Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17]C)=O)=[C:4]2[N:3]=1.[NH3:19]>>[SH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([NH2:19])=[O:17])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Reactant: N
Product: NC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Reaction time: 24 h

Procedure:
A solution of 1.80 g of methyl 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate in 800 ml of 25 percent aqueous ammonia was allowed to stand at 20° for 24 hours. The solution was concentrated to a small volume in a vacuum, made acidic with 1N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in a vacuum. The residual crystal slurry was treated with petroleum ether and filtered. There was obtained 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Clc1cccc2c1CCCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCCc2c(Cl)cccc21
Yield: 36.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 184 mg of 5-chloro-1,2,3,4-tetrahydroquinoline (can be prepared according to WO 20040116388), and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 141 mg of 2-[2-(5-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ccccc21
Product: CC1c2ccccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 64 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][OH:14])=[CH:4][C:3]=1[I:24].N1C=CC=CC=1.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:12]([CH:15]([CH3:16])[CH3:17])[CH2:13][O:14][C:32]([O:34][CH3:35])=[O:33])=[CH:4][C:3]=1[I:24]
Reactant: CCOC(=O)c1cn([C@H](CO)C(C)C)c2cc(F)c(I)cc2c1=O
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cn([C@H](COC(=O)OC)C(C)C)c2cc(F)c(I)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 16 (13.4 g, 29.9 mmol) and pyridine (9.7 mL, 120 mmol) in anhydrous chloroform (60 mL) at 0° C. was added dropwise a solution of methyl chloroformate (9.2 mL, 120 mmol) in chloroform (30 mL). The mixture was stirred 1 h at 0° C., and then was washed with 2 N HCl (2×60 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil (mixture of 16 and 17) was treated with pyridine (5 mL, 62 mmol) and methyl chloroformate (4.6 mL, 60 mmol) under the same conditions above another four times to achieve approximately 90% conversion. The crude product, a yellow oil, was purified on an AnaLogix chromatography system with 33-50% EtOAc/heptanes to give 7.6 g (50%, greater than 98% purity) of 17 as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11](F)[C:8]=1[C:9]#[N:10]>>[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([O:4][CH2:3][C@@H:2]([NH2:1])[CH3:5])[C:8]=1[C:9]#[N:10]
Reactant: C[C@H](N)CO
Reactant: N#Cc1c(N)cccc1F
Product: C[C@H](N)COc1cccc(N)c1C#N

Procedure:
Prepared as in Example 24d from (S)-2-aminopropan-1-ol and 2-amino-6-fluorobenzonitrile as brown solid (73%). 1H NR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.5 Hz, 3H), 3.08 (m, 1H), 3.71 (d, J=6.1 Hz, 2H), 5.95 (s, 2H), 6.15 (d, J=8.3 Hz, 1H), 6.2 (d, J=8.3 Hz, 1H), 7.13 (t, J=8.3 Hz, 1H). MS 192 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:22](Br)[CH:23]=[CH2:24]>>[OH:1][C:2]1[C:11]([CH2:24][CH:23]=[CH2:22])=[C:10]([O:12][CH3:13])[CH:9]=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(O)cc(OC)cc1/C=C/c1ccccc1
Reactant: C=CCBr
Product: C=CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Yield: 58 %

Procedure:
Use Compound 7 and allyl bromide as materials, and follow the method described in Example 7 to obtain a white solid as the product (58%). 1H NMR (400 MHz, DMSO-d6): 3.22 (d, J=7.6 Hz, 2H), 3.75 (s, 3H), 3.89 (s, 3H), 4.93 (dd, J1=16.0 Hz, J2=12.0 Hz, 1H), 4.96 (dd, J1=6.4 Hz, J2=12.0 Hz, 1H), 6.30 (m, 1H), 6.70 (s, 1H), 6.82 (d, J=16.0 Hz, 1H), 7.30 (m, 2H), 7.42 (d, J=7.6 Hz, 2H), 7.48 (t, J=7.6 Hz, 2H), 9.83 (s, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[F:16][CH:17]([F:20])[CH2:18]I>CN(C=O)C>[F:16][CH:17]([F:20])[CH2:18][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: FC(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2CC(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 59 mg, 1.48 mmol) in DMF (2 mL) was slowly added a solution of 1H-indole-5-carboxylic acid methyl ester 19a (200 mg, 1.14 mmol) in DMF (1 mL) at 0° C. The resulting solution was stirred at 0° C. for 20 min and 1,1-difluoro-2-iodoethane 23a (263 mg, 1.37 mmol) was added. The reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to afford compound 23b.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl.[CH3:16]O>>[NH2:2][CH2:3][C:4]1([CH2:11][C:12]([O:14][CH3:16])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[ClH:1]
Reactant: CO
Reactant: NCC1(CC(=O)O)CCCCCC1
Agent: Cl
Product: COC(=O)CC1(CN)CCCCCC1

