Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH2:26]([C:21]([NH:20][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22](=[O:23])[NH:24][CH3:25])[CH2:28][CH3:29])[CH3:27]
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=400.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH:5]1[NH:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]1=[O:13])[CH:2]([CH3:4])[CH3:3].Br[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:17]1[CH:16]=[C:15]([N:9]2[CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6](=[O:13])[C:7]([CH3:11])([CH3:12])[C:8]2=[O:10])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC(C)CC1NC(=O)C(C)(C)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 5-isobutyl-3,3-dimethylpyrrolidine-2,4-dione (500 mg), 4-bromo-2-chlorobenzonitrile (709 mg), cesium carbonate (1.33 g), tris(dibenzylideneacetone)dipalladium(0) (125 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (237 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless oil (yield: 744 mg, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([NH2:23])=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=CC=C[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@H](C(O)=O)CC(C)C)=O)(C)(C)C.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.N1CCC[C@H]1C(N)=O>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([NH2:23])=[O:22])=[O:18])[CH2:10][CH:11]([CH3:16])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Following the general procedure described previously for t-butyloxycarbonyl-L-phenylalanyl-L-prolinamide, a solution of t-butyloxycarbonyl-L-leucine (32.64 g), in tetrahydrofuran was activated by treatment with N-methylmorpholine (18.22 ml), followed by isobutylchloroformate (16.99 ml) at -5° C. After 15 minutes, L-prolinamide hydrochloride (15.0 g) was added as a solution in dimethylformamide, followed by N-methylmorpholine (18.22 ml) and the mixture stirred overnight at room temperature. The reaction was worked up as described previously to give the desired product, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH:20][C:22](=[O:24])[CH3:23])[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@@H](NC(C)=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (R)-3-amino-3-[4-(tert-butoxycarbonylamino)phenyl]-propanoic acid methyl ester [7.2 g, Reference Example 7(c)] in dimethylformamide (30 ml), was treated with acetic anhydride (2.4 ml) and diisopropylethylamine (4.6 ml). After stirring at ambient temperature for 10 minutes the mixture was poured into water (500 ml) and then extracted twice with ethyl acetate (200 ml). The combined organic extracts were washed with brine (200 ml) then dried over magnesium sulphate and then evaporated. The resulting white foam (8.5 g) was dissolved in dichloromethane (75 ml) and the solution was treated with trifluoracetic acid (17 ml). After stirring at ambient temperature for 3 hours the reaction mixture was evaporated. The residue was treated with toluene (70 ml), concentrated to dryness and the resultant material treated with dichloromethane (200 ml). The resultant suspension was treated with saturated aqueous potassium carbonate solution (20 ml) with stirring at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulphate, and then evaporated to give the title compound (4.1 g) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH:30]=[C:29]([C:32](O)=[O:33])[O:28][C:27]=2[CH:35]=1>>[OH:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH:30]=[C:29]([C:32]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:33])[O:28][C:27]=2[CH:35]=1
Reactant: O=C(O)C1=COc2ccc(O)cc2O1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Product: O=C(C1=COc2ccc(O)cc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 76 %

Procedure:
That compound is obtained in a yield of 76% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 7-hydroxy-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH3:10].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.CN1C(=O)N(C)CCC1>C1COCC1>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][C:13]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([O:11][CH2:9][CH3:10])=[O:21]
