Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:32][C@@H:31]2[C@:18]([CH3:35])([CH2:19][CH:20]=[C:21]3[C@H:30]2[CH2:29][CH2:28][C:27]2[C@:22]3([CH3:34])[CH:23]=[CH:24][C:25](=[O:33])[CH:26]=2)[C@H:3]1[C:4](=[O:17])[CH2:5]OS(C1C=CC(Br)=CC=1)(=O)=O.[CH3:36][C:37]([CH3:58])([CH3:57])[CH2:38][NH:39][C:40]1[N:45]=[C:44]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:43]=[C:42]([N:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)[N:41]=1>>[CH3:36][C:37]([CH3:58])([CH3:57])[CH2:38][NH:39][C:40]1[N:45]=[C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH2:5][C:4](=[O:17])[C@@H:3]3[C@:18]4([CH3:35])[C@H:31]([C@H:30]5[C:21](=[CH:20][CH2:19]4)[C@:22]4([CH3:34])[C:27](=[CH:26][C:25](=[O:33])[CH:24]=[CH:23]4)[CH2:28][CH2:29]5)[CH2:32][C@H:2]3[CH3:1])[CH2:48][CH2:47]2)[CH:43]=[C:42]([N:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)[N:41]=1
Reactant: CC(C)(C)CNc1nc(N2CCCC2)cc(N2CCNCC2)n1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(NCC(C)(C)C)n2)CC1
Yield: 74.1 %

Procedure:
16α-Methyl-21-(4-bromobenzenesulfonyloxy)-pregna-1,4,9(11)-triene-3,20-dione is reacted with 2-(2,2-dimethylpropylamino)-4-(1-piperazinyl)-6-pyrrolidinopyrimidine as described in Example 13 to obtain the title compound in a yield of 74.1%, m.p.:130° C.
Reaction SMILES: C([O:4][CH:5]([C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:6]([F:9])([F:8])[F:7])(=O)C.[CH3:17][S:18]([O-:20])=[O:19].[Na+].N1CCC[C@H]1C(O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I.O>[F:7][C:6]([F:9])([F:8])[CH:5]([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:15]=1)[OH:4]
Reactant: CS(=O)[O-]
Reactant: CC(=O)OC(c1cncc(Br)c1)C(F)(F)F
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])O
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cncc(C(O)C(F)(F)F)c1
Temperature: 95 °C
Reaction time: 72 h
Yield: 16.7 %

Procedure:
In DMSO (3.0 mL) was dissolved 1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethyl acetate (429 mg, 1.44 mmol) obtained in Step 3. To the solution were added sodium methanesulfinate (176 mg, 1.73 mmol), copper iodide (I) (41.1 mg, 0.216 mmol), L-proline (49.7 mg, 0.432 mmol) and sodium bicarbonate (36.3 mg, 0.432 mg) and the mixture was stirred at 95° C. for 72 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure and the residue was dissolved in methanol (10.0 mL). Potassium carbonate (597 mg, 4.32 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and water was added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give 2,2,2-trifluoro-1-(5-(methylsulfonyl)pyridin-3-yl)ethanol (61.4 mg, 17% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][C:15]1[C:19](B2OC(C)(C)C(C)(C)O2)=[C:18]([CH3:29])[O:17][N:16]=1.O.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O>[NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[CH3:29])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)c(F)cc1N
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2c(C)noc2C)c(F)cc1N
Temperature: 120 °C

Procedure:
To methyl 2-amino-5-bromo-4-fluorobenzoate (20 g, 80.6 mol.) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (24.2 g, 108.9 mol., 1.35 mmol) was added to a solvent mixture of 1,2-dimethoxymethane (120 ml) and water (60 ml). To the above mixture were added PEPPSI-Ipr (3120 mg, 4.2 mmol, 0.05 equiv.) and Cs2CO3 (78.8 g, 241 mol., 3 equiv.). The reaction mixture was heated at 120° C. for 2 h in a pressure tube. The reaction mixture was then diluted with EtOAc (100 ml), washed with bring (50 ml×2). The organic solvent was evaporated and the residue was dissolved in DCM and purified with combi-flash column chromatography (product came out at 50% EtOAc/Hexane) to afford methyl 2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate.
