Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[C:8]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=2[O:34][CH3:35])=[CH:7]1)(=[O:3])[NH2:2].Cl.CN(C)CCCN=C=NCC.[C:48]1([CH3:58])[C:49]([S:54]([NH2:57])(=[O:56])=[O:55])=[CH:50][CH:51]=[CH:52][CH:53]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:12][CH:13]=2)[C:8]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:57][S:54]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[CH3:58])(=[O:55])=[O:56])=[O:30])=[CH:27][C:26]=2[O:34][CH3:35])=[CH:7]1)(=[O:3])[NH2:2]
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(CCC(N)=O)c2ccc(C(=O)NCC3CCCC3)cc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(CCC(N)=O)c2ccc(C(=O)NCC3CCCC3)cc12
Yield: 36.4 %

Procedure:
A solution of 4-[1-(2-carbamoylethyl)-5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]-3-methoxybenzoic acid (77 mg), 4-(dimethylamino)pyridine (20 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (37 mg), and ortho-toluenesulphonamide (28 mg) in dichloromethane (2.0 ml) was stirred under a nitrogen atmosphere for 48 hours. The mixture was diluted with dichloromethane; washed with 10% v/v hydrochloric acid, water, and brine; and evaporated. The resulting white solid was crystallized from ethyl acetate/hexane to give the title compound (37 mg; 37%) as a white solid; mp 140°-145° C. (d).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=CN1CCNCC1
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCN1CCNCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A 20 g (0.18 mole) quantity of N-formylpiperazine, 37.2 ml (0.18 mole) of 1-bromodecane and 25 g (0.18 mole) of potassium carbonate were suspended in 20 ml of N,N-dimethylformamide and the suspension was stirred at 80° C. for 3 hours. The suspension was further extracted with 300 ml of benzene, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 80 ml of methanol, and 20 ml of concentrated hydrochloric acid was added thereto and the mixture was refluxed for 3 hours. The solvent was evaporated under reduced pressure and the precipitated crystals were washed with acetone, giving 35.6 g (yield: 66%) of N-decylpiperazine as the hydrochloride.
Reaction SMILES: [C:1]([C:3]1[C:4]([SH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[OH-].[K+].Cl[CH2:15][C:16]#[N:17]>CN(C=O)C>[NH2:2][C:1]1[C:3]2[C:4](=[N:5][C:6]([CH3:10])=[CH:7][C:8]=2[CH3:9])[S:11][C:15]=1[C:16]#[N:17]
Reactant: Cc1cc(C)c(C#N)c(S)n1
Reactant: N#CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(N)c(C#N)sc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
The 3-cyano-4,6-dimethyl-2-mercaptopyridine (500 mg, 3.04 mmol) was stirred in DMF (6.0 mL). An aqueous 10% KOH solution (1.71 mL, 3.04 mmol) was added, followed by chloroacetonitrile (0.19 mL, 3.04 mmol). The reaction was stirred at RT for 15 minutes, LC/MS indicates initial thio-alkylation is complete. A second equivalent of 10% KOH (1.71 mL, 3.04 mmol) was added and the resulting slurry was warmed to 50° C. and stirred about 30 min. LC/MS indicates reaction is done. The slurry was cooled to RT, then poured into 80 g of crushed ice and allowed to warm until the ice melted. The cold slurry was poured through filter paper, washing the solid with cold water. The solid was collected and dried in a vacuum oven to give 580 mg (94%) of the pure product as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.09 (s, 1H), 6.50 (s, 2H), 2.70 (s, 3H), 2.49 (s, 3H). LC/MS: RT=0.56 min., m/z=204.0 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:23](=[O:25])[CH3:24])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
In 150 ml of CH2Cl2 were dissolved 23 g of the compound obtained in step 2; and, 12.9 ml of pyridine and 7.8 ml of acetyl chloride was slowly added at room temperature thereto. The reaction solution was washed with 0.2N HCl and with saturated NaHCO3 aqueous solution, dried over Na2SO4 and concentrated under reduced pressure to obtain residue, which was used for subsequent reaction without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1[N:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 24.3 %

Procedure:
General procedure C was followed using acetylpiperazine (35 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (18 mg, 24%), m.p. 144-146° C.; umax (CHCl3)/cm−1 3008, 2909, 2856, 1638, 1558, 1470, 1441, 1282, 1240, 1152, 1098; m/z (ESI) C11H14Cl2N3O requires 274.0508, found [M+H]+ 274.0513.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[CH:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[O:5].[ClH:14]>CCOCC>[ClH:14].[CH2:1]([O:3][C:9](=[NH:10])[C:8]1[CH:11]=[CH:12][CH:13]=[C:6]([CH:4]=[O:5])[CH:7]=1)[CH3:2]
