Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:6][CH:5]=1)([OH:3])=O.Cl.C[N:31](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.O>CN(C)C=O.N>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[NH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:27][CH:28]=1)(=[O:3])[NH2:31]
Reactant: O=C(O)c1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of N-(4-carboxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (120 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (90.0 mg) and 1-hydroxybenzotriazole (63.4 mg) in anhydrous dimethylformamide (2 mL) was stirred for an hour at ambient temperature. After addition of 28% ammonia solution (10 drops), the mixture was stirred for 15 hours at ambient temperature and poured into water. The resulting precipitates were collected by filtration, washed with water and purified by a silica gel column chromatography eluting with 10% methanol in chloroform. The obtained product was triturated with diisopropyl ether to give N-(4-carbamoylbenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (107 mg) as yellow powders.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33]C)=O)[C:19]([C:35]([F:38])([F:37])[F:36])=[CH:18][N:17]=1.O[Li].O.C1C=CC2N(O)N=[N:48]C=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[NH4+].[NH4+].CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C.CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:48])=[O:33])[C:19]([C:35]([F:36])([F:37])[F:38])=[CH:18][N:17]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C)CC3)cc2C)ncc1C(F)(F)F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li]O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
Methyl 2-(2-(2-(2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I55) (476 mg, 0.906 mmol) and LiOH.H2O (113 mg, 2.71 mmol) in a mixture of THF (20 mL), water (4 mL) and MeOH (2 mL) were stirred at room temperature for 24 hours. The volatiles were evaporated under reduced pressure to give a light yellow solid which was dissolved in dry DMF (10 mL) and dry THF (10 mL), HOBT (171 mg, 1.26 mmol), EDCI (196 mg, 1.26 mmol), ammonium carbonate (458 mg, 4.87 mmol) and DIPEA (829 μL, 4.87 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The volatiles were evaporated under reduced pressure and the residue taken up in ethyl acetate. The resulting solution was washed with 10% NaHCO3, the layers separated and the organic layer was dried (MgSO4). The volatiles were evaporated under reduced pressure and the residue chromatographed (SiO2, 0-100% MeOH/DCM) to give the title compound (12) (358 mg, 52%) as a cream solid; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.58 (d, J=89 Hz, 1H), 7.34 (s, 1H), 7.28-7.19 (m, 4H), 7.14-7.09 (m, 2H), 5.66 (s, 1H), 5.49 (s, 1H), 3.65 (s, 2H), 3.13-3.04 (m, 4H), 3.04-2.97 (m, 2H), 2.54-2.41 (m, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 2.08 (td, J=11.3, 3.8 Hz, 2H), 1.88-1.80 (m, 4H). LCMS Method C: rt 4.91 min; m/z 512.2 [M+1]+, 510.2 [M−1]−.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl[C:17]1[N:22]2[CH:23]=[CH:24][N:25]=[C:21]2[CH:20]=[N:19][CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[N:22]5[CH:23]=[CH:24][N:25]=[C:21]5[CH:20]=[N:19][CH:18]=4)[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: Clc1cncc2nccn12
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cncc2nccn12
Yield: 3.5 %

Procedure:
1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 240 mg, 1.0945 mmol) was reacted with 5-chloro-imidazo[1,2-a]pyrazine (I-186a: 202 mg, 1.3135 mmol), 1,4-dioxane (3 mL), copper iodide (24 mg), trans N,N′-dimethyl-cyclohexane-1,2-diamine (48 mg) and potassium phosphate (581 mg, 2.7364 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3), followed by preparative HPLC afforded 13 mg of the product (3.53% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].Cl.[CH3:27]O>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:27])=[O:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)O)=C(C)C1=O
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O

Procedure:
2,3-Dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the free form)(4 parts) was esterified with methanol (500 volume parts) saturated with hydrogen chloride gas in a manner similar to that described in Example 13. The procedure provided 2,3-dimethoxy-5-methyl-6-(9'-methoxycarbonylnonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the form of methyl ester) (4.2 parts) as orange-colored needles melting at 37°-37.5° C.
