Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(NC(C2(C(O)=O)CC2)=O)=CC=1.CN1CCOCC1.Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26].[CH2:32]([N:34]([CH2:55][CH3:56])[CH2:35][C:36]#[C:37][C:38]1[S:46][C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[O:47][C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH:39]=1)[CH3:33]>C1COCC1>[CH2:55]([N:34]([CH2:32][CH3:33])[CH2:35][C:36]#[C:37][C:38]1[S:46][C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[O:47][C:48]2[CH:49]=[CH:50][C:51]([NH:54][C:25](=[O:26])[O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:52][CH:53]=2)[CH:39]=1)[CH3:56]
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3)c2s1
Reactant: CC(C)COC(=O)Cl
Agent: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(=O)OCC(C)C)cc3)c2s1
Temperature: -78 °C

Procedure:
A 25 mL, single-neck, round-bottomed flask was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (42 mg, 0.1694 mmol) and THF (2 mL) under nitrogen and cooled to −78° C. on a dry ice bath. N-methylmorpholine (0.037 mL, 0.34 mmol), and isobutyl chloroformate (0.019 ml, 0.15 mmol) were added. After 15 minutes 4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin -7-yloxy)benzenamine (40 mg, 0.11 mmol) in THF (1 mL) was added, and the reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated and the residue was purified on a Biotage 15M column (95:5 EtOAc/MeOH). The product was a white waxy solid (0.8 mg, 2%). 1H NMR (CDCl3, 400 MHz) δ 8.47 (d, J=5.5 Hz, 1H), 7.57 (s, 1H), 7.49 (m, 2H), 7.14 (m, 2H), 6.68 (br s, 1H), 6.54 (d, J=5.5 Hz, 1H), 3.98 (d, J=6.6 Hz, 2H), 3.72 (s, 2H), 2.65 (q, J=7, 14 Hz, 4H), 2.00 (m, 1H), 1.14 (t, J=7.0 Hz, 6H), 0.99 (d, J=7.0 Hz, 6H). LRMS (ESI pos) m/e 452 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Br:49][C:50]1[S:54][C:53]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[N:52][CH:51]=1>O1CCCC1.C(OCC)(=O)C.CCCCCCC>[Br:49][C:50]1[S:54][C:53]([N:55]2[CH2:56][CH2:57][N:58]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:59][CH2:60]2)=[N:52][CH:51]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Brc1cnc(N2CCNCC2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of 0.31 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) in 7 ml tetrahydrofuran were added successively 0.46 mmol TBTU, 1.24 mmol N-ethyldiisopropylamine and 0.34 mmol 1-(5-bromo-thiazol-2-yl)-piperazine. The reaction mixture was stirred at RT for 16 h and then concentrated in vacuo. Chromatography (SiO2, ethyl acetate/heptane) afforded the title compound as a white foam (yield 87%). MS (m/e): 490.3 ({81Br}M+H+, 100%), 488.3 ({79Br}M+H+, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([B:21]3[O:22][C:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[O:25]3)=[CH:19][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(O)c2ccccc2n1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Product: Cc1cc(OCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c2ccccc2n1
Yield: 28 %

Procedure:
Alkylation of 2-Methyl-quinolin-4-ol with 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was carried out according to procedures in Step 2A for Example 1C to give 2-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-quinoline in 28% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 2.6 (s, 3 H) 5.4 (s, 2 H) 7.0 (s, 1 H) 7.5 (m, 1 H) 7.6 (d, J=8.1 Hz, 2 H) 7.7 (m, 1 H) 7.7 (d, J=8.1 Hz, 2 H) 7.9 (d, J=8.1 Hz, 1 H) 8.1 (dd, J=8.3, 0.8 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([C:17]2[C:18]([NH:34][C:35]3[C:36]4[CH:37]=[N:38][N:39](C5CCCCO5)[C:40]=4[CH:41]=[CH:42][CH:43]=3)=[N:19][CH:20]=[C:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:22]=2)[N:3]=1.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([C:17]2[C:18]([NH:34][C:35]3[C:36]4[CH:37]=[N:38][NH:39][C:40]=4[CH:41]=[CH:42][CH:43]=3)=[N:19][CH:20]=[C:21]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=3)[CH:22]=2)[N:3]=1
Reactant: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2Nc2cccc3[nH]ncc23)c2nc[nH]c2n1
Reaction time: 2 h
Yield: 8.22 %

