Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]=[C:15]([F:17])[C:14]([C:18]([C:20]4[C:28]5[C:23](=[N:24][CH:25]=[C:26]([CH3:29])[CH:27]=5)[N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]=[C:15]([F:17])[C:14]([C:18]([C:20]4[C:28]5[C:23](=[N:24][CH:25]=[C:26]([CH3:29])[CH:27]=5)[NH:22][CH:21]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cnc2c(c1)c(C(=O)c1ccc(Nc3ccc(C4CC4)nc3)nc1F)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc2[nH]cc(C(=O)c3ccc(Nc4ccc(C5CC5)nc4)nc3F)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To [6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (74, 134 mg, 0.25 mmol) in 10 mL of tetrahydrofuran, tetrabutylammonium fluoride, trihydrate (85.53 mg, 0.27 mmol) is added and the reaction stirred at room temperature for 30 minutes. Water is added and the mixture is extracted with ethyl acetate. The organic layer is washed with water and brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-3051, 82 mg). MS (ESI) [M+H+]+=388.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:27]([O:29]CC)=[CH2:28])CCC.FC1C(C(C2N3N=C(C(=O)C)C=CC3=NC=2)C)=C(F)C=C2C=1C=NN2C>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:27](=[O:29])[CH3:28])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: [Pd]
Agent: CC(=O)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 51.4 %

Procedure:
The title compound as a light yellow solid (500 mg, 51%) was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (950 mg, 3.21 mmol), tributyl(1-ethoxy-vinyl)stannane (1.142 ml, 3.37 mmol) and tetrakis-(triphenylphosphine)-palladium (186 mg, 0.161 mmol) in DMF using the same procedure as described in the synthesis of compound 31.4. LCMS (method B): [MH]+=304.1, tR=1.71 min.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([CH3:26])[C@@H:10]([OH:25])[CH2:11][N:12]([CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)C1C=CC=CC=1.CC(O)=O.CCOCC>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]([CH3:26])[C@@H:10]([OH:25])[CH2:11][N:12]([CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1
Reactant: CCN(CCCc1ccc(F)cc1)C[C@H](O)[C@@H](C)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCN(CCCc1ccc(F)cc1)C[C@H](O)[C@@H](C)N
Reaction time: 8 h

Procedure:
Pd(OH)2 was carefully wetted down under N2 with 5 mL of MeOH then the product of Step f (0.95 g) dissolved in 5 mL of MeOH was added followed by 5 mL of HOAc. The mixture was hydrogenated overnight on a Parr shaker at 50 psi. Worked up by filtering off the catalyst under N2 through a fiberglass filter paper and vacuum. The filtrate was stripped to obtain white glass. To white glass was added Et2O/saturated NaHCO3 (25 mL) The layers were separated. The aqueous was basified further with 1N NaOH to pH=12 and extracted 3 times with Et2O. The Et2O extracts from the 1N NaOH layer were combined, dried (Na2SO4) and stripped to give 0.40 g of and amber oil as product. MS (ESI) detects (M+H)+=269.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:36])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19](=[O:35])[C@H:20]([CH:32]([CH3:34])[CH3:33])[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(C)(C)C>C(Cl)Cl>[CH2:25]([O:24][C:22]([NH:21][C@H:20]([C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:13]([OH:36])=[O:12])=[O:35])[CH:32]([CH3:34])[CH3:33])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Trifluoroacetic acid (200 ml) was added to a mixture of N-benzyloxycarbonyl-L-valyl-L-proline tert-butyl ester (80.0 g) in methylene chloride ((300 ml) at 0° C. over approximately 30 minutes. After stirring at 0° C. for one hour, the reaction mixture was allowed to rise to ambient temperature and stirred an additional 3 hours. The reaction mixture was then concentrated under vacuum and reconcentrated four times from toluene to remove residual trifluoroacetic acid. The resulting viscous oil was dried under vacuum for 16 hours. The crude product was purified on by chromatography on silica gel, using methylene chloride as eluant, to give N-benzyloxycarbonyl-L-valyl-L-proline (A) (63.6 g) as a pale yellow viscous oil; NHR (d6 -DMSO): 0.92(2d,6H), 1.65-2.05(2 m,4H), 2.25(m,1H), 3.60(m,1H), 3.80(m,1H), 4.05(dd,1H), 4.25(m,1H), 5.02(2d,2H), 7.35(m,5H), 7.50(d,1H).
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[CH2:11](Br)[CH:12]=[CH2:13].[I-].[CH3:16][N:17]([CH:19]=[O:20])[CH3:18]>CCOCC>[C:19]([N:17]1[CH2:18][CH2:13][CH:12]([CH2:11][CH2:12][CH:13]=[C:16]([N:17]2[CH2:18][CH2:19][NH:17][C:19]2=[O:20])[CH3:18])[CH2:11][CH2:16]1)([O:20][C:12]([CH3:13])([CH3:16])[CH3:11])=[O:20]
Reactant: C=CCBr
Reactant: CN(C)C=O
Agent: [I-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: CCOCC
Product: CC(=CCCC1CCN(C(=O)OC(C)(C)C)CC1)N1CCNC1=O
Reaction time: 20 h
Yield: 15 %

