Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccsc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccsc2C1
Temperature: 25 °C

Procedure:
A solution of 1.753 g (7.711 mmol) of N-tert-butoxycarbonyl-2-(3-thienyl)ethylamine, 0.46 g (15.4 mmol) of powdered paraformaldehyde and 73 mg (0.39 mmol) of p-toluenesulfonic acid monohydrate in 150 ml of toluene was refluxed under dehydrating conditions for 0.5 hours in a Dean-Stark trap. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, after which it was washed with aqueous sodium hydrogen carbonate; the organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield the desired product.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23]O)[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[NH:40]1[CH:44]=[CH:43][CH:42]=[N:41]1>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23][N:40]2[CH:44]=[CH:43][CH:42]=[N:41]2)[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: c1cn[nH]c1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](Cn2cccn2)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
A solution of methanesulfonic anhydride (0.65 g, 3.72 mmol) in DCM (5 mL) was added slowly to a solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.08 g, 3.38 mmol) and triethylamine (1.42 mL, 1.02 g, 10.1 mmol) in DCM (10 mL) with stirring under nitrogen and external ice bath cooling. Stirring was continued at 0° C. for 2 h then pyrazole (0.3 g, 4.4 mmol) was added in one portion. Stirring at 20° C. was continued for 18 h, then mixture was partitioned between saturated aqueous NaHCO3 (40 mL) and DCM (3×20 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-40% Et2O in 40-60 petroleum ether) gave the title compound (0.811 g) as an oil. MS: [M+H]+=371.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][CH2:18]Br>C(O)C>[Br:16][CH2:17][CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=Cc1ccc(OCCBr)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (3 g, 0.024 mol) in ethanol (30 mL) was added potassium carbonate (6.6 g, 0.047 mol) and 1,2-dibromoethane (21 mL, 0.24 mol). The reaction mixture was stirred at 70° C. for 20 hours. The salts were filtrated and the filtrate was concentrated. The crude was dissolved in ethyl acetate and the organic layer was washed with water, sodium hydroxide 2N and brine, dried, and filtered. The organic solvent was removed under reduced pressure to give the title compound as a yellow-orange solid (88%), which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:29][C:12]2=[CH:13][C:14]3[C:15](=[O:28])[N:16]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH:39]([NH2:41])[CH3:40].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][CH:39]([NH:41][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:29][C:12]2=[CH:13][C:14]3[C:15](=[O:28])[N:16]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:40]
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Reactant: CC(N)Cc1cc(F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Yield: 83.8 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)-imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.59 g, 1.43 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.29 g, 1.72 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a brown solid product, 0.65 g, 83.8% yield. MS: 540.8 [M−H]−. 1H-NMR (DMSO-d6, 300 MHz): δ 13.42 (s, 1H), 11.26 (s, 1 Hz), 10.86 (d, 1H, J=8.0 Hz), 8.12 (s, 1H), 8.01 (s, 1H), 7.32-7.31 (m, 1H), 7.24-7.21 (m, 1H), 7.13-7.11 (m, 1H), 6.88-6.84 (m, 1H), 6.14 (d, 1H, J=7.5 Hz), 4.19-4.14 (m, 2H), 3.37-3.33 (m, 3H), 3.15 (m, 2H), 3.01-2.99 (m, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 1.78-1.77 (m, 2H), 1.33 (d, 3H, J=6.5 Hz).
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.NCCC1C=CC(S(N)(=O)=O)=CC=1.CN1C=CC=C(C(O)=O)C1=O.C(=O)([O-])[O-].[K+].[K+].[CH:41]1([N:47]=[C:48]=[O:49])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>CC(C)=O>[CH:41]1([NH:47][C:48](=[O:49])[NH2:10])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cn1cccc(C(=O)O)c1=O
Agent: NCCc1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: NC(=O)NC1CCCCC1
Reaction time: 8 h

Procedure:
2.9 g of 4-(β-<1,2-dihydro-1-methyl-2-oxo-nicotinamido>-ethyl)-benzenesulfonamide (melting point 235 - 237° C, prepared from 4-(β-aminoethyl)-benzenesulfonamide and the mixed anhydride of 1,2-dihydro-1-methyl-2-oxo-nicotinic acid in dilute acetone) in 100 ml acetone/100 ml dioxane were refluxed for 3 hours while stirring together with 2.5 g of pulverized potassium carbonate. 1.4 g of cyclohexyl-isocyanate were then added and the mixture was stirred for 8 hours at boiling temperature. The solvent was distilled off under reduced pressure, water was added to the residue, the whole was filtered, the filtrate acidified, the reaction product was filtered off with suction and recrystallized from dilute ethanol. The N-[4-(β-<1,2 -dihydro-1-methyl-2-oxo-nicotinamido>-ethyl)-benzenesulfonyl]N'-cyclohexyl urea obtained melted at 210 - 212° C.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.CCOCC>CO>[CH3:1][O:12][C:11]([C@@H:8]1[CH2:7][C@@H:6]([OH:5])[CH2:10][NH:9]1)=[O:13]
Reactant: CC(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C

