Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.F[B-](F)(F)F.[CH3:28][O+](C)C.O>C(Cl)Cl>[CH3:28][O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19-Hydroxyandrost-4-ene-3,17-dione is dissolved in methylenechloride and trimethyloxonium fluoroborate added thereto. After stirring at room temperature for a period of two hours, water is added to the reaction mixture, the organic layer is separated, dried over magnesium sulfate and the solvent removed under vacuum. The residue is crystallized from an acetone-hexane solution to yield the desired 19-methoxyandrost-4-ene-3,17-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([O:17][CH2:18][CH2:19][N:13]3[C@H:12]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][C@@H:11]23)[CH:16]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([O:17][CH2:18][CH2:19][N:13]3[C@H:12]3[CH2:20][CH2:21][N:22]=[CH:23][C@H:11]23)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccccc3Cl)cc3c1N2CCO3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccccc1-c1cc2c3c(c1)[C@H]1C=NCC[C@@H]1N3CCO2
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of tert-butyl(6bR,10aS)-5-(2-chlorophenyl)-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate in CH2Cl2 (2.4 mL) was added TFA (0.6 mL) and the reaction mixture was stirred for 3 h. The reaction mixture was concentrated in vacuo, diluted with CH2Cl2 (100 mL), washed with NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound (130 mg, 95%) as a light yellow oil. 1H NMR (CDCl3) δ1.78-1.99 (m, 2H), 2.11 (br-s, 1H), 2.76-2.95 (m, 4H), 3.09-3.20 (m, 2H), 2.32-2.39 (m, 1H), 2.41-2.46 (m, 1H), 4.44-4.52 (m, 2H), 6.76 (dd, 1H, J=1.5, 13.2 Hz), 7.19-7.36 (m, 4H), 7.42 (dd, 1H, J=1.4, 7.7 Hz) ppm.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:28]4[C:24](=[N:25][NH:26][N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[N:52]=[C:51]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:50]=1.[H-].[Na+].C(=O)=O>ClC1C=CC=CC=1.CN(C)C=O>[C:8]1([N:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:28]4[C:24](=[N:25][N:26]([C:49]5[C:58]6[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=6)[N:52]=[C:51]([C:59]6[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=6)[CH:50]=5)[N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2cc(-n3nc4c(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)ccc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)c4n3)c3ccccc3n2)cc1
Temperature: 50 °C

Procedure:
A mixture of Intermediate D (605 mg, 1.0 mmol), 4-chloro-2-phenylquinoline (481 mg, 2.0 mmol), 60% NaH (80 mg, 2.0 mmol), and dimethylformamide (15 mL) was stirred under argon and heated at 50° C. for 3 hours. After cooling, the mixture was diluted with chlorobenzene (50 mL) and treated with a piece of dry ice to reduce the pH. The volatiles were removed under reduced pressure, and the residue was chromatographed using silica gel and hexane/dichloromethane (2:1) as an eluent to give 4,7-bis(4-(N,N-diphenylamino)phenyl)-2-(2-phenylquinolin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 17) as orange-pink crystals, 640 mg (79%). 1H NMR (400 MHz, CDCl3): δ 8.70 (m, 3H, 2-phenylquinazolin-4-yl), 8.22 (d, J=8.4 Hz, 1H, 2-phenylquinazolin-4-yl), 8.12 (d, J=8.8 Hz, 4H, p-phenylene), 7.97 (ddd, J=8.4, 6.9 and 1.4 Hz, 1H, 2-phenylquinazolin-4-yl), 7.76 (s, 2H, benzotriazole), 7.68 (ddd, J=8.5, 7.0 and 1.1 Hz, 1H, 2-phenylquinazolin-4-yl), 7.53 (m, 3H, 2-phenylquinazolin-4-yl), 7.25-7.30 (m, 8H, Ph), 7.21 (d, J=8.4 Hz, 4H, p-phenylene), 7.16-7.19 (m, 8H, Ph), 7.05 (tt, J=7.3 and 1.1 Hz, 4H, Ph), 2.86 (s, 3H, quinaldine). UV-vis spectrum (dichloromethane): λmax=452 nm. Fluorimetry (dichloromethane): λmax=654 nm.