Reactant: BrCCCCBr
Reactant: CCOC(=O)C(C)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of LDA (14 mL, 28 mmol, 2.0 M in heptane) was added dropwise to a stirred solution of 202 (5.0 g, 28.06 mmol) in anhydrous THF (50 mL) at −78° C. After 1 h, the reaction mixture was added to a −78° C. cold solution of 1,4-dibromobutane (10.06 g, 23.1 mmol) in THF. After the addition of DMPU (5 mL), the reaction mixture was stirred for 1 h, then warmed to room temperature and stirred overnight. The mixture was poured into saturated aqueous NH4C1 solution (500 mL) and extracted with ethyl acetate (4×100 mL). The combined organic phases were washed with brine (100 mL), 1 M HCl (50 mL), saturated aqueous NaHCO3 solution (50 mL), and brine (100 mL). The solution was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was distilled to give 205d as an oil (7.16 g, 99%). Bp 130-131° C./0.2 mm Hg. 1H NMR (CDCl3), δ (ppm): 7.40-7.15 (m, 5H), 4.13 (q, 2H, J=6.7), 3.36 (t, 2H, J=6.7), 2.02 (m, 2H), 1.86 (m, 2H), 1.56 (s, 3H), 1.34 (m, 2H), 1.18 (t, 3H, J=6.7). 13C NMR (CDCl3), δ (ppm): 176.13, 143.91, 128.51, 126.81, 126.03, 60.93, 50.22, 38.53, 33.56, 33.30, 23.58, 22.77, 14.22. HRMS (FAB): Calcd for C15H2179BrO2 (MH+): 313.0803. found 313.0786.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:20][CH2:21][CH2:22][CH3:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCN(OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred solution at 0° C. of N--t-Butoxycarbonyl-O-benzylhydroxylamine, prepared as in Example 1175A, in anhydrous THF was added portionwise a 60% dispersion of sodium hydride (1.2 equiv.) in mineral oil. Mixture stirred 30 minutes ar 0° C., and then, 1-iodobutane (1.2 equiv.) was added dropwise. Reaction stirred one hour at 0° C., and than, overnight at room temperature. Reaction concentrated in vacuo. Residue taken up in EtOAc and washed with water, 1.0M NaHCO3, 1N H3PO4, and brine. Organic layer dried with Na2SO4, filtered, and evaporated.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[C:54]1([N:60]=[C:61]=[O:62])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][CH:47]1[CH2:51][CH2:50][N:49]([C:61]([NH:60][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:62])[CH2:48]1
Reactant: O=C(CC1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and phenyl isocyanate as starting materials in 44% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.42 (m, 2H), 9.07 (s, 1H), 8.32 (m, 2H), 8.21 (s, 1H), 8.13 (s, 1H), 7.68 (s, 1H), 7.50 (d, 2H), 7.31 (d, 1H), 7.20 (m, 2H), 7.07 (d, 1H), 6.89 (m, 1H), 3.60 (m, 2H), 3.40 (m, 1H), 3.12 (m, 1H), 2.99 (m, 4H), 2.60 (m, 1H), 2.09 (m, 2H), 1.67 (m, 2H). LCMS for C30H30ClN8O2 (M+H)+: m/z=569.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[O:30])[C:21]3[C:20](=[O:31])[N:19]([CH3:32])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][OH:30])[C:21]3[C:20](=[O:31])[N:19]([CH3:32])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2CO)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
4-[7-(2-Formylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (27 mg) was dissolved in anhydrous tetrahydrofuran (0.5 ml) and ethanol (0.5 ml), and sodium borohydride (20 mg) was added thereto. The reaction solution was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 28 mg of 4-[7-(2-hydroxymethylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. This product (8 mg) was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 1.60 mg of 7-(2-hydroxymethylphenyl)-1,3-dimethyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione trifluoroacetate [MS m/e (ESI) 371(MH+—CF3COOH)] and 0.46 mg of 7-(2-trifluoroacetoxymethylphenyl)-1,3-dimethyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione trifluoroacetate [MS m/e (ESI) 467(MH+—CF3COOH)].
