Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:2].C(Cl)Cl.[C:24]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:24]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([N:3]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:1][CH3:2])=[O:36])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CCN[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1ccccc1C(=O)c1ccccc1)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1

Procedure:
Twenty-four grams of trans N-(2-ETHYLAMINOCYCLOHEXYL)-p-TOLUENESULFONAMIDE from Example III,200 ml of methylenechloride, 24ml of triethylamine and 20 grams of ψ-acid chloride of o-benzoylbenzoic acid were mixed together and refluxed 4 hours. The mixture was extracted successively with water, 15% hydrochloric acid, and saturated sodium carbonate solution. The methylenechloride solution was dried over magnesium sulfate, then evaporated to dryness. The residue was slurried with ethyl acetate and filtered. Recrystallization from ethyl acetate afforded trans-2-BENZOYL-N-[2-(p-TOLUENESULFONAMIDO)CYCLOHEXYL]-N-ETHYL BENZAMIDE, mp. 201.5°-204°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:13]([CH2:24]Cl)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:13]([CH2:24][N:35]1[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]1=[O:36])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC2CC2)c(=O)c2ccc(OCc3ccccc3)cc12
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC2CC2)c(=O)c2ccc(OCc3ccccc3)cc12
Yield: 95.1 %

Procedure:
A solution of 6-benzyloxy-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone (5.96 g, 14, mmol) and potassium phthalimide (3.89 g, 21 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[(6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (7.14 g, 95.1%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@:4]([N:9]=[C:10]=[O:11])([CH:6]([CH3:8])[CH3:7])N.[CH2:13]([N:15]([C:18]1[S:19][CH:20]=[C:21]([CH2:23][OH:24])[N:22]=1)[CH2:16][CH3:17])[CH3:14]>ClCCl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:9][C:10]([O:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[S:19][CH:20]=1)=[O:11]
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Reactant: CCN(CC)c1nc(CO)cs1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)c1nc(COC(=O)N[C@H](C(=O)OC)C(C)C)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of 5.11 mmol of α-isocyanato-valine methyl ester in 10 ml of dichloromethane was treated with 0.864 g (4.65 mmol) of 2-(N,N-diethylamino)-4-(hydroxymethyl)thiazole and 0.46 mmol of 4-dimethylaminopyridine. The resulting solution was stirred at ambient temperature for 16 h, after which it was diluted with 200 ml of chloroform, washed successively with 10% citric acid, aqueous NaHCO3, and saturated brine. After drying over Na2SO4, the solvent was removed in vacuo, and the residue was chromatographed on silica gel using 1-2% methanol in chloroform to provide 1.31 g (82%) of the desired compound, Rf 0.51 (4% methanol in chloroform) as an oil. 1H NMR (CDCl3) δ 0.89 (d, J=7 Hz, 3 H), 0.96 (d, J=7 Hz, 3 H), 1.24 (t, J=7 Hz, 6 H), 2.15 (m, 1 H), 3.51 (q, J=7 Hz, 4 H), 3.74 (s, 3 H), 4.29 (dd, J=8, 4 Hz, 1 H), 5.03 (s, 2 H), 5.34 (br d, J=8 Hz, 1 H), 6.42 (s, 1 H). Mass spectrum: (M+H)+ =344.
Reaction SMILES: [N+:1]([O-])([N+]([O-])=O)=[O:2].C([O-])(=O)C.[Na+].[Cl:12][CH2:13][CH2:14][NH:15][C:16]([N:18]=[N+:19]=[N-:20])=[O:17].CC(O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:13][CH2:14][N:15]([N:1]=[O:2])[C:16]([N:18]=[N+:19]=[N-:20])=[O:17]
Reactant: [N-]=[N+]=NC(=O)NCCCl
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=NC(=O)N(CCCl)N=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Nitrogen tetroxide (0,3 mole) was slowly added to a suspension of anhydrous sodium acetate (0.6 mole) in 300 ml of carbon tetrachloride at -10° C. After warming to 0° C., 2-chloroethylcarbamoyl azide (0.2) was slowly added with a spatula to the stirred suspension. A white precipitate was formed (AcOH). After 15 minutes, the reaction mixture was poured into ice water. The separated organic phase was extracted twice with 50 ml of a cold solution of NaHCO3 (1 molar) and was then washed neutral with 2×50 ml of ice cold water saturated with NaCl. It was then dried over anhydrous sodium sulfate. No attempt was made to isolate N-(chloroethyl)-N-nitrosocarbamoyl azide as it is potentially explosive. The NMR spectroscopic examination of the CCl4 solution (internal standard TMS) showed the complete absence of an NH- signal and showed a pattern which is typical for the A2B2 system of the nitrosated 2-chloroethylamino group. δ=3.50 ppm (t, 2H, --CH2 -- N--NO); 4.15 ppm (t, 2H, Cl--CH2 --).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:43])([F:44])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: O=C(NCC(F)(F)F)C1(CCCCCBr)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (a) of Example 94 were used as the starting compounds. Thus, ethyl 4-[4-[5-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]pentyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: C(OC([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH2:17][CH3:18])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O)C.[OH-].[Na+]>>[CH2:17]([C:11]1[N:10]=[C:9]2[C:14]([C:15]([OH:16])=[CH:6][CH:7]=[N:8]2)=[CH:13][CH:12]=1)[CH3:18]
Reactant: CCOC(=O)c1c[nH]c2nc(CC)ccc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc2c(O)ccnc2n1
Yield: 73 %