Reaction SMILES: ClC(F)(Br)C(F)(F)Br.C(OCC)=C.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:22](=[O:25])(O)[O-:23].[Na+].[Br:27][C:28]([F:36])([F:35])[C:29]([Cl:34])([F:33])[CH2:30]C=O.Cl([O-])=O.[Na+].OO>>[Br:27][C:28]([F:36])([F:35])[C:29]([Cl:34])([F:33])[CH2:30][C:22]([OH:23])=[O:25]
Reactant: O=CCC(F)(Cl)C(F)(F)Br
Reactant: O=C([O-])O
Agent: C=COCC
Agent: FC(F)(Br)C(F)(Cl)Br
Agent: O=S([O-])S(=O)[O-]
Product: O=C(O)CC(F)(Cl)C(F)(F)Br

Procedure:
A one pot reaction of 1-chloro-1,2-dibromotrifluoroethane (VI) with ethyl vinyl ether in the presence of sodium hydrosulfite/sodium bicarbonate followed by oxidation of the intermediate, 4-bromo-3-chloro-3,4,4-trifluorobutanal (VII), without isolaton, with sodium chlorite/hydrogen peroxide to give 4-bromo-3-chloro-3,4,4-trifiuorobutanoic acid (VIII) in overall unexpected yields;
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]1[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:21].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(O)(C)(C)C.C1C=CC=CC=1>[CH2:22]([C:8]1([CH3:7])[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(Cc1ccccc1)C2

Procedure:
Potassium tert-butoxide (1.68 g., 0.015 mole) in dry tert-butyl alcohol (40 ml.) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone in benzene (50 ml.). After refluxing for 30 minutes, benzyl bromide (1.72 g., 0.01 mole) in benzene (10 ml.) is added dropwise. After refluxing for an additional 30 minutes the mixture is cooled, water (10 ml.) is added and the mixture is evaporated to dryness. The residue is washed with water and taken up in ether. The ether solution is washed with water and a saturated sodium chloride solution, dried over solium sulfate and evaporated. The syrupy residue is 2-benzyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone (3 g.) is used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([O:22]C(=O)/C=C\N3C=NC(C4C=C(C(F)(F)F)C=C(OC)C=4)=N3)=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[NH2:45][NH2:46]>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:45][NH2:46])=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NN
Reactant: COc1cc(-c2ncn(/C=C\C(=O)OC(=O)/C=C\n3cnc(-c4cc(OC)cc(C(F)(F)F)c4)n3)n2)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 50-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (isobutyl carbonic) (Z)-3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic anhydride was cooled at 0° C. and added Hydrazine hydrate (0.911 g, 5.7 eq.). Reaction mixture was stirred at 0° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 50% EtOAc-hexane as mobile phase. SM Rf=0.6 and Product Rf=0.4. Reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.920 g of Crude compound which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]([C:10]1[N:14]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1)([F:9])[CH2:3][O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37].C(=O)([O-])[O-].[K+].[K+].[H-].[Na+]>CC(C)=O.CN(C=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:8][CH:6]([OH:7])[CH2:5][O:4][CH2:3][C:2]([F:9])([F:1])[C:10]1[N:14]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: Oc1ccccc1Cl
Reactant: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)COCC4CO4)n3c2)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: OC(COCC(F)(F)c1nnc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12)COc1ccccc1Cl

Procedure:
To a round bottom flask was added 3-(1,1-difluoro-2-(oxiran-2-ylmethoxy)ethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridine, prepared as described in Example 15, and 2-chlorophenol in acetone followed by potassium carbonate (sodium hydride in DMF at RT will also work). The reaction mixture was refluxed overnight. Potassium carbonate was filtered off. The filtrate was concentrated down and purified by prep TLC followed by prep HPLC to afford 1-(2-chlorophenoxy)-3-(2,2-difluoro-2-(6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethoxy)propan-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 92%).