Reaction SMILES: O1CCCC1.[CH:6]([O:9][C:10](=[O:33])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])([CH3:8])[CH3:7].[S].[H][H]>[Pt].CC(O)C>[CH:6]([O:9][C:10](=[O:33])[C@H:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1)[NH:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20])([CH3:8])[CH3:7]
Reactant: CC(C)OC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: [H][H]
Agent: [Pt]
Agent: [S]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)OC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 10 °C

Procedure:
To 80 mL of tetrahydrofuran, there was added 31.3 g (content: about 50 wt %) of the wet crystals of Nα-(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine isopropyl ester at room temperature in a nitrogen gas atmosphere and the mixture was then stirred. To the mixture, there were added 80 mL of 2-propanol and 0.86 g of 3% Pt—S/C (wet product, obtained by applying platinum onto carbon and then poisoning the same with sulfur), hydrogen gas was then introduced into the reaction system and the reaction system was stirred at ordinary pressure. The reaction system was stirred at room temperature overnight as it was, and then the catalyst was removed from the reaction solution by filtration through Celite after the confirmation of the progress of the reaction according to HPLC. The resulting filtrate (initial amount of 178 g) was concentrated by distilling the solvent off under reduced pressure till the amount of the filtrate reached 91 g and 40 mL of 2-propanol was added to the concentrate to thus adjust the concentration of the condensate. To this liquid whose concentration had been adjusted, there was dropwise added 150 mL of water at room temperature to thus separate out a crystalline solid and the resulting suspension was maintained at a temperature of not higher than 10° C. overnight. The resulting crystals were filtered off, washed with 100 mL of water and the resulting wet crystals were dried at 60° C. under reduced pressure to thus give 13.16 g of the title compound as a white crystalline solid (overall yield of these two steps: 86%).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Brc1ccccn1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccccn1)OCC2c1ccc(C(C)C)cc1
Yield: 53 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromopyridine, the title compound was obtained in the same manner as in Example 107.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: COc1cccc(C(=O)Nc2cc(C(=O)NCc3ccccc3)ccn2)c1
Yield: 46 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 3-methoxybenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-methoxybenzamido)isonicotinamide was obtained as a colorless solid in 46% yield: mp 95-96° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 8.64 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.56 (dd, J=5.1, 1.4 Hz, 1H), 7.43-7.25 (m, 8H), 7.11-7.07 (m, 1H), 6.80 (t, J=4.7 Hz, 1H), 4.63 (d, J=5.8 Hz, 2H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.8, 165.1, 160.0, 151.9, 148.6, 144.2, 137.4, 135.0, 129.9, 128.8, 128.0, 127.8, 118.9, 118.8, 118.6, 112.4, 110.5, 55.5, 44.2; MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:27]C1C=CC(C(=O)C)=CC=1>C1COCC1.CCCCCC>[Br:27][C:5]1[CH:6]=[CH:7][C:2]([C:8]([CH3:15])=[CH2:9])=[CH:3][CH:4]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a slurry of triphenylmethylphosphonium bromide (71.4 g, 200 mmole), in 500 ml dry THF at 0° C., were slowly added dropwise 135 ml (200 mmole) 1.44 M n-butyllithium in hexane. The mixture was stirred 30 minutes at 0° C., and a solution of 39.8 g (200 mmole) p-bromoacetophenone, in 100 ml dry THF, was slowly added dropwise. The mixture was allowed to warm slowly to ambient temperature, whereafter stirring was continued overnight. The stirred mixture was next filtered and the solvent removed by careful distillation at atmospheric pressure, the resulting residue was diluted with hexane, filtered, and the hexane removed by distillation. The remaining material was distilled, using a water aspirator vacuum, to produce 23.2 g (58.3% yield) of p-bromo-α-methylstyrene, bp 95°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH:28]CC6C=CC(OC)=CC=6)=[N:25][N:24]=5)[CH:21]=4)[N:16](S(C4C=CC(C)=CC=4)(=O)=O)[CH:15]=3)[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2N=C(C3C4C(=CC=C(C5OC(N)=NN=5)C=4)N(S(C4C=CC(C)=CC=4)(=O)=O)C=3)C=NC=2)=CC=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH2:28])=[N:25][N:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(-c5ccc(F)cc5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(-c4ccc(F)cc4)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2ccc3[nH]cc(-c4cncc(-c5ccc(F)cc5)n4)c3c2)o1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A