Reaction SMILES: [CH3:1][CH:2]1[C:18](=[O:19])[C:17]2([CH3:23])[C:20]([O:22][CH:3]1[CH2:4][CH:5]([O:33]C(C)=O)[CH:6]=[CH:7][C:8]([CH3:32])=[CH:9][CH2:10][CH:11]([OH:31])[CH:12]=[CH:13][C:14]([CH3:30])=[CH:15][CH:16]2[NH:24][C:25]([C:27]([CH3:29])=[O:28])=[O:26])=[O:21]>CO>[CH3:1][C@H:2]1[C:18](=[O:19])[C@@:17]2([CH3:23])[C:20]([O:22][C@@H:3]1[CH2:4][C@H:5]([OH:33])[CH:6]=[CH:7][C:8]([CH3:32])=[CH:9][CH2:10][C@H:11]([OH:31])[CH:12]=[CH:13][C:14]([CH3:30])=[CH:15][C@H:16]2[NH:24][C:25]([C:27]([CH3:29])=[O:28])=[O:26])=[O:21]
Reactant: CC(=O)OC1C=CC(C)=CCC(O)C=CC(C)=CC(NC(=O)C(C)=O)C2(C)C(=O)OC(C1)C(C)C2=O
Agent: CC(=O)C(=O)N[C@@H]1/C=C(C)/C=C/[C@@H](O)C/C=C(C)/C=C/[C@@H](O)C[C@H]2OC(=O)[C@]1(C)C(=O)[C@@H]2C
Agent: CC(=O)OC1/C=C/C(C)=C/CC(O)/C=C/C(C)=C/C(NC(=O)C(C)=O)C2(C)C(=O)OC(C1)C(C)C2=O
Solvent: CO
Product: CC(=O)C(=O)N[C@@H]1C=C(C)C=C[C@@H](O)CC=C(C)C=C[C@@H](O)C[C@H]2OC(=O)[C@]1(C)C(=O)[C@@H]2C
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
In 20 ml of methanol was dissolved 102 mg of lankacidin A. To the solution was added a 80 ml aqueous solution of 2.0 g of the enzyme prepared in Reference Example 11. The mixture was stirred at room temperature for 35 minutes, then methanol was distilled off. The residue was extracted with methyl isobutyl ketone-tetrahydrofuran (1:1). The extract was dried on MgSO4, then the solvent was distilled off. To the residue was added ether to give a white powdery crystalline substance, which was collected by filtration and dried to obtain 24.85 mg of the title compound. This product was in agreement with lankacidin C obtained by a fermentative method in NMR, IR and TLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[NH:19][N:18]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:13][N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([N:19]3[C:20]4[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=4[C:17]([C:16]([F:15])([F:27])[F:26])=[N:18]3)=[CH:3][CH:4]=2)[CH2:9][CH2:10][C:11]1=[O:14]
Reactant: CN1C(=O)CCC1c1ccc(Br)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CN1C(=O)CCC1c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 180 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
A mixture of 5-(4-bromophenyl)-1-methyl-2-pyrrolidinone (141 mg, 0.56 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (111 mg, 0.58 mmol), copper (I) iodide (10 mol %, 11 mg, 0.06 mmol), N,N-dimethylglycine (20 mol %, 12 mg, 0.12 mmol) and potassium carbonate (162 mg, 1.17 mmol) in dimethylsulfoxide (3 ml) was stirred at 180° C. in a microwave reactor for a total of 2 h. The reaction mix was filtered through a 5 g pre-packed silica column washing through with dichloromethane (20 ml), the filtrate was washed with water (50 ml) and the organic layer dried over sodium sulphate. The solvent was removed by rotary evaporation and the sample purified by mass directed auto prep. The final product was partitioned between dichloromethane (3 ml) and water (3 ml). The organic layer was separated and solvent removed by rotary evaporation to give the title compound as a brown oil (14 mg, 7%)
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:25])[O:22][C:21](=[O:23])[C:18]2([CH2:20][CH2:19]2)[C:17](=[O:24])[O:16]1>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:20][CH2:19][CH:18]2[C:17](=[O:24])[O:16][C:15]([CH3:25])([CH3:14])[O:22][C:21]2=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(CCN2CCC(Cc3ccccc3)CC2)C(=O)O1

Procedure:
Following the procedure described in S. Danishefsky and R. K. Singh, J. American Chemical Society, 97:3239-3241(1975), a mixture of 0.5 g of 4-benzylpiperidine, 10 mL of toluene, and 0.5 g, of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane 4,8-dione was stirred for 20 h, cooled, and, the white solid product collected by filtration and dried under vacuum. The yield of 5-[2-(4-benzyl-piperidin-1-yl)-ethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione was 0.94 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11](=[N:24][NH2:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.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:8][C:5]1[CH:6]=[CH:7][C:2]([NH:25][N:24]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: COc1cc(F)ccc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1NN=C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-5-fluoroanisole (0.52 ml, 4.10 mmol), benzophenone hydrazone (0.98 g, 5.00 mmol), sodium-tert-butoxide (561 mg, 5.80 mmol), in toluene (8.0 ml) was charged with Pd2(dba)3 (77.0 mg, 0.08 mmol) and 2-(di-t-butylphosphino)biphenyl (50.0 mg, 0.17 mmol) and heated to 80° C. under argon. The mixture was stirred overnight and checked with LCMS and TLC. The mixture was allowed to cool to room temperature and the reaction mixture was diluted with EtOAc (20 ml) and filtered. Material was used crude in the next step.
Reaction SMILES: C(NC(C)C)(C)C.[C:8](#[N:12])[CH2:9][CH2:10][CH3:11].[CH2:13]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C@H:33]3[CH2:38][CH2:37][C@H:36]([CH2:39]I)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(C1C=CC(C2C=CC([C@H]3CC[C@H](C(O)=O)CC3)=CC=2)=CC=1)CCCCCCC.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])(=O)(=O)C.[Na+].[I-]>CC(C)=O.O1CCCC1>[CH2:13]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C@H:33]3[CH2:38][CH2:37][C@H:36]([CH2:39][CH:9]([C:8]#[N:12])[CH2:10][CH3:11])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](CI)CC3)cc2)cc1
Reactant: CCCC#N
Agent: CCCCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](C(=O)O)CC3)cc2)cc1
Agent: CS(=O)(=O)[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CC(C)NC(C)C
Product: CCCCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](CC(C#N)CC)CC3)cc2)cc1
Temperature: 25 °C

Procedure:
With air and moisture excluded, 9.4 ml of diisopropylamine, 4.6 g of butyronitrile and 30 g of trans-4-(4'-octylbiphenyl-4-yl)cyclohexylmethyl iodide [obtainable from trans-4-(4'octylbiphenyl-4-yl)cyclohexanecarboxylic acid (which can in turn be prepared by saponification of the nitrile) by reduction with LiAlH4, conversion of the alcohol into the corresponding mesylate and subsequent Finkelstein reaction with NaI in acetone] are added in sequence to 50 ml of tetrahydrofuran at -50°. After heating to room temperature, stirring is carried out for a further hour and 4-octyl-4'-[trans-4-(2-cyanobutyl)-cyclohexyl]biphenyl is obtained after the usual working up.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CO>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cn(-c2cccc(F)c2C#N)cn1

Procedure:
In analogy to example 5a, 2,6-difluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After extractive workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) the title compound was obtained as an off-white solid (yield: 29%). 1H-NMR (300 MHz, DMSO): δ=2.19 (d, J=0.8 Hz, 3H), 7.39 (s with fine splitting, 1H), 7.56-7.64 (m, 2H), 7.92 (mc, 1H), 8.04 (d, J=1.2 Hz, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([CH2:9][CH2:10][S:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][O:15][C:14]2[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=4)[N:30]=3)=[CH:26][C:13]1=2)(=O)[NH2:7].[OH-].[Na+]>CN(C)C=O>[Cl:39][C:33]1[CH:32]=[C:31]2[C:36]([CH:37]=[CH:38][C:29]([CH2:28][O:27][C:25]3[CH:24]=[CH:23][C:14]4[O:15][CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[CH:12]([S:11][CH2:10][CH2:9][C:6]#[N:7])[C:13]=4[CH:26]=3)=[N:30]2)=[CH:35][CH:34]=1
Reactant: NC(=O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
Under ice cooling and stirring, 1.35 ml of phosphorus oxy-chloride was added dropwise over 40 minutes to 1.78 g of 11-(2-carbamoylethylthio)-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 63 dissolved in 14 ml of dimethylformamide and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added 250 ml of a 1% sodium hydroxide aqueous solution, crystals precipitated were collected by filtration and the crystals were dissolved in chloroform. After this chloroform solution was washed with water and dried over anhydrous sodium sulfate, the solvent was removed to obtain 1.62 g of the title compound.
