL) and water (50 mL) and stirred for 4 h at 80° C. The acetonitrile was evaporated off and the solids were filtered off, washed with water and taken up in DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product A4 (1.57 g) was obtained as a white solid. Overall yields (A2 to A4) are 70%. 1H NMR (400 MHz, CDCl3, 300K): 6=1.23 (2H, m), 1.41 (9H, s), 1.76 (2H, m), 3.13 (2H, m), 3.26 (2H, s), 3.37 (2H, m), 3.39 (2H, s), 3.81 (3H, s), 4.58 (2H, s), 6.87 (2H, d, J=8.6 Hz), 7.22 (d, J=8.6 Hz). 13C NMR (100 MHz, CDCl3, 300K): δ=28.8, 30.0, 46.3, 47.1, 49.8, 51.7, 55.7, 80.2, 114.6, 128.4, 130.5, 154.9, 159.8, 166.4, 206.8. MS (ES) C22H30N2O5 requires: 402. found: 425.2 [M+Na]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])#[N:6]>CN(C)C=O.ClCCl>[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([Cl:3])=[O:11])#[N:6]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)Cl)c1

Procedure:
Thionyl chloride (10 ml) and dimethylformamide (1 drop) were added to a solution of 3-cyanobenzoic acid (10 g) in dichloromethane (100 ml), and the mixture was refluxed far 3 hours. After the reaction, the solvent was evaporated under reduced pressure to give 3-cyanobenzoyl chloride. Then, the oil was dissolved in dichloromethane (25 ml), and the solution was dropwise added to a solution of 4-aminopyridine (5 g) and diisopropylethylamine (8.9 g) in dichloromethane (50 ml), which was followed by stirring at room temperature for 1 hour. The precipitated crystals were collected by filtration, and recrystallized from chloroform-methanol-ether to give 5.3 g of N-(4-pyridyl)-3-cyanobenzamide.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:12][CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[N:36](C2N=C3C(N=C(OC4CCNCC4)N3C)=C(N3CCOCC3)N=2)[C:35]2[CH:60]=[CH:61][CH:62]=[CH:63][C:34]=2[N:33]=1)[CH3:31].F[C:65](F)(F)C(O)=O>>[NH:15]1[CH2:14][CH:13]([O:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:3]=[C:2]([N:36]2[C:35]4[CH:60]=[CH:61][CH:62]=[CH:63][C:34]=4[N:33]=[C:32]2[CH:30]([CH3:31])[CH3:65])[N:10]=3)[CH2:16]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(OC2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CCNCC3)n(C)c2n1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CNC3)n(C)c2n1

Procedure:
The compound was prepared from tert-butyl 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yloxy)azetidine-1-carboxylate in a similar manner as that of 4-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-8-(piperidin-4-yloxy)-9H-purin-6-yl)morpholine, following General Procedures of Buchwald coupling shown in Scheme 3 and Boc-deprotection. The compound was either used either as a mixture with unknown equivalent of trifluoroacetic acid or as a free base after treatment with aqueous base. LCMS: M+H+=449.4.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C.O>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(O)COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 36.7 %

