Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:11]([S:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)([CH2:14][CH2:15][CH2:16][N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=3)[CH2:18]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1OC.[ClH:39].[CH2:40]([O:42][CH2:43][CH3:44])C>C(O)C>[ClH:39].[CH3:40][O:42][C:43]1[CH:44]=[C:19]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=2[C:11]([S:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)([CH2:14][CH2:15][CH2:16][N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=3)[CH2:18]2)[C:12]#[N:13])[CH:20]=[CH:21][C:22]=1[O:27][CH3:28]
Reactant: CCOCC
Reactant: COc1ccc(C(C#N)(CCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccccc2C(C#N)(CCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Reaction time: 15 h

Procedure:
To a solution of 1.43 g of α-(3,4-dimethoxyphenyl)-3,4-dihydro-6,7-dimethoxy-α-[(4-methylphenyl)thio]-2(1H)-isoquinolinepentanenitrile in 40 mL of diethyl ether, with stirring, is added 0.617 mL of a 4.71M solution of hydrogen chloride in absolute ethyl alcohol. The reaction mixture is then stirred for 15 hours while sealed. The title product is then collected by filtration, washed with ether, and dried under vacuum to give 1.32 g of the desired product as pink crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(N(C(C)C)CC)(C)C>ClC(Cl)C>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:11]([NH:10][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc(Cl)ncc2Br)C1