Reaction SMILES: [Cl:1]C1C=C(C2C=CC=CC=2C(F)(F)F)N=C(N)C=1[N+]([O-])=O.[H-].[Na+].[C:24]([C:28]1[C:29]([Cl:37])=[C:30]([C:34](O)=[O:35])[N:31]([CH3:33])[N:32]=1)([CH3:27])([CH3:26])[CH3:25].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[C:24]([C:28]1[C:29]([Cl:37])=[C:30]([C:34]([Cl:1])=[O:35])[N:31]([CH3:33])[N:32]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (87.5 mg, 0.275 mmol, prepared as described in STEP B above) in THF (10 mL) was treated with NaH (33.1 mg, 0.826 mmol, 60% dispersion in oil), and the mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (77.6 mg, 0.358 mmol, prepared as described in Example B above) in DCM (10 mL) was treated with oxalyl chloride (31.2 μL, 0.358 mmol), and DMF (2 drops), and the mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carbonyl chloride as a solid. The solid was taken up in anhydrous THF (6 mL) and this acid chloride solution was then added to the sodium anilide solution, as prepared above, and the resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted twice with EtOAc (40 mL and 25 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on an 8-g SEPRA Si 35 SPE column (Flow rate=10 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, then 1:19 to 1:3 over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a colorless glassy solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H18N5O3Cl2F3: 516.2 (M+H). Measured: 516.2.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([F:18])[F:17])=[CH:12][C:11]=3[O:19][CH3:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:2]3[N:21]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([CH:16]([F:18])[F:17])=[CH:12][C:11]=5[O:19][CH3:20])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cc(C(F)F)ccc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Product: COc1cc(C(F)F)ccc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12

Procedure:
4-{4-[8-(4-Difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.150 g, 0.484 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.161 g, 0.581 mmol) in a manner analogous to Example 311a and 311b to give product (0.191 g, 72%). MP=95-100° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.57 (s, 1H), 8.78 (d, 1H), 7.70 (d, 1H), 7.55 (m, 3H), 7.32 (s, 1H), 7.25 (m, 1H), 7.15 (d, 2H), 7.10 (br m, 1H), 7.05 (m, 1H), 4.10 (m, 2H), 3.78 (s, 3H), 2.78 (br m, 2H), 2.55 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H): MS=550 (MH)+.