solution of 5-(3-(6-(4-fluorophenyl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (200 mg, 0.309 mmol) in TFA (1 ml) was heated to 100° C. in microwave for 30 min. The mixture was cooled to RT and TFA was removed in vacuo to give the crude material (130 mg, 80%). MS (ESI, pos. ion) m/z: 527 (M+1). To a solution of crude 5-(3-(6-(4-fluorophenyl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (130 mg, 0.247 mmol) in p-dioxane (1.3 mL) was added aq 10% NaOH (0.65 mL). The mixture was heated at 100° C. for 2 h and quenched with ice cold H2O. The resulting precipitate was filtered and washed with H2O. The crude was recrystallized with 10% MeOH/CHCl3 to give 5-(3-(6-(4-fluorophenyl)-pyrazin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (25 mg, 27.3%) as an off-yellow solid. MS (ESI, pos. ion) m/z: 374.0 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 12.11 (s, 1H), 9.17 (s, 1H), 9.06 (s, 1H), 9.00 (s, 1H), 8.53 (m, 1H), 8.37-8.34 (m, 2H), 8.75-8.73 (m, 1H), 7.64 (d, J=8 Hz, 1H), 7.49 (m, 2H), 7.12 (s, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].C1COCC1.[CH3:19][NH2:20]>C(Cl)Cl>[CH3:19][NH:20][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccsc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (500 mg, 2.077 mmol) in DCM (20 ml), methanamine 2N solution in THF (4.155 ml, 8.31 mmol) was added and the reaction was stirred for 1 hour at RT. The mixture was partitioned between 2N HCl and DCM and the aqueous phase was extracted with DCM. The combined organic layers were dried over sodium sulfate and the solvent was removed affording methyl 3-(N-methylsulfamoyl)thiophene-2-carboxylate (Int. 32) (430 mg, 1.828 mmol, MS/ESI+235.8 [MH]+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([O:30][C:31]([F:34])([F:33])[F:32])[CH:8]=1)(=[O:5])=[O:4].C(O)(=[O:39])C.C(O)(=O)C.IC1C=CC=CC=1>CC(O)=O.CC(OC(C)=O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:36][C:2]([F:35])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]([O:30][C:31]([F:32])([F:33])[F:34])[C:10]([C:13]2[N:14]=[N:15][C:16]([NH:19][CH:20]3[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[CH:17][CH:18]=2)=[C:11]([OH:39])[CH:12]=1)(=[O:4])=[O:5]
Reactant: CC1(C)CC(Nc2ccc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Ic1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CC(Nc2ccc(-c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Temperature: 75 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
A mixture of 4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyl trifluoromethanesulfonate (86 mg, 0.16 mmol), iodobenzene diacetate (71.5 mg, 0.222 mmol) and Pd(OAc)2 (3.6 mg, 0.016 mmol) in AcOH (0.6 mL) and Ac2O (0.6 mL) was heated at 75° C. for 3 hours. The mixture was then heated at 80° C. overnight after addition of another 40 mg of iodobenzene diacetate. The reaction mixture was cooled to room temperature and concentrated. The residue was loaded onto an SCX column, washed with MeOH and diluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated. The residue was treated with 7 M NH3/MeOH and stirred at 40° C. for 4 h. The crude material was purified via flash column chromatography to give the title compound as a beige solid (32 mg, 36.1%). MS (M+1)=559.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22](O)=[O:23])=[N:16]1)=[O:8].C(Cl)(Cl)Cl.C(Cl)(=O)OCC.[NH3:35]>C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([NH2:35])=[O:23])=[N:16]1)=[O:8]
Reactant: O=C(O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NC(=O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1
Reaction time: 0.17 h

Procedure:
To a solution of 0.258 g. of 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid in 7.5 ml. of chloroform are added 0.14 ml. of triethylamine and then 0.1 ml. of ethyl chlorocarbonate with ice-cooling. After stirring for 10 minutes, to the resulting mixture is added 0.5 ml. of concentrated aqueous ammonia, and the whole mixture is further stirred for 30 minutes. The precipitated crystals are collected by filtration, washed successively with water, ethanol and ether, and then dried to give 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxamide as crystals. The filtrate is extracted with chloroform and the chloroform layer is washed with water, dried over sodium sulfate, followed by evaporation of the solvent to give additional crystals identical with the abovementioned crystals. Recrystallization of the combined crystals from chloroform-ethanol gives colorless needles, melting at 228° to 229° C. (decomposition).