Procedure:
The product from Example 8d (4.70 g, 19.1 mmol) was reacted with NaOH (0.808 g, 20.2 mmol) following the procedure of Example 7c giving the title compound as a light green solid (2.43 g, 73%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C1CCCCC=1>CO>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CO
Solvent: C1=CCCCC1
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Dov-Leu-Dil-OBut (5) was prepared as follows: A solution of Z-Leu-Dil-OBut (3, 2.22 mM) was dissolved in anhydrous methanol (10 mL) and cyclohexene (10 mL) was added in a nitrogen atmosphere. To the solution was added 5% Pd--C (1.15 g) and the mixture was heated at reflux for 6 minutes. The catalyst was removed by filtering through a layer of celite, the solvent removed under reduced pressure, and the residue dried in high vacuum for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[CH3:11][N:12]=[C:13]=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:8]([CH2:9][CH3:10])[C:13]([NH:12][CH3:11])=[O:14])=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: CCNc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: CCN(C(=O)NC)c1ccc(Cl)nc1
Yield: 93.6 %

Procedure:
In 30 ml of toluene was dissolved 2.4 g (0.015 mole) of 2-chloro-5-ethylaminopyridine, followed by addition of 3.4 g of methyl isocyanate. The mixture was refluxed for 15 hours. After cooling, the resulting crystals were collected by filtration, washed with a small amount of Et2O and dried. The procedure gave 3.0 g of N-(6-chloro-3-pyridyl)-N-ethyl-N'-methylurea as pale yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[OH-].[K+].[N+:10]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])#[C-:11]>CO>[S:1]1[CH:5]=[CH:4][C:3]([C@@H:6]2[O:7][CH:11]=[N:10][C@H:12]2[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[O:14])=[CH:2]1
Reactant: [C-]#[N+]CC(=O)N1CCOCC1
Reactant: O=Cc1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccsc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
SLA 09052A was prepared in accordance with method D using thiophene-3-carbaldehyde (0.768 mL, 5.35 mmol), KOH (0.273 mg, 4.86 mmol) in methanol (5 mL) and 2-isocyano-1-morpholinoethanone SLA 07118 (0.75 g, 4.86 mmol). The solution was stirred for 2 h at 0° C. After work-up the residue was purified by column chromatography (florisil, EtOAc). After evaporation and drying, trans-(4,5-dihydro-5-(thiophen-3-yl)oxazol-4-yl)(morpholino)methanone SLA 09052A (0.327 g, 25% yield) was obtained as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[F:16])C.O.O.[OH-].[Li+].Cl>O1CCCC1>[CH2:14]([S:11]([C:9]1[CH:8]=[CH:7][C:6]([F:16])=[C:5]([CH:10]=1)[C:4]([OH:17])=[O:3])(=[O:12])=[O:13])[CH3:15]
Reactant: CCOC(=O)c1cc(S(=O)(=O)CC)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To 10.8 mmol 5-ethanesulfonyl-2-fluoro-benzoic acid ethyl ester in 26 ml tetrahydrofuran was added 26 ml water and 16.1 mmol lithium hydroxide monohydrate and the reaction mixture was stirred at room temperature for 45 minutes. After such time, the reaction mixture was acidified with 1N HCl, tetrahydrofuran was evaporated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give the title compound as a white solid (96%). MS (m/e): 232.1 ([M+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1Cl
Reactant: NCc1ccccc1
Solvent: O
Product: N#Cc1c(N)nc2ccc(N3CCOCC3)cc2c1NCc1ccccc1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-(morpholin-4-yl)quinoline and 6 mL of benzylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 2.3 g of the title compound is obtained, m.p.: 202° C.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH:15][CH2:16][CH2:17][N:18]([CH2:23][CH2:24][OH:25])[C:19](=[O:22])[CH2:20][OH:21]>>[C:1]([O:15][CH2:16][CH2:17][N:18]([CH2:23][CH2:24][O:25][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:19](=[O:22])[CH2:20][O:21][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(CO)N(CCO)CCO
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCC)C(=O)COC(=O)CCCCCCCCCCC

