Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][N:4]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC.O>CC(N(C)C)=O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][N:4]=1)[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CNc1ccc(I)cn1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CI
Product: CN(C)c1ccc(I)cn1
Temperature: 90 °C
Yield: 56.9 %

Procedure:
The obtained 2-(N-monomethylamino)-5-iodopyridine (99, 1.00 g, 4.27 mmol), potassium carbonate (2.95 g, 21.36 mmol) and iodomethane (145 mg, 8.546 mmol) were dissolved in dimethylacetamide (30 mL), and the reaction mixture was heated at 90° C. for 24 hours, followed by adding water. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-(N,N-dimethylamino)-5-iodopyridine (100, 603 mg, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:18])[CH:11]=[C:12]([CH2:16][OH:17])[N:13]([OH:15])[CH:14]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH:27](Br)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:28]1([CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:15][N:13]2[CH:14]=[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[C:10](=[O:18])[CH:11]=[C:12]2[CH2:16][OH:17])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(COc2cn(O)c(CO)cc2=O)cc1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CO)cc2=O)cc1

Procedure:
5.54 g of 5-p-methoxybenzyloxy-1-hydroxy-2-hydroxymethyl-4-pyridone is suspended in 40 ml of N,N-dimethylformamide, and then 2.24 g of potassium t-butoxide is added with ice cooling to dissolve. 4.94 g of benzhydryl bromide is added thereto and reacted at room temperature for 2.5 hours.
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:27])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([CH:28]2[CH2:30][CH2:29]2)[C:10]1=[O:31])C1C=CC=CC=1.C([Cl:35])(=O)C>CO.[Pd]>[ClH:35].[CH:28]1([N:11]2[C:12]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:17]([F:27])=[CH:16][C:13]=3[C:14](=[O:15])[N:9]([OH:8])[C:10]2=[O:31])[CH2:29][CH2:30]1
Reactant: CN1CCN(c2nc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3C2CC2)CC1
Reactant: CC(=O)Cl
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2nc3c(cc2F)c(=O)n(O)c(=O)n3C2CC2)CC1
Product: Cl

Procedure:
Following the procedure of Example 32, the reaction of 3-benzyloxy-1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example L-2, 65 mg, 0.157 mmol), 10% Pd/C (30 mg) in MeOH (3 mL) under a hydrogen atmosphere, followed by adding a few drop of acetyl chloride into the reaction mixture provided 45 mg of the title compound as powder, mp >300° C. (decomp.).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]([C:26]1[CH:34]=[CH:33][C:29](C(Cl)=O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:35]([N:37]1[C:49]2[CH:48]=[CH:47][C:46]([NH2:50])=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36]>>[CH2:35]([N:37]1[C:49]2[CH:48]=[CH:47][C:46]([NH:50][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6](=[O:7])[C:29]3[CH:28]=[CH:27][C:26]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:34][CH:33]=3)=[O:18])=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)c3ccc(Oc4ccccc4)cc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=547.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]#[CH:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([NH:18][CH2:19][CH2:20][OH:21])[CH:17]=2)[C:12](O)=[O:13])=[N:6][CH:7]=1.C(N(CC)CC)C.[BH4-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]#[CH:25])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][OH:21])[CH:15]=[C:11]([CH2:12][OH:13])[CH:10]=2)=[N:6][CH:7]=1
Reactant: C#CCOc1nc(Nc2cc(NCCO)cc(C(=O)O)c2)ncc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: C#CCOc1nc(Nc2cc(CO)cc(NCCO)c2)ncc1Br

Procedure:
To a mixture of 3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5-[(2-hydroxyethyl)amino]benzoic acid and triethylamine (57 μl) in tetrahydrofuran (4 ml) was added ethyl chloroformiate (37 μl) at −10° C. After stirring for 15 minutes at 0° C. sodium borohydride (44 mg) and methanol (3.6 ml) were added and stirring continued over night at room temperature. After dilution with water the reaction mixture was extracted with ethyl acetate and the organic layer subsequently washed with saturated NaHCO3-solution and brine After drying (Na2SO4) and evaporation the residue was subjected to chromatography on-silica gel (hexanes/ethyl acetate) to yield the title compound (59 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CC(=O)O
Reactant: COc1c(C=O)cccc1Oc1ccccc1Cl
Agent: Cl
Agent: O=C=O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1c(C=CC(=O)O)cccc1Oc1ccccc1Cl
Yield: 62.8 %