Procedure:
A solution 5-bromo-2,4-dichloro-pyrimidine 4 g, 17.6 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (3.6 g, 17.6 mmol) and diisopropylethylamine (3.1 ml, 18 mmol) in dichloroethane (200 ml) was warmed to 40-50° C. for 16 hours. The reaction was cooled and washed with water, dried (MgSO4), and filtered. The oil was purified by silica gel chromatography (10-25% ethyl acetate/hexane) to give (S)-3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as an oil that was taken to the next step. The oil was diluted with dichloromethane (100 ml) cooled to 5° C. and treated with trifluoroacetic acid (40 ml). After stirring at room temperature for 5 hours, all solvent was evaporated. The residue was dissolved in chloroform (150 ml) and washed with cold dilute aqueous sodium carbonate. The organics were dried (MgSO4) and evaporated to give an oil that solidified on standing in ether/hexane to give 3.5 g (68%) of (5-bromo-2-chloro-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine as a solid. 1H NMR (300 MHz), dmso-d) δ ppm, 8.23 (s, 1H), 7.17 (s, 1H), 3.99 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([NH:8][C:9]([NH:11][C:12](=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2[Cl:21])=[O:10])[CH:7]=1.[CH3:25][N:26]=[C:27]=[O:28]>C(#N)C>[Cl:21][C:14]1[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=1[C:12]([NH:11][C:9](=[O:10])[NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:27]([NH:26][CH3:25])=[O:28])[CH:3]=[CH:4][C:5]=1[O:23][CH3:24])=[O:22]
Reactant: COc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)Nc1ccc(OC)c(NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
600 mg (1.7 mmol) of 1-(5-amino-2-methoxyphenyl)-3-(2-chloro-4,5-difluoro-benzoyl)urea were dissolved in 5 ml of acetonitrile, and 69 mg (1.7 mmol) of methyl isocyanate were added. After stirring at room temperature for one hour, the resulting precipitate was filtered off with suction. 638 mg (91%) of the desired product were obtained.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][N:14]=2)=[C:9]([Cl:22])[C:8]=1[Cl:23])C.Cl>C(O)C.[OH-].[Na+]>[O:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])=[C:8]([Cl:23])[C:9]=2[Cl:22])=[N:14]1
Reactant: CCOC(=O)COc1ccc(-c2noc3ccccc23)c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(-c2noc3ccccc23)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 6.88 g (0.187 m) of ethyl-4-(1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetate of Example 2D in 70 ml of ethanol, 4 ml of 10 N NaOH is added. The mixture is refluxed for 1 hour. The salt which forms is filtered off, and combined with 250 ml of water at 90° C., giving a suspension. Concentrated HCl is added until the mixture is acidic. The mixture is stirred 1 hour at ambient temperature and the product is filtered off. The crude product is recrystallized from ethanol/H2O and then recrystallized from toluene to give 4.1 g (65%) of pure 4-(1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetic acid, m.p. 166°-167° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[C:5]([F:21])[CH:4]=1)#[CH:2].N1C2C(=CC=CC=2)C=CC=1>C1COCC1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[F:19][C:18]1[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][C:5]=2[F:21])=[C:11]([CH:15]=[CH:16][C:17]=1[F:20])[C:12]([OH:14])=[O:13]
Reactant: C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: C1CCOC1
Product: C=Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
The product of Example 1, Step C, 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (540 mg, 1.86 mmol) and quinoline (220 mg) were dissolved in THF (50 mL), then Lindlar catalyst (11 mg) added. This mixture was stirred under an atmosphere of hydrogen (60 psi) for 3 periods of 15 minutes and monitored carefully by TLC (50% EtOAc/hexanes as eluant). The reaction mixture was filtered through Celite® which was washed well with EtOAc and the resulting filtrate concentrated (to 100 mL) under reduced pressure. This organic solution was then washed with 1 M HCl (2×100 mL), water (100 mL) and saturated NaCl solution (100 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The resulting crude solid was purified by flash chromatography on silica (10% EtOAc/hexanes as eluant) to afford 3,4-difluoro-2-[(2-fluoro-4-vinylphenyl)amino]benzoic acid as a crystalline yellow solid (390 mg, 72%); m.p. (EtOAc/hexanes) 162–166° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.20 (br s, 1 H), 9.30 (br s, 1 H), 7.52 (ddd, J=8.3, 6.1, 1.8 Hz, 1 H), 7.41 (dd, J=12.8, 1.7 Hz, 1 H), 7.19 (dd, J=8.3, 1.7 Hz, 1 H), 7.08 (dd, J=16.6, 9.3 Hz, 1 H), 7.00 (td, J=8.7, 5.2 Hz, 1 H), 6.67 (dd, J=17.6, 10.9 Hz, 1 H), 5.78 (d, J=17.6 Hz, 1 H), 5.22 (d, J=11.0 Hz, 1 H). Anal. Calcd for C15H10F3NO2: C, 61.4; H, 3.3; N, 4.9. Found C, 61.4; H, 3.4; N, 4.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:32][C:33](=[O:49])[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)Cl)[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:35]([C:37]3[CH:38]=[CH:39][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:41][CH:42]=3)=[CH:34][C:33]([O:32][CH2:30][CH3:31])=[O:49])[CH:25]=[CH:24]4)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccc(-c2ccccc2)cc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 8 %

Procedure:
The title compound was synthesized from 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester and 3-biphenyl-4-yl-3-chloro-acrylic acid ethyl ester using the procedure described in Example 18, step (d), in an 8% yield as a mixture of E/Z isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.Cl.[F:30][C:31]1([F:37])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1.O(C(C)(C)C)[Na].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:31]1([F:37])[CH2:36][CH2:35][CH2:34][N:33]([C:6]2[CH:5]=[CH:4][C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)=[C:2]([F:1])[CH:7]=2)[CH2:32]1
Reactant: FC1(F)CCCNC1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CCCC(F)(F)C3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 54.8 %