Reaction SMILES: Cl.C([O:5][C@H:6]([CH2:21][NH:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)([CH3:25])[CH3:24])[C@@H:7]([NH:17][C:18](=[O:20])[CH3:19])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)(=O)C.[OH-].[Na+]>CO>[Br:32][C:28]1[CH:27]=[C:26]([C:23]([NH:22][CH2:21][C@@H:6]([OH:5])[C@@H:7]([NH:17][C:18](=[O:20])[CH3:19])[CH2:8][C:9]2[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=2)([CH3:25])[CH3:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H](CNC(C)(C)c1cccc(Br)c1)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC(C)(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
To a solution of 107 mg (0.21 mmol) of hydrochloride 31 in 10 mL of methanol is added 1 mL of 1N NaOH. The mixture is stirred for 45 min at ambient temperature, then quenched with 1N KH2PO4 and diluted with ethyl acetate. The organic phase is washed with brine, dried over Na2SO4, filtered and concentrated to a glassy solid. This is dissolved in methanol and treated with ethereal HCl to afford 70 mg (0.14 mmol, 68%) of compound 32 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.69 (s, 1H), 7.56 (m, 2H), 7.35 (t, J=8 Hz, 1H), 6.71 (m, 2H), 6.63 (m, 1H), 3.98 (m, 2H), 2.98 (m, 1H), 2.8 (m, 1H), 2.68 (m, 1H), 2.39 (m, 1H), 1.92 (s, 3H), 1.83 (s, 6H); IR (diffuse reflectance) 3311, 3283, 3257, 3249, 3058, 3007, 2757, 1655, 1646, 1628, 1596, 1551, 1459, 1116, 697 cm−1. MS (CI)m/z(rel intensity) 457 (15), 455 (MH+,97), 458 (17), 457 (99), 456 (15), 455 (97), 377 (5), 259 (9), 216 (6), 214 (6), 96 (27), 69 (5). HRMS (ESI) calcd for C21H25N2O2F2Br+H1 455.1146, found 455.1145. Anal. Calcd for C21H25BrF2N2O2.HCl+H2O: C, 49.47; H, 5.54; N, 5.49; Found: C, 49.45; H, 5.50; N, 5.54.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl.[CH3:12][O:13][C:14](=[O:19])[C@H:15]([CH2:17][SH:18])[NH2:16].CCN=C=NCCCN(C)C.CN1CCOCC1>CC#N.CCOC(C)=O>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:16][C@@H:15]([CH2:17][SH:18])[C:14]([O:13][CH3:12])=[O:19])=[O:10]
Reactant: COC(=O)[C@@H](N)CS
Reactant: O=C(O)c1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CS)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Separately, salicylic acid (152 mg, 1.10 mmol) was taken up in CH3CN (10 mL) along with L-cysteine methyl ester hydrochloride (189 mg, 1.10 mmol), EDCI (350 mg) and N-methylmorpholine (120 μL). The reaction mixture was stirred at room temperature for 3 h. It was then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude (R)-methyl 2-(2-hydroxybenzamido)-3-mercaptopropanoate. This material was then taken up in CH3CN (3 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2,5-dioxo-2H-pyrrol-1(5H)-yl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (315 mg, 0.7 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded (R)-methyl 3-(1-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2,5-dioxopyrrolidin-3-ylthio)-2-(2-hydroxybenzamido)propanoate (140 mg). Mass calculated for C39H51N3O7S: 705.34; found: [M+H]+=706.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][N:17]([CH3:25])[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([N:17]([CH3:25])[CH3:16])=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CN(C)c1ccc(N)cc1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(N(C)C)cc2)c1C(=O)OC
Yield: 71 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), N,N-dimethyl-1,4-phenylenediamine (0.42 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.73 g of the product at 70:30 hexanes-ethyl acetate, in 71% yield: 1H NMR (CDCl3) δ 2.95 (s, 6H), 3.86 (s, 3H), 3.88 (s, 3H), 6.71-6.76 (m, 2H), 6.88 (d, J=7.4 Hz, 1H), 7.00-7.09 (m, 3H), 7.20 (t, J=7.9 Hz, 1H), 8.10 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:19](=[N:27]O)(Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:27][O:11][C:9]=2[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: CC(=O)Cc1ccnc(Br)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
To a stirred solution of Compound 16 (1.71 g, 8.0 mmol) and Et3N (2.23 mL, 16 mmol) in EtOH (16 mL) was added a solution of benzoylchloride oxime (1.62 g, 10.4 mmol) in EtOH (16 mL) over 90 min. The solution was stirred at 25° C. for 90 min. Then, the solution was heated to reflux for 24 h. The solution was cooled to 25° C. and concentrated. The crude material was taken up in CH2Cl2 (50 mL) and poured into saturated aqueous NaHCO3 (50 mL), extracted with CH2Cl2 (3×50 mL), dried (Na2SO4), and filtered. Flash chromatography (SiO2, 20% EtOAc-hexanes) provided the title compound (1.32 g, 4.19 mmol, 52%).