Procedure:
2-Methoxy-3-(2-chlorophenoxy)benzaldehyde (7.0 g) and malonic acid (5.60 g) were dissolved in pyridine (60 ml). To the solution was added piperidine (0.6 ml) and the mixture was heated gradually to 80° C., while carbon dioxide was produced. Thereafter, the mixture was refluxed under heating for 30 minutes. After cooling, the reaction mixture was poured into water (300 ml), acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then evaporated. The crystalline residue (7.10 g) was recrystallized from diisopropyl ether to give 3-[2-methoxy-3-(2-chlorophenoxy)phenyl]acrylic acid (5.1 g). mp 145°-147° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 1 (40 mg, 0.1 mmol) in dioxane (0.5 mL) was added HCl (4 N in dioxane 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was removed and the crude was purified by recrystallization with MeOH-ether to yield the title product (27 mg, 90%); LCMS; 95% ESI+, Calcd: 238.4 m/z; Found: 284.4 (M+1) m/z; 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.76 (m, 1H), 1.86-2.04 (m, 2H), 2.07-2.14 (m, 1H), 3.20 (br, 2H), 3.87 (br, 1H), 4.05 (dd, J1=10.4 Hz, J2=8.4 Hz, 1H), 4.18 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 5.05 (s, 2H), 6.91-6.99 (m, 4H), 7.30-7.44 (m, 5H):
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15][CH3:16])=[N:7][C:6]3[C:17]([CH3:21])=[CH:18][CH:19]=[N:20][C:5]2=3)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:30])C=1.CCOCC>C(Cl)Cl>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15]([CH3:16])=[O:30])=[N:7][C:6]3[C:17]([CH3:21])=[CH:18][CH:19]=[N:20][C:5]2=3)[CH2:2][CH2:3]1
Reactant: CSC1=Nc2c(C)ccnc2N(C2CC2)c2ncccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccnc2c1N=C(S(C)=O)c1cccnc1N2C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 11-cyclopropyl-4-methyl-6-methylthio-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.8 g, 0.0027 mol) in methylene chloride (10 mL) was cooled in an ice water bath. To the resulting clear yellow solution was added m-chloroperbenzoic acid (0.55 g, 0.0027 mol) in one portion and the reaction mixture was stirred at 0° C. for 30 min. A cloudy yellow solution was obtained which was quenched by the addition of Ca(OH)2 (1 g, 0.0135 mol). The reaction mixture was stirred at room temperature for 15 min., filtered through a pad of Celite, and concentrated to obtain a yellow oil. Trituration with ether afforded 0.7 g of the title compound, m.p. 188°-190° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1)[CH2:18][CH3:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(CC(=O)O)cc1
Reactant: CCCc1ccc(CNCC(=O)OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Mg+2]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc(CC(=O)N(CC(=O)OC)Cc2ccc(CCC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
Methyl 2-((4-propylbenzyl)amino)acetate (24.5 mg, 0.0983 mmol) and 2-(4-propylphenyl)acetic acid (17.5 mg, 0.0983 mmol) were dissolved in 1 mL of well-dried DCM under argon condition and then EDC (56.5 mg, 0.295 mmol), HOBt (39.8 mg, 0.295 mmol) and DIPEA (84.3 μL, 0.491 mmol) were added and the reaction mixture was stirred for 20 hours at room temperature. Upon completion of the reaction, the reaction was terminated by adding 3 mL of water, and the reaction mixture was extracted with DCM (3 mL×4). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 31.1 mg (0.0789 mmol, 80%) of the desired compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]([OH:13])=O)[CH2:8]2.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(O)=O>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[C:11]([N:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)=[O:13])[CH2:9]2
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C1C2CC3CC(C2)CC1C3)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 24.2 mg (0.134 mmol) adamantane-2-carboxylic acid, 20 mg (0.168 mmol) indoline, 64.7 mg (0.2 mmol) TBTU and 43.4 mg (0.336 mmol) DIPEA in 1 mL DMF was stirred at room temperature overnight. Formic acid was added and the mixture was subjected to column chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 14.1 mg (30%) of the title compound. MS(m/e): 282.4 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:10]([NH:12][C:13]2[C:14]([CH3:28])=[C:15]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:34]1[CH:39]=[C:38]([CH:40]=[O:41])[C:37]([CH:42]=O)=[CH:36][CH:35]=1.O>C(O)(=O)C>[CH:29]1([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:1]3[CH2:42][C:37]4[C:38](=[CH:39][CH:34]=[CH:35][CH:36]=4)[C:40]3=[O:41])=[CH:4][CH:5]=2)[C:10]([NH:12][C:13]2[C:14]([CH3:28])=[C:15]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:16]=[CH:17][CH:18]=2)=[O:11])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN)cc1)C1CCCC1
Reactant: O=Cc1ccccc1C=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Reaction time: 1 h