Reactant: CCO
Reactant: N#Cc1cccc(C=O)c1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)c1cccc(C=O)c1
Reaction time: 144 h

Procedure:
59.7 ml (1.025 mol) of absolute ethanol are added to a solution of 86.7 g (0.662 mol) of 3-formylbenzonitrile in 530 ml of absolute ether and the whole is cooled to 0°. The reaction solution is saturated with dry hydrochloric acid gas and then left to stand for six days at 0°. After filtering off a fine precipitate, 1 liter of ether is added to the reaction solution, whereupon the title compound crystallises out; m.p. 126°-128° (with foaming).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15](O)=[O:16])[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:65][C@@H:66]1[CH2:70][CH2:69][NH:68][CH2:67]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15]([N:68]2[CH2:69][CH2:70][C@@H:66]([F:65])[CH2:67]2)=[O:16])[N:7]=1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)O)N2)n1
Reactant: F[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)N3CC[C@@H](F)C3)N2)n1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To a solution of (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetic acid (0.05 mmol, 22.6 mg) in DMF (0.5 mL) was added HBTU (0.075 mmol, 28 mg), Et3N (0.125 mmol, 17 μL) and (R)-3-fluoropyrrolidine (0.06 mmol, 7.5 mg). The reaction mixture was stirred over night at r.t. and LCMS shows completion of the reaction. Purified by prep LCMS to afford the title compound (Compound 85, 13.0 mg, 50%) as light brown solid. 1H NMR (400 MHz, methanol-d4) δ ppm 2.05-2.40 (m, 2H) 2.72 (s, 3H) 3.06 (dd, J=16.93, 10.36 Hz, 1H) 3.27-3.38 (m, 1H) 3.39-3.62 (m, 4H) 3.63-3.78 (m, 2H) 3.82 (s, 3H) 4.47-4.67 (m, 2H) 4.87 (dd, J=10.36, 3.03 Hz, 1H) 5.11-5.36 (m, 1H) 6.69 (d, J=8.34 Hz, 1H) 6.97 (d, J=7.33 Hz, 1H) 7.06 (dd, J=9.35, 2.53 Hz, 1H) 7.13 (t, J=8.34 Hz, 1H) 7.50-7.70 (m, 2H). MS (ES) [M+H] calculated for C26H28F2N7O3, 524.53; found 524.50.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[CH2:17][O:18][CH:19]([CH:24]=[CH2:25])[C:20]([F:23])([F:22])[F:21]>CO>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[N:2][OH:3])[CH2:17][O:18][CH:19]([CH:24]=[CH2:25])[C:20]([F:23])([F:22])[F:21]
Reactant: C=CC(OCC(=O)c1ccccc1F)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CC(OCC(=NO)c1ccccc1F)C(F)(F)F
Temperature: 45 °C
Yield: 97.6 %

Procedure:
To a reactor was added hydroxylamine hydrochloride (0.34 kg, 4.95 mol), sodium acetate (0.47 kg, 5.70 mol) and MeOH (2.68 L). To this suspension was charged a solution of 1-(2-fluorophenyl)-2-(1,1,1-trifluorobut-3-en-2-yloxy)ethanone (0.998 kg, 3.806 mol) in MeOH (1.8 L) and the reaction mixture was heated to 40−50° C. Upon completion (ca. 2 h) the reaction mixture was cooled to rt, and filtered over Celite (0.5 wt) and rinsed with EtOAc (3.0 L). The filtrate was concentrated under vacuum and to the resulting residue was added methyl tert-butyl ether (6.3 L), water (0.94 L) and sat. aq. NaHCO3 (2.5 L). The organic phase was washed once with water (1.6 L) and sat. aq. NaCl (0.1 L). The organic phase was concentrated under vacuum to afford the title compound as an oil (1.03 kg, 95.0%). 1H NMR (500 MHz, CDCl3) δ ppm 7.49-7.35 (m, 2H), 7.24-7.06 (m, 2H), 5.78-5.65 (m, 1H), 5.54-5.40 (m, 2H), 4.89-4.81 (m, 1H), 4.53 (d, J=12.6 Hz, 1H), 4.47 (d, J=12.6 Hz, 0.5H), 4.27-4.18 (m, 1H), 4.13-4.05 (m, 0.5H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][CH:14](O)[CH3:15])[CH2:7][CH2:8][CH3:9]>>[C:1]([O:5][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][SH:3]
Reactant: CCCCOCCOC(C)O
Reactant: O=C(O)CS
Product: CCCCOCCOCCOC(=O)CS
Temperature: 6 °C
Yield: 92.4 %

Procedure:
Thioglycolic acid (40.9 ml, 0.589 mole) obtained from Evans Chemetics, Inc. was added dropwise with stirring to butoxyethoxyethanol (butyl Carbitol) (95.53 g, 0.589 mole) obtained from Fisher Scientific Company with 12% Dowex cation exchange resin HGR-W (10% crosslinking, 11.46 g) as a catalyst. A temperature increase of 6° C. occurred immediately upon addition of the reactants. The solution was further heated and the byproduct, water, was distilled over at 89° C. and collected. When 50% of the water had been collected, a 30% excess of butoxyethoxyethanol (33 mls) was added to increase the rate of product formation. After 3.5 hours a 92.4% yield of butoxyethoxyethyl thioglycolate was obtained and thereafter vacuum distilled at 10 mm Hg and a temperature range of 25°-100° C. in order to remove the unreacted starting materials.