Procedure:
This compound was prepared from 131 g (0.6 mole) of lauroyl chloride and 32.6 g (0.2 mole) of N,N-bis(hydroxyethyl)hydroxyacetamide by the procedure of Example 1. Its structure was established by infrared and nuclear magnetic resonance spectroscopy. It was a low-melting solid and had nD30 1.4597 and m.p. 29.6° C.
Reaction SMILES: [Cl-].C(N(C(C)C)CC)(C)C.[OH:11][C@@H:12]([C@H:14]1[C:35](=[O:36])[N:16]2[CH:17]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:18](=O)[C@H:19]([CH3:20])[C@H:15]12)[CH3:13].FC(F)(F)S(O)(=O)=O.FC(F)(F)S(O)(=O)=O.[SH:53][C@@H:54]1[CH2:58][N:57]([CH3:59])[C@H:56]([C:60]([N:62]2[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]2)=[O:61])[CH2:55]1>C(#N)C>[CH3:68][N:65]1[CH2:66][CH2:67][N:62]([C:60]([C@@H:56]2[CH2:55][C@H:54]([S:53][C:18]3[C@H:19]([CH3:20])[C@@H:15]4[C@@H:14]([C@H:12]([OH:11])[CH3:13])[C:35](=[O:36])[N:16]4[C:17]=3[C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:23])[CH2:58][N:57]2[CH3:59])=[O:61])[CH2:63][CH2:64]1
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 50 %

Procedure:
540 μl of diphenylphosophoryl chloride and 470 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 920 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 10 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 1400 μl of diisopropylethylamine and a solution of 1350 mg of (2S,4S)-4-mercapto-2-(4-methyl-1-piperazinylcarbonyl)-1-methylpyrrolidine bis(trifluoromethanesulfonate) (prepared as described in Preparation 51) in 5 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by chromatography through a Lobar column (Merck, LiChroprep RP-8, size B). The column was successively eluted with 65% by volume aqueous methanol and with 70% by volume aqueous methanol. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 730 mg of the title compound, as a powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:21]1([N:18]2[CH2:17][CH2:16][CH:15]([CH2:14][C:11]3[N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:35]5[CH2:36][CH2:37][N:32]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[CH2:33][CH2:34]5)=[CH:4][CH:5]=4)[O:13][N:12]=3)[CH2:20][CH2:19]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: ClCc1ccc(-c2nc(CC3CCN(C4CCCC4)CC3)no2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: c1ccc(N2CCN(Cc3ccc(-c4nc(CC5CCN(C6CCCC6)CC5)no4)cc3)CC2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 23, starting from 4-[5-(4-chloromethylphenyl) [1,2,4]oxadiazol-3-ylmethyl]-1-cyclopentyl-piperidine and 1-phenylpiperazine.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:25][CH2:26]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1ccc(CCN2CCNCC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)N1CCN(CCc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
Benzene sulphonyl chloride (0.15 g), the foregoing amine (0.193 g) and potassium carbonate (0.118 g) were heated together in MeCN (10 ml). Reaction was monitored by mass spectroscopy, and was completed after 2 h. The reaction mixture was cooled to room temperature, quenched with water and extracted into ethyl acetate. The organic extracts were combined, washed with water, dried (MgSO4) and concentrated to give a dark orange solid. This solid was purified by dry flash chromatography using SiO2, CH2Cl2 to 5% MeOH:CH2Cl2, followed by recrystallisation using pet. ether and CH2Cl2 to give the title product as a pale yellow solid (23%). MS: (M+H)+=367. δH (360 MHz, CDCl3): 2.50-2.60 (6H, m), 2.66-2.74 (2H, m), 3.02-3.10 (4H, m), 6.70-6.80 (2H, m), 7.05-7.14 (1H, m), 7.50-7.56 (2H, m), 7.56-7.62 (1H, m), 7.74-7.80 (2H, m). CHN C18H20 F2N2O2S: calc. C=59.00, H=5.50, N=7.65%; found C=59.12, H=5.43, N=7.56%.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[CH3:18][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH3:18][C:2]1[C:11]([NH:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2
Reactant: Brc1c(NC2=NCCN2)ccc2nccnc12
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(NC2=NCCN2)ccc2nccnc12
Temperature: 145 °C
Yield: 56.8 %