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:9]([CH3:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[NH:4][N:3]=1.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[F:37][C:38]1([C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[CH2:41][NH:40][CH2:39]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:9]([CH3:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([N:40]2[CH2:39][C:38]([C:42]3[CH:43]=[CH:44][C:45]([C:46]#[N:47])=[CH:48][CH:49]=3)([F:37])[CH2:41]2)=[O:15])[NH:4][N:3]=1
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1cc(C)c(-c2[nH]nc(Cl)c2C)cc1C(=O)O
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1cc(C)c(-c2[nH]nc(Cl)c2C)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 5-(3-chloro-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid (compound 250.6) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 423 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1)#[N:2].I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=3)[C:21]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: N#Cc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(C#N)nc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 12.8 %

Procedure:
A solution of 2-cyanopyridine 5-boronic acid pinocol ester (18 mg, 0.08 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA21 (2.5 mg, 14% yield). ESI-MS (M+H)+ m/z calcd 280.1, found 280.1.
Reaction SMILES: [CH3:1]B(O)O.Br[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[Cl:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCCCCCC.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].C(Cl)Cl>[Cl:14][C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[CH3:1]
Reactant: COc1ccc(Br)c(Cl)c1
Reactant: CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCCCCCC
Product: COc1ccc(C)c(Cl)c1

Procedure:
A solution of PdCl2(dppf)-DCM adduct (0.922 g, 1.129 mmol), methylboronic acid (2.70 g, 45.2 mmol), 4-bromo-3-chloroanisole (6.39 ml, 45.2 mmol), and potassium phosphate (28.8 g, 135 mmol) in 150 mL dioxane and 50 mL water was heated to 110° C. for 2 hours. The reaction mixture was then diluted with heptane, the organics dried over MgSO4 and concentrated to afford 2-chloro-4-methoxy-1-methylbenzene. m/z (ESI) 141.0 (M−CH3)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Temperature: 0 °C
Yield: 44 %

Procedure:
2,3-Dichlorobenzoic acid, obtained from Aldrich, (40 g, 0.21 mole) was added portion wise to a −20° C. concentrated H2SO4, obtained from Acros, (233 mL) solution which was fitted with a mechanical overhead stirrer. During the addition process, a separate flask containing concentrated H2SO4 (50 mL) was cooled to 0° C. and fuming HNO3, obtained from Acros, (16.6 mL) was slowly added. This solution was then added dropwise to the 2,3-Dichlorobenzoic acid solution at a rate which kept the reaction mixture at or slightly below −15° C. After the addition was complete the resulting solution was allowed to warm to 10° C. over 3 hours. The crude solid material was filtered through a fritted filter funnel, washed with cold H2O (200 mL), and dried under a stream of air followed by high vacuum to yield 21.7 g (44%) of product (246) which contained 4% of the undesired regioisomer (2,3-Dichloro-6-nitrobenzoic acid 247) based on 1H NMR analysis. The filtrate was slowly poured over ice and additional solid precipitated. This solid was observed to be a 3:1 mixture of 2,3-dichloro-6-nitrobenzoic acid (247) to 2,3-dichloro-5-nitrobenzoic acid (246) based on 1H NMR analysis.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CCN)CCCCC=1.C1(=O)CCCCC1>C(OC(=O)C)C>[C:23]1([CH2:22][CH2:21][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: NCCC1=CCCCC1
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CSc1cnc(NC(=O)N(CCC2=CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-(1-cyclohexenyl)-ethylamine, cyclohexanone and 2-aminothiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[OH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=O)=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH3:28][N:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:38]([NH:40][NH2:41])=O)[C:32]=2[CH:31]=[CH:30]1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:18][N:17]1[C:38]([C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:32]=2[CH:31]=[CH:30][N:29]3[CH3:28])=[N:40][N:41]=[C:15]1[C:14]1[CH:19]=[CH:20][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: Cn1ccc2c(C(=O)NN)cccc21
Reactant: CNC(=O)c1ccc(O)cc1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccc(O)cc2)nnc1-c1cccc2c1ccn2C
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Methyl trifluoromethanesulfonate (200 μL, 1.76 mmol) was added to 4-hydroxy-N-methylbenzamide (6-A) (133 mg, 0.881 mmol) and the mixture stirred at 65° C. for 10 min. Toluene (0.6 mL) was added and the suspension stirred rapidly at 65° C. for 30 min. Toluene (0.4 mL), triethylamine (370 μL, 2.67 mmol) and a solution of 1-methyl-1H-indole-4-carbohydrazide (6-B) (100 mg, 0.528 mmol) in toluene (1.0 mL) and DMF (250 μL) were added and the mixture stirred at 65° C. for 3 h and then at 125° C. for 18 h. The mixture was evaporated in vacuo and the residue purified by preparative TLC (silica gel, methylene chloride:methanol, 95:5) to provide 4-[4-methyl-5-(1-methyl-1H-indol-4-yl)-4H-1,2,4-triazol-3-yl]phenol (6-C). 1H NMR (500 MHz, CD3OD): δ 3.63 (s, 3H); 3.92 (s, 3H); 6.53 (d, 1H); 7.00 (d, 2H); 7.37 (m, 3H); 7.64, (m, 3H).