Procedure:
A solution of N-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (111 mg, 0.164 mmol) in DCM (3.0 mL) was treated with TFA (1.0 mL) and allowed to stand for 2 h. The mixture was concentrated, azeotroped with toluene, purified by prep HPLC, and the pure fractions were concentrated and triturated with MeOH to give pure N-(3-(2-methyl-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-yl)-1H-indazol-4-amine trifluoroacetate (8.4 mg, 0.013 mmol, 8.22% yield) as an orange crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ 13.12 (br. s., 1H); 12.61 (br. s., 1H); 9.68 (br. s., 1H); 8.63 (s, 1H); 8.36 (d, J=2.15 Hz, 1H); 8.26 (s, 1H); 8.08 (d, J=7.63 Hz, 1H); 7.87 (d, J=8.22 Hz, 2H); 7.59 (d, J=8.22 Hz, 2H); 7.31 (t, J=8.02 Hz, 1H); 7.16 (d, J=8.41 Hz, 1H); 4.17 (s, 2H); 3.16 (s, 3H); 2.93 (s, 3H). m/z (ESI, +ve ion) 511.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[Br:18][C:19]([F:27])([F:26])[C:20]([F:25])([F:24])[C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:18][C:19]([F:27])([F:26])[C:20]([F:25])([F:24])[C:21]([NH:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])=[O:22]
Reactant: NC(=O)C(F)(F)C(F)(F)Br
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)C(F)(F)Br

Procedure:
First, 4.6 g (17 mmol) of 2-chloro-1,3-dinitro-5-trifluoromethylbenzene and 4.0 g (18 mmol) of 3-bromo-2,2,3,3-tetrafluoropropionamide were dissolved in 40 ml of acetone, to which 5.0 g (36 mmol) of potassium carbonate was added, and the mixture was heated under reflux for 4 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3-bromo-N-(2,6-dinitro-4-trifluoromethylphenyl)-2,2,3,3-tetrafluoropropionamide.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[SH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][S:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: BrCc1ccccn1
Agent: Br
Product: COC(=O)c1ccc(SCc2ccccn2)cc1

Procedure:
1 g of 2-(bromomethyl)pyridine hydrobromide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(pyridin-2-ylmethylthio)benzoate. 500 mg of methyl 4-(pyridin-2-ylmethylthio)benzoate was reacted via Procedure R to give methyl 4-(pyridin-2-ylmethylsulfonyl)benzoate. 470 mg of methyl 4-(pyridin-2-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(pyridin-2-ylmethylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(pyridin-2-ylmethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-2-ylmethylsulfonyl)benzamide. MS (Q1) 464.1 (M)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[O:16])[CH:11]=[CH:12][CH:13]=1.[CH:18]1([NH:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:32][CH2:33]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH:18]1([NH:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:32][CH2:33][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([NH2:17])=[O:16])[CH:9]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(CCCCN(CCCl)Cc1ccccc1)NC1CCCCCC1
Reactant: NC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)Nc1cccc(OCCN(CCCCC(=O)NC2CCCCCC2)Cc2ccccc2)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (0.92 g, 6.6 mmole) is added to a solution of 3-hydroxyphenylurea (1 g, 6.6 mmole) in dimethylformamide (20 ml) and said mixture is stirred for 10 minutes at 20° C. A solution of N-cycloheptyl-5-[benzyl-(2-chloroethyl)amino]pentanamide (2.21 g, 6 mmole) in dimethylformamide (20 ml) is then added dropwise, the mixture being kept under agitation for 4 hours at 80° C. The solvent is evaporated under reduced pressure, then the residue is taken up in dichloromethane (50 ml) and washed with water. The organic phase is collected and dried then, after evaporation of the solvent, the desired compound is obtained in the form of an oil. It is purified by flash chromatography over silica gel in a mixture of dichloromethane/methanol (95/5) to give 1.75 g (60%) of pure compound. NMR-1H (CDCl3),;1.30-1.90 (m, 16H), 2.12 (t, 2H, J=6 Hz), 2.53 (t, 2H, J=6 Hz), 2.80 (t, 2H, J=6 Hz), 3.63 (s, 2H), 3.95 (m, 1H), 4.07 (t, 2H, J=6 Hz), 4.93 (s, 1H), 5.55 (m, 1H), 6.68 (m, 2H), 7.19 -7.30 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([N:13]2[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)[CH:5]=[C:4]([CH3:19])[N+:3]=1[O-:20].[OH-].[K+].C(O)CO.[ClH:27]>O>[ClH:27].[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:13]2[CH2:14][CH2:15][S:16][CH2:17][CH2:18]2)[CH:5]=[C:4]([CH3:19])[N+:3]=1[O-:20]
Reactant: CCOC(=O)c1c(N2CCSCC2)cc(C)[n+]([O-])c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1cc(N2CCSCC2)c(C(=O)O)c(C)[n+]1[O-]