Procedure:
To a stirred solution of 13 (1.5 g, 17 mmol) in DMF (75 mL) at ambient temperature was added LiN(TMS)2 (1M in hexanes, 17 mL) to effect a precipitate. Allyl bromide (1.6 mL, 19 mmol) was then added to the reaction mixture. After 15 min the homogeneous mixture was treated again with LiN(TMS)2 (14 mL) followed by the iodide 10 (5.9 g, 17 mmol) after 5 min. The reaction was stirred for 20 hr then diluted with ether. The ether portion was washed with water (2×), 5% KHSO4 and brine, dried (Mg SO4), and concentrated. Flash chromatography (40% ethyl acetate/hexanes) gave 14 (0.8 g, 15%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](/[C:52]1[CH:53]=[CH:54][C:55]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[N:56][CH:57]=1)=[N:50]\[H].ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[O:1]=[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]1[O:22][N:48]=[C:49]([C:52]2[CH:53]=[CH:54][C:55]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[N:56][CH:57]=2)[N:50]=1
Reactant: [H]/N=C(\NO)c1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2noc(CN3CCC(c4ccccc4)(c4ccccc4)C3=O)n2)cn1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)-tert-butyl 5-(N-hydroxycarbamimidoyl)pyridin-2-ylcarbamate for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 8.85 (d, J=1.7, 1H), 8.22 (dd, J=2.2, 8.8, 1H), 8.07 (d, J=8.8, 1H), 7.48-7.28 (m, 10H), 4.89 (s, 2H), 3.57 (t, J=6.5, 2H), 2.89 (t, J=6.5, 2H), 1.55 (s, 9H); MS (DCI) m/z 512.2 (M+H)+.
Reaction SMILES: C([C:4]1[C:5]([CH3:13])=[N:6][N:7]2[C:11]([CH3:12])=[CH:10][S:9][C:8]=12)(=O)C>Cl>[CH3:12][C:11]1[N:7]2[N:6]=[C:5]([CH3:13])[CH:4]=[C:8]2[S:9][CH:10]=1
Reactant: CC(=O)c1c(C)nn2c(C)csc12
Agent: Cl
Product: Cc1cc2scc(C)n2n1
Yield: 83.2 %

