Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[CH:3]=[N:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]1[CH2:25][O:24][CH:23]=[CH:22][CH2:21]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:24]1[CH2:25][CH2:20][CH2:21][CH2:22][CH:23]1[N:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[CH:3]=[N:2]1
Reactant: C1=COCCC1
Reactant: O=C(O)c1cn[nH]c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnn(C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
To a suspension of 1H-pyrazole-4-carboxylic acid (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50° C. to give 61.2 g of a white powder (yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[CH:46]=[N:45][N:44]=[C:43]1[NH2:47].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:43]4[S:42][CH:46]=[N:45][N:44]=4)(=[O:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 68.6 mg, 0.112 mmol), 1,3,4-thiadiazol-2-amine (12.51 mg, 0.124 mmol), and cesium carbonate (110 mg, 0.337 mmol). The vial was flushed with Ar (g), then acetonitrile (562 μl) was added. After stirring overnight, the mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-4% MeOH/DCM). Some fractions were discarded, and the remainder containing product were combined and concentrated to 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (35.19 mg, 0.067 mmol, 59.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=14.50 (br. s., 1H), 8.80 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.6 Hz, 1H), 7.95-7.89 (m, 1H), 7.87-7.79 (m, 1H), 7.62-7.53 (m, 2H), 7.49-7.41 (m, 2H), 7.32 (dt, J=3.0, 8.5 Hz, 1H), 7.27 (s, 1H), 3.71 (s, 3H). m/z (ESI) 527.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:14][CH2:13][C:12]([F:16])([F:15])[F:11]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: NCC(F)(F)F
Product: FC(F)(F)CNCc1cccc(Cl)c1Cl

Procedure:
Amine 27 was prepared according to the reaction sequence described for Amine 3, but using instead 2,3-dichlorobenzaldehyde as the starting aldehyde and 2,2,2-trifluoroethylamine as the starting amine. The title compound was isolated as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:35])[N:12]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13]([C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])=[N:14]2>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:21][C@H:19]([C:13]1[N:12]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:11](=[O:35])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[Cl:8])[N:14]=1)[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of (5)-tert-butyl 1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate (1 g, 2.5 mmol) in dichloromethane (3 mL). The resultant was stirred at room temperature for 3 hours. The solvents was removed in vacuuo to afford (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one 2,2,2-trifluoroacetic acid salt. ES/MS m/z=300.1 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1([CH:22]([F:24])[F:23])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1.FC(F)C1(C(F)F)CNC2C=C([N+]([O-])=O)C=CC=2[O:29]1.C(=O)([O-])[O-].[K+].[K+].BrC1C=CC=CN=1.C1OCCOCCOCCOCCOCCOC1>ClCCl.[Cu].ClC1C=CC=CC=1Cl>[F:25][CH:2]([F:1])[C:3]1([CH:22]([F:24])[F:23])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:29])[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)N(c1ccccn1)CC(C(F)F)(C(F)F)O2
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC(C(F)F)(C(F)F)O2
Agent: [Cu]
Agent: Brc1ccccn1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)N(c1cccc[n+]1[O-])CC(C(F)F)(C(F)F)O2
Temperature: 170 °C

Procedure:
2-(2,2-bis(Difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine-4-yl)pyridine. The product of step c. (0.81 g) potassium carbonate (1.6 g), copper bronze (0.37 g), 2-bromopyridine (0.83 mL), 18-crown-6 (0.079 g), and 1,2-dichlorobenzene (8 mL) were stirred and heated at 170° C. for six hours. The reaction mixture was cooled, diluted with dichloromethane and chromatographed, eluting with dichloromethane, to give the pyridine as a light amber syrup (0.77 g); NMR: 4.34 (s,2), 6.55 (t,2), 7.07 (m,1), 7.37 (m,2), 7.82 (m,2), 8.23 (s,1), 8.39 (d,1); MS: m/z=358(M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+](C1C=[CH:15][CH:16]=[C:17](N)[C:18]=1[C:19](O)=O)([O-])=O.C(C1C=CC=C1)(C)C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[C:18]3[CH2:19][C:15]([C:6]=2[CH:5]=1)=[CH:16][CH:17]=3)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: O=[N+]([O-])c1ccccc1
Agent: CC(C)C1C=CC=C1
Product: O=[N+]([O-])c1ccc2c(c1)C1=CC=C2C1