Procedure:
38.2 g (0.129 mol) of ethyl 2,6-dimethyl-4-thiomorpholinylpyridine-3-carboxylate 1-oxide(see Table 1, Example 19), 10.6 g (0.189 mol) of solid potassium hydroxide and 100 ml of ethylene glycol were heated at 170° C. for 5 hours. The mixture was then diluted with water, neutralized with 6 N hydrochloric acid, and the water and ethylene glycol were removed by distillation under reduced pressure. The residue was taken up in ethanol, insolubles were removed by filtration, and the solution was boiled with active charcoal, filtered once more and ethanolic HCl was added. The mixture was evaporated to dryness, and the hydrochloride was recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](N(C)C)(=[O:10])=[O:9])=[C:6]([OH:14])[C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2[O:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.[C:25](C1OC2C(S(C)(=O)=O)=C(Cl)C=CC=2N=1)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2[O:22][CH2:23][CH3:24])=[C:6]([OH:14])[C:7]=1[S:8]([CH3:25])(=[O:10])=[O:9]
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)C)c2O)c(=O)c1=O
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(C)(=O)=O)c2o1
Product: CCOc1c(Nc2ccc(Cl)c(S(C)(=O)=O)c2O)c(=O)c1=O

Procedure:
The title compound is prepared analogously to 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N,N-dimethyl-benzenesulfonamide (Ex. 3 step 2) by replacing 2-tert-butyl-6-chloro-benzooxazole-7-sulfonic acid dimethylamide (Ex. 3 step 2) with 2-tert-Butyl-6-chloro-7-methanesulfonyl-benzooxazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.C[NH:22][C@@:23]([C:27](O)=[O:28])([CH3:26])[CH2:24][CH3:25].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:22][C@:23]([CH3:26])([CH2:24][CH3:25])[C:27]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([O:11][C:8]2[CH:7]=[C:6]3[C:5](=[CH:10][CH:9]=2)[CH2:4][O:3][C:2]3([CH3:19])[CH3:1])=[CH:13][CH:14]=1)=[O:28]
Reactant: CC1(C)OCc2ccc(Oc3ccc(N)cc3)cc21
Reactant: CC[C@](C)(NC)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2ccc3c(c2)C(C)(C)OC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
4-[(3,3-dimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]aniline (Intermediate 70, 120 mg, 0.47 mmol) and methyl-D-isovalinic acid hydrochloride (80 mg, 0.52 mmol) were suspended in a mixture of acetonitrile (1.5 mL) and ethyl acetate (0.5 mL). A 50% w/w solution of T3P in ethyl acetate (1.1 equiv) was added drop wise. The reaction mixture was stirred for 30 minutes at room temperature and then at 80° C. for 4 hours. The reaction mixture was cooled to room temperature and treated with ethyl acetate and saturated Na2CO3 solution and stirred vigorously for 10 min. Two layers were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using dichloromethane/Methanol from 100:0 to 90:10 as eluent to afford the title compound (140 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:20]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:17](CO)[N:12]3[N:11]=2)=[CH:5][CH:4]=1.C([Li])CCC.C[O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][N:37]=1)[CH:33]=O>O1CCCC1>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:20]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([CH2:33][C:32]4[CH:35]=[CH:36][NH:37][C:30](=[O:29])[CH:31]=4)[N:12]3[N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(C=O)ccn1
Reactant: OCc1cccc2nc(Nc3ccc(C(F)(F)F)cc3)nn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1cc(Cc2cccc3nc(Nc4ccc(C(F)(F)F)cc4)nn23)cc[nH]1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-Methoxypyridin-4-yl)(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methanol. The reaction was performed in two batches of starting material (0.397 g and 0.310 g) according to the following procedure and recombined for work-up and purification. A suspension of 5-bromo-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyridin-2-amine (0.397 g, 1.111 mmol) in dry tetrahydrofuran (6.0 mL) was cooled to −78° C. The mixture was then reacted with n-butyl lithium (0.933 mL, 2.333 mmol, 2.5 M in hexanes). The reaction was stirred at low temperature for 1 h. A solution of 2-methoxyisonicotinaldehyde (0.32 g, 2.333 mmol) in dry tetrahydrofuran (3 mL) was then added dropwise. Low temperature was maintained for 2 h. Checked after 30 min, the reaction had progressed to a mixture of desired product contaminated with de-halogenated starting material. The reaction was quenched with water and the crude was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was purified by biotage column chromatography using the following gradient: 800 mL gradient 10-50% ethyl acetate in hexanes, then 1.100 L at 50% ethyl acetate in hexanes. Desired fractions were combined and evaporated to dryness. (2-Methoxypyridin-4-yl)(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)methanol (0.574 g, 1.382 mmol, 69.8% yield) was collected as a yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ (ppm) 8.04 (d, J=5.47 Hz, 1H), 7.63-7.70 (m, 3H), 7.54 (d, J=8.59 Hz, 2H), 7.47 (d, J=9.37 Hz, 1H), 7.32 (d, J=7.03 Hz, 1H), 7.04 (s, 1H), 7.01 (d, J=5.47 Hz, 1H), 6.32 (s, 1H), 3.86 (s, 3H); MS (ESI): m/z 416.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7]=1[OH:8].[C:20](O)(=O)[CH:21]([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:7]3[O:8][C:20]([CH:21]([CH3:23])[CH3:22])=[N:1][C:2]=3[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(N)c(O)c(-c2ccc(F)cc2)c1
Reactant: CC(C)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: N#CC(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2oc(C(C)C)nc2c1
Temperature: 150 °C
Yield: 55 %