Procedure:
In an anologous manner as described in Example 2 1-aminomethyl-1-cycloheptane acetic acid hydrochloride is esterified with methanol in the presence of hydrogen chloride. After working up and crystallisation from isopropanol/ether/hexane, methyl 1-aminomethyl-1-cycloheptane-acetate is obtained as hydrochloride in the form of colourless crystals having a melting point of 115° - 116° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]([F:25])([F:24])[F:23])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]([O:28]C)=[O:27])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO>O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]([F:25])([F:23])[F:24])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]([OH:28])=[O:27])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
Into a 25-mL round-bottom flask, was placed (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate (40 mg, 0.10 mmol, 1.00 equiv), sodium hydroxide (20 mg, 0.50 mmol, 5.00 equiv), methanol (5 mL), water (1 mL). The resulting solution was stirred for 5 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted in 5 mL of water. The PH value was aqueous solution was adjusted to 4 with aq hydrochloric acid (1N). The resulting solids were collected by filtration. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 90% in 8 min, up to 100% in 1.5 min); Detector, UV 220 254 nm. This resulted in 12 mg (30%) of (R)-2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1Br
Reactant: CCCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Br)c(C#N)c1
Temperature: -8 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A round bottom flask was charged with the 2-bromo-5-iodobenzonitrile (2.00 g, 6.49 mmol) and THF (9 mL). Solution cooled down to −8° C. (ice/brine bath). Turbo Grignard 1.3M in THF (5.50 mL, 7.14 mmol) is then added in one portion and the reaction stirred for 15 minutes at −8° C. Butyraldehyde (0.698 μL, 7.79 mmol) is then charged in another flask and the preformed anion is added over the aldehyde/THF (4 mL) via canula and then, reaction allowed to warmed at room temperature overnight under magnetic stirring. Ammonium chloride (sat. aq.) added to the mixture. Extracted 3× with Ethyl Acetate. Combined organic layers washed with water (1×), with brine (1×), dried over sodium sulfate, filtered and concentrated to afford the crude material. Purification by silica gel flash chromatography (Ethyl Acetate/Heptane) provide the title compound as a yellow oil (1.33 g, 80.6%). 1H NMR (400 MHz, DMSO-d6) δ 0.83 (t, J=7.41 Hz, 3H) 1.18-1.34 (m, 2H) 1.46-1.57 (m, 2H) 4.52-4.58 (m, 1H) 5.37 (d, J=4.88 Hz, 1H) 7.56 (dd, J=8.58, 1.95 Hz, 1H) 7.79 (d, J=8.39 Hz, 1H) 7.81 (d, J=2.15 Hz, 1H); MS (M): 255.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2([CH:11]3[CH2:12][C:8]4([C:13]([OH:15])=[O:14])[CH:9]([CH2:10]3)[CH:7]24)[C:4](=[O:16])[NH:3]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:14][C:13]([C:8]23[CH2:12][CH:11]4[C:5]5([C:4](=[O:16])[N:3]([CH2:22][C:21]6[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=6)[C:2](=[O:1])[N:6]5[CH2:22][C:21]5[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=5)[CH:7]2[CH:9]3[CH2:10]4)=[O:15])=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1NC(=O)C2(N1)C1CC3C2C3(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(Cc2ccc(F)cc2)C(=O)C2(C3CC4C2C4(C(=O)OCc2ccc(F)cc2)C3)N1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A solution of 1.1 g (5.0 mmole) of 2′,5′-dioxo-spiro{tricyclo[2.2.1.02,6]heptane-3,4′-imidazoline}-1-carboxylic acid in 30 mL of N,N-dimethylformamide was treated with an excess of p-fluorobenzyl bromide (4.73 g, 25 mmole) and potassium carbonate (3.45 g, 25 mmole) at 60° C. for 36 hours. After cooling to room temperature, the mixture was diluted to 500 mL with water and extracted with 2×250 mL of ethyl acetate. The extracts were washed with water, dried over sodium sulfate and concentrated in vacuum to give 2.7 g of the title compound, again as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccccc1
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To a solution of ethanolamine (1.09 g, 17.8 mmol) in THF was added benzoyl chloride (520 mg, 3.60 mmol) dropwise at 0° C. under N2 atmosphere. The reaction mixture was stirred for 10 min and then quenched with 1M HCl. The mixture was then diluted with EtOAc and washed with sat. aq. NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was crystalized to give N-(2-hydroxyethyl)benzamide (593 mg, 97%) as a white crystalline solid. 1H NMR (CDCl3, 300 MHz) δ3.41 (s, 1H), 3.49-3.59 (m, 2H), 3.75 (t, 2H, J=5.2 Hz), 7.10 (s, 1H), 7.32-7.38 (m, 2H), 7.42-7.48 (m, 1H), 7.72-7.76 (m, 2H) ppm.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:35]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:28]=[C:27]([NH2:36])[C:26]=2[N:25]=[C:24]1[CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl>[NH2:36][C:27]1[C:26]2[N:25]=[C:24]([CH2:37][CH2:38][CH2:39][CH3:40])[N:23]([CH2:22][CH2:21][CH2:20][CH2:19][O:18][NH:17][C:15]([NH:14][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:16])[C:35]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCONC(=O)Nc1ccccc1
Temperature: 50 °C
Yield: 12.2 %

