Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13](=[O:19])[C:14]2[S:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:5]2[CH2:6][CH:7]([CH:9]=[O:10])[O:8][C:4]=2[C:3]=1[Cl:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32](O)[CH2:33][OH:34]>C1C=CC=CC=1.O>[CH2:33]1[O:34][CH:9]([CH:7]2[CH2:6][C:5]3[CH:11]=[C:12]([C:13](=[O:19])[C:14]4[S:18][CH:17]=[CH:16][CH:15]=4)[C:2]([Cl:1])=[C:3]([Cl:20])[C:4]=3[O:8]2)[O:10][CH2:32]1
Reactant: O=CC1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C1OCCO1)C2
Reaction time: 3 h

Procedure:
A benzene mixture (250 ml.) containing 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde (3.2 g., 0.01 mole), p-toluenesulfonic acid (0.2 g.) and ethyleneglycol (15 ml.) is heated under reflux for three hours. The water formed in the reaction is co-distilled with the benzene and is removed by a Dean-Stark apparatus. After three hours, the reaction mixture is cooled, washed twice with dilute sodium bicarbonate (2×50 ml.) once with water (50 ml.) and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give the 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde ethyleneacetal.
Reaction SMILES: Cl[CH:2]([C:9]1[N:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].[O-2].[Mg+2]>C(O)C.[Pd]>[CH2:2]([C:9]1[N:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: ClC(c1ccccc1)c1cccnn1
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCO
Product: c1ccc(Cc2cccnn2)cc1
Yield: 93.8 %

Procedure:
A solution of (±) 3-α-chlorobenzylpyridazine (2.05 g.) in ethanol (50 ml.) was treated with hydrogen, in the presence of magnesium oxide (0.4 g.) and palladium on charcoal (5% Pd; 0.2 g.), for 1 hour at ambient temperature and normal atmospheric pressure. The solution was then filtered and the filtrate was evaporated to dryness. The residue was dissolved in hot chloroform (100 ml.), cooled, washed with water (50 ml.), dried over magnesium sulphate and evaporated to give 3-benzylpyridazine (1.6 g.), m.p. 61°-64° C., in the form of a light brown coloured solid.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[S:15][C:14]2[C:13](=[O:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1)=[O:6]>C1COCC1.O>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:12]3[C:13](=[O:16])[C:14]4[S:15][C:7]([C:5]([OH:6])=[O:4])=[CH:8][C:9]=4[N:10]=[CH:11]3)=[CH:18][CH:19]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCCN(c2ccc(-n3cnc4cc(C(=O)O)sc4c3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 2M LiOH solution (1.2 mL) was added to a solution of 3-[4-(4-methylperhydro-1,4-diazepin-1-yl)phenyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-6-carboxylic acid methyl ester (477.8 mg) in THF (5 mL) and water (5 mL), and the mixture was stirred at room temperature for 5 h. The solvent was then removed in vacuo and the crude product was purified by preparative HPLC. The product with the molecular weight of 384.45 (C19H20N4O3S) was obtained in this way; MS (ESI): 385 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH2:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:19])=[O:3]
Reactant: COc1ccccc1OC(=O)Cl
Reactant: OCCCCCO
Product: COc1ccccc1OC(=O)OCCCCCO

