Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([C@:22]1([CH2:65][O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:24]([C@@H:42]([CH2:62][CH3:63])[CH2:43][O:44][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:23]1=[O:64])[CH:20]=[CH2:21]>C1COCC1.CCOC(C)=O>[CH2:19]([C@@:22]1([CH2:65][O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:24]([C@@H:42]([CH2:62][CH3:63])[CH2:43][OH:44])[C:23]1=[O:64])[CH:20]=[CH2:21]
Reactant: C=CC[C@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O

Procedure:
A 1M solution of TBAF in THF (2.15 mL, 2.15 mmol) was added to a solution of (3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one (Example 414, Step A; 860 mg, 1.074 mmol) in THF. The reaction was heated to reflux for 3 hours. After cooling, it was diluted with EtOAc and washed with HCl (1N in water). The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated to give the crude material as a glass which was purified by chromatography on silica eluting with 20% EtOAc in hexane, to provide the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]1[CH2:8][C@@H:7](O)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]1[CH2:8][C@@H:7]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105 %

Procedure:
A solution of 20 g (71.6 mmol) of N-Cbz-cis-4-hydroxy-D-proline methyl ester, 15 mL (107 mmol) of triethylamine and 0.4 g (3.3 mmol) of 4-dimethylaminopyridine in 200 mL of CHCl3 was treated with 15.1 g (79.2 mmol) of p-toluenesulfonyl chloride in portions. The reaction was stirred at room temperature for 18 hours and was washed successively with 100 mL of H2O, 100 mL of 1N aqueous citric acid, and 100 mL of H2O. The organic fraction was dried over Na2SO4 and evaporated in vacuo to give 31.4 g of an oil which was purified by flash chromatography (SiO2 ; 50 percent EtOAc in hexanes) to afford 18.2 g (42 mmol; 59 percent) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Na+].[F:19][C:20]([F:24])=[C:21](F)[F:22]>C1C=CC=CC=1.O1CCCC1>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:21]([F:22])=[C:20]([F:24])[F:19])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: FC(F)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(OC(F)=C(F)F)cc2)CC1
Temperature: 140 °C

Procedure:
A solution of 10 g of p-(trans-4-n-propylcyclohexyl)phenol in a mixture of 40 ml of benzene and 10 ml of tetrahydrofuran is reacted with sodium hydride analogously to Example 1. After tetrafluoroethene has been condensed in, the mixture is heated at 140° C. for about 20 hours and treated as described in Example 1. p-(trans-4-n-propylcyclohexyl)trifluorovinyloxybenzene is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.N[C:27]1[C:28]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:29]([C:35]([F:38])=[CH:36][CH:37]=1)[CH2:30][O:31][C:32](=[O:34])[CH3:33]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:10]1[N:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:28]2[C:29]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:35]([F:38])[CH:36]=[CH:37][C:27]=2[N:11]=1)[CH3:9])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)ccc(N)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC(=O)OCc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester 3.94 g, 20.9 mmol) in DCM (20 mL) was added triethyloxonium tetrafluoroborate (3.35 g, 17.6 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (20 mL). Acetic acid 3-amino-6-fluoro-2-phenylaminobenzyl ester (2.3 g, 8.38 mmol) was added and the reaction heated at 75° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off white solid. LCMS (Method C): RT=3.37 min, [M+H-tBu]+=372, 100%, [M+H]+=428, 40%.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]1[N:16]=[C:15]([Cl:17])[C:14]([N+:18]([O-:20])=[O:19])=[C:13](Cl)[N:12]=1.O>C1COCC1.CCOC(C)=O>[Cl:10][C:11]1[N:12]=[C:13]([NH:5][CH3:3])[C:14]([N+:18]([O-:20])=[O:19])=[C:15]([Cl:17])[N:16]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A 2 M solution of methylamine and triethylamine (1.8 mL) in THF (4.6 mL) were added to a solution of 2,4,6-trichloro-5-nitropyrimidine (2 g) in THF (30 mL) under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. After water was added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=99:1 to 90:10), whereby 2,6-dichloro-N-methyl-5-nitropyrimidine-4-amine (680 mg) was obtained as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27]C)[N:16]=2)[CH:12]=[CH:11][CH:10]=1.Cl.N1C=CC=CC=1.C(Cl)(Cl)Cl>O>[OH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:17]1[N:16]=[C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])[N:14]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1-c1cccc(-c2cccc(-c3ccccc3OC)n2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccccc1-c1cccc(-c2cccc(-c3ccccc3O)n2)n1
Temperature: 160 °C
Yield: 72.2 %