Reaction SMILES: [O:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[NH:5][CH3:6])[CH3:2].CO[C:13](=[O:35])[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:25]=2[C:26]#[N:27])[C:17]([Cl:32])=[CH:16][C:15]=1[O:33][CH3:34]>C1(C)C=CC=CC=1.ClCCCl.N#N>[Cl:32][C:17]1[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:25]=2[C:26]#[N:27])=[CH:19][C:14]([C:13]([N:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:1][CH3:2])[CH3:6])=[O:35])=[C:15]([O:33][CH3:34])[CH:16]=1
Reactant: COC(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OC
Reactant: CNc1ccccc1OC
Agent: N#N
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)N(C)c1ccccc1OC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 7.4 %

Procedure:
To a mixture of 2-methoxyl-N-methylaniline (27.7 mg, 0.2 mmol) and Et3AI (196 μL, 1.9 M in toluene, 0.2 mmol) in 1,2-dichloroethane (1 mL) which was preheated at 50° C. for 10 min under N2 atmosphere, was added 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid methyl ester (50 mg, 0.14 mmol). The mixture was sealed in N2 atmosphere and heated at 80° C. for 16 hrs. Upon cooling to rt, the mixture was quenched with 2 N HCl (5 mL) and diluted with 1,2-dichloroethane. The organic layer was separated and concentrated. The residue was purified via reverse phase preparative LCMS to yield 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-(2-methoxy-phenyl)-N-methyl-benzamide 38-1 (4.9 mg). MS [M+H]+ 475.9; tR=5.91 min (method 3)
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1)=[O:6])([CH3:4])[CH3:3].[CH3:22][Mg]Br.C1COCC1>C(Cl)Cl>[CH3:4][C:2]([S@:5]([NH:7][CH:8]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:11][N:10]=1)[CH3:22])=[O:6])([CH3:1])[CH3:3]
Reactant: C[Mg]Br
Reactant: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ncc1OCC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of (R,E)-2-methyl-N-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.1 g, 3.4 mmol, Step-6) in DCM (50 mL) is added dropwise a solution of methylmagnesium bromide in THF (0.97 M, 7.0 mL, 6.8 mmol) at −78° C. After stirring at −78° C. for 1 h, the reaction is quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous layer is extracted with DCM (100 mL×2). The combined organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (1:3) to give 1.09 g (94% yield) of the title compound as colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[OH:1][CH:2]([CH2:24][O:25][C:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
A solution of 9 (28 mmol) in 80 ml of dichloromethane/pyridine (1:1) is added dropwise with triphenylmethyl chloride (36 mmol) and stirred at room temperature for 48 hours. The solvent is removed, and the residue is added twice with 50 ml of toluene and concentrated. The residue is diluted with 100 ml of H2O and extracted three times with 50 ml of dichloromethane. The combined organic phases are washed with 50 ml of cold 5% HCl and 50 ml of saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by chromatography on silica gel using heptane/ethyl acetate (2:1). Yield: 81% of a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=3)[N:7]=2)[CH:14]=[C:13]([CH3:15])[C:12]=1[OH:16]
Reactant: Nc1cccc(O)c1
Reactant: Cc1cc(Nc2nc(Cl)ncc2F)cc(Cl)c1O
Product: Cc1cc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc(Cl)c1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: retn, time: 18.20 min.; purity: 94%; MS (m/e): 360 (M+); 1□□□ (DMSO-d6): δ 9.26 (1H, s), 9.23 (1H, s), 9.16 (1H, s), 8.89 (1H, s), 8.14 (1H, d, J=4.5 Hz), 7.66 (1H, d, J=2.1 Hz), 7.60 (1H, d, J=2.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.06 (1H, t, J=8.4 Hz), 6.41 (1H, d, J=8.4 Hz), 2.30 (3H, s).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=1.[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[Cl:8][C:9]1[C:14]([NH:15][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])=[C:13]([NH:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=1
Reactant: Cc1nc(Cl)c(N)c(NCCOc2ccccc2)c1C
Reactant: CCCCC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1c(Cl)nc(C)c(C)c1NCCOc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.39 ml), anhydrous acetonitrile (100 ml), and 2-chloro-5,6-dimethyl-N4-(2-phenoxyethyl)pyridine-3,4-diamine (2.92 g) from Part A of Example 2 were combined and cooled to 0° C. in an ice bath. Valeryl chloride (0.59 ml) was slowly added to the reaction mixture. After 2 hours, the reaction mixture was heated to 55° C. for 24 hours, at which point HPLC analysis indicated the reaction was complete. The reaction mixture was cooled and the solvent was removed under reduced pressure. The resulting oil was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sulfate and the solvent was removed under reduced pressure. The product was then passed through a silica gel column using 50/50 ethyl acetate/hexane as the eluant. The resulting light brown solid was used in the next step.