Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([N:34]([CH3:36])[CH3:35])=C(C#N)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].[CH3:41][C:42]([OH:44])=[O:43].CS(C)=O>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([N:34]([CH3:35])[CH3:36])=[C:41]([C:42]([OH:44])=[O:43])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)c1c(C#N)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CN(C)c1c(C(=O)O)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Temperature: 70 °C

Procedure:
To a suspension of 4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (31.8 mg, 0.06 mmol) in EtOH (1 mL) was added NaOH (0.2 mL of a 5M aq. solution, 1 mmol). The reaction was heated at 70° C. for 60 hours and then cooled to room temperature. HOAc (60 μL, 1 mmol) was added followed by DMSO (1.5 mL). After sonication and filtration to remove solids, the filtrate was purified by mass triggered reverse phase HPLC (C-18) eluting with acetonitrile/water+0.1% TFA to afford 4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (TFA salt). MS ESI calc'd for C26H37ClN6O3 [M+H]+=553. found=553. 1H NMR (600 MHz, DMSO-d6) δ 8.75-8.77 (m, 2H), 8.27 (m, 1H), 3.93 (dd, J=12.0, 1.8 Hz, 1H), 3.75-3.81 (m, 2H), 3.47-3.52 (m, 2H), 3.38 (m, 1H), 3.15 (s, 6H), 3.03 (m, 1H), 2.81 (m, 1H), 2.26 (m, 1H), 1.85 (m, 1H), 1.69 (m, 1H), 1.51-1.63 (m, 2H), 1.31-1.41 (m, 2H), 1.13 (m, 1H), 1.05 (m, 1H), 0.83 (m, 1H), 0.64-0.73 (m, 6H), 0.34-0.46 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29].[C:32]1([O:38][CH2:39][CH:40]2[O:42][CH2:41]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[OH:42][CH:40]([CH2:39][O:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:41][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNCC(O)COc1ccccc1
Yield: 51.5 %

Procedure:
In 1,300 ml of methanol were dissolved 13 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 4.5 g of glycidyl phenyl ether, and the solution thus formed was refluxed under heating for 16 hours. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted with chloroform-methanol (96:4 v/v). Crude crystals were recrystallized from ethanol to give 9 g of dimethyl 4-[2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.[CH2:15]([O:17][C:18](=[O:36])[C@@H:19]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][NH2:24])[CH3:16].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:36])[C@@H:19]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][NH:24][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:16]
Reactant: CCOC(=O)[C@H](CNC(=O)CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CCCCNc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)CCCCNc1ccccn1)NS(=O)(=O)c1ccccc1

Procedure:
Acid 3-3 (186 mg, 0.55 mmol), amine 3-6 (150 mg, 0.46 mmol), NMM (0.20 mL, 1.8 mmol) and BOP (302 mg, 0.68 mmol) were combined in 3 mL DMF. After 5 d the DMF was removed on a rotary evaporator, the residue was diluted with EtOAc, then washed with water, sat. NaHCO3, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 25% i-PrOH/EtOAc) provided 3-7 as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OCc1ccccc1
Yield: 74 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.4 g (1.10 mmol) thereof was dissolved in 5 ml of acetone, and 0.21 g (1.21 mmol) of benzyl bromide as a reaction reagent (XII) and 0.15 g (1.10 mmol) of potassium carbonate as a base were added. The resultant mixture was refluxed under heat for 3 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Its organic layer was separated, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate=2:3) to give 0.37 g (yield 74%) of 4-methoxy-5-methyl-6-(5-benzyloxy-1-ethylpyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 62) as an end compound which comes under the general formula (XI). Table 21 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (I).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Crude tert-butyl 4-[4-(2,2,2-trifluoroethoxy)phenyl]piperazine-1-carboxylate (32.47 g, approx 57 mmol) was dissolved in DCM (300 ml) and TFA (69 mL) was added. The reaction was stirred at room temperature overnight then evaporated to dryness, azeotroping with toluene. The residue was partitioned between DCM and saturated sodium bicarbonate solution. The organic phase was separated, dried (MgSO4), filtered and concentrated to yield 1-[4-(2,2,2-trifluoroethoxy)phenyl]piperazine as a solid (13.48 g, 91%)
Reaction SMILES: C([Si]([O:18][CH2:19][CH2:20][CH2:21][CH:22]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[O:23][CH3:24])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:22]([O:23][CH3:24])[CH2:21][CH2:20][CH2:19][OH:18])=[CH:30][CH:29]=1
Reactant: COC(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(CCCO)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a solution of tert-butyl-[4-(4-chloro-phenyl)-4-methoxy-butoxy]-diphenyl-silane (343 mg, 0.75 mmol) in 20 mL THF was added at room temperature TBAF (7.5 mL, 7.5 mmol, 1M in THF). The mixture was stirred for 3 h and the reaction quenched by the addition of 10 mL saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The mixture was concentrated and the product isolated by flash column chromatography eluting with 6% to 60% ethyl acetate/hexane to provide 120 mg of the title compound.