Reaction SMILES: COC(=O)[CH:4]([C:17]#[N:18])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[Cl-].[Na+].O>CS(C)=O.[Cl-].[Na+].O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:6])([CH3:7])[CH2:4][C:17]#[N:18])=[C:9]([O:15][CH3:16])[CH:10]=1
Reactant: COC(=O)C(C#N)C(C)(C)c1ccc(F)cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(F)ccc1C(C)(C)CC#N
Reaction time: 4 h
Yield: 80.9 %

Procedure:
A mixture of 4.2 g (15.03 mmol) of 2-cyano-3-(4-fluoro-2-methoxyphenyl)-3-methylbutyric acid methyl ester and 2.5 g (42.77 mmol) of sodium chloride in 40 mL of DMSO with 2 mL of water was warmed to reflux. Gas evolution was clearly evident early in the reaction. After 4 hours, the reaction was cooled and diluted with 100 mL of brine and extracted with four 75 mL portions of EtOAc. The combined organic layers were washed with six 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to afford an oil which solidified under vacuum. The tan solid was triturated with hexanes and collected by filtration to afford 2.52 g (81%) of 3-(4-fluoro-2-methoxyphenyl)-3-methylbutyronitrile, m.p. 80° C.-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:21]([NH:28][CH2:29][CH2:30][OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([N:28]([CH2:29][CH2:30][OH:31])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[F:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: OCCNCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1F)N(CCO)Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoyl chloride (1 g, 4.21 mmol) in THF (14.04 mL) was added DIEA (1.103 mL, 6.32 mmol) and 2-(benzylamino)ethanol (0.764 g, 5.05 mmol) at room temperature. The reaction mixture was stirred for overnight. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine. After dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the crude N-benzyl-4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide was used for the next step (83%). LCMS (m/z): 352/354 (MH+), 0.83 min.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[F:14][C:15]([F:34])([F:33])[C:16]([NH:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][CH2:31][CH3:32])=[CH:17][C:18]([OH:20])=O>CCCCCC>[F:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH2:30][CH2:31][CH3:32])=[C:22]2[C:27]=1[C:18](=[O:20])[CH:17]=[C:16]([C:15]([F:14])([F:34])[F:33])[NH:21]2
Reactant: CCCOc1ccc(F)cc1NC(=CC(=O)O)C(F)(F)F
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCCOc1ccc(F)c2c(=O)cc(C(F)(F)F)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
Diphenyl ether (15 ml) was added to ethyl ester of 4,4,4-trifluoro-3-(5-fluoro-2-propoxyphenylamino)buta-2-enoic acid (19.7 g, 59.0 mmol), and the mixture was stirred for 1.5 hours while heating under reflux. The reaction mixture was cooled to room temperature, n-hexane was added, and the precipitate was collected by filtration. The substance remaining on the filter was washed with n-hexane, and dried to thereby obtain 16.2 g of powdery white 5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one (yield: 94%).