Procedure:
A mixture of a 6,6′-bis(2-methoxyphenyl)-2,2′-bipyridyl ligand (0.3 g) and pyridine hydrochloride (10 g) was heated for 4 hours at 160° C. under a nitrogen atmosphere. After cooling the reaction solution to a room temperature, chloroform (20 ml) and water (20 ml) were added to the reaction solution for separation. Thereafter, the organic layer was concentrated. Purification by silica gel chromatography (chloroform as a developing solvent) was carried out, to obtain 0.2 g of 6,6′-bis(2-hydroxyphenyl)-2,2′-bipyridyl.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:47].[Li+]>O1CCCC1.O>[Br:47][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(C(C)=O)c2cccc(CO)c2)cc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(C)=O)c2cccc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 6 g of N-[3-(hydroxymethyl)phenyl]-N-[[4-(tetradecyloxy)phenyl]methyl]acetamide in 100 ml of tetrahydrofuran is added 1.56 g of triethylamine and 1.76 g of methanesulfonyl chloride followed by stirring at ambient temperature for 1 hour. Added 11.14 g of lithium bromide and continued stirring for an additional hour. The mixture is poured into water and extracted with ether. The organic layer is washed with a solution of saturated sodium bicarbonate and brine then dried and evaporated to a residue which is crystallized from petroleum ether to give 6.6 g of the desired product as a white solid, m.p. 56°-58° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:30]=[C:29](Cl)[N:28]=[C:27]([C:32]([F:35])([F:34])[F:33])[N:26]=1>C(Cl)Cl.O>[Cl:24][C:25]1[N:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[N:28]=[C:29]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc(C(F)(F)F)n2)CC1
Reaction time: 8 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (1.4 g, 7.1 mmol, Aldrich) was dissolved in methylene chloride (10. mL) and to this solution was added N,N-diisopropylethylamine (2.5 mL, 14 mmol) and 4,6-dichloro-2-(trifluoromethyl)pyrimidine (1.7 g, 7.8 mmol, Synchem). The reaction was stirred overnight. The mixture was diluted with water and the product was extracted with EtOAc. The organic layer was washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford product which was used without further purification in Step 2. LCMS (M+H)+: 381.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:25]1([NH:28][C:22](=[O:24])[CH2:21][NH:20][C:17]2[S:18][CH:19]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)[N:16]=2)[CH2:27][CH2:26]1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Reactant: NC1CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)NC1CC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 31.2 mg (0.54 mmol) of cyclopropylamine. Yield: 53 mg.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([OH:14])[CH:6]=1)[CH3:2].[CH2:16](Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:14][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])[C:4]([NH:3][CH2:1][CH3:2])=[O:15])[CH3:17]
Reactant: CCBr
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(OCC)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
To a solution of N-ethyl-3-hydroxy-4-nitrobenzamide (2.10 g) obtained in Example 131a) in acetone (100 ml) were added ethyl bromide (0.75 ml) and potassium carbonate (1.38 g), and the reaction mixture was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. Ethyl acetate and water were added to the residue. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-brown solid (0.72 g, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[CH:50]([N:53]([CH3:62])[C:54](N1C=C[N+](C)=C1)=[O:55])([CH3:52])[CH3:51].C(Cl)Cl.C(N(CC)CC)C>>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:19]2[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:16]3[CH:15]=[C:14]([CH2:43][N:44]4[CH2:49][CH2:48][N:47]([C:54]([N:53]([CH:50]([CH3:52])[CH3:51])[CH3:62])=[O:55])[CH2:46][CH2:45]4)[CH:13]=[N:12][C:11]=3[NH:10][C:4]3[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[N:18]=2)=[CH:36][CH:37]=1
Reactant: CC(C)N(C)C(=O)n1cc[n+](C)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)N(C)C(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1