Procedure:
A solution of 8.15 g (0.075 mol) of 1-chloro-2-methyl-2-propanol in 20 ml of ethanol is run over the course of 25 minutes into a solution, kept at about 60° C., of 15 g (0.068 mol) of p-(p-chlorophenoxy)phenol and of 3 g (0.075 mol) of sodium hydroxide pellets in 20 ml of water and 20 ml of ethanol. The mixture is heated to the reflux temperature for 2 hours and the ethanol is driven off under reduced pressure. The residue is extracted with diethyl ether and after drying and evaporation of the solvent gives 7.3 g of a yellow oil. This oil is purified by crystallisation from a mixture of cyclohexane and petroleum ether (1:2 by volume) followed by washing with 2 N NaOH. 4 g of a white powder which is insoluble in water are obtained.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.S(Cl)(Cl)=O.[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([Sn](C)(C)C)[N:29]=3)=[C:22]([F:39])[CH:21]=1>C1(C)C=CC=CC=1>[O:16]1[CH2:17][CH2:18][CH2:19][O:14][CH:15]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([C:6]([CH:4]2[CH2:3][C:2]([F:1])([F:9])[CH2:5]2)=[O:8])[N:29]=3)=[C:22]([F:39])[CH:21]=1
Reactant: C[Sn](C)(C)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reactant: O=C(O)C1CC(F)(F)C1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 3,3-difluorocyclobutanecarboxylic acid (542.6 mg, 3.99 mmol) in thionyl chloride (5.24 mL, 71.8 mmol) was heated at 70° C. for 1 h and then concentrated in vacuo. 2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)-5-(trimethylstannyl)thiazolo[5,4-b]pyridine (1.08 g, 2.254 mmol) was added to the residue, and the mixture was taken up in toluene (20.0 mL) and stirred under argon at 80° C. for 16 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (0-60% EtOAc/hexanes) to provide (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)(3,3-difluorocyclobutyl)methanone as an off-white solid. MS (ESI) m/z: Calculated: 434.1; Observed: 435.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][O:13][C:14]([CH3:23])([C:19]([F:22])([F:21])[F:20])[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([CH3:23])([C:19]([F:20])([F:21])[F:22])[C:15]([OH:17])=[O:16])=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the impure ester fraction from the previous example (fraction A) of (±)-methyl 2-[4-(4 -chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate (15.7 g.), potassium hydroxide (3.0 g.), methanol (300 ml.) and water (30 ml.) is stirred at ambient temperature for 18 hours. The suspension is filtered, and the filtrate is evaporated. The residue is mixed with water, and the mixture is washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid then extracted with ether. The extract is dried with sodium sulphate and evaporated. The residue is crystallised from cyclohexane and from a mixture of toluene and light petroleum (b.p. 60°-80° C.) to give (±)-2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acid, m.p. 135°-136° C. (5.7 g.). The above process is repeated with (±)-methyl 2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate obtained as an oil in Example 16, to give (±)-2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid, m.p. 120°-121° C. (11.1 g.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5](CC=C)[C:6]([O:8]C(C)(C)C)=[O:7].N1[C:22]([CH3:23])=[CH:21]C=CC=1C.[Si:25](OS(C(F)(F)F)(=O)=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[Cl-].[NH4+]>C(Cl)Cl>[Si:25]([O:8][C:6]([NH:5][CH:4]([CH2:23][CH:22]=[CH2:21])[C:3]([O:2][CH3:1])=[O:16])=[O:7])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C=CCN(CC(=O)OC)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1cccc(C)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCC(NC(=O)O[Si](C)(C)C(C)(C)C)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.5 ml) of N-(t-butoxycarbonyl)-allylglycine methyl ester (183 mg, 0.8 mmol) and 2,6-lutidine (0.186 ml, 1.6 mmol) was added t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.275 ml, 1.2 mmol) at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (3 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 260 mg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:5]([O:19][Si](C(C)(C)C)(C)C)[CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl.C[O:38][C:39](=O)[C@@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1O.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:68]CC1>CO>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:39](=[O:38])[C@@H:40]2[CH2:44][C@@H:43]([OH:68])[CH2:42][N:41]2[C:10]1=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:19]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Reactant: COC(=O)[C@@H]1CCCN1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(N=C2N(c3ccccc3Br)C(=O)[C@@H]3C[C@@H](O)CN23)c(O)c1
Yield: 78 %