Procedure:
In the synthesis shown in Scheme 1, a 3-nitrobenzene, generated from a 6-nitro-anthranilic acid (A), is reacted with a cyclic 1,4-diene (B), such as 5-isopropyl-cyclopentadiene, to form a 5-nitro-benzonorbornadiene (C) in a Diels-Alder reaction. Under standard catalytic reduction conditions (for example, using Raney nickel or palladium on carbon in a solvent such as methanol), both the 5-nitro group and the 2,3-double bond of the 5-nitro-benzonorbornadiene (C) are reduced to form the 5-amino-benzonorbornene (D). Reaction of the 5-amino-benzonorbornene (D) with a heterocyclyl-carboxylic acid or heterocyclyl-carboxylic acid derivative (E), where Q may be hydroxyl, fluoro, chloro or bromo, in a solvent such as dichloromethane gives a fungicidal heterocyclyl-carboxylic acid benzonorbornen-5-yl-amide (F). An example of (D) is 5-amino-9-isopropyl-benzonorbornene, which is a precursor of an amide of, for example, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c(Sc2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2ccc(F)cc2)c1
Yield: 82.6 %

Procedure:
Methyl 5-(4-fluorophenylthio)pyrrole-3-carboxylate (1.5 g.) was combined with 10 ml. of methanol and 10 ml. of 1 N sodium hydroxide and refluxed for 2 hours. The methanol was allowed to evaporate, the aqueous residue was diluted with approximately one volume of water and extracted twice with ether. The aqueous phase was cooled in an ice-water bath and acidified to pH 2.0 with conc. hydrochloric acid. The gummy solid which precipitated was extracted into ethyl acetate. The three combined ethyl acetate extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Trituration with hexane gave crystalline 5-(4-fluorophenylthio)pyrrole-3-carboxylic acid (1.17 g., m.p. 116-118, m/e 237), recovered by filtration.
Reaction SMILES: C(OP([CH:9]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)/[CH:29]=[C:9](\[CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1cccc(F)c1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 111.5 %

Procedure:
A solution of 4-tert-butyl 1-ethyl 2-(diethoxyphosphoryl)succinate (28.60 g) in tetrahydrofuran (70 ml) was added dropwise to a suspension of 60% oily sodium hydride (3.39 g) in tetrahydrofuran (100 ml) under ice-cooling during 20 minutes, the mixture was stirred at the same temperature for an hour. Next, a solution of 3-fluorobenzaldehyde (10.00 g) in tetrahydrofuran (30 ml) was added thereto and the mixture was stirred at room temperature for 3 hours. Ice-water was added to the reaction mixture under ice-cooling and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over sodium sulfate and concentrated in vacuo to give 4-tert-butyl 1-ethyl(2E)-2-(3-fluorobenzylidene)succinate (27.7 g) as a crude yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:7](=[O:8])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:11])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Product: Cc1nc(NC(=O)c2cc(Cl)ccc2F)sc1C(=O)NCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 5-chloro-2-fluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 22% yield. m.p. 175-178° C.; 1H NMR (CDCl3, 300 MHz) δ 8.12 (dd, J=2.8, 6.6 Hz, 1H), 7.53 (ddd, J=2.8, 4.4, 8.8 Hz, 1H), 7.38-7.24 (m, 6H), 7.17 (dd, J=8.8, 11.3 Hz, 1H), 6.01 (t, J=4.7 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 404.1 (M+1).
Reaction SMILES: C(NCC)C.[NH:6](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:7]([C:11]([NH:13][C@H:14]([C:22]([NH:24][C@H:25]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20])=[O:12])[CH:8]([CH3:10])[CH3:9]>CN(C)C=O>[NH2:6][C@H:7]([C:11]([NH:13][C@H:14]([C:22]([NH:24][C@H:25]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:21])=[O:12])[CH:8]([CH3:10])[CH3:9]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)C(C)C)C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
31.5 ml of diethylamine are added to a solution of 21 g (30 mmol) of Fmoc-Val-Arg-Ile-OBzl in 200 ml of dimethylformamide. The mixture is left to stand at room temperature for 10 minutes, and is concentrated in vacuo. The residue is triturated with diethyl ether and filtered off with suction.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=1.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=2)=[C:4]([F:10])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1cc(F)c(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 73.9 %