Reaction SMILES: [Li].[C:2](#[N:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(O)(C)C.[NH4+].Br[CH2:17][C:18]([O-:20])=[O:19].[Cl-].[NH4+]>C1COCC1.N>[C:2]([C:3]1([CH2:17][C:18]([OH:20])=[O:19])[CH:8]=[CH:7][CH2:6][CH:5]=[CH:4]1)#[N:9]
Reactant: N#Cc1ccccc1
Reactant: O=C([O-])CBr
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: N#CC1(CC(=O)O)C=CCC=C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
Lithium (0.87 g, 125 mmol) was added in portions to a stirred solution of benzonitrile (5.1 mL, 5.2 g, 50 mmol) and t-BuOH (4.8 mL, 3.7 g, 50 mmol) in THF (5 mL) and NH3 (25 mL). After stirring at −78° C. for 30 minutes, a solution of bromoacetic acid ammonium salt (prepared by mixing bromoacetic acid [13.90 g, 100.0 mmol], THF (15 mL), and N2 (50 mL) at −78° C. and stirring for 1.5 hours) was added dropwise to the reaction. After stirring at −78° C. for 1 hour, ammonium chloride (20.9 g, 391 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature while the NH3 was removed with a stream of N2. Water (75 mL) was added, and the mixture extracted with MTBE (3×50 mL). The stirred aqueous layer was cooled to 0-5° C. acidified to pH=1 with 37% HCl, and extracted with MTBE (3×50 mL). The combined organic extracts of the acidified aqueous layer were dried (MgSO4) and concentrated under reduced pressure to afford 2.49 g (31%) of product as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[C:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([CH2:26][S:27][C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+].COC1C=CC(CCSC2NC(C)=C(C(OCC)=O)C(C3C=CC=CC=3SC)N=2)=CC=1>CN(C)C=O.CCOCC>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][S:27][C:28]2[NH:30][C:16]([CH3:17])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[S:2][CH3:1])[N:29]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(=Cc1ccccc1SC)C(C)=O
Reactant: COc1ccc(CSC(=N)N)cc1
Agent: CC(=O)[O-]
Agent: CCOC(=O)C1=C(C)NC(SCCc2ccc(OC)cc2)=NC1c1ccccc1SC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1ccccc1SC

Procedure:
A mixture of 2-[[2-(methylthio)phenyl]methylene]-3-oxobutanoic acid, ethyl ester (2.0 g., 7.5 mmole), S-(4-methoxybenzyl)thiopseudourea, hydrochloride (1.76 g., 7.5 mmole) and sodium acetate (0.66 g. 8.0 mmole) in dimethylformamide (10 ml.) is stirred and heated at 70° for 6 hours. The cooled mixture is diluted with ether and washed with water, sodium bicarbonate, and brine. The dried solution is evaporated to give 3.0 g. of an oil. Flash chromatography using ethyl acetate:hexanes (1:4) gives 2.13 g. of 1,4-dihydro2-[[(4-methoxybenzyl)methyl]thio]-6-methyl-4-[2-(methylthio)phenyl]-5-pyrimidinecarboxylic acid, ethyl ester as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[NH2:35][C@@H:36]([C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1)[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:35][C@@H:36]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=3)[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11]([F:14])([F:15])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCC(F)(F)CC2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCC(F)(F)CC3)cnc2N)cc1F)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To 4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (48 mg, 0.124 mmol) were added DMSO (1 mL), Hünig's base (0.108 mL, 0.619 mmol), (S)-tert-butyl (2-amino-2-(3-chlorophenyl)ethyl)carbamate (50.3 mg, 0.186 mmol) and then HATU (94 mg, 0.248 mmol). The reaction was stirred for 1 h at room temperature. To the reaction was added 0.5 mL of DMSO, filtered, purified by prep HPLC, and lyophilized to give 11 mg of the desired product used as is (12% yield). LCMS (m/z): 604.2 (MH+), 1.05 min.