Procedure:
The standard procedure was followed using N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)carbodiimide (102 mg, 0.24 mmol), diisopropylethylamine (60 μL, 0.26 mmol), hydroxy L-proline methyl ester hydro chloride (44 mg, 0.26 mmol) and TBAF (0.29 mL, 0.29 mmol) in THF (2.5 mL) and methanol (0.1 mL) to give 80 mg (78%) of 4-[[(6R,7aS)-2-(2-bromophenyl)-hexahydro-6-hydroxy-1-oxo-3H-pyrrolo[1,2-c]imidazol-3-ylidene]amino]-3-hydroxybenzonitrile as a tan powder. MS(EI) m/e 427 (100 (M+)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([OH:33])=[O:32])=[N:29][CH:30]=1>>[CH:31]([OH:33])=[O:32].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:28]3[CH:27]=[CH:26][C:25]([C:21]4[S:20][CH:24]=[CH:23][N:22]=4)=[CH:30][N:29]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: O=C(O)c1ccc(-c2nccs2)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(-c4nccs4)cn3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A9B) and 5-thiazol-2-yl-pyridine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as an off-white amorphous material. MS (ISP): m/z=462.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:14]=1)[C:8]([OH:10])=[O:9]>CCCCCC>[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:14]=1)[C:8]([O-:10])=[O:9]
Reactant: O=C(O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: CCNCC
Solvent: CCCCCC
Product: CC[NH2+]CC
Product: O=C([O-])C(Cl)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
Anhydrous diethylamine (0.11 moles) is added dropwise to a stirred solution of α-chloro-γ-(2'-chloro-4-biphenylyl)butyric acid (0.10 moles) in 100 ml. of n-hexane at 0°C. The precipitate is collected on a filter, washed with n-hexane, and dried in a vacuum desiccator to obtain α-chloro-γ-(2'-chloro-4-biphenylyl)butyric acid, diethylammonium salt.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:20])[C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[N:34]1[C:38]2C=[CH:40][CH:41]=[CH:42][C:37]=2N=N1.N1CCCCC1>CN(C)C=O.O>[C:1]([NH:4][CH:5]([CH3:20])[C:6]([NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:34]1[CH2:40][CH2:41][CH2:42][CH2:37][CH2:38]1)=[O:19])=[O:7])(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)NC(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: CC(=O)NC(C)C(=O)NC(Cc1ccccc1)C(=O)N1CCCCC1
Temperature: 50 °C

Procedure:
N-[2-(Acetylamino)propionyl]phenylalanine obtained in Experimental Example 21 (10 mg, 0.036 mmol) is suspended in N,N-dimethylformamide (5 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14 mg, 0.073 mmol), 1-hydroxybenzotriazole (15 mg, 0.11 mmol) and piperidine (40 μl, 0.40 mmol) are added to the suspension at room temperature, followed by stirring at 50° C. Fog 24 hours. To the reaction mixture is added water, and the resulting mixture is extracted three times with chloroform. The organic layer is washed with 10% hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the solvent is distilled away under reduced pressure, the residue is purified by silica gel column chromatography to obtain 1-{2-[N-(2-(acetylamino)propionyl)amino]-3-phenylpropionyl}piperidine.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>CN1CCCC1=O>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:18]2[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][OH:12])[CH2:16][CH2:17]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: OCCC1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(N2CCC(CCO)CC2)cc1
Reaction time: 72 h
Yield: 70.7 %

Procedure:
A solution of 9.84 grams of methyl 4-fluorobenzoate (63.9 mmol) and 12.40 grams of 4-(2-hydroxyethyl)piperdine (96 mmol) in 50 mL N-methylpyrrolidin-2-one was heated to 110°-120° C. and stirred for 72 hours. The dark solution was cooled and poured into 400 mL water. The tan precipitate was filtered off and washed well with water to yield 11.89 grams of crude product as a tan powder (71%). The crude material was recrystallized once from 100 mL ethanol which gave 4.75 grams (40% recovery) of a tan powder. Melting point 110°-115° C. 2H NMR δ (acetone-d6): 1.27 (2H, quad of doub, J=3.8 hz & 12.2 hz); 1.47 (2H, quad, J=6.6 hz); 1.71 (1H, mult); 1.80 (2H, br doub); 2.83 (2H, trip of doub, J=2.5 hz & 12.6 hz); 3.62 (2H, trip, J=6.6 hz); 3.78 (3H, s); 3.92 (2H, br doub); 6.93 (2H, doub); 7.81 (2H, doub). 13C NMR δ (acetone-d6): 32.59, 33.36, 40.30, 48.61, 51.55, 59.81, 114.30, 119.26, 132.0, 155.29, 167.18.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:19])[C:10]=1C1C=CC(C#N)=CC=1)[C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[S:5]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:19])[C:10]=1[C:29]1[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=1)[C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[S:5]2
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C#N)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C(F)(F)F)cc1
Yield: 107.8 %