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:22]([N:24]=C=O)=[O:23].[OH-].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:16][C:22]([NH2:24])=[O:23])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)aniline (5.16 g) in dry DCM (50 ml) was treated dropwise with a solution of trichloroacetyl isocyanate (2.36 ml) in dry DCM (6 ml) over 10 min. The reaction mixture was stirred at room temperature for 10 min prior to addition of 2M NaOH (50 ml). The reaction mixture was stirred at 70° C. for 5 h and room temperature for 16 h. The aqueous phase was extracted with DCM and the combined organic layers washed with water and concentrated in vacuo. The residue was purified by chromatography (biotage, EtOAc-Petrol 2:1) to give the title compound. LCMS RT=3.78 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26]C)=[O:25])=[O:21].CN(C)C=O.[F-].[Cs+].[H][H]>CO.[Pd]>[CH2:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:1])=[C:3]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:4](=[O:19])[N:5]2[CH3:18])=[CH:10][CH:9]=1)[CH3:13]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(C#C[Si](C)(C)C)cc2n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred solution of methyl 2-(4-hydroxy-1-methyl-2-oxo-7-(2-(trimethylsilyl)ethynyl)-1,2-dihydroquinoline-3-carboxamido)acetate (0.59 g, 1.5 mmol) in N,N-dimethylformamide (5.0 mL, 1.5 mmol) and methanol (1.0 mL, 1.5 mmol) was added cesium fluoride (0.23 g, 1.5 mmol) under nitrogen. After stirring at room temperature for 1 hour, the mixture was concentrated to remove solvents. The resulting solid was adsorbed onto silica and purified using flash chromatography (15-80% EtOAc:Hex gradient) to afford a yellow solid. The solid was suspended in methanol (10 mL) with Pd/C (20 mol %) and exposed to hydrogen from a balloon for 16 h. The crude reaction mixture was filtered through Celite, and the filter pad was washed with dichloromethane (5×10 mL) under argon. The filtrate was concentrated to give a white solid that was further purified on silica by flash chromatography (100% chloroform). The solid was then treated with 5 N aqueous NaOH (3 mL) in THF (3 mL) for 5 hours. The mixture was acidified to pH 1 using 5 N aqueous HCl, and the resulting precipitate was collected by filtration. After washing the solid with water (5×10 mL) and ether (2×10 ml), the desired material was obtained after drying in a vacuum oven overnight at 50° C. (0.21 g, 38% yield, 3 steps).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[ClH:20].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][S:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Sc1cnc2ccccc2n1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(CSc2cnc3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
In 50 ml of acetone was dissolved 2.0 g of 2-mercaptoquinoxaline. To the solution were added 2.02 g of 2-picolyl chloride hydrochloride, 4.0 g of potassium carbonate and 5 ml of water. The resulting mixture was stirred at room temperature for 0.5 hr., and the solvent was removed under reduced pressure. The residue was extracted with chloroform after addition of chloroform and water. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. To the residue were added 20 ml of ethanol and 1.03 ml of conc. hydrochloric acid and then added ether. Thus precipitated crystals were washed with ethanol-ether (1:1) and dried under reduced pressure to give 2.09 g of 2-(2-pyridylmethylthio)quinoxaline hydrochloride as a yellow crystalline powder.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (170 mg, 0.94 mmol) and N,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperature for 10 minutes and then a solution of 4-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (190 mg, 0.628 mmol) in methylene chloride (4 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was used directly in the next step without purification (121 mg, 60%). LCMS calculated for C16H15Cl2N2O (M+H)+: m/z=321.0; Found: 321.0
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)[Cl:30].[ClH:32]>COCCOC>[ClH:30].[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([Cl:32])=[O:25])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Reactant: ClCCl
Agent: Cl
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1

Procedure:
A solution of 37.6 g. of 4-hexadecylaminohydrocinnamic acid, prepared as described in Example 4, in 1200 ml. of methylene chloride and 300 ml. of 1,2-dimethoxyethane is stirred under reflux while hydrogen chloride gas is bubbled in for 1 hour. The mixture is then treated with 65.5 g. of thionyl chloride and stirred under reflux for another 1 hour. The dark solution is evaporated in vacuo to yield 4-(hexadecylamino)hydrocinnamoyl chloride hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1>O>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: OC1CCNC1
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
2 g (0.012 mol) of 2-amino-6-chloro-3-nitropyridine, 30 ml of dioxane and 10 ml of water, and 1.8 g of 3-pyrrolidinol are charged to a fully equipped round-bottomed flask. The mixture is brought to 70° C. for one hour with stirring and then the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2.36 g of yellow powder are obtained, Yd=87.4%.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)CO>[N:12]1([C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1cc2ccccc2cn1
Reactant: C1CNCCN1
Solvent: OCCO
Product: c1ccc2cc(N3CCNCC3)ncc2c1
Temperature: 150 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
A mixture of 3-chloroisoquinoline (200 mg, 1.22 mmol) and piperazine (2.10 g, 24.4 mmol) in ethylene glycol (2 ml) was heated to 150° C. and stirred at that temperature for 24 hours. The reaction was allowed to cool down to room temperature. The crude mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuo. The residue was and purified on silica gel by flash column chromatography to give the title compound as a pale brown solid (131 mg, 50% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1>CC(C)=O>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29]=[O:30])=[CH:23][CH:22]=1
Reactant: Cc1ccc(CCC(=O)Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: Cc1ccc(CCC=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of triphenylphosphine (0.117 moles, 30.8 g) in acetone (200 ml) is added under a nitrogen stream at r.t. with Cu (I) bis-(triphenyl-phosphine)-tetrahydroborate (0.067 moles, 40.69 g), then 3-(4-methylphenyl)propanoyl chloride (0.055 moles, 10 g) dissolved in acetone (85 ml) is dropped in 45'. The mixture is stirred at r.t. under nitrogen for 1 h. The precipitated solid is filtered, washing with acetone and the filtrate is evaporated under vacuum. The residue is dissolved in chloroform (340 ml), added with cuprous chloride (0.135 moles, 13.38 g) and stirred under nitrogen stream for 1 h at r.t. The mixture is filtered through celite, the filtrate is evaporated to dryness and the resulting residue is taken up into ethyl ether and petroleum ether, filtered and evaporated under vacuum to obtain an oil. Yield: 6.7 g (83%)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[H-].[Na+].[Cl:18][CH:19]=[CH:20][CH2:21]Cl>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[N:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:21][CH:20]=[CH:19][Cl:18]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Br
Reactant: ClC=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
A solution of 3.2 (350 mg, 1.29 mmol) in DMF (7 ml) was cooled to 0° C. and NaH (93 mg, 3.85 mmol) was added. The resulting mixture was stirred for 15 mins and 1,3 dichloropropene (358 μl, 3.85 mmol) was added. The mixture was allowed to warm to 25 ° C. and stirred for 15 h. The mixture was then concentrated. H2O (10 ml) was added to the residue and the solution was extracted with EtOAc (3×10 ml). The combined organic layers were dried with MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc/Hex 1:9) to afford 3.3 (400 mg, 89%) as a pale yellow oil. FABMS (NBA/NaI) 346 (M+H+ expected 346).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])[C:7]([OH:9])=O.[C:20](OC(=O)CC)(=O)[CH2:21]C.O>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])[C:7](=[O:9])[CH2:20][CH3:21]
Reactant: CCC(=O)OC(=O)CC
Reactant: Cc1ccc(C(=O)NC(CCCCCl)C(=O)O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)C(CCCCCl)NC(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
6-Chloro-2-(p-toluoylamino)hexanoic acid (10.0 g) was dissolved in 15 ml of dry pyridine, and 15 ml of propionic anhydride was added and stirred for 2.5 hours at 90° C. To the mixture was added 15 ml of water slowly so that the maximum temperature did not exceed 85° C., and stirred for 20 minutes at 80° C. The reaction solution was cooled, poured into ice-cold water and extracted with diethyl ether. The extract was washed with 10% hydrochloric acid, an aqueous solution of saturated sodium hydrogen carbonate and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=8:1-4:1) to provide 6.0 g of the objective compound as colorless crystals. M.p. 85-86° C.