Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[C:45]=1[CH3:46]>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[N:38]=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]4[C:45]=3[CH3:46])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: Cc1c(CCl)nc2ccccn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4nc5ccccn5c4C)cc3)C(=O)C(C)(C)O2)cc1
Yield: 1925.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.1 g, 0.32 mmol) was added to a mixture of cesium carbonate (0.52 g, 1.62 mmol) and DMF (20 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3-methylimidazo[1,2-a]pyridine (87 mg, 0.48 mmol) was added. The mixture was heated at for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((3-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.8 g, 77%) as an off-white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.25 (d, 1H), 7.45 (d, 3H), 7.25 (t, 1H), 7.15-6.95 (Ar, 7H), 5.2 (s, 2H), 3.85 (s, 3H), 2.45 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=455.3. HPLC: (96.3%, Condition-A).
Reaction SMILES: [OH:1][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])N1C1C=CC=CC=1.Cl.[O:27]1CCOCC1>C(O)(=O)C>[OH:27][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])[O:1]1
Reactant: C1COCCO1
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)N(c1ccccc1)C2=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(O)(c1ccccc1)OC2=O
Reaction time: 4 h
Yield: 54.9 %

Procedure:
A solution of 109 (3.11 g, 9.39 mmol), 6N hydrochloric acid (150 mL), and dioxane (150 mL) was heated at reflux under Ar for 18 h. Acetic acid (50 mL) was added and refluxing was continued for an additional 4 h. The organic solvents were removed in vacuo and the remaining aqueous was extracted with ethyl acetate (3×), washed with brine and dried with sodium sulfate (anh.). Filtration followed by removal of the solvent in vacuo gave 110 as a white solid (1.32 g, 5.16 mmol, 54.9%)
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH2:42][CH3:43])=[C:36](B(O)O)[CH:37]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([O:41][CH2:42][CH3:43])=[C:34]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:33]=1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CCOc1ccc(Cl)cc1C1=COCCN1C(=O)OC(C)(C)C
Yield: 24 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 5-chloro-2-ethoxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (24% yield); 1H-NMR (d6-DMSO) 1.05 (9H, brs), 1.26 (3H, t), 3.62 (2H, t), 3.92 (2H, q), 4.15 (2H, t), 6.21 (1H, s), 6.90 (1H, d), 7.09 (1H, m), 7.22 (1H, dd); 13C-NMR (d6-DMSO) 14.9, 27.7, 63.9, 67.05, 67.1, 111.9, 126.9, 127.3, 132.0; MS ES(+) 240.0 (M++1); Anal. Calcd for C17H22ClNO4: C, 60.09; H, 6.53; N, 4.12. Found: C, 59.60; H, 6.46; N, 4.35. IR λmax=1701, 1394 cm−1.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[O:17][C:18]([F:21])([F:20])[F:19])#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH:26]=[CH:27][CH:28]=1>>[ClH:22].[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([CH2:13][C:12]3[N:8]([CH2:7][C:6]4[CH:15]=[CH:16][C:3]([C:1]#[N:2])=[C:4]([O:17][C:18]([F:21])([F:20])[F:19])[CH:5]=4)[CH:9]=[N:10][CH:11]=3)[CH2:31][C:30]2=[O:35])[CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1OC(F)(F)F
Reactant: O=C1CNCCN1c1cccc(Cl)c1
Product: Cl
Product: N#Cc1ccc(Cn2cncc2CN2CCN(c3cccc(Cl)c3)C(=O)C2)cc1OC(F)(F)F

Procedure:
The titled compound was prepared from the product of Step F (264 mg, 0.89 mmol) and the product of Step J of Example 1 using the procedure described in Step K of Example 1. Purification by silica gel column chromatography (50-65% acetoneldichloro methane) and conversion to the dihydrochloride salt using excess ethereal HCl solution gave the titled product as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:19]=1)[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH3:3].[CH:20](/[C:25]([OH:27])=[O:26])=[CH:21]/[C:22]([OH:24])=[O:23].O[CH2:29][CH:30]([CH2:32][OH:33])O>>[N:2]1([C:22]([O-:24])=[O:23])[CH2:1][CH2:29][CH2:30][C:32]1=[O:33].[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:3].[CH:20](/[C:25]([OH:27])=[O:26])=[CH:21]/[C:22]([OH:24])=[O:23]
Reactant: OCC(O)CO
Agent: CN(C)CCC(c1ccc(Cl)cc1)c1ccccn1
Agent: O=C(O)/C=C\C(=O)O
Product: O=C([O-])N1CCCC1=O