Procedure:
At RT, 50 mg (0.11 mmol) of (+/−)-tert-butyl 3-[3-({[4-(aminomethyl)phenyl](cyclopentyl)acetyl}amino)-2-methylphenyl]propanoate and 16.4 mg (0.12 mmol) of phthaldialdehyde were dissolved in 2.5 ml of glacial acetic acid, and the mixture was left to stand for 1 h. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative RP-HPLC. This gave 53 mg (85% of theory) of the target compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9](=[O:11])[O:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:13]C(N)=O>C1(C)C(C)=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:13][C:7]2=[O:8]
Reactant: NC(N)=O
Reactant: O=C1OC(=O)c2c(I)cccc21
Solvent: Cc1ccccc1C
Product: O=C1NC(=O)c2c(I)cccc21
Yield: 60.1 %

Procedure:
A solution of 4-iodo-2-benzofuran-1,3-dione (0.55 g, 2.01 mmol) and urea (0.24 g, 3.99 mmol) in xylene (5 mL) was heated to reflux overnight. After cooling, the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 5–10% ethyl acetate/isohexane gave 4-iodo-1H-isoindole-1,3 (2H)-dione as a pale yellow solid (330 mg, 60%).
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[N:30]3)=[CH:27][CH:28]=2)[C:8]2[CH:21]=[CH:20][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[CH:41]([NH2:44])([CH3:43])[CH3:42]>C(=O)=O>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[N:30]3)=[CH:27][CH:28]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:20][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:41]([NH3+:44])([CH3:43])[CH3:42]
Reactant: CC(C)N
Agent: O=C(O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)C2CCCCC2)cc1
Agent: O=C=O
Solvent: CCO
Product: CC(C)[NH3+]

Procedure:
(+\−)-3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid (Example 101) was resolved by SFC (Column: Chiralpak AD-H 25×4.6 mm; mobile phase: 25% ethanol in CO2; modifier: 0.2% isopropylamine; flow rate: 2.5 mL/min) to provide 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 1 (retention time: 6.93 min) and 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 2 (retention time: 9.58 min) as their isopropylammonium salts. The salts were dissolved in water and the pH adjusted to 3.5 by addition of 1N aqueous HCl. The mixtures were extracted with dichloromethane. The organic layers were dried over MgSO4 and concentrated to provide 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 1 and 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 2. Spectral data for Isomer 1: 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.77 (s, 1H), 7.65-7.72 (m, 3H), 7.60 (d, J=8.8 Hz), 7.32 (d, J=8.2 Hz, 2H), 6.82-6.88 (m, 1H), 6.71-6.78 (m, 1H), 4.15 (d, J=6.2 Hz, 1H), 3.65-3.73 (m, 2H), 2.63-2.73 (m, 2H), 1.83-1.93 (m, 1H), 1.59-1.82 (m, 4H), 1.46-1.56 (m, 1H), 0.94-1.28 (m, 6H). MS (M+H)=516.2.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C:19]2([CH2:21][CH2:20]2)[C@@H:18]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]2=[O:29])[C@@H:12]2[O:13]C(C)(C)[O:15][C@H:11]12)(C(C)(C)C)(C)C>C(O)(C(F)(F)F)=O.O>[OH:13][C@@H:12]1[C@H:11]([OH:15])[C@@H:10]([CH2:9][OH:8])[C:19]2([CH2:21][CH2:20]2)[C@H:18]1[N:22]1[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]1=[O:29]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)C1(CC1)[C@H]2n1ccc(=O)[nH]c1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccn([C@H]2[C@H](O)[C@H](O)[C@@H](CO)C23CC3)c(=O)[nH]1
Temperature: 50 °C
Yield: 79.3 %