Procedure:
A mixture of 25.0 g of 7-acetyl-3,6-dimethylpyrazolo [5,1-b]thiazole and 200 ml of concentrated hydrochloric acid is refluxed for 10 hours. The reaction solution is concentrated, and the residue is neutralized with 10% sodium hydroxide and then extracted with chloroform. The extract is washed with water, dried over anhydrous sodium sulfate and distilled to remove chloroform. The residue is purified by silica gel chromatography (eluent: dichloromethanemethanol) to give 16.3 g of the oily title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:24]([O-])=O)=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.C(O)(=O)C>C1C=CC=CC=1.[Fe]>[NH2:24][C:15]1[C:13]2[NH:14][C:10]([NH:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:11][C:12]=2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[C:16]=1[OH:23]
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Agent: [Fe]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c(N)c1O
Yield: 95.2 %

Procedure:
To a solution of methyl 2-[(2,6-dichlorophenyl)amino]-6-hydroxy-7-nitro-1H-benzimidazole-5-carboxylate (Step-3 of Intermediate-55, 0.500 g) in benzene (2.0 mL) were added iron powder (0.500 g) and acetic acid (2.0 mL). The reaction mass was refluxed for 3 h. Decant the reaction mass removed the solvent under vacuum. The obtained solid mass was washed with water. The reaction mass was extracted with MeOH:DCM (5%). The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.440 g of the desired product. 1HNMR (DMSO-d6): δ 3.87 (s, 3H), 4.45 (s, 2H), 7.28-7.47 (m, 1H), 7.53-7.59 (m, 3H), 11.00 (s, 2H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[CH2:29]O)=[O:23])=[CH:18][CH:17]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:31]([CH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:22]([C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:23])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CO
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Diisopropylethylamine (0.36 ml, 2.1 mmol) and 0.15 ml (1.9 mmol) of methanesulfonyl chloride were added under ice cooling to a solution of 397 mg (1.4 mmol) of (S)-(4-bromophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone synthesized in the same manner as in step (i) of Reference Example 8 in methylene chloride (15 ml) solution, and the mixture was stirred for 2 hr. The reaction solution was diluted with 45 ml of ethyl acetate and was washed with a saturated aqueous ammonium chloride solution. The aqueous layer was extracted twice with 5 ml of ethyl acetate. The organic layers were combined and were washed with 25% brine. The organic layer was dried over anhydrous sodium sulfate and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was dissolved in 10 ml of N,N-dimethylformamide. Sodium azide (146 mg, 2.2 mmol) was added to the solution, and the mixture was stirred at 50° C. for 5 hr. The reaction solution was diluted with 20 ml of ethyl acetate, and the diluted solution was washed five times with 10 ml of 12.5% brine. The organic layer was dried over anhydrous sodium sulfate and was filtered, and the filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give 194 mg (yield 45%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[C:6]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[C:18]([O:17][C:15]([NH:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=1)[C:3]([OH:22])=[O:2])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(NC(=O)OC(C)(C)C)cc(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
3-tert-butoxycarbonylamino-5-(methylsulfonyl)-benzoic acid methyl ester (8.45 g; 25.65 mmol) was suspended in 1,4-dioxane (75 ml) and 100 ml of NaOH 1N solution. The reaction mixture was stirred at room temperature overnight. Then, it was concentrated in vacuo. The crude was suspended in water and treated with citric acid until pH 4. Then ethyl acetate was added, the organic phase separated, dried with MgSO4 and concentrated in vacuo. 6.85 g (22 mmol; 84% yield) of 3-tert-butoxycarbonylamino-5-(methylsulfonyl)-benzoic acid were obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[CH:14]=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:29])[CH3:28])=[CH:5][CH:4]=1)=[O:2].C1COCC1.C(OC(C)C)(C)C>>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:13]3[CH:14]=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:29])[CH3:28])=[CH:7][CH:8]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(C=O)cc1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(CO)cc1
Yield: 80 %