Procedure:
To a solution of methyl 5-amino-4′-fluoro-6-hydroxybiphenyl-3-carboxylate (10.0 mg, 38.0 μmol), and isobutyric acid (2.60 mg, 29.0 μmol), and solid support triphenylphosphine (75% by weight; 40.2 mg, 0.12 mmol) in acetonitrile (0.38 mL) was added trichloroacetonitrile (7.68 μL, 77.0 μmol). The mixture was heated in a microwave reactor for 15 min at 150° C. The mixture was cooled to ambient temperature, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (5 mg). LC-MS [M+1]=332.1.
Reaction SMILES: C(NCCO)C1C=CC=CC=1.Cl.ClCCNCC1C=CC=CC=1.S(Cl)(Cl)=O.Cl.[CH2:29]([NH:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.NC1C(C)=CC=CC=1.Br[CH:56]([CH2:60]Br)[C:57]([NH2:59])=[O:58]>>[CH2:29]([N:36]1[CH2:37][CH2:38][N:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH3:46])[CH2:60][CH:56]1[C:57]([NH2:59])=[O:58])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccccc1NCCNCc1ccccc1
Reactant: NC(=O)C(Br)CBr
Agent: Cl
Agent: ClCCNCc1ccccc1
Agent: OCCNCc1ccccc1
Solvent: Cc1ccccc1N
Solvent: O=S(Cl)Cl
Product: Cc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1