Procedure:
Acetyl chloride (7.6 ml; 107 mmol) was added slowly to MeOH (70 ml). The reaction was exothermic. (2S,4R)-4-Hydroxy-2-pyrrolidinecarboxylic acid (10 g; 76.2 mmol) was added and the mixture was refluxed for 4 hours. At this time, another portion of 3 ml of acetyl chloride in 30 ml of MeOH was added. The mixture was refluxed an additional 3 hours. The reaction was cooled to room temperature and ~750 ml of Et2O was added. The resulting colorless crystals were filtered and dried to afford 11.89 g of the title A compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:10]([F:15])[F:14])=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(Br)nc1
Temperature: 85 °C
Yield: 55 %

Procedure:
A mixture of 6-bromopyridin-3-ol (1.20 g, 6.90 mmol), sodium 2-chloro-2,2-difluoroacetate (1.577 g, 10.35 mmol), and potassium carbonate (1.239 g, 8.97 mmol) in 10 mL of anhydrous DMF was heated at 85° C. for 1.5 days. The reaction mixture was diluted with 50 mL of EtOAc, washed with 50 mL of H2O, followed by washing with 50 mL of NaOH (1N) solution, the EtOAc layer was dried (Na2SO4) and concentrated to give a light brown oil that was purified by Shoko silica gel chromatography instrument eluting with 0-10% EtOAc in hexanes (0-10% over 25 min; GRACE column: 80 g pre-packed). Desired fraction were combined and concentrated to give the titled compound as a colorless oil: 0.85 g, 55% yield. MS m/z=223.9, 225.9 [M+H]+. Calculated for C6H4BrF2NO: 222.9, 224.9.
Reaction SMILES: CCCCCC.[OH:7][CH:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:34]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]2[CH2:12][CH2:11][N:10]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][CH:8]2[OH:7])=[CH:19][CH:18]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Temperature: 80 °C
Reaction time: 15 h
Yield: 47.4 %

Procedure:
In an analogous manner to that described in Example 22(k), by acylating (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzoyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; Rf : 0.84 (SiO2, hexane:ethyl acetate=1:1). (d) A mixture of 1.0 g (3.41 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide in 30 ml of dimethylformamide was stirred at room temperature for 2 hours and at 80° C. for 15 hours. Subsequently, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide were again added and the mixture was stirred at 80° C. for a further 6 hours. The reaction mixture, cooled to room temperature, was poured into 300 ml of an ice/water mixture and extracted three times with 250 ml of ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The yellow oil (1.82 g) was separated on silica gel using an eluent gradient of 4:1 to 3:2 of a mixture of hexane and ethyl acetate as the eluent. There were obtained 620 mg (72% of theory) of tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate which, after recrystallization from a mixture of methylene chloride and hexane, gave 361 mg (28% of theory) as a white, crystalline product; MS: 383 (M)+.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([CH3:31])[C:21]=1[CH2:22][OH:23].N1C=CN=C1>CN(C)C=O>[Si:1]([O:23][CH2:22][C:21]1[C:24]([CH3:31])=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:20]=1[CH3:19])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 109.5 %

Procedure:
To a solution of tert-butyldiphenylsilyl chloride (30.7 g) in dimethylformamide (90 ml) was added 2,6-dimethyl-3-nitrobenzyl alcohol (18.4 g), and imidazole (8.99 g) was added thereto under ice-cooling. The mixture was stirred for 15 minutes at the same temperature and then for 3 hours at ambient temperature. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-nitrobenzene (46.67 g) as pale yellow oil.
Reaction SMILES: N[C:2]1([O:11]O)[CH2:7][CH:6]([CH3:8])[CH2:5][C:4]([CH3:10])([CH3:9])[CH2:3]1.C(=O)C.[O-]O>>[CH3:8][CH:6]1[CH2:5][C:4]([CH3:10])([CH3:9])[CH2:3][C:2](=[O:11])[CH2:7]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: CC=O
Agent: [O-]O
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
1-Amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g; 78% pure) was added with stirring to acetaldehyde (12 g.) in light petroleum (b.p. 40° - 60°C) (50 c.c.) with cooling to below 0°C. When the hydroperoxide had dissolved, the organic layer was separated, treated with solid magnesium sulphate and stored at 0°C overnight. The solution was then filtered, washed and distilled as in Example 52 and gave, in addition to dihydroisophorone, the same product (13.0 g.) as Example 52.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:16]=[CH:15][C:8]([C:9](N(OC)C)=[O:10])=[C:7]([Cl:17])[CH:6]=1.[Cl-].[NH4+]>O1CCCC1>[Br:4][C:5]1[CH:16]=[CH:15][C:8]([C:9](=[O:10])[CH3:1])=[C:7]([Cl:17])[CH:6]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Br)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 37.1 %