Reaction SMILES: [S:1]1[C:5]([N:6]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.OP(O)(O)=O.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([C:4]1[C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=2[S:1][C:5]=1[N:6]([CH2:20][CH2:21][C:22]([F:25])([F:23])[F:24])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)(=[O:8])=[O:9])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CCC(F)(F)F)c2cc3ccccc3s2)cc1
Agent: O=P(O)(O)O
Product: COC(=O)c1ccc(S(=O)(=O)N(CCC(F)(F)F)c2sc3ccccc3c2C(C)=O)cc1
Temperature: 100 °C

Procedure:
To compound 385-A (0.388 g, 0.87 mmol) was added acetic anhydride (10 mL) and 85% H3PO4 (0.10 mL), and the reaction was heated at 100° C. for three days. Additional acetic anhydride (10 mL) was added, the reaction mixture heated for an additional 4 more days. The reaction mixture was cooled, concentrated under vacuum, partitioned between EtOAc (100 mL) and saturated NaHCO3 (50 mL), filtered, the organic layer washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2) eluting with an EtOAc-heptane gradient to afford 0.197 g of compound 385-B as a colorless oil. 1H-NMR (DMSO-d6): δ 2.64 (s, 3H), 2.91-2.72 (m, 2H), 4.01-3.87 (m, 5H), 7.54-7.43 (m, 2H), 7.87 (d, 2H), 7.99-7.92 (m, 1H), 8.19-8.08 (m, 3H); MS: m/z 486.1 (MH+).
Reaction SMILES: C(Cl)Cl.FC(F)(F)C([N:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)=O.[S:36]([OH:46])(=[O:45])([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)=[O:37].[OH-].[Na+:48]>>[CH2:18]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:44][C:41]2[CH:42]=[CH:43][C:38]([S:36]([O-:46])(=[O:37])=[O:45])=[CH:39][CH:40]=2)=[O:14])=[CH:16][CH:17]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[Na+:48]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])cc2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A methylene chloride solution of N-trifluoroacetyl-4-(hexadecylamino)benzoyl chloride (4.8 g.) is added to a solution of 1.8 g. of sulfanilic acid in 1N sodium hydroxide at 0° C. After 3 hours, the solution is warmed to 60° C. briefly and the whole evaporated to dryness. The residue is extracted with a small amount of cold water and the resulting white solid crystallized from aqueous ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[N:5]=[CH:6][NH:7]2.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:4]1[C:3]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:2]=2[Cl:1])[N:7]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]cnc(=O)c2c(Cl)c1OC
Product: COc1cc2ncnc(Cl)c2c(Cl)c1OC
Temperature: 85 °C
Yield: 65 %

Procedure:
A mixture of 5-chloro-6,7-bis(methyloxy)-4(1H)-quinazolinone (100 mg, 0.42 mmol, prepared according to J. Med. Chem. (1999) 42 3860) in POCl3 (2 mL) was heated at 80-90° C. for 8 hours before being concentrated. The residue was treated with saturated aqueous NaHCO3 and extracted with EtOAc. The organic extract was dried (Na2SO4) and concentrated to give 4,5-dichloro-6,7-bis(methyloxy)quinazoline (70 mg, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (s, 1 H), 7.56 (s, 1 H), 4.05 (s, 3 H), 3.87 (s, 3 H). MS (m/z) 258.9 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[OH:14].[CH3:15][C:16](OC(C)=O)=[O:17]>N1C=CC=CC=1>[OH:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:14][C:16](=[O:17])[CH3:15])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(O)c2cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2ncnc(O)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 7-Methoxy-quinazoline-4,6-diol (6.2 g, 32.3 mmol), Ac2O (100 mL) and pyridine (10 mL) was heat to 100° C., and stirred for 3 hours. The reaction was then cooled to room temperature and poured to ice water (300 mL). The product was isolated by filtration, washed with water (200 mL) and dried to give 7.61 g (32.4 mmol, 100%) of desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[C:6]([OH:12])[CH:5]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([O:12][CH3:14])[C:7]([CH3:11])=[C:8]([OH:10])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(C)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)c(C)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.1 g (28.2 mmol) of 3,5-Dihydroxy-4-methyl-benzoic acid methyl ester was dissolved in 100 ml of DMF and treated at 0° C. with 7.8 g (56.4 mmol) of potassium carbonate and 4.0 g (28.2 mmol) of methyl iodide. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The compound was purified by preparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% trifluoroacetic acid).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.C1COCC1>[N:1]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a 0° C. suspension of pipecolic acid (0.15 g, 1.16 mmol) and potassium carbonate (4.64 mmol) in water (5 mL) and THF (5 mL) was added benzyl chloroformate (0.24 g, 1.41 mmol). The mixture was rapidly stirred for one hour then allowed to warm to ambient temperature. After 6 hours, the reaction was diluted with water and washed with ether. The aqueous layer was acidified and extracted with methylene chloride. The organic phase was washed with brine then dried over sodium sulfate. The solvent was evaporated and the residue recrystallized from hexane-ethyl acetate to yield 0.23 g (75% yield) of the title compound as a white solid. MS(CI) m/e 264 (M+H)+. 1H NMR (300 MHz, CDCl3) δ1.24-1.80 (m, 5H), 2.26 (br t, 1H), 2.93-3.14 (m, 1H), 4.00-4.19 (m, 1H), 4.87-5.05 (m, 1H), 5.15 (br s, 2H), 7.27-7.41 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][C@@H:8]([NH:15][S:16]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])(=[O:18])=[O:17])[C:7]1=[O:25].[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([CH2:40]O)=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][C@@H:8]([N:15]([CH2:40][C:37]2[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[S:16]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])(=[O:18])=[O:17])[C:7]1=[O:25]
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)CCC(F)(F)F)C2=O)c(OC)c1
Reactant: COc1ccc(CO)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2CCC(F)(F)C[C@@H](N(Cc3ccc(OC)nc3)S(=O)(=O)CCC(F)(F)F)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3,3-Trifluoro-propane-1-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-amide (0.15 g, 0.31 mmol), (6-methoxy-pyridin-3-yl)-methanol (0.06 g, 0.38 mmol), triphenyl phosphine (0.17 g, 0.62 mmol) were dissolved in dry THF (15 ml) at 0-5° C. (ice-water bath) under an argon atmosphere followed by the dropwise addition of diisopropyl azodicarboxylate (0.12 ml, 0.62 mmol) in dry THF (1.5 ml). The reaction mixture was further stirred for 1 h at r.t. and then concentrated under reduced pressure. The crude oil was purified over silica gel (first: heptane-ethylacetate, 97:3-0:100; second: dichloromethane-methanol, 98:2-90:10): white solid 214 mg (81%);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][O:33][CH2:34][CH3:35])[C:28]([CH:36]([CH3:38])[CH3:37])=[CH:27][C:10]=1/[CH:11]=[N:12]/[NH:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[CH:20]2)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][O:33][CH2:34][CH3:35])[C:28]([CH:36]([CH3:37])[CH3:38])=[CH:27][C:10]=1[C:11]1[N:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[CH:20]3)[C:14](=[O:15])[NH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCOc1cc(OCc2ccccc2)c(/C=N/NC(=O)Nc2ccc3c(ccn3C)c2)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCOc1cc(OCc2ccccc2)c(-c2n[nH]c(=O)n2-c2ccc3c(ccn3C)c2)cc1C(C)C

Procedure:
To a stirred suspension of (E)-2-(2-(benzyloxy)-4-(ethoxymethoxy)-5-isopropylbenzylidene)-N-(1-methyl-1H-indol-5-yl)hydrazinecarboxamide in ethanol was added NaOH and stirred. To the resultant mixture, was added K3Fe(CN)6 at once and the resultant mixture was stirred at reflux temperature till the reaction is complete, checked by TLC. The mixture was cooled and the inorganics were filtered off. The residues were thoroughly washed with EtOH and filtrates were collected. The combined filtrates were concentrated and crude mixture was washed with water and extracted with EtOAc. Drying and concentration produced brown solid, which was filtered and washed with ether. The crude was carried out to the next reaction without further purification.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[N:17][CH:18]=[C:19]([CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)[CH:20]=3)[N:12]=[C:11]([CH3:41])[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>CS(O)(=O)=O>[CH3:40][O:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:41])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:18][N:17]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CC4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CC3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A suspension of N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-((1-(methylsulfonyl)piperidin-4-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.1923 g, 0.265 mmol) in TFA (1.022 mL, 13.26 mmol) was treated with a couple of drops of methanesulfonic acid (0.017 mL, 0.265 mmol) and the yellow solution was heated at 80° C. overnight. The volatile material was removed and the residue was carefully diluted with 5% 2 M NH3 in MeOH/DCM. The solution was concentrated with SiO2 and chromatographed through a Redi-Sep pre-packed silica gel column (pure DCM→10% MeOH in DCM w/NH3). Following concentration of the eluent, the resulting yellow solid was washed with IPA to give 4-(2-(6-methoxypyridin-3-ylamino)-5-((1-(methylsulfonyl)piperidin-4-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (88 mg, 0.182 mmol, 68.5% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.66 (s, 1H); 8.60 (d, J=2.54 Hz, 1H); 8.54 (d, J=2.54 Hz, 1H); 8.17 (dd, J=8.90, 2.64 Hz, 1H); 8.14 (d, J=2.15 Hz, 1H); 7.84 (br. s., 1H); 7.71 (br. s., 1H); 6.81 (d, J=8.80 Hz, 1H); 3.84 (s, 3H); 3.45-3.62 (m, 2H); 2.82 (s, 3H); 2.61-2.72 (m, 2H); 2.43 (s, 3H); 1.67-1.68 (m, 2H); 1.46-1.64 (m, 1H); 1.15-1.32 (m, 2H). m/z (ESI, +ve ion) 485.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH2:12][N:13](CC)[CH2:14][CH3:15].N(CC)CC>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH2:14][CH3:15])[CH2:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-iodo-benzoyl chloride (75 g) in 500 mL CH2Cl2 was added a mixture of Et3N (50 mL) and Et2NH (100 mL) at 0° C. After the addition, the resulting reaction mixture was warmed up to room temperature in 1 hr and was then washed with saturated ammonium chloride. The organic extract was dried (Na2SO4), filtered and concentrated. Residue was recrystallized from hot hexanes to give 80 g of INTERMEDIATE 5.
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=O)=CC=1)([O-])=O.[CH3:43][O:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH3:43][O:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[O:31][C:32]=4[C:33]([F:35])([F:34])[F:36])=[O:27])=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[O:10])[CH2:51][CH2:52]1
Reactant: COC(=O)CC1CCNCC1
Reactant: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCN(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a mixture of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester (150 mg, 0.26 mmol) in 1-methyl-pyrrolidin-2-one (10 mL) at room temperature was added piperidin-4-yl-acetic acid methyl ester (0.04 g, 0.25 mmol) followed by N,N-diisopropylethylamine (0.14 mL, 0.8 mmol). The mixture was stirred in a 90° C. oil bath overnight. The mixture was blown to dryness and the crude was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, gradient elution with 0%-60% ethyl acetate in hexane) to give [1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-acetic acid methyl ester (70 mg). LCMS calcd for C31H33F3N4O5 (m/e) 598, obsd 599 (M+H).