Procedure:
The reaction of 2-methoxyphenol chloroformate with 1,5-pentanediol is conducted on a 0.01 mole scale using the same conditions as described in Example IV. A 1.4 g yield of the pure product is obtained as an oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([C:31]2[CH:35]=[CH:34][N:33]([Si](C(C)C)(C(C)C)C(C)C)[CH:32]=2)[CH:30]=1>O>[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([C:31]2[CH:35]=[CH:34][NH:33][CH:32]=2)[CH:30]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cncc(Br)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cncc(-c2cc[nH]c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Tetrabutylammonium fluoride (1M tetrahydrofuran solution: 1 ml) was added to a tetrahydrofuran (2 ml) solution containing 3-bromo-5-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)pyridine (71 mg), followed by stirring at room temperature for 2 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 2:1), and a white solid of 3-bromo-5-(1H-pyrrol-3-yl)pyridine (28 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:21]=[O:22])[N:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:10](=[O:12])[CH:11]=1.[Br:28]NC(=O)CCC(N)=O>C(#N)C>[Br:28][C:11]1[C:10](=[O:12])[N:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:8]([CH:21]=[O:22])=[CH:7][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: O=Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1c(F)cccc1F
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC#N
Product: O=Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 ml one neck round bottom flask 4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde (0.36 g, 0.95 mmol) was dissolved in acetonitrile (5 mL). The reaction mixture was cooled to 0° C. in ice bath and charged with N-bromosuccinamide (0.17 g, 0.95 mmol). The mixture was allowed to stir at 0° C. for 2 hours under nitrogen atmosphere After 2 hours, the solvent was evaporated under vacuum. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.73-7.67 (m, 2H), 7.62-7.54 (m, 1H), 7.35 (dt, J=10.40, 2.56 Hz, 1H), 7.27 (t, J=8.35 Hz, 2H), 7.19 (dt, J=8.60, 2.44 Hz, 1H), 5.72 (s, 1H), 5.50 (s, 2H); ES-MS m/z 455.9836 (M+H calcd for C19H11BrF4NO3, requires 455.9859).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH2:9])[CH2:7][CH3:8].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][CH3:8]
Reactant: O=C1CCCC1
Reactant: CC[C@@H](N)c1nnco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC[C@@H](NC1CCCC1)c1nnco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
(1R)-1-(1,3,4-oxadiazol-2-yl)propan-1-amine (610 mg, 4.798 mmol) in THF (6.972 mL) was treated with cyclopentanone (407.6 mg, 428.6 μL, 4.846 mmol) then acetic acid (288.1 mg, 272.8 μL, 4.798 mmol). The reaction was stirred at ambient temperature for 20 minutes then treated with sodium triacetoxyborohydride (1.485 g, 7.005 mmol). The reaction was stirred at ambient temperature for 5 hours then basified with aqueous NaHCO3. The mixture was extracted with DCM (×10), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc/petrol) to give the sub-title compound as a colourless solid (694 mg, 74%); 1H NMR (400.0 MHz, CDCl3) d 0.81 (3H, t), 1.10-1.87 (10H, m), 2.85 (1H, m), 3.95 (1H, t), 8.33 (1H, s); MS ES (+) 196.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([NH2:5])=[O:4].[C:7]([Si:11](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Si:11]([O:1][CH:2]([CH3:6])[C:3]([NH2:5])=[O:4])([C:7]([CH3:10])([CH3:9])[CH3:8])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(O)C(N)=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=O
Temperature: 90 °C

Procedure:
2-hydroxy-propanamide (227 mg, 2.55 mmol), DMF (2 ml), tert-butylchlorodiphenyl-silane (1.0 ml, 1057 mg), imidazole (266 mg, 3.91 mmol) and 4-dimethylaminopyridine (93 mg, 0.764 mmol) dissolved in DMF (2 ml) were stirred under nitrogen atmosphere over the weekend. After the weedend the temperature was raised to 90° C. and was left to react for another 4 h. The mixture was then evaporated and extracted with DCM/water and the combined organic phases were evaporated. The product was purified by column chromatography. 1H-NMR (400 MHz; DMSO-d6): δ 1.04 (d, 9H), 1.12 (d, 3H), 4.00 (q, 1H), 7.04 (bs, 1H), 7.24 (bs, 1H), 7.40-7.51 (m, 6H), 7.58-7.66 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29]C(=O)OCC)(=[O:28])=[O:27].ClCCCl.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH2:29])(=[O:28])=[O:27])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CCOC(=O)NS(=O)(=O)NCC(OC)OC
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 0 °C

Procedure:
A mixture of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (68 mg, 0.20 mmol; from Step D) and ethyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (154 mg, 0.600 mmol, 3.0 equiv.) in 1,2-dichloroethane (2.50 mL, 31.7 mmol) was stirred at 0° C. To this mixture was added trifluoroacetic acid (1.00 mL, 13.0 mmol) and triethylsilane (105 μL, 0.66 mmol, 3.3 equiv.)=drop-wise. The reaction mixture was stirred at 0° C. for 3 h. HPLC indicated 97.5% conversion to the desired product. The reaction mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate to pH ˜8. The mixture was extracted in ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was stirred in a mixture of heptane and diethyl ether overnight. The solids were collected by filtration, washed with heptane to give the desired product (95 mg, 88%) as a crude off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.08 (m, 1H), 7.70 (m, 2H), 7.59 (t, 1H, J=8.7 Hz), 6.56 (s, 1H), 4.04 (d, 2H, J=7.2 Hz), 3.35 (m, 2H), 3.11 (m, 2H), 1.15 (t, 3H, J=7.2 Hz); C15H15BrFN7O7S (MW 536.29), LCMS (EI) m/e 536/538 (M++H).
Reaction SMILES: C[C@@H:2]([C@@H:9]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4[C@@H](O)C[C@H]3[C@@H]2CC1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[O:30]1C=[CH:34][CH2:33][CH2:32][CH2:31]1.CO>O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:8]1[O:7][CH:5]1[CH2:4][CH2:3][CH2:2][CH2:9][O:6]1
Reactant: C1=COCCC1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CO
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 245.3 %