Procedure:
Triethylamine (495 μL, 3.55 mmol) and phenyl isocyanate (316 mg, 1.65 mmol) were added to a mixture of 1-[4-(aminooxy)butyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (580 mg, 1.77 mmol) in chloroform (10 mL). The reaction was heated at 50° C. overnight and became homogeneous. The solution was diluted with 1 chloroform, washed with brine (2×), dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure to provide the crude product as an orange solid (700 mg). The crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in ratios ranging from 100:0 to 95:5) to provide 90 mg of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-N′-phenylurea as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1(/[CH:9]=[CH:10]/[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][CH:15]=2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[CH3:36][O:35][C:33]([CH2:32][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])/[CH:22]=[CH:23]/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:15]=1)=[O:34]
Reactant: O=C(/C=C/c1ccccc1)Nc1ccc(OC(=O)/C=C/c2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CN(C(=O)/C=C/c1ccccc1)c1ccc(OC(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.4 %

Procedure:
Sodium hydride (60%, 162 mg, 4.06 mmol) was washed with anhydrous THF (×2) and then suspended in anhydrous THF (20 mL). To this was added (E)-3-phenylacrylic acid 4-[(E)-(3-phenylacryloyl)amino]phenyl ester 11 (1.00 g, 2.71 mmol) followed by methyl bromoacetate (0.51 mL, 5.41 mmol). The reaction mixture was stirred at room temperature for 3 days. It was then diluted with ethyl acetate and washed with brine (×3), dried (Na2SO4) and evaporated. The resultant residue was purified by flash column chromatography on silica gel, eluting with petrol/ethyl acetate (2:1→1:1) and then ethyl acetate, to afford the title compound (0.734 g, 61%). 1HNMR (300 MHz) (CDCl3) δ 3.77 (3H, s), 4.52 (2H, s), 6.43 (1H, d, J=16 Hz), 6.65 (1H, d, J=16 Hz), 7.25-7.40 (7H, m), 7.45 (4H, m), 7.61 (3H, m), 7.75 (1H, d, J=16 Hz) and 7.91 (1H, d, J=16 Hz).
Reaction SMILES: [CH3:1][CH2:2]N=C=NCCCN(C)C.[CH:12]1[CH:13]=[CH:14][C:15]2[N:20](O)N=[N:18][C:16]=2[CH:17]=1>CS(C)=O>[N:20]1[C:15]2[C:16](=[CH:17][CH:12]=[CH:13][CH:14]=2)[N:18]=[CH:2][CH:1]=1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Solvent: CS(C)=O
Product: c1ccc2nccnc2c1