Procedure:
0.025 g of chlorpheniramine maleate are dissolved in 0.05 g of glycerine and 9.925 g of 1.5% aqueous chitosonium pyrrolidone carboxylate, giving a clear, colorless solution (0.25% chlorpheniramine maleate). This lotion is useful in the treatment of rashes and inflammation due to allergic reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:21][CH3:22])[C:18]([OH:20])=[O:19].B(F)(F)F.CCOCC>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]3[O:20][C:18](=[O:19])[C:17]([CH2:21][CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:13]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCC(O)(C(=O)O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: CCC1(c2ccccc2)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)benzaldehyde (2.16 g.) and 2-hydroxy-2-phenylbutyric acid (1.8 g.) in anhydrous diethyl ether (50 ml.) was added boron trifluoride etherate (2.2 g.). After stirring at room temperature for 12 hours, the solution was washed with 10% w/v sodium acetate solution (2×20 ml.) and then with water (2×20 ml.) and dried (Na2SO4). The solution was filtered and evaporated to give an oil which on crystallisation from methanol gave 2-[4-(4-chlorophenyl)phenyl]-5-ethyl-5-phenyl-1,3-dioxolan-4-one (1.7 g.) m.p. 80°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].[O:37]1[CH2:49][CH:38]1[CH2:39][O:40][C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[C:43]#[N:44]>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][NH:27][CH2:49][CH:38]([OH:37])[CH2:39][O:40][C:41]3[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=3[C:43]#[N:44])=[CH:23][CH:24]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCN)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCNCC(O)COc3ccccc3C#N)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 4.1 g (8.3 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-aminoethyl)-phenoxy]-ethyl}-ester 5-methyl ester and 1.6 g of 2-(2,3-epoxypropoxy)-benzonitrile in 20 ml of isopropanol is heated under reflux for 2 hours and then concentrated to dryness by evaporation under reduced pressure. The residue is dissolved in 20 ml of 1N methanesulphonic acid and extracted with 40 ml of ethyl acetate. The aqueous phase is separated off and rendered alkaline with 2N sodium hydroxide solution. The crude product obtained by extraction with ethyl acetate is "flash" chromatographed over silica gel using toluene/isopropanol/concentrated ammonia (170:30:3) as eluant. 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{{{2-{{p-{2-[3-(o-cyanophenoxy)-2-hydroxypropylamino]-ethyl}-phenoxy}}-ethyl}}}-ester 5-methyl ester is obtained in the form of an amorphous foam.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[CH2:20]Br>C(O)C>[CH2:2]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH:7][CH2:20][C:19]1[C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=1[Cl:17])[CH3:3]
Reactant: O=[N+]([O-])c1cccc(Cl)c1CBr
Reactant: CCOC(=O)[C@@H](C)N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](C)NCc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A mixture of 18.24 g of D-alanine ethyl ester hydrochloride in 60 ml of ethanol was added dropwise to a mixture of 25 ml of triethylamine in 60 ml of ethanol and the resulting mixture was heated to 80° C. The solution obtained was added dropwise at this temperature to a solution of 15 g of 2-chloro-6-nitrobenzyl bromide in 60 ml of ethanol. The mixture was stirred at 80° C. overnight and then evaporated to dryness. The residue was treated with 150 ml of deionised water and extracted twice with 100 ml of methylene chloride. The methylene chloride extracts were washed with water, dried over sodium sulphate and evaporated. The resulting product was purified by chromatography on silica gel with methylene chloride/5% methanol. There were obtained 16 g (93% of theory) of N-(2-chloro-6-nitrobenzyl)-D-alanine ethyl ester; nD25 =1.5247; [α]D =-6.9° (c=1% in ethanol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH2:2][O:1][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=1)=[O:31]
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Reactant: COc1cccc(N=C=O)c1
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2cccc(OC)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH3:22])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26]>C(Cl)Cl>[OH:27][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH3:22])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COS(=O)(=O)C(F)(F)F
Agent: Cc1nccn1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: O=S(=O)(O)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution of 4-(2-methyl-imidazole-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 4.24 mmol) in methylene chloride was cooled in an ice bath, and trifluoromethanesulfonic acid methyl ester (0.56 mL, 4.9 mmol) was added via a pipet. After stirring at ice temperature for 3 h, the solvent was evaporated to give 4-(2-methyl-imidazole-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester triflate salt as yellow solids.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:12][C:13](=[O:30])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([CH3:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[C:16]([N+:27]([O-])=O)[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:12][C:13](=[O:30])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([CH3:26])[CH2:22][CH:23]([CH3:24])[CH3:25])=[C:16]([NH2:27])[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CC(C)Nc1ccc(C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)CC(C)Nc1ccc(C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc1N
Reaction time: 4 h
Yield: 96.7 %