Procedure:
A mixture of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 3,3-difluoropiperidine hydrochloride (94.6 mg, 0.6 mmol), NaO-t-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd2(dba)3 (18.3 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to 90° C. for 14 h under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (132 mg, 55% yield) as a yellow solid: mp 182-187° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 1.68-1.81 (2H, m), 1.97-2.16 (2H, m), 3.34-3.43 (2H, m), 3.67 (21-1, t, J=11.9 Hz), 3.76 (3H, s), 6.73-7.10 (4H, m), 7.24-7.50 (5H, m), 7.78 (1H, d, J=1.9 Hz), 8:39 (1H, d, J=1.9 Hz). Anal. Calcd for C25H22F3N5O2: C, 62.36; H, 4.61; N, 14.55. Found: C, 62.60; H, 4.60; N, 14.31.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[Br:24][C:25]1[CH:26]=[C:27]([NH:34]C(=O)OC(C)(C)C)[CH:28]=[C:29]([CH2:31][CH2:32][OH:33])[CH:30]=1>>[Br:24][C:25]1[CH:26]=[C:27]([NH:34][C:18]2[N:17]=[C:16]([NH:15][C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH:28]=[C:29]([CH2:31][CH2:32][OH:33])[CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)cc(CCO)c1
Product: OCCc1cc(Br)cc(Nc2ncc(Cl)c(Nc3cccc(O)c3)n2)c1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using N-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2,5-dichloropyrimidin-4-amine and tert-butyl [3-bromo-5-(2-hydroxyethyl)phenyl]carbamate as the starting materials in 77% yield. LCMS for C18H17BrClN4O2 (M+H)+: m/z=434.9, 436.9.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:2](=[O:7])[CH:3]([CH2:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4](=[O:5])[CH3:6])[CH3:10]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium metal (60 mmol, 1.4 g) was suspended in 80 mL (milliliter) toluene under nitrogen. Ethyl acetoacetate (88 mmol (millimole), 11.4 g) was added dropwise, and the resulting mixture was stirred until all sodium was consumed. The reaction mixture then was cooled in an ice bath (0-5° C.) and 2-bromoacetophenone (60 mmol, 12 g) in 140 mL toluene was added dropwise. The reaction was stirred overnight with gradual warming to room temperature. Analysis of the reaction mixture by GC and TLC showed that the reaction was complete. The reaction mixture then was washed with 200 mL water, then the organic and aqueous layers were separated. The organic layer was dried over MgSO4 (magnesium sulfate). The toluene was removed from the organic layer under vacuum to provide a yellow oil which was purified by Kugelrohr distillation (b.p. 135-145° C. at 0.35 Torr.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O-:29])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:20]=2)([CH2:13][OH:14])[C:9]([O:11]C)=O)=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:5]([CH3:8])([CH3:6])[CH3:4])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:20]=2)([CH2:13][OH:14])[CH2:9][OH:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C(CO)(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)[O-])CC2)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(CO)(CO)c3ccc(F)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A solution of 4-(5-(2-(4-fluorophenyl)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate (700 mg, 1.5 mmol) in 20 mL of THF was cooled to −10° C., followed by the addition of LiBH4 (180 mg, 7.5 mmol) slowly. This mixture was allowed to warm to RT and stirred overnight. The reaction was quenched by MeOH (3 mL) and then concentrated in vacuo. The residue was purified by silica gel column (DCM:MeOH, 10:1) to obtain the desired product (300 mg, yield 47%) as a yellow foam. MS (ES+) C22H29FN4O4 requires: 432. found 433 [M+H]+; purity: 67% (UV254).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=1>>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:29]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 2g (93 mg, 0.44 mmol) was reacted with the product from Example 18b (123 mg, 0.44 mmol) for 23 h following the procedure from Example 1g giving the title compound after purification of the crude product by HPLC with TFA as a trifluoroacetic acid salt solid (72 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H), 1.84 (dq, J=14.75, 7.46 Hz, 2H), 2.04 (s, 3H), 2.35 (s, 3H), 2.99 (t, J=7.35 Hz, 2H), 6.31 (d, J=6.99 Hz, 1H), 7.15 (d, J=8.09 Hz, 1H), 7.20-7.33 (m, 4H), 7.50 (d, J=8.46 Hz, 2H), 7.81 (d, J=8.46 Hz, 1H), 8.41 (d, J=6.99 Hz, 1H), 9.00 (d, J=8.46 Hz, 1H), 10.05 (s, 1H), 11.02 (s, 1H); MS (ESI+) m/z 443 (M+H)+; (ESI−) m/z 441 (M−H)−.
Reaction SMILES: [C:1]([N:4]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=[O:28])=[C:19]([F:33])[CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([OH:29])=[O:28])=[C:19]([F:33])[CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCCC(C)(C)C(=O)O)c(F)c2)c2ccccc21
Temperature: 40 °C
Yield: 82.6 %