Procedure:
4-Amino-2,5-difluorophenol (4.95 g) was dissolved in dimethyl sulfoxide (50 ml) under a nitrogen flow, and potassium tert-butoxide (4.05 g) was added at room temperature, followed by stirring for 25 min. 4-Chloropyridine-2-carboxamide (2.70 g) was added thereto, followed by stirring at 80° C. for 2.5 hr. The reaction mixture was allowed to cool down to room temperature, and a 1N aqueous solution of sodium hydroxide (74.25 ml) was added, followed by stirring for 10 hr. The precipitated solid was collected by filtration, and the resultant solid was washed with water. This solid was dried under hot air at 100° C. for 24 hr to provide the titled compound as purple powder (3.38 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][NH2:32])[CH:28]=[CH:29][CH:30]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:32][CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: NCc1cccc(Cl)c1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)NCc2cccc(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (17 mg, 0.054 mmol) and (3-chlorophenyl)methanamine (8.34 mg, 0.059 mmol) in THF (268 μL) was added PyBroP (27.5 mg, 0.059 mmol), DIEA (28.1 μL, 0.161 mmol) and HOBT (9.02 mg, 0.059 mmol). The reaction mixture was stirred overnight at room temperature. All volatile material was removed in vacuo and dissolved in DCM. The crude product dissolved in DCM was loaded to flash chromatography column (gradient EtOAc in heptane) providing 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(3-chlorobenzyl)-2-fluorobenzamide in 87% yield. LCMS (m/z): 441.1 (MH+), 0.79 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.74 (m, 1H), 7.63 (m, 2H), 7.35 (m, 4H), 6.14 (s, 1H), 4.48 (m, 2H), 3.92 (m, 2H), 3.43 (m, 2H), 1.73 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:10][C:3]=12.C(OC([NH:31][C:32]1[CH:37]=[C:36](B(O)O)[C:35]([Cl:41])=[CH:34][N:33]=1)=O)(C)(C)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][C:9]([CH:11]4[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:15][CH2:16]4)=[CH:10][C:3]=23)[C:35]([Cl:41])=[CH:34][N:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)ccnc3[nH]2)CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(B(O)O)c(Cl)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(N)ncc4Cl)ccnc3[nH]2)CC1

Procedure:
A mixture of Example 17E (565 mg, 1.682 mmol), (2-((tert-butoxycarbonyl)amino)-5-chloropyridin-4-yl)boronic acid (550 mg, 2.02 mmol), (PPh3)2PdCl2—CH2Cl2 adduct (70.9 mg, 0.10 mmol), tricyclohexylphosphine (28.3 mg, 0.10 mmol), Pd(dppf)2Cl2 (82 mg, 0.10 mmol), cesium carbonate (1.64 g, 5.05 mmol) and 1M Na2CO3 aqueous solution (5.05 mL, 5.05 mmol) in dioxane (18 mL) in a sealed tube was heated at 10° C. for 3 days. After cooling, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was concentrated and the residue was purified by reverse phase chromatography (C18 column), eluted with a gradient of 10%-70% acetonitrile in 0.1% TFA water solution to provide the title compound. LC/MS: 428 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 37.6 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), tert-butyl 2-aminoacetate (18.29 mg, 0.139 mmol), HATU (45.9 mg, 0.121 mmol), and 4-methylmorpholine (37.6 mg, 0.372 mmol) were added to DMF (1 mL). It was stirred for 20 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 15 min, 20 mL/min, 220 nM, product retention=16.4 min) to provide (R/S)-tert-butyl 2-(2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)acetate (20 mg, 0.035 mmol, 37.9% yield): LCMS=488.1 [M+H−C4H9]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.12 (2 H, d, J=8.35 Hz), 7.50-7.75 (7 H, m), 5.17 (1 H, s), 3.90 (2 H, s), 1.44 (9 H, s); HPLC peak RT=9.1 min (Method A).
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[Br:13]Br>>[Br:13][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:12][C:3]([CH2:1][CH3:2])([CH2:10]3)[CH2:4]1)[CH2:6]2
Reactant: CCC12CC3CC(CC(C3)C1)C2
Reactant: BrBr
Product: CCC12CC3CC(CC(Br)(C3)C1)C2
Yield: 90.3 %