Procedure:
Using N-(3-(4-formylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 292, the title compound was synthesized in the same manner as in Example 21. Yield: 80%. Melting point: 162-163° C. (THF-diisopropyl ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[N:6][CH:7]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(Br)c2)c1
Reactant: COCCN
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCCNc1cncc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of N-[3-(5-bromopyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (35.0 mg, 0.128 mmol), 2-methoxyethanamine (9.61 mg, 0.128 mmol), Pd2(dba)3 (7.83 mg, 0.0086 mmol), Xantphos (14.9 mg, 0.026 mmol), and Cs2CO3 (69.7 mg, 0.214 mmol) in 1,4-dioxane (0.855 mL, 0.1 M) was purged with argon and heated to 90° C. for 12 hours. The reaction mixture was cooled to room temperature and DMSO (1.00 mL) and Si-Thiol (23.4 mg, 1.84 mmol/g) were added to the reaction mixture. The reaction mixture was stir at room temperature for 4 hours and then passed through a filter, concentrated in vacuo, and the crude residue was purified by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v formic acid modifier) to afford N-(3-{5-[(2-methoxyethyl)amino]pyridin-3-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine as the formic acid salt. MS APCI calc'd for C20H21F3N4O [M+H]+ 404. found 404. 1H NMR (600 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.80 (d, J=4.9 Hz, 1H), 7.97 (d, J=5.6 Hz, 2H), 7.87 (s, 1H), 7.50 (s, 1H), 7.24 (d, J=4.9 Hz, 1H), 7.09 (d, J=6.1 Hz, 2H), 3.49 (t, J=5.5 Hz, 2H), 3.33-3.22 (m, 5H), 2.32 (s, 3H).
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C:19]([C@@H:21]([C@H:31]([CH2:44][OH:45])[O:32][CH2:33][P:34]([O:40][CH:41]([CH3:43])[CH3:42])([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[O:22]C(=O)C1C=CC=CC=1)=[O:20])(=O)C1C=CC=CC=1.N>CO>[N:18]1[C:10]([NH2:9])=[C:11]2[C:15]([N:14]([C:19]([C@@H:21]([C@H:31]([CH2:44][OH:45])[O:32][CH2:33][P:34]([O:40][CH:41]([CH3:43])[CH3:42])([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[OH:22])=[O:20])[CH:13]=[N:12]2)=[N:16][CH:17]=1
Reactant: CC(C)OP(=O)(CO[C@@H](CO)[C@@H](OC(=O)c1ccccc1)C(=O)n1cnc2c(NC(=O)c3ccccc3)ncnc21)OC(C)C
Agent: N
Solvent: CO
Product: CC(C)OP(=O)(CO[C@@H](CO)[C@@H](O)C(=O)n1cnc2c(N)ncnc21)OC(C)C
Yield: 83.8 %

Procedure:
A solution of 11 (431 mg, 0.80 mmol) in MeOH saturated with ammonia (100 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=9:1) to give compound 15 (278 mg, 0.67 mmol) as a white powder in 84% yield which was characterized as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[OH-:18].[K+]>O1CCOCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:18])=[N:7][C:6]=1[NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)([O-:17])=[O:16]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NC1CCOCC1
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(O)nc1NC1CCOCC1
Yield: 98.4 %

Procedure:
6-Chloro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (0.186 g, 0.722 mmol), 1 M aqueous potassium hydroxide solution (8.0 mL, 16.0 mmol) and dioxane (20 mL) were heated to 100° C. for 4 h. After cooling, the pH was adjusted to ˜7 and the mixture was extracted with EtOAc. The EtOAc extract was concentrated under reduced pressure to give the title compound (0.170 g). LCMS m/z=240.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 1.65-1.80 (m, 2H), 2.05-2.15 (m, 2H), 3.60-3.70 (m, 2H), 4.00-4.10 (m, 2H), 4.20-4.30 (m, 1H), 5.92 (d, J=9.8 Hz, 1H), 8.32 (d, J=9.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nnc(S)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1nnc(SCc2ccccc2)s1
Yield: 71.6 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (2.0 g), benzyl bromide (2.6 g), and potassium hydroxide (0.8 g) were stirred in methanol (50 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.4 g of the aimed compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[N:5]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=1.C([Li])(C)(C)C.CN([CH:34]=[O:35])C>>[Cl:16][C:12]1[CH:11]=[C:10]([S:7]([N:5]2[CH:6]=[C:2]([CH:34]=[O:35])[CH:3]=[C:4]2[C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)n1cc(Br)cc1-c1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Product: O=Cc1cc(-c2ccc3c(c2)OCO3)n(S(=O)(=O)c2cccc(Cl)c2)c1