Reaction SMILES: N1CC[O:4]CC1.[Li]CCCC.CCCCCC.Br[C:19]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22].[N+](C1C=CC=CC=1O)([O-])=O.Cl>C1COCC1>[OH:4][C:19]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: C1COCCN1
Reactant: COc1cc(C=O)c(Br)c(OC)c1
Agent: Cl
Agent: O=[N+]([O-])c1ccccc1O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(O)c(OC)c1
Temperature: -50 °C
Reaction time: 0.58 h
Yield: 54.9 %

Procedure:
Morpholine (2.05 g, 24 mmol) and THF (40 mL) were placed in a dry, three-necked, round bottomed flask equipped with a stirring bar, septum cap, dropping funnel, thermometer, and argon inlet. The flask was cooled in a dry ice-acetone bath to −50° C., and a solution of n-BuLi in hexane (1.6M, 15 mL, 24 mmol) was added all at once. After 10 min a solution of the 2-bromo-3,5-dimethoxybenzaldehyde 37 (4.9 g, 20 mmol) in THF (30 mL) was added dropwise via a syringe over a period of 4 min, and the mixture was cooled to ˜−75° C. over 20 min. n-BuLi in hexane (1.6M, 20 mL, 32 mmol) was then added dropwise over 45 min, keeping the temperature at −75° C. After complete addition of n-BuLi the solution was stritted for 35 min. A solution of nitrophenol (6.90 g, 46 mmol) in 10 mL THF was added from the dropping funnel, keeping the temperature at −75° C. The resulting dark mixture was stirred at −75° C. for 4 h and then allowed to warm to room temperature. It was acidified to pH 1 with 6N HCl and stirred for 15 min. After dilution with brine (100 mL), THF was removed in-vacuo. The aqueous solution was extracted with diethyl ether (4×40 mL). The combined organic layers were extracted with 2 N NaOH (3×40 mL). The combined NaOH extracts were washed with diethyl ether (3×20 mL) and then acidified to pH 1 with concentrated HCl. The resulting mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were washed with brine, dried (MgSO4) and adsorbed on silica gel. The product was purified by flash chromatography, eluting with EtOAc/hexane (1:2) to give 38 (2.0 g, 55%) as a yellow solid. m/z=183.06 (M+H). 1H NMR (500 MHz, CDCl3): δ: 10.71 (1H, s, OH), 9.91 (1H, s, CHO), 6.77 (1H, d, J4,6=2.8 Hz, H-6), 6.61 (1H, d, J4,6=2.8 Hz, H-4), 3.92 (3H, s, OMe), 3.84 (3H, s, OMe). 13C NMR CDEPT 135 (500 MHz, CDCl3): δ: 196.11 (CHO), 107.93 (C-6), 103.90 (C-4), 56.29 (OMe), 55.83 (OMe).