Procedure:
Methyl magnesium bromide (44 mL, 61.6 mmol, 1.4 M in tetrahydrofuran) was added to tetrahydrofuran (50 mL) at −78° C. (4-Bromo-2-chloro-N-methoxy-N-methyl-benzamide (3.52 g, 12.7 mmol) (from step 6-I) in tetrahydrofuran (30 mL) was added. The mixture was stirred at −78° C. for 45 minutes and then at room temperature for 1.5 hours. The reaction mixture was poured into ice water and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate (3 times) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized from ethyl acetate/hexanes to give 1-(4-bromo-2-chloro-phenyl)-ethanone as a white solid (1.1 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1.[C:28]([O:32][C:33](=[O:43])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:42][C:39]2[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:33](=[O:43])[O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:37][CH:38]=2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)c2cc(Cl)ncn2)cc1

Procedure:
To a cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride in DCM (30 mL), obtained as described above for Intermediate 7, step 1 (1.43 g; 8.10 mmol) was added dropwise, during a period of 15 minutes, a solution of (4-amino-benzyl)-carbamic acid tert-butyl ester (Astatech, 1.50 g; 6.75 mmol) and DIEA (2.33 ml; 13.5 mmol) in DCM (5 mL). At the end of addition the reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The resulting precipitate was filtered and dried under vacuum. The mother liquors were dried on MgSO4, concentrated under vacuum to give a residue, which was precipitated from cyclohexane. The two solids were combined to give the title compound as a brown solid.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[CH:29]1[C:34](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:33][CH:32]=[C:31]([OH:40])[CH:30]=1>O1CCCC1>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:37]([O-:39])(=[O:38])/[CH:36]=[CH:35]/[C:34]1[CH:33]=[CH:32][C:31]([OH:40])=[CH:30][CH:29]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: C1CCOC1
Product: O=C([O-])/C=C/c1ccc(O)cc1

Procedure:
Sitagliptin free base (2.0 gms) and coumaric acid (0.80 gms) were dissolved in Tetrahydrofuran (100 ml) at 60° C. to 65° C. and the resultant solution left for slow solvent evaporation at room temperature for 18 hours. Precipitated solids were filtered and dried at 50° C. to 55° C. for 6 hours to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[N:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:15][C:13]1[N:14]=[C:9]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Nc1cccnc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2cccnc2)c1=O
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with pyridin-3-amine (940 mg, 10 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (5.4 g, 20 mmol), i-propanol (50 mL), and di-i-propylethylamine (10 mL). The mixture was heated at reflux for 5 h. After the completion of the reaction, it was cooled to room temperature. The solvent was removed under reduced pressure. The crude was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 186a (1.4 g, 50%) as a yellow solid. MS-ESI: [M+H]+ 281.6.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:15]([Cl:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][Mg]Br>C1COCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH3:22])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[C:15]([Cl:21])=[N:16][CH:17]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide (123.5 mg, 0.317 mmol) was dissolved in THF (2.6 ml) and cooled in an ice water bath under nitrogen. Then, methylmagnesium bromide (0.65 ml, 1.4 M solution in toluene/tetrahydrofuran (75:25), 0.91 mmol) was added via syringe, and the reaction was allowed to slowly warm to room temperature. After 2 hours and 45 minutes, more methylmagnesium bromide (0.50 ml) was added, and stirring was continued at room temperature. After 75 minutes, more methylmagnesium bromide (0.93 ml) was added, and stirring was continued. After another hour, the reaction quenched with saturated ammonium chloride. The layers were separated, and the aqueous phase was extracted with 10:1 DCM/MeOH. Organic extracts combined, concentrated, and taken on to the next step. MS (ESI pos. ion) m/z: 405 (MH+, 79Br), 407 (MH+, 81Br). Calculated exact mass for C14H14BrClN2O3S 404 (79Br), 406 (81Br).
Reaction SMILES: C1([C@H]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)C)C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>ClCCl>[CH2:24]([O:23][C:21]([N:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C[C@H]1CCN([C@H](C)c2ccccc2)C1
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 16 h
Yield: 76 %

Procedure:
A 12 g (45.9 mmol) portion of (3R)-ethyl 1-[(R)-1-phenylethyl]pyrrolidine-3-acetate known in literatures was dissolved in 100 ml of dichloromethane to which was subsequently added dropwise 7.87 ml (55.1 mmol) of benzyl chloroformate at room temperature. After completion of the dropwise addition, the mixture was stirred for 16 hours at the same temperature. After completion of the reaction, the reaction mixture was concentrated. Thereafter, the resulting residue was applied to a silica gel column chromatography to yield 10.1 g (76%) of the title compound as an oily substance from the eluate of n-hexane:ethyl acetate=5:1.
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([OH:25])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:43][C@H:44]([C:48]([OH:50])=[O:49])[CH:45]([CH3:47])[CH3:46].[OH-].[Na+].Cl>CN(C)C=O>[C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([NH:43][C@H:44]([C:48]([OH:50])=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of N-hydroxysuccinimide ester of 3-(9-octadecenoyloxy)-11-eicosenoic acid (3 g) in N,N-dimethylformamide (30 ml) was added a solution of L-valine (4.42 g) and a 1N sodium hydroxide solution (37 ml) at 0° C. The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was acidified with 1N hydrochloric acid solution, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give powder of N-[3-(9-octadecenoyloxy)-11-eicosenoyl]-L-valine (2.7 g).