Procedure:
Compounds of structure H may be prepared as illustrated in Scheme 2. Reaction of a carboxylic acid E with various hydrazides in the presence of EDCI and HOBt in DMSO yields quinoxaline F. Quinoxaline F may then be treated with phosphorus oxychloride to give quinoxaline G. Subsequent reaction of quinoxaline G with ammonia at elevated temperature then provides compounds H.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]([CH:17]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:33](Br)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].O>C(O)C>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]([CH:17]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:15][CH2:8][CH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH3:6])=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: O=C(C(c1ccccc1)c1ccc(O)cc1)C(c1ccccc1)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(C(=O)C(c2ccccc2)c2ccc(OCCCCCCCCCCCCCC)cc2)c2ccccc2)cc1
Reaction time: 12 h
Yield: 167 %

Procedure:
To a solution of 4-hydroxyphenyl-benzyl ketone (10.5 g) in a solution of potassium hydroxide (3.0 g) in ethanol (100 ml) was added tetradecylbromide (16 g). The reaction mixture was stirred at gentle reflux temperature for 12 hours, cooled and poured into water. The product was extracted into chloroform, washed further with water, dried over MgSO4, filtered and evaporated. Recrystallisation of the residue from methanol gave the above compound as a colourless crystalline solid (17.5 g, 86%) m.p. 72°-74° C.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].CS(O[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:21]=[O:22])(=O)=O>CN(C)C=O>[CH2:7]([N:6]([CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:21]=[O:22])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCNCCCCC
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCN(CCCCC)Cc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a solution of dipentylamine (258 mg) and diiosopropylethylamine (212 mg) in dimethylformamide (2 ml) was added 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (350 mg). After stirring at room temperature for 2 weeks, the reaction mixture was partially concentrated under reduced pressure and the residue was purified by flash column chromatography using petroleum ether:diethyl ether (1:3) as eluant. The pure fractions were combined and evaporated under reduced pressure to give 3-[(dipentylamino)methyl]-4-phenylmethoxybenzaldehyde (356 mg) as a gum. 1H NMR (CDCl3) δ9.90 (s, 1H, CHO); 5.15 (s, 2H); 3.70 (s, 2H); 2.50 (m, 4H); 1.55 (m, 4H); 1.30(m, 8H); 0.90 (t, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]=[C:15]=[S:16]>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:15]([NH:14][CH3:13])=[S:16])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)NCc1ccc(C(C)(C)C)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
At 20 to 30° c., a solution of 163 g (1 mol) of 4-tert.-butylbenzylamine in 100 ml of anhydrous acetonitrile was dripped, while cooling, into a mixture of 73 g (1 mol) of methyl isothiocyanate in 80 ml of anhydrous acetonitrile. The mixture was stirred for 3 hours at 20° C. and then for a further hour at 80 to 90° C. before being evaporated down. The crude product was precipitated with hexane from ethyl acetate, washed with hexane and dried under reduced pressure at 60° c.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[CH:11]1([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:7][CH:6]=2)=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(Nc1ccc(O)nc1)C1CCCCC1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(NC(=O)C2CCCCC2)cn1)c1ccccc1
Yield: 70.7 %

Procedure:
A solution of cyclohexanecarboxylic acid (6-hydroxy-pyridin-3-yl)-amide (0.66 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 18 hours. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.75 g, 71% yield) as a slightly coloured solid.
Reaction SMILES: Cl.[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:3]1.C(N(CC)CC)C.[C:28](#[N:31])[CH:29]=[CH2:30]>CO>[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH2:12][CH2:13][N:14]([CH2:30][CH2:29][C:28]#[N:31])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:3]1
Reactant: COC(=O)CCNCCC1COc2ccccc2C1
Reactant: C=CC#N
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCN(CCC#N)CCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
30 g (0.1 mol) of N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 5.84 g (0.11 mol) of acrylonitrile are added to the solution and the whole is stirred for 15 hours at room temperature. The reaction mixture is then concentrated under a water-jet vacuum, the residue is taken up in diethyl ether and the ethereal solution is washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-N-(2-methoxycarbonylethyl)-amine is thus obtained in the form of a yellow oil.