Procedure:
A sealable reaction tube was charged with 5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline (104 mg., 0.36 mmol) (prepared as noted above), tetramethyl tin (214 mg., 1.2 mmol) and (Ph3P)2PdCl2 (10 mg) and dry dimethylformamide (2 ml) in a reaction tube. The reaction mixture was purged with dry nitrogen gas. The tube was sealed and heated to 145° C. for 6 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuou The dark brown residue was chromatographed (SiO2 ; 5/1 CHCl3 /CH3OH saturated with NH3 (g)) to yield 46.5 mg (53%) of the title compound as a light yellow solid. An analytical sample was prepared by recrystallization from CHCl3 /CH3OH and had a melting point of 183°-186° C. The title compound was characterized by 1H and 13CNMR, IR and mass spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:20](Br)[CH3:21]>CN(C)C=O>[O:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)NCCO2
Temperature: 110 °C
Reaction time: 5 h

Procedure:
5.16 g of methyl 3-amino-4-hydroxybenzoate are dissolved in 100 ml of dimethylformamide in a 500 ml round-bottomed flask. 17.06 g of potassium carbonate and then 7.98 ml of dibromoethane are subsequently added. The reaction medium is heated at 110° C. with stirring for five hours. After evaporating the solvent, water and ethyl acetate are added. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and then dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane/ethyl acetate 6/4 mixture. 3.61 g of methyl 3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[C:18]1([OH:29])[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[C:18]1([O:29][CH3:32])[C:19](=[O:28])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(C(C)C)cc2OCc2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 12 %

Procedure:
2-(2-benzyloxy-4-isopropyl-phenyl)-2-hydroxy-indan-1,3-dione (0.10 g, 0.25 mmol) was completely dissolved in anhydrous DMF (2 ml). This solution was added with sodium hydride (0.007 g, 0.31 mmol) and methyl iodide (0.04 g, 0.28 mmol), and stirred at room temperature for 13 hrs. The reaction mixture was extracted with dichloromethane, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (12 mg, 12%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][P:11](Cl)([CH3:13])=[O:12]>C1COCC1>[CH3:10][P:11]([CH3:13])([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CP(C)(=O)Cl
Solvent: C1CCOC1
Product: CP(C)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
To a cooled (0° C.) flask containing 34.0 mL (2.0 M in Et2O, 68.4 mmol) of 4-fluorophenylmagnesium bromide, under an atmosphere of N2, was added a solution of dimethylphosphinic chloride (3.50 g, 31.1 mmol) in 84 mL of THF, dropwise via cannulation, over 20 min. The green reaction mixture was stirred at 0° C. for 1 h, then quenched at 0° C. with 30 mL of saturated NH4Cl resulting in the formation of a white precipitate. The mixture was concentrated on a rotary evaporator and partitioned between EtOAc (200 mL) and H2O (200 mL), upon which the layers were separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organics washed with brine, then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 5% MeOHIDCM) to provide 2.08 g of an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.83 (m, 2H), 7.35 (td, J=8.9, 1.7 Hz, 2H), 1.66 (s, 3H), 1.61 (s, 3H). 31P NMR (121 MHz, DMSO-d6) δ 37.186. 19F NMR (282 MHz, DMSO-d6) δ−105.14.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:17][C:11]3=[C:10]2Cl)=[CH:4][CH:3]=1.[OH-:25].[Na+].O.Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:17][C:11]3=[C:10]2[OH:25])=[CH:4][CH:3]=1
Reactant: Clc1c2nc(-c3ccccc3)nc-2ccn1Cc1ccc(Br)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1c2nc(-c3ccccc3)nc-2ccn1Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 81 %

Procedure:
5-[(4-Bromophenyl)methyl]-4-chloro-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-96) (see example 63) (0.200 g) was dissolved in DMF (5 mL) and 2N aqueous sodium hydroxide solution (10 mL) was added. The resulting mixture was heated at 60° C. for 24 h. Then water (50 mL) was added and the resulting mixture was neutralized by addition of 2N HCl. The precipitate was collected by filtration to give the crude product.