Procedure:
To a 50 mL round-bottomed flask was added 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.350 g, 0.526 mmol), 1-(isopropyl(methyl)carbamoyl)-3-methyl-1H-imidazol-3-ium (0.479 g, 2.63 mmol), DCM (25 mL, 0.526 mmol), triethylamine (0.366 mL, 2.63 mmol). After 1 hour the mixture was washed with 1.0N HCl (2×5 mL) and brine, the organic layer was dried over sodium sulfate, filtered and concentrated under a vacuum to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N-isopropyl-N-methylpiperazine-1-carboxamide, which was treated with trifluoroacetic acid (5 mL, 67.3 mmol), trifluoromethanesulfonic acid (0.2 mL, 0.278 mmol). The solution was stirred at 80° C. for one hour. The dark solution was cooled down to room temperature and concentrated to slurry. The slurry was neutralized to pH 8 with NaHCO2. The precipitate was dissolved in DCM/MeOH and adsorbed onto a plug of silica gel and chromatographed through a silica gel column (40 g), eluting with a gradient of 5% to 10% 2 M NH3-MeOH in DCM, to provide 4-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N-isopropyl-N-methylpiperazine-1-carboxamide (0.033 g, 0.063 mmol, 26.7% yield). m/z (ESI, Positive ion) 525.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.85 Hz, 6H) 2.44 (s, 3H) 2.64 (s, 3H) 2.97 (dd, J=5.38, 4.60 Hz, 4H) 3.09 (d, J=7.24 Hz, 1H) 3.25 (d, J=4.89 Hz, 4H) 3.95 (s, 3H) 4.12 (s, 2H) 7.83 (br. s., 1H) 7.96 (br. s., 1H) 8.33-8.37 (d, 1H) 8.40 (s, 1H) 8.44 (s, 1H) 8.87 (dd, J=2.15, 0.39 Hz, 1H) 12.01 (s, 1H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.Br.[NH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])=[O:15].C(N(CC)CC)C.Cl>CN(C)C=O.O>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:9])[NH:12][CH2:13][C:14]([NH:16][C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])=[O:15])[CH:2]=1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of m-tolylisocyanate (0.846 g, 6.35 mmol) in dimethylformamide (3 ml) is added to a solution of the salt 3a prepared in Preparation 3 (1.937 g, 5.78 mmol) in dimethylformamide (8 ml). Triethylamine (32 ml) is added at 0° C. The mixture is stirred at 0° C. for 30 minutes and then at room temperature overnight. Water and then 10% hydrochloric acid are added. The mixture is extracted with ethyl acetate. The extract is washed with water and dried (sodium sulfate), and then the solvent is distilled off under reduced pressure. The residue is recrystallized from acetonitrile to obtain the objective compound 4a (1.39 g; yield 62%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[NH:21][C:20]=2[CH3:32])[CH2:13][CH2:12]1.C(Cl)Cl>CCOCC>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[NH:21][C:20]([CH3:32])=[C:19]2[CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:16][CH2:15]1
Reactant: COc1cc2[nH]c(C)c(CCN3CCN(N)CC3)c2cc1OC
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2[nH]c(C)c(CCN3CCN(NC(=O)Nc4ccccc4)CC3)c2cc1OC
Reaction time: 2 h

Procedure:
3.5 G of phenylisocyanate are added dropwise to a stirred solution of 7.78 g of 3-[2-(4-aminopiperazin-1-yl) ethyl]-5,6-dimethoxy-2-methylindole in 100 ml. of dry methylene chloride while maintaining the reaction temperature below 35° C. After 2 hours, 50 ml. of ether are added, the product is filtered and washed with ether. The product is recrystallized from ethyl acetate to give a white solid, m.p. 170°-173°C. of 1-[1-(5,6 -dimethoxy-2-methylindol-3-ylethyl)piperazin-4-yl]-3-phenylurea.
Reaction SMILES: C[Si](C)(C)CC[S:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:8]([F:18])[CH:7]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1.CCOC(C)=O>CN(C=O)C>[F:18][C:8]1[CH:7]=[C:6]([SH:5])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1
Reactant: C[Si](C)(C)CCSc1cc(F)cc(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1cc(S)cc(-c2ccccc2)c1
Reaction time: 1.5 h