Procedure:
2-Benzylaminoethanol (18.8 ml, 20 g, 0.13 mol) was converted to N-(2-chloroethyl)-N-benzylamine hydrochloride with thionyl chloride (19 ml, 31 g, 0.26 mol) according to the procedure described in J. Chem. Soc. 1955, 896. N-(2-chloroethyl)-N-benzylamine hydrochloride (4.0 g, 19 mmol) was converted to N-benzyl-N'-(2-methylphenyl)-1,2-diaminoethane hydrochloride by the procedure of Syn. Comm. 18, 45-50 (1988), using o-toluidine (6.1 ml, 6.1 g, 57 mmol) in place of aniline. 1-benzyl-4-(2-methylphenyl)piperazine-2-carboxamide was prepared from 2,3-dibromopropionamide (7.9 g, 34 mmol) by the procedure of J. Med. Chem. 35, 743-750 (1992) using N-benzyl-N'-(2-methylphenyl)-1,2-diaminoethane hydrochloride (4.95 g, 18 mmol) in place of N-benzyl-N'-phenyl-1,2-diaminoethane hydrochloride.
Reaction SMILES: NC1C=CC(S(C(C)C)(=O)=O)=C([C@H]2[C@H](C(OC)=O)CCN2C(OC(C)(C)C)=O)C=1.[ClH:30].[CH:31]([S:34]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][C:38]=1[C@H:47]1[C@@H:51]([C:52]([O:54][CH3:55])=[O:53])[CH2:50][CH2:49][NH:48]1)(=[O:36])=[O:35])([CH3:33])[CH3:32]>>[ClH:30].[CH:31]([S:34]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][C:38]=1[C@@H:47]1[C@H:51]([C:52]([O:54][CH3:55])=[O:53])[CH2:50][CH2:49][NH:48]1)(=[O:36])=[O:35])([CH3:33])[CH3:32]
Reactant: COC(=O)c1ccc(S(=O)(=O)C(C)C)c([C@@H]2NCC[C@@H]2C(=O)OC)c1
Agent: COC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)C(C)C
Agent: Cl
Product: COC(=O)c1ccc(S(=O)(=O)C(C)C)c([C@H]2NCC[C@H]2C(=O)OC)c1

Procedure:
61D was prepared from 61B using a procedure similar to that used in the preparation of 61C. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.29 (d, J=6.60 Hz, 3H) 1.33 (d, J=6.85 Hz, 3H) 2.46-2.64 (m, 1H) 2.61-2.83 (m, 1H) 3.39-3.47 (m, 3H) 3.45-3.65 (m, 2H) 3.68-3.79 (m, 1H) 3.77-3.84 (m, 3H) 3.83-3.95 (m, 1H) 5.86 (d, J=8.31 Hz, 1H) 7.58 (d, J=8.80 Hz, 1H) 7.89 (s, 1H) 7.96 (d, J=8.80 Hz, 1H).
Reaction SMILES: CC([O:5][C:6]([CH2:8][CH:9]([OH:35])[CH2:10][CH:11]([OH:34])[CH:12]=[CH:13][C:14]1[C:23]([CH:24]2[CH2:26][CH2:25]2)=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:7])(C)C.[OH-].[Na+]>CO.O>[CH:18]1[CH:19]=[CH:20][C:21]2[N:22]=[C:23]([CH:24]3[CH2:26][CH2:25]3)[C:14](/[CH:13]=[CH:12]/[C@@H:11]([OH:34])[CH2:10][C@@H:9]([OH:35])[CH2:8][C:6]([OH:7])=[O:5])=[C:15]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:16]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)C=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
From pitavastatin tertiary butyl ester: 50 g of pitavastatin tert-butyl ester was taken in 250 ml of methanol and stirred for 10 minutes at 25° C. 6 g of sodium hydroxide is dissolved in 60 ml of water and slowly added to the reaction mixture. Stirred the reaction mixture to 2 hrs at 25°. Distilled off the solvent completely under reduced pressure. To the obtained solid added 50 ml of dichloro methane and stirred for 10 minutes. Cooled the reaction mixture to 0° C. and adjusted the pH to 3.0 with 20% aqueous HCl solution. 60 g of sodium chloride is added to the reaction mixture and stirred for 15 minutes. Raised the temperature to 25° C. and stirred for 30 minutes. Filtered the solid precipitated. Water was added to the solid and stirred for 10 minutes. Filtered the solid and washed with water. Dried the obtained solid to get the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C([O-])=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(N3CCN(C(=O)[O-])CC3)cn2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 186.6 %

Procedure:
Intermediate 328a (1.4 g, 3.3 mmol) was suspended in 4.0 M HCl/dioxane (10 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 328b (1.1 g, 96%). MS: [M+H]+ 321.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:21]([C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(O)=O.CO>[CH3:20][N:16]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2](/[N:1]=[CH:29]/[C:27]4[O:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=4)=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)[O:18][C:17]1=[O:19]
Reactant: Cn1nc(C2CCN(c3ccc(N)cc3)CC2)oc1=O
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CO
Solvent: CC(=O)O
Product: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 86 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7b, 0.27 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-methyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9b, 341 mg, 86%).