Procedure:
1-Bromo-3-ethyladamantane was prepared from 1-ethyladamantane (K. Gerzon et al, J. Med. Chem., 6, 760, 1963) by stirring 0.944 grams (5.76 mmol) of 1-ethyladamantane with 10 ml of liquid bromine for 4 hours, over which time the temperature was increased to reflux. The heat was removed and after cooling, a 40 ml portion of carbon tetrachloride was added. The mixture was poured into 120 ml of ice water and enough solid sodium sulfite was added with stirring to destroy the excess bromine. The layers were separated and the aqueous phase was extracted with three portions of carbon tetrachloride. The combined extracts were washed with water, then 5% aqueous sodium bicarbonate solution, then dried over magnesium sulfate (anhydrous). Evaporation of solvent yielded a yellow liquid which was distilled to afford 1.263 grams (90.3%) of 1-bromo-3-ethyladamantane, bp 114°-115° C. (3.5 mm).
Reaction SMILES: C([O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([Cl:26])[CH:11]=1)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[CH2:19]([O:18][C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=1[Cl:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)cc(Cl)c1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)cc(Cl)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-benzyloxy-3-chloro-5-methoxy-benzoic acid benzyl ester (CAB02162, 3.83 g, 10.0 mmol) in THF (20 mL) was added dropwise with a syringe to a suspension of lithium aluminium hydride (500 mg, 13.15 mmol) in THF (30 mL). The mixture was stirred at room temperature for 30 minutes and 2N NaOH (5 mL) was added. The mixture was stirred for another hour, the aluminium salts were filtered off, the filtrate was dried over sodium sulphate and concentrated under reduced pressure. The resulting oil was heated to 120° C. under high vacuum in a kugelrohr-destillation-apparatus to remove benzyl alcohol for 10 h. The product was obtained as a light yellow oil and was used without any further purification. Yield: 2.70 g (97%). 1H-NMR (400 MHz, CDCl3) δ=2.09 (2, 1H, —OH), 3.86 (s, 3H, —OCH3), 4.56 (s, 2H), 5.02 (s, 2H), 6.83 (d, J=2.0 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 7.31-7.41 (m, 3H), 7.52-7.55 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C@@H:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C@@H:16]([CH:22]([CH3:24])[CH3:23])[CH2:15]1.O1CCOCC1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:23][CH:22]([C@H:16]1[CH2:15][C@H:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:32]4[S:31][CH:35]=[CH:34][CH:33]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][S:17]1(=[O:21])=[O:20])[CH3:24]
Reactant: OB(O)c1cccs1
Reactant: CC(C)[C@H]1C[C@H](c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@H]1C[C@H](c2c[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CCS1(=O)=O
Reaction time: 0.08 h
Yield: 21.5 %

Procedure:
(racemic)-5-Bromo-3-[trans-2-(1-methylethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]-1H-indole-7-carboxamide (60 mg, 0.145 mmol) was placed in a microwave vial and dissolved with 1,4-Dioxane (2 mL) and Water (1.000 mL). 2-Thienylboronic acid (37.1 mg, 0.290 mmol) and K2CO3 (60.2 mg, 0.435 mmol) were added. Argon was bubbled in the mixture for 10 min with stirring, PdCl2(dppf) (5.60 mg, 0.012 mmol) was added, and argon was bubbled another 10 mins. The vial was sealed and put under microwave 5 mins at 100° C. with high absorption parameter. The reaction was complete after the microwave treatment. The crude was run through a thiol-SPE cartridge eluting with 2 mL of methanol and the eluted solvents are evaporated. The brown oil was dissolved in 2-3 mL of DMSO, and purified on a Gilson HPLC. The desired fractions were concentrated, giving 13 mg of the title compound.