Procedure:
Methyl 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenyl)-2,2-dimethylpentanoate (70 mg, 0.12 mmol, 1 eq.) was dissolved in methanol/tetrahydrofuran (2/1) (3 ml). A solution of sodium hydroxide (8 mg, 0.20 mmol, 1.7 eq.) in water (1 ml) was added and reaction mixture heated to 40° C. for 8 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by silica gel chromatography (methylene chloride/methanol: 99/1 to 98/2 gradient) gave pure 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenyl)-2,2-dimethylpentanoic acid (56 mg, 84%).
Reaction SMILES: CO.[C:3]([O:7][C:8]([C@@H:10]1[CH2:14][S:13][CH:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:11]1[C:21](=[O:44])[CH2:22][NH:23][C:24](=[O:43])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35]CC2C=CC=CC=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C([O-])=O.[NH4+]>[Pd].[OH-].[Na+]>[C:3]([O:7][C:8]([C@@H:10]1[CH2:14][S:13][CH:12]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[N:11]1[C:21](=[O:44])[CH2:22][NH:23][C:24](=[O:43])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(C2CCCCC2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CSC(C2CCCCC2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
30 cm3 of methanol are added slowly under an inert atmosphere into a round-bottomed flask containing 2.0 g of benzyl (4R) -3-{3- [2- (4-tert-butoxycarbonyl-2-cyclohexyl-3-thiazolidinyl)-2-oxoethyl]-ureido}phenyl-acetate (isomer A), 1.7 g of ammonium formate and 2.0 g of palladium on charcoal (10% Pd). The reaction medium is heated to reflux for 2 hours and then cooled to a temperature in the region of 25° C. The catalyst is separated by filtration and the filtrate is concentrated to dryness under reduced pressure at 40° C. The residue obtained is dissolved in 25 cm3 of 0.1N aqueous sodium hydroxide solution and washed with twice 10 cm3 of diethyl ether. The aqueous phase is brought to pH 2 by adding 1N aqueous sulphuric acid solution. The precipitated product is separated by filtration, washed with twice 10 cm3 of water and dried in the air. 1.0 g of (4R) -3-{3- [2- (4-tert-butoxycarbonyl-2-cyclohexyl-3-thiazolidinyl)-2-oxoethyl]ureido}phenylacetic acid (isomer A), melting point 115° C., is thereby obtained; [α]D25 =-32.9°±1.2° (C %=1.2; DMF).
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4C(F)(F)F)[CH:14]=[CH:15][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:29]C1C=CC=CC=1C(Cl)=O>>[Cl:29][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:7]2[CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[O:10][B:9]([OH:11])[C:8]=2[CH:12]=1)=[O:28]
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1Cl
Product: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1Cl

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with 2-chlorobenzoyl chloride replacing 2-trifluoromethylbenzoyl chloride. Data: LCMS (M/Z): 356 (M+H); 1H NMR (acetone) δ: 9.51 (br. s., 1H), 8.18 (d, J=1.8 Hz, 1H), 7.79 (dd, J=8.2, 2.0 Hz, 1H), 7.60 (dd, J=7.0, 1.7 Hz, 1H), 7.36-7.52 (m, 5H), 5.13 (d, J=4.8 Hz, 1H), 2.32 (quin, J=8.2 Hz, 1H), 1.82-1.92 (m, 1H), 1.63-1.74 (m, 2H), 1.52-1.59 (m, 2H), 1.30-1.40 (m, 1H), 1.07-1.15 (m, 1H), 0.80-0.89 (m, 1H).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH3:22])[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])=[CH:3][CH:2]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH3:22])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:21])=[CH:3][CH:2]=1
Reactant: CC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Yield: 63.3 %