Procedure:
The title compound was prepared by treatment of Step 2 intermediate, Intermediate 22 (2.0 g, 5.845 mmol) with 4-trifluoromethylphenylboronic acid (1.50 g, 8.18 mmol) in the presence of Pd[(C6H5)3P]4 (270 mg, 0.233 mmol) and sodium carbonate (3.71 g, 35.07 mmol) in a mixture of toluene, ethanol and water to afford 2.27 g of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 7.42-7.48 (m, 2H), 7.65-7.67 (m, 2H), 8.00-8.03 (m, 2H), 8.86-8.88 (m, 2H); ESI-MS (m/z) 361.32 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:12]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][C:7]2[O:11][CH2:12][O:10][C:8]=2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)c(O)cc1F
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2c(cc1F)OCO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a stirred solution of 2-fluoro-4,5-dihydroxy-benzaldehyde (8.0 g) and BrClCH2 (24.8 g, 190 mmol) in dry DMF (50 mL) was added Cs2CO3 (62.0 g, 190 mmol) in portions. The resulting mixture was stirred at 60° C. overnight and then poured into water. The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and evaporated in vacuo to give crude product, which was purified by column chromatography on silica gel (5-20% ethyl acetate/petroleum ether) to afford 6-fluoro-benzo[1,3]dioxole-5-carbaldehyde (700 mg, two steps yield: 24%). 1H-NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 7.23 (d, J=5.6, 1H), 6.63 (d, J=9.6, 1H), 6.08 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[C:4]([F:19])[CH:3]=1.OC([C:27]([CH3:29])=[CH2:28])C(OCC)=O.Cl.[CH3:31][OH:32]>C(N(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:31](=[O:32])[C:17](=[C:27]([CH3:29])[CH3:28])[O:16][C:15]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CO
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 75 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
Methyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (2.87 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (4.32 g, 30 mmol), ferric chloride (162 mg, 1.0 mmol) and tributylamine (92.7 mg, 0.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 3 hours. After completion of the reaction, the reaction solution was allowed to cool to 70 to 80° C., and a mixed solution consisting of methanol (5 mL) and 6N hydrochloric acid (0.25 mL) was added thereto and mixed homogeneously. Then, the reaction solution was left to stand at room temperature. The precipitated solid was collected by filtration, washed with a mixed solution consisting of methanol (8 mL) and 6N hydrochloric acid (0.8 mL) and then water (10 mL) and dried completely under reduced pressure to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.93 g, yield 54.5%).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1>C(OCC)C>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:12]1[NH:11][CH:10]=[C:9]([CH3:8])[CH:13]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cc[nH]c1
Solvent: CCOCC
Product: Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a solution of 2,2,2-trichloroacetyl chloride (5.05 mL, 45.3 mmol) in dry diethyl ether (12 mL) was slowly added a solution of 3-methyl-1H-pyrrole (3.15 g, 39.37 mmol) in 30 mL of dry diethyl ether during 1 h 15 min. Once the addition was finished, the reaction mixture was stirred at 45° C. during 1 hour 30 minutes more. Next, more diethyl ether was added and the organic phase was washed with an aqueous solution of potassium carbonate to neutralize de media, water and brine. The organic phase was dried (Na2SO4) and concentrated to dryness to give a residue that was purified by flash chromatography silica (hexane/dichloromethane) to afford 4.7 g of the title compound (55% yield).