Procedure:
To a solution of 100.0 g (0.2557 mole) of methyl hyodeoxycholate and 5.68 g of p-toluenesulfonic acid in 2000 ml of p-dioxane was added 153.7 g (1.62 mole, 148.6 ml) of dihydropyran over a period of 30 min under argon atmosphere. After stirring overnight at room temperature, the pH of the solution was adjusted to approximately pH 8 by the addition of 55 ml of 50/50 methanol/29% ammonium hydroxide. The solution was concentrated to a yellow oil under reduced pressure and the residue stirred in heptane 4 hr, then filtered to remove the precipitated p-toluenesulfonic acid. The filtrate was heated with charcoal, filtered, and evaporated to yield 116.8 g (80%) of the di-tetrahydropyranyl ether as a colorless viscous oil.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[Br:14][C:15]1[CH:16]=[C:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=2[N+:11]([O-:13])=[O:12])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: Brc1cccc(Br)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 180 °C
Reaction time: 48 h

Procedure:
A mixture of 4-acetyl-2-nitroaniline (3.41 g, 18.94 mmol), 1,3-dibromobenzene (4.6 ml, 38.06 mmol), potassium carbonate (2.62 g, 19 mmol) and a catalytic amount of copper bronze is heated with stirring to 180° C. under a stream of nitrogen for 2 days. After cooling the solid reaction cake is extracted with a mixture of dichloromethane and methanol (9:1). The extract is concentrated under reduced pressure. The residue is extracted with ethyl acetate. This extract is concentrated under reduced pressure and the residue is eluted through silica gel with a mixture of petroleum ether and ethyl acetate (4:1) to afford the pure product. Yield 0.67 g (10.6%). M.p. 142-144° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>O>[CH3:9][O:8][C:4]1[C:5]([NH:13][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=[CH:2][N:3]=1
Reactant: COc1cccc(Cl)n1
Reactant: CCCN
Solvent: O
Product: CCCNc1cccnc1OC
Yield: 40.2 %

Procedure:
In the same reacting apparatus as in Example 1, 20 g of 2-chloro-6-methoxypyridine, 25 g of n-propylamine and 80 ml of water were charged and they were subjected to reacting each other at 180° C. for 5 hours. After completion of the reaction, the similar experimental procedure was carried out to give 9.3 g of 2-methoxy-n-propylaminopyridine of b.p. 90°-91° C./4 mmHg.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:3]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>C(OCC)(=O)C>[CH2:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[N:3][C:4]=2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH3:12]
Reactant: CCn1cnc2c(Nc3cccc(C(F)(F)F)c3)nc(Cl)nc21
Reactant: NCCCO
Solvent: CCOC(C)=O
Product: CCn1cnc2c(Nc3cccc(C(F)(F)F)c3)nc(NCCCO)nc21

Procedure:
200 mg (0.58 mmol) of 2-chloro-9-ethyl-6-(3-trifluoromethyl-phenyl-amino)-9H-purine and 2 ml of 3-amino-1-propanol are stirred at 140° C. for 2 h and the mixture is allowed to cool and is diluted with 60 ml of ethyl acetate. The organic phase is washed with water and dried over sodium sulfate. After removal of the solvent, the residue is recrystallized from ethyl acetate and diethyl ether. 9-Ethyl-2-(3-hydroxy-propyl-amino)-6-(3-trifluoromethyl-phenyl-amino)-9H-purine is obtained; m.p. 136–137° C.; FAB-MS: (M+H)+=381; Rf=0.7 (ethyl acetate:methanol=9:1).
Reaction SMILES: [CH2:1]([CH:3]([C:7]([CH3:9])=[O:8])[C:4]([NH2:6])=[O:5])[CH3:2].[OH-].[Na+].[CH3:12]I>CO>[CH2:1]([C:3]([CH3:12])([C:7]([CH3:9])=[O:8])[C:4]([NH2:6])=[O:5])[CH3:2]
Reactant: CCC(C(C)=O)C(N)=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)(C(C)=O)C(N)=O
Yield: 86.6 %

Procedure:
2-Ethylacetoacetamide (21.0 g, 163 mmol) and 50 mL of methanol were charged to a 100 mL, 4-necked flask which was equipped with a thermometer, a nitrogen blanket line atop a condenser, an addition funnel, and a magnetic stirrer. The mixture was stirred until a homogeneous solution was obtained. To the solution was added 14.3 g of 50% aqueous sodium hydroxide solution (179 mmol, 1.1 eq), and the resulting mixture was stirred at ambient temperature for 30 minutes. Methyl iodide (25.4 g, 179 mmol, 1.1 eq) was then added to the reaction mixture through the addition funnel in 30 minutes. Upon the completion of the addition, the reaction mixture was stirred for 14 hours at ambient temperature. After this period, all volatile components were removed at 60° C./20 mmHg. The solid residue was dissolved in 100 mL of water and extracted with ethyl acetate (3×100 mL). After the ethyl acetate was removed in vacuo from the combined extracts, 20.2 g of a white solid was obtained. Crude yield: 87%.
Reaction SMILES: [F:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[Mg]Br>>[F:1][C:2]1[C:13]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[CH3:18])=[O:5]
Reactant: COc1ccc([Mg]Br)c(C)c1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)c(C)c1