Procedure:
Hydrogenolysis of 500 mg of the 5-[(1,1'-biphenyl)-4-yl]-3-phenylmethoxy-4-hydroxy-5-methyl-2(5H)-furanone was performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided 240 mg (63% yield) of 5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone as a white powder: mp 206-212° C. dec. (MeOH/H2O), 1H NMR (acetone-d6) δ 7.69-7.33 (m, 9H), 1.88 (s, 3H). 13C NMR (acetone-d6) δ 169.5, 157.1, 141.6, 141.0, 139.8, 129.6, 128.3, 127.6, 127.6, 126.6, 117.9, 81.2, 24.5. Anal Calcd for C17H14O4 : C, 72.33; H, 5.00. Found: C, 72.07; H, 5.14.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:21]1[C:29]2[N:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[C:24]=2[CH:23]=[CH:22]1.C(=O)([O-])O.[Na+].C(O)C>O.C1(C)C=CC=CC=1>[N:15]1([C:4]2[C:5]3[O:10][C:9]4[N:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:6]=3[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][N:28]=[C:29]4[NH:21][CH:22]=[CH:23][C:24]=34)[N:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)c2oc3ncccc3c2n1
Reactant: CC1(C)OB(c2ccnc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: c1cnc2oc3c(N4CCOCC4)nc(-c4ccnc5[nH]ccc45)nc3c2c1
Temperature: 120 °C

Procedure:
Under Ar(g) to a mixture of compound 5 (20 mg, 0.069 mmol), 7-azaindole-4-boronic acid pinacol ester (18.5 mg, 0.076 mmol), dichloro-bis(triphenylphosphine)palladium (II) (2.4 mg, 0.003 mmol) and sodium hydrogen carbonate (17.4 mg, 0.21 mmol) was added ethanol (1 mL) followed by toluene (1.6 mL) and then water (0.5 mL). The reaction mixture was then heated in a microwave at 120° C. (300 W) for 1 h, and was subsequently cooled to rt; the mixture was then partitioned between CH2Cl2 and water, and the organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 30-90% EtOAc/Hex) furnished D (20 mg, 0.054 mol, 78%) as an off-white solid.
Reaction SMILES: [CH:1]1([C@@H:7]([NH2:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]([C@@H:13]1[CH2:18][C@@H:17]2[O:19][C@:16]2([CH3:20])[CH2:15][CH2:14]1)=[CH2:12]>O>[CH:1]1([C@@H:7]([NH:9][C@@H:15]2[CH2:14][C@@H:13]([C:11]([CH3:12])=[CH2:10])[CH2:18][CH2:17][C@@:16]2([CH3:20])[OH:19])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)[C@H]1CC[C@@]2(C)O[C@H]2C1
Reactant: C[C@H](N)C1CCCCC1
Solvent: O
Product: C=C(C)[C@H]1CC[C@@](C)(O)[C@H](N[C@@H](C)C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 109.75 h
Yield: 33.7 %

Procedure:
A 100-mL, single-neck flask equipped with a magnetic stirring bar and a reflux condenser fitted with a nitrogen bubbler was charged with 4.75 g (0.037 mol) of (S)-(−)-1-cyclohexylethylamine, 23.00 g (0.151 mol) of (S)-(−)-limonene oxide, and 2.0 mL of deionized water. The mixture was heated to reflux and held there for 109.75 h. The reaction mixture was cooled to room temperature and filtered to remove an insoluble white solid. The excess limonene oxide was then distilled off at reduced pressure leaving an orange oil that crystallized upon standing over night. The solid was recrystallized from approximately 20 mL of n-heptane to give 3.48 g of (1R,2R,4S)-2-((1S)-1-cyclohexylethylamino)-1-methyl-4-(1-methylethenyl) cyclohexanol, as a white solid, mp 63-64° C.