Procedure:
The title compound is prepared from 4-bromo-1-(m-chlorobenzensulfonyl)-2-(3,4-methylenedioxyphenyl)-pyrrole, tert-butyl lithium and DMF following the procedure of Example 3a. 1H-NMR (300 MHz, CDCl3): 9.89 (s, 1H); 8.08 (d, J=2.0 Hz, 1H); 7.6-7.5 (m, 1H); 7.4-7.25 (m, 4H); 6.8-6.7 (m, 1H); 6.65-6.55 (m, 1H); 6.55 (d, J=2.0, 1H); 6.05 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[CH:20]=1)=O)(C)(C)C.[ClH:30].CCOCC>CO>[ClH:30].[N:21]1([C:19]2[CH:18]=[N:17][CH:16]=[C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[CH:20]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCc3ccccc32)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1ccc2c(c1)CCN2c1cncc(OC[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[[N-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-(1-indolinyl)pyridine (71 mg, 0.18 mmol) in MeOH (0.2 mL) was added 2N anhydrous HCl/ether (1 mL) under Ar at room temperature. The mixture was stirred at room temperature overnight. After the solvent was evaporated, the residue was dissolved in deionized water. The aqueous solution was washed twice with EtOAc, then filtered over a cotton plug. The water was removed under reduced pressure at 35° C. After lyophilization from water, the hydrochloride (71 mg) was obtained as yellow solid. [α]20D+7.0 (c 1.0 g/L, MeOH). 1H NMR (D2O, 400 MHz) δ 7.97 (s, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 7.12 (d, 1H, J=7.2 Hz), 7.05 (m, 2H), 6.82 (t, 1H, J=7.2 Hz), 4.45 (dd, 1H, J=3.2 Hz, J=10.4 Hz), 4.31 (dd, 1H, J=7.6 Hz, J=10.4 Hz), 4.15 (m, 1H), 3.78 (t, 2H, J=8.4 Hz), 3.45 (t, 2H, J=7.2 Hz), 3.01 (t, 2H, J=8.4 Hz), 2.32 (m, 1H), 2.14 (m, 2H), 1.97 (m, 1H). 13C NMR (D2O, 100 MHz) δ 156.2, 142.5, 141.9, 132.2, 126.7, 125.3, 121.9, 121.5, 118.2, 114.2, 109.6, 67.3, 58.1, 51.0, 45.6, 26.6, 25.5, 23.0. HRMS (ESI) calcd for C18H22N3O (M+H+) m/z 296.1763, found 296.1758. Anal. Calcd. for C18H21N3O.3.0HCl.0.1H2O: C, 53.18; H, 6.00; N, 10.34; Cl, 26.16. Found: C, 53.27; H, 6.18; N, 10.26; Cl, 26.03.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[C:9]=2[N:10]=1>CCS>[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:9]=2[N:10]=1
Reactant: COc1cccc2sc(N)nc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: Nc1nc2c(O)cccc2s1
Reaction time: 2 h

Procedure:
A solution of AlCl3 (5 mmole) in EtSH (10 mL) was cooled to 0° C. and treated with 2-amino-4-methoxybenzothiazole (1 mmole). The mixture was stirred at 0–5° C. for 2 h. Evaporation and extraction gave 2-amino-4-hydroxybenzothiazole as white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:26](=[O:28])[CH3:27])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](CC(C)C)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Yield: 83 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (106 mg) with acetic anhydride (40 uL) provided 89 mg (83%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.