Procedure:
50 mg of (S)-2-[4-(1,3-Dimethyl-butylamino)-3-nitro-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester were dissolved in 0.5 ml, ethanol, 5 mg of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 4 h. The catalyst was removed by filtration over celite, and the reaction mixture was concentrated to yield 45 mg (99%) of (S)-2-[3-Amino-4-(1,3-dimethyl-butylamino)-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C@H:12]([C:19](=[O:21])[NH2:20])[NH:13]OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C@H:12]([C:19](=[O:21])[NH2:20])[NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)ON[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@H](N)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
t-Butyloxy-D-isoglutamine benzyl ester (3.70 g, 11 mmol) was dissolved in trifluoroacetic acid (20 ml) and the solution was stirred at room temperature for 30 minutes. The solvent was then distilled off, ether was added and the solvent was distilled off again under reduced pressure. Petroleum ether was added to the residue to give crystals, which were dried in the presence of sodium hydroxide in a desiccator, giving D-isoglutamine benzyl ester trifluoroacetate. This product was dissolved in acetonitrile (10 ml) and, under ice-cooling, the solution was neutralized with triethylamine. Then, p-nitrophenyl 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoate (4.74 g, 10 mmol) was added and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in ethyl acetate (70 ml). The solution was washed with 5% aqueous solution of sodium bicarbonate (30 ml×3), 1 N hydrochloric acid (30 ml×3) and saturated aqueous sodium chloride (30 ml×3) in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was precipitated as a gel from ethyl acetate-ethyl ether. The same procedure was repeated twice to give 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-D-isoglutamine benzyl ester (3.74 g), melting at 83°-85° C. [α]D25 +4.4° (c=0.5, methanol), Rf3 = 0.68, Rf=0.33 (chloroform-methanol=19:1, v/v, silica gel plate) (briefly Rf4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: C=C(C)COc1ccc(Cl)cc1Cc1cccc(C(=O)OCC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C(C)COc1ccc(Cl)cc1Cc1cccc(C(=O)O)n1
Yield: 70.3 %

Procedure:
Ethyl 6-({5-chloro-2-[(2-methyl-2-propen-1-yl)oxy]phenyl}methyl)-2-pyridinecarboxylate (60 mg, 0.17 mmol) was stirred at 60° C. for 2 hours in ethanol (3 ml) and 2M sodium hydroxide solution (0.4 ml). The reaction mixture was cooled and evaporated. The residue was diluted with water and extracted with diethyl ether. The aqueous phase was then acidified with glacial acetic acid and extracted with ethyl acetate (2×20 ml), dried (MgSO4) and evaporated to give the title compound as a yellow oil (38 mg).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccn2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.67 min.; [M+H]+: 417.04 g/mol.
Reaction SMILES: [CH:1]1([CH:5]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=4)[N:21](S(C4C=CC(C)=CC=4)(=O)=O)[CH:20]=3)[N:13]=2)[CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3][CH2:2]1.C1(C(NC2C(F)=CN=C(C3C4C(=NC=C(F)C=4)N(S(C4C=CC(C)=CC=4)(=O)=O)C=3)N=2)CC([O-])=O)CCC1.C[O-].[Na+]>CO>[CH:1]1([CH:5]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=4)[NH:21][CH:20]=3)[N:13]=2)[CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1CCC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC(=O)[O-])C4CCC4)n3)c3cc(F)cnc32)cc1
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1CCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a racemic solution of methyl 3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)propanoate, 51a, (0.151 g, 0.280 mmol) in methanol (1.5 mL) was added NaOMe (1.5 mL of 25% w/v solution, 6.941 mmol). After stirring the reaction mixture at room temperature for 5 minutes, the mixture was quenched with aqueous saturated NH4Cl solution and diluted with EtOAc and water. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The resulting crude residue was dissolved in a minimum volume of dichloromethane and purified via silica gel chromatography (0-100% EtOAc/Hexanes gradient) to afford 108 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.29 minutes (M+H) 388.07.
Reaction SMILES: N([C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[N:4]=1)N.[OH-].[Na+].Cl[O-].[Na+]>ClCCl>[Cl:9][C:8]1[CH:3]=[N:4][C:5]([C:10]([F:12])([F:11])[F:13])=[CH:6][CH:7]=1
Reactant: NNc1nc(C(F)(F)F)ccc1Cl
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Cl)cn1
Reaction time: 6.5 h
Yield: 271.8 %