Procedure:
To S-(2-trimethylsilylethyl)-3-fluoro-5-phenylthiophenol (2.4 g) in DMF (50 mL) was added Bu4NF (16 mL of a 1M THF solution). After 90 min., EtOAc was added and this solution was washed with 1N HCl, H2O and brine. Concentration and chromatography (silica gel; hexane/EtOAc (9:1)) provided the title compound as a liquid.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:29][N:15]1[C:16](=[O:27])[C:17]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[C:13]([C:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[CH2:6][CH2:5][CH2:4][N:3]4[CH:2]=2)[C:14]1=[O:28]
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1C(=O)C(c2c[nH]c3ccccc23)=C(c2cn3c4c(cccc24)CCC3)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrole-2,5-dione (0.1 g, 0.27 mmol) in 4.5 ml of dimethylformamide was treated with potassium carbonate (0.038 g, 0.27 mmol) and stirred for 1 h at rt. Methyl iodide was added (0.034 ml, 0.55 mmol) and the solution was stirred overnight at room temperature. The mixture was treated with cold water and stirred. Crystals were collected by filtration, washed with water and dried under vacuum to give 0.098 g (95%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])O.[Na+].[I:17]Cl>CO>[I:17][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c(N)ccc(I)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a well stirred solution of 2-methyl-3-nitroaniline (10 g, 66 mmol) in methanol (150 mL) was added sodium hydrogencarbonate (264 mmol) followed by 1.0 M solution of iodine monochloride (72 mmol) at room temperature. After stirring for 1 h, the solvent was removed, diluted with ether, washed with 10% aqueous sodium thiosulfate solution. The solvent was removed and the crude iodide was in the next step.
Reaction SMILES: [C@@H:1]1([CH2:10][OH:11])[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][C@@H:2]12.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.O>[CH3:23][C:22]([Si:19]([CH3:21])([CH3:20])[O:11][CH2:10][C@@H:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][C@@H:2]12)([CH3:25])[CH3:24]
Reactant: OC[C@@H]1NCCN2CCC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1NCCN2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of cis-Octahydropyrrolo[1,2-a]pyrazin-1-ylmethanol (D72, 198 mg) in anhydrous DCM (10 mL) under a Nitrogen atmosphere at room temperature, triethylamine (350 microL) and t-butyldimethylsilylchloride (286 mg) were added. The resulting solution was stirred at room temperature overnight then diluted with water (5 mL). The aqueous phase was extracted with DCM (2×10 mL). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified by flash chromatography (DCM/0.5M NH3 in MeOH from 100/0 to 90/10) to give the desired compound (195 mg) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:36][CH2:37][C:38](Br)=[O:39]>ClCCl.O>[Br:36][CH2:37][C:38]([NH:24][C:23]1[CH:25]=[CH:26][C:20]([C:17]2[N:16]=[C:15]([C:4]3[CH:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]4[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=4)[N:5]=3)[O:19][N:18]=2)=[CH:21][CH:22]=1)=[O:39]
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N)cc4)no3)cc2C)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(NC(=O)CBr)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}-aniline (Step 1, 150 mg, 0.434 mmol) and N,N-diisopropylethylamine (113 μL, 0.651 mmol) in dichloromethane (5 mL) was added bromoacetyl bromide (46 μL, 0.521 mmol) dropwise at a temperature of 0° C. After 5 minutes, the reaction mixture was allowed to warm to rt. After a further 2 h, the reaction mixture was diluted with an equal volume of dichloromethane, and 20 mL water were added. After separation of the organic from the aqueous layer, the organic phase was dried over anhydrous sodium sulfate. Subsequent filtration and evaporation of the solvent yielded the title compound which was obtained in pure form after stirring with cyclohexane (195 mg, 96%): 1H NMR (400 MHz, DMSO-d6) 10.70 (s, 1H), 8.03 (d, 2H), 7.80 (d, 2H), 7.18 (d, 2H), 7.10 (d, 2H), 6.90 (s, 1H), 5.44 (s, 2H), 4.09 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H); ES-MS m/z 466/468, HPLC RT (Method F) 2.45 min.