Procedure:
Compound 16 (0.2 g, 0.47 mmol) was dissolved in 20 mL of CF3COOH/H2O (2:1, v/v) and heated to 50° C. for 3 hr. The solvent was removed under vacuum and the residue was co-evaporated with ethanol (10 mL×3) under vacuum. The residue was purified by column chromatography on a silica gel (7% MeOH/CH2Cl2) to give 17 (100 mg, 79%) as white foam. mp 114-116° C.; [α]24D 9.84° (c 0.26, MeOH); UV (MeOH) λmax 265 nm (ε11713, pH 2), 265 nm (ε11887, pH 7), 264 nm (ε9153, pH 11); 1H NMR (500 MHz, CD3OD-d6) δ 7.50 (d, J=8.5 Hz, 1H), 5.68 (d, J=8.5 Hz, 1 H), 4.77-4.73 (m, 2 H), 4.62 (d, J=3 Hz, 1 H), 3.71 (dd, J=4.5 & 11.0 Hz, 1 H), 3.62 (dd, J=5 & 11.0 Hz, 1 H), 2.26 (m, 1 H), 0.87 (m, 2H), 0.81 (m, 1H), 0.33 (m, 1H) ; 13C NMR (125 MHz, CD3OD) δ 165.1, 152.2, 146.3, 109.9, 74.3, 72.4, 63.4, 51.1,29.8, 28.7, 10.9; HR-MS Calcd. For (C12H16N2O5+H)+ 269.1059, found 269.1261.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25](O)=[O:26])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][C:41]([NH2:45])([C:43]#[CH:44])[CH3:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]([NH:45][C:41]([CH3:42])([CH3:40])[C:43]#[CH:44])=[O:26])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1
Reactant: C#CC(C)(C)N
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: C#CC(C)(C)NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from the product of example 148 step (i) (0.14 g), carbonyldiimidazole (0.064 g) and 1,1-dimethylpropargylamine (0.06 g) using the method of example 115 step (i). Purification was by chromatography eluting with ethyl acetate/isohexane (2/3). Yield 0.03 g as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:31]([CH3:32])=[CH:30][C:12]([C:13]([NH:15][CH2:16][C:17]([C:19]2[CH:24]=C(C)N=C(CC(C)C)[CH:20]=2)=[O:18])=O)=[CH:11][C:10]=1[CH2:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N+:37](S(N=C(OC)[O-])(=O)=O)([CH2:40][CH3:41])[CH2:38][CH3:39].[CH2:50]1[CH2:54]OC[CH2:51]1>>[CH2:1]([O:8][C:9]1[C:31]([CH3:32])=[CH:30][C:12]([C:13]2[O:18][C:17]([C:19]3[CH:20]=[C:38]([CH3:39])[N:37]=[C:40]([CH2:41][CH:50]([CH3:54])[CH3:51])[CH:24]=3)=[CH:16][N:15]=2)=[CH:11][C:10]=1[CH2:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C(=O)NCC(=O)c2cc(C)nc(CC(C)C)c2)cc(C)c1OCc1ccccc1
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Reactant: C1CCOC1
Product: CCc1cc(-c2ncc(-c3cc(C)nc(CC(C)C)c3)o2)cc(C)c1OCc1ccccc1
Reaction time: 16 h

Procedure:
To a solution 4-benzyloxy-3-ethyl-N-[2-(2-isobutyl-6-methyl-pyridin-4-yl)-2-oxo-ethyl]-5-methyl-benzamide (70 mg, 0.153 mmol) in THF (2 mL), Burgess reagent (95 mg, 0.377 mmol) is added and the mixture is refluxed for 2 h. Another portion of Burgess reagent (50 mg, 0.231 mmol) is added and stirring is continued at rt for 16 h. The solvent is evaporated and the crude product is purified on prep. TLC with heptane:EA 1:2 to give 4-[2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-oxazol-5-yl]-2-isobutyl-6-methyl-pyridine (24 mg) as a yellow oil; LC-MS: tR=1.33*, [M+1]+=441.04.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[F:20][C:21]([F:38])([F:37])[C:22](=[O:36])[CH2:23][C:24]1([CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=2)[O:27][CH2:26][CH2:25]1>C1COCC1.C1COCC1.C(C1C=CC=CC=1)C.CCCCCCC>[F:38][C:21]([F:20])([F:37])[C:22]([CH2:5][C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=[CH:2][CH:3]=1)([OH:36])[CH2:23][C:24]1([CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=2)[O:27][CH2:26][CH2:25]1
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(F)cc21
Reactant: Cc1ccnc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC1(CC(O)(Cc2ccnc3ccccc23)C(F)(F)F)CCOc2ccc(F)cc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
To a chilled (−78° C.) solution of 105.2 μL (0.79 mmol) of lepidine in 5 mL of THF at −78° C. was added 398 μL (0.79 mmol) of a 2 M solution of lithium diisopropyl amide in THF/ethyl benzene/heptane. The reaction was then warmed to −30° C. After 30 minutes, the mixture was cooled to −78° C. and then 200 mg (0.724 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-one (Example 1) in 1 μL of THF was added. The reaction mixture was warmed to room temperature for 1 hour and monitored by TLC. The reaction mixture was then cooled to −78° C., quenched with saturated ammonium chloride solution, warmed to room temperature, and THF was removed by concentrating in vacuo. The residue was extracted with diethyl ether, dried over sodium sulfate, and concentrated. The residue was purified on PLC plate (hexanes-EtOAc (6:4)) to afford a mixture of two diastereomers. The diastereomers were partially purified by a second PLC plate (CH2Cl2-MeOH (95:5)). One of the diastereomers was triturated with diethyl ether and the solid was collected by filtration to afford 20 mg (6%) of the title compound as a single diastereomer (M+1=420). The other diastereomer was chromatographed a second time on a PLC plate (CH2Cl2-MeOH (95:5)). The solids were triturated with diethyl ether and collected by filtration to afford 10 mg (3%) of the second diastereomer (M+1=420).