Procedure:
Prepared according to Method A step B from 2- fluoro-3-trifluoromethyl-N-methoxy-N-methylbenzamide (4.05 g, 16.1 mmol) and 2-methyl-4-methoxyphenylmagnesium bromide (42 mL, 0.5 M in THF) to give 1.76 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[C@@H:10]([CH2:12][O:13][CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[CH3:26][C:25]([NH:11][C@@H:10]([C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH2:12][O:13][CH3:14])=[O:27]
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 0.17 h

Procedure:
N-benzyl-O-methyl-D-serinamide (5 g), was mixed with DCM (25 ml) at ambient temperature and stirred for 10 minutes to get a clear solution. To this solution, dimethylaminopyridine (0.025 g) was added at ambient temperature. Acetic anhydride (2.695 g) was slowly added over 10-12 minutes at ambient temperature. The solution was stirred for 30 minutes at room temperature. The reaction mixture was washed with 5% sodium bicarbonate (15 ml) solution, deionized water (15 ml), and brine (10 ml). The layers were separated and solvent was completely recovered under vacuum at 35° C. to 40° C. to get crude product. Yield=5.9 gm.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:13]([N:16]=CC2C=CC=CC=2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]>O.C(O)C>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(N=Cc2ccccc2)ccc1OC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(N)ccc1OC(C)=O
Yield: 41.7 %

Procedure:
Ethyl 2-acetoxy-5-benzylideneaminobenzoate (10.0 g, 32.2 mmole) was refluxed in water-ethanol (3:1, 750 ml) for about 1 hour, after which time the mixture was cooled and the precipitate isolated by filtration. After a further recrystallization this gave the title compound (3.0 g, 42%), m.p. 82.5°-83° C. Found (Calc. for C11H13NO4) C 58.96 (59.19). H 5.98 (5.83), N 6.22 (6.28).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][C:19]=3[F:37])=[O:16])[N:12]=[N:11]2)=[CH:6][CH:5]=1.[ClH:39].CCOCC>O1CCOCC1>[ClH:39].[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:20][C:19]=3[F:37])=[O:16])[N:12]=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cn(-c4ccc(OC(F)F)cc4)nn3)c(F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cn(-c2ccc(OC(F)F)cc2)nn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(4-(difluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamido)-3-fluorophenyl)morpholine-4-carboxylate (62 mg, 0.116 mmol) was dissolved in dioxane (0.6 ml) and a solution of HCl in dioxane (4M, 0.35 ml, 1.39 mmol) was added. The reaction mixture was stirred for 2 h at 60° C. After cooling ether was added, the solid was filtered off, washed with ether and dried in vacuo to afford (S)-1-(4-(difluoromethoxy)phenyl)-N-(2-fluoro-4-(morpholin-2-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (53 mg, 97%) as a white solid. MS (ISP): 434.4 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:30][N:31]([C@@H:48]([C:56](=[O:59])[NH:57][CH3:58])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:32](=[O:47])[C@H:33]([NH:45][CH3:46])[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[CH:14][C:15](=[O:17])[N:45]([CH3:46])[C@@H:33]([C:32](=[O:47])[N:31]([CH3:30])[C@@H:48]([C:56](=[O:59])[NH:57][CH3:58])[CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
4-Carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester (0.60 g; 2.45 mmol) was dissolved in methylene chloride (50 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) was added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.5 g; 1.24 mmol, prepared as in example 1) was added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2×20 cm) using ethyl acetate as eluent to afford 0.270 g of 4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[O:16][CH2:15][CH2:14][C:13]3=[O:20])=[CH:6][CH:5]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O.N1CCCC1>C(O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[C:14]1[C:13](=[O:20])[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=3)[CH:11]=2)[O:16][CH2:15]1
Reactant: O=C1CCOc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Reactant: O=Cc1ccccn1
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1C(=Cc2ccccn2)COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21

Procedure:
A solution of 400 mg 6-(4-(trifluoromethoxy)phenyl)chroman-4-one (1.3 mmol, 1.0 eq), 150 μL 2-pyridine carboxaldehyde (1.6 mmol, 1.2 eq) and 130 μL pyrrolidine (1.6 mmol, 1.2 eq) in 10 mL ethanol was refluxed 3 h. The reaction was concentrated and purified on silica gel column eluting with EA:Hex. 160 mg of a yellow solid was collected. m/z=398.0