Procedure:
19.91 g of 2-hydrazino-3-chloro-6-trifluoromethyl pyridine from the small batch and 30.19 g from the large batch were combined (50.10 g total, 0.237 mol) in a 2 L, three-neck flask with a mechanical stirrer and an addition funnel. Dichloromethane (190 g) and sodium hydroxide (237 g, 1N solution) were added to the flask. Sodium hypochlorite (NaOCl) (354 g, 0.238 mol, 5% solution) was charged to the addition funnel. The sodium hypochlorite solution was added over 1 hour as the solution turned yellow, then orange, and then purple-brown. The conversion was approximately 36% at the end of the sodium hypochlorite addition. The solution was stirred for an additional 6.5 hours, at which point the conversion was about 98%. Agitation was stopped and the solution was left overnight. The next morning, sodium hypochlorite (9 g, 0.006 mol, 5% solution) was added, and the solution was stirred for 1.5 hours, at which point sampling indicated that there was less than 1% starting material. The layers were separated and the aqueous layer was extracted twice with dichloromethane (100 mL). The organic layers were combined, washed with water, dried with magnesium sulfate, filtered, and concentrated on the rotovap to give 46.44 g of crude 3-chloro-6-trifluoromethyl pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:47])[C@H:26]([CH:44]([CH3:46])[CH3:45])[NH:27][C:28](=[O:43])[C@H:29]([CH:40]([CH3:42])[CH3:41])[NH:30][C:31](=[O:39])[C@H:32]([CH2:34][O:35][CH2:36][CH:37]=[CH2:38])[NH2:33].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:23][O:24][C:25](=[O:47])[C@H:26]([CH:44]([CH3:46])[CH3:45])[NH:27][C:28](=[O:43])[C@H:29]([CH:40]([CH3:42])[CH3:41])[NH:30][C:31](=[O:39])[C@H:32]([CH2:34][O:35][CH2:36][CH:37]=[CH2:38])[NH:33][C:14](=[O:15])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[O:11])[C@@H:9]1[CH2:20][CH2:21][CH2:22][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: C=CCOC[C@H](N)C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Temperature: 0 °C
Yield: 92.3 %

Procedure:
N-tert-butoxycarbonyl L-prolyl L-proline 2 (3.80 g, 12.2 mmol) and O-allyl L-seryl L-valyl L-valine methyl ester 9 (4.35 g, 12.2 mmol) were dissolved in DMF (25 mL) and the solution cooled to 0° C. HOBt hydrate (1.87 g, 12.2 mmol) was added under stirring. EDC hydrochloride (2.57 g, 13.4 mmol) was added to the reaction mixture in small portions. The reaction mixture was stirred overnight and the solvent evaporated. The residue was taken up in EtOAc (50 mL) and washed with 2M HCl (3×25 mL), 7.5% (w/w) K2CO3 (3×25 mL) and saturated brine (20 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a white solid (7.34 g, 93%); δH (300 MHz; d6-DMSO) 8.10 (1H, d, J 8, NH(Valx)), 7.98 (1H, d, J 8, NH(Ser(All))), 7.60 (1H, d, J 9, NH(Valy), rotomer 1), 7.59 (1H, d, J 9, NH(Valy), rotomer 2), 5.83 (1H, ddt, J 5, 11 and 17, CH═CH2), 5.24 (1H, ddt, J 1, 3 and 17, CH═CHH), 5.14-5.09 (1H, m, CH═CHH), 4.46-4.37 (3H, m, CαH(Pro1)/CαH(Pro2)/CαH(Ser(All))), 4.32 (1H, dd, J 7 and 9, CαH(Valy)), 4.15-4.10 (1H, m, CαH(Valx)), 3.93 (2H, m, J 1 and 5, CH2CH═CH2), 3.67-3.50 and 3.36-3.24 (6H, m, CδH2(Pro1)/CδH2(Pro2)/CH2(Ser(All))), 3.61 (3H, s, OCH3), 2.26-1.71 (10H, m, CH2(Pro)/CH(CH3)2), 1.37 (9H, s, (CH3)3, rotomer 1), 1.30 (9H, s, (CH3)3, rotomer 2), 0.89-0.80 (12H, m, CH3); δC (75 MHz; d6-DMSO) 171.6, 171.5, 171.3, 171.1, 170.9, 170.4, 169.1, 169.1, 153.3, 152.9, 134.8, 116.5, 78.3, 78.1, 71.1, 69.3, 59.1, 57.4, 57.2, 56.9, 52.9, 51.4, 46.5, 46.4, 46.3, 46.3, 30.9, 30.6, 29.6, 29.5, 29.4, 28.7, 28.5, 28.1, 27.9, 24.4, 24.3, 23.6, 23.0; m/z (ESI) 674.3737 ([M+Na]+; C32H53N5O9Na requires 674.3741)