Reaction SMILES: C(C1C=CC(O/C=C/OC2C=CC(C3C=CC=CC=3)=CC=2)=CC=1)(C)(C)C.I/[CH:28]=[CH:29]/[O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I>[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([O:51]/[CH:28]=[CH:29]/[O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[CH:47][CH:46]=1
Reactant: I/C=C/Oc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(O)cc1
Agent: [Cu]I
Agent: CC(C)(C)c1ccc(O/C=C/Oc2ccc(-c3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Product: COc1ccc(O/C=C/Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: 80 °C

Procedure:
Compound 7 was prepared according to the general method described for compound 6 above, employing 4 (0.2 g, 0.62 mmol, 1 eq) and 4-methoxyphenol (0.077 g, 0.62 mmol, 1 eq), Cs2CO3 (0.50 g, 1.6 mmol, 2.5 eq), CuI (0.59 g, 0.31 mmol, 0.5 eq) and L1 (0.057 g, 0.31 mmol, 0.5 eq) heating the reaction mixture at 80° C. for 48 h to furnish the crude product which was purified by column chromatography using hexane as the eluent to afford 7 as white crystals (40 mg, 40%): mp 112-115° C. 1H NMR (300 MHz, CDCl3): 7.61-7.52 (m, 4H, HAr), 7.47-7.40 (m, 2H, HAr), 7.36-7.30 (m, 1H, HAr), 7.10 (d, 2H, J=8.6 Hz), 7.00 (d, 2H, J=9.0 Hz), 6.91-6.84 (m, 4H, HAr and HC(O)═C(O)H), 3.80 (s, 3H, —CH3) ppm. 13C NMR (75 MHz, CDCl3): 156.3, 154.3, 150.5, 139.5, 135.6, 135.1, 132.7, 131.4, 129.0, 127.8, 127.3, 125.8, 116.1, 115.0, 113.8, 54.7 ppm; IR (cm−1): 3059, 1658, 1605, 1517, 1485, 1420, 1319, 1264, 1226, 1173, 1122, 896, 838, 737, 639; HRMS (ESI), Calculated for C21H18O3 [M−H]− 317.1178. Found 317.1158; HPLC analysis: 92% purity.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH2:11]([Mg]Br)[CH3:12].C1COCC1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:11][CH3:12])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(O)c1c(Cl)ncnc1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Charge 4,6-dichloro-pyrimidine-5-carbaldehyde (2.5 g, 1.0 eq) and toluene (50 mL) in a round bottom flask. Cool the reaction mass to −10° C. Add ethyl magnesium bromide (3M) in THF solution (5.1 mL, 1.1 eq) drop wise at −10° C. Slowly allow the reaction mass to come to RT in 1 h. Charge chilled ammonium chloride solution to the reaction mass and extract with diethyl ether. Wash ether layer with saturated aq. sodium chloride solution. Dry the ether layer over anhydrous sodium sulfate and concentrated it under reduced pressure to get the desired product (2.3 g, 79.3%).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH2:31])([CH3:7])[CH3:6])C.FC(F)(F)C(O)=O.C(N(CC)CC)C.Cl[C:48]([O:50][CH2:51][CH3:52])=[O:49].CNCCNC>C(Cl)Cl.CO.C(Cl)Cl.CO>[CH2:51]([O:50][C:48]([NH:31][CH2:30][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:32])=[O:3])=[O:49])[CH3:52]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CN
Agent: CNCCNC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OC(C)(C)C(=O)O
Temperature: 45 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
General Parallel Synthesis Procedure: 2-{2-Aminomethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester: trifluoroacetic acid salt (381 mg, 0.650 mmol max.) was dissolved in CH2Cl2 (25 mL) and washed with saturated NaHCO3 solution (15 mL). The organic layer was dried (NaSO4), filtered, and concentrated to 2-{2-aminomethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester (245 mg, 0.59 mmol, 86%). A portion of this free base (13 mg, 0.030 mmol) in CH2Cl2 (0.8 mL) was treated with triethylamine (0.050 mL, 0.36 mmol) then ethyl chloroformate (0.020 mL, 0.21 mmol). The reaction mixture was shaken overnight and dimethylethylenediamine (0.050 mL, 0.47 mmol) was added. The reaction mixture was shaken for 2 h, diluted with MeOH (0.5 mL), and passed through an SCX column (1 g, equilibrated with 4 mL MeOH/CH2Cl2 1/1). The methyl ester-amide product was eluted with MeOH/CH2Cl2 (1:1, 8 mL) and concentrated. The residue was dissolved in THF (1 mL) and EtOH (1 mL) and treated with 2N NaOH (0.5 mL). The solution was heated at 45° C. for 45 min, cooled, concentrated, and acidified with 1N HCl (2.5 mL). The mixture was diluted with diluted with CH2Cl2 (0.5 mL), transferred to a 3-mL ChemElute cartridge, and eluted with CH2Cl2 (8 mL). The solvent was removed under a stream of N2. The crude product was dried under vacuum and purified by mass-directed HPLC to give a foam (2.7 mg, 19%). %). MS (ES+) m/z 483.5 [M+H]+.