Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I.[Cl-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:33])[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(Br)cc4)CC3)c2cc1OC
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCN(C(=O)N(C)c4ccc(Br)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 1.01 g (2.15 mmol) of N-(4-bromophenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide obtained in Example 45 in 15 ml of dimethylformamide was added 171.9 mg (4.30 mmol) of 60% sodium hydride under ice-cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 0.27 ml (4.34 mmol) of methyl iodide, followed by overnight stirring at room temperature. The resulting mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel column chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.[C:24](=O)([O:35]C1C=CC([N+]([O-])=O)=CC=1)[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33]>C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:5][C:4]([CH3:7])([O:3][C:1](=[O:2])[NH:8][CH:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][C:24](=[O:35])[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=C(OCCOCCO[N+](=O)[O-])Oc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(COC(=O)OCCOCCO[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a solution or N-Boc-L-Serine (1.66 g, 8.12 mmol), diisopropylethyl amine (DIPEA) (1.41 ml, 8.12 mmol), N,N-dimethylaminopyridine (DMAP) (1.19 g, 9.74 mmol) and scandium triflate (1.20 g, 2.43 mmol) in CH2Cl2 (40 ml), cooled to −10° C., a solution of 2-[2-(nitrooxy)ethoxy]ethyl 4-nitrophenyl carbonate in CH2Cl2 (40 ml) was added drop-wise. The reaction was slowly warmed to room temperature and stirred for 24 h. Then the organic phase was washed with pH 3 aqueous buffer and concentrated under reduced pressure. The crude was partitioned between aqueous 5% aqueous Na2HPO4 and diethyl ether and extracted twice with diethyl ether. The aqueous phase was acidified to pH 3 and extracted with CH2Cl2. The organic phase was finally dried over sodium sulphate and concentrated under reduced pressure to give the title compound as an oil. (2.4 g, 80%)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]([N:28]1[C:32]([CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:31][C:30]([CH:37]=O)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[C:32]([CH2:33][CH:34]([CH3:35])[CH3:36])=[CH:31][C:30]([CH2:37][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Product: CC(C)Cc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1C(C)(C)C
Yield: 68 %

Procedure:
Compound 95 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.[CH:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([CH3:36])[CH3:35]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:47]2[CH2:48][CH2:49][CH:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[O:37][CH:34]([CH3:36])[CH3:35])[CH2:45][CH2:46]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: CC(C)Oc1ccccc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1ccccc1C1CCN(C2CCC(NC(=O)OC(C)(C)C)CC2)CC1
Reaction time: 48 h
Yield: 48 %

Procedure:
A (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester Compound 1b (1.54 g, 7.21 mmol), NaBH(OAc)3 (64.45 g, 21.0 mmol) and HOAc (0.3 mL) were added to a solution of 4-(2-isopropoxy-phenyl)-piperidine Compound 1a (1.32 g, 6.01 mmol) in CH2Cl2 (100 mL). The mixture was stirred under N2 for two days, then the reaction was quenched with MeOH. The mixture was evaporated and the resulting residue was redissolved with CH2Cl2, washed using 10% aqueous Na2CO3 and brine, then dried (Na2SO4). The crude product was purified by column chromatography to provide {4-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-carbamic acid tert-butyl ester Compound 1c as a mixture of cis/trans isomers (MS 416; yellowish oil; 1.19 g, 48% yield).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.[CH3:23][O:24][CH2:25][C@@H:26]([NH2:28])[CH3:27].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[CH3:23][O:24][CH2:25][C@@H:26]([NH:28][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:27]
Reactant: COC[C@H](C)N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
In a round-bottomed flask were combined 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.32 mmol) and (S)-1-methoxypropan-2-amine hydrochloride (61 mg, 0.49 mmol). DMF (1.5 mL) was added followed by N,N-diisopropylethylamine (0.15 mL, 0.86 mmol) and HATU (135 mg, 0.36 mmol). The yellow reaction mixture was stirred at room temperature overnight then water was added. The resulting suspension was filtered and the filter cake was washed with water and petroleum ether then dried under high vacuum to provide 129 mg (90%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white powder.
Reaction SMILES: C([CH:4]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)[C:5]([CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)=[O:6])C=C.[O:32]1CC[CH2:34][CH2:33]1.O.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([CH:4]([C:5](=[O:6])[CH2:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[CH2:34][CH2:33][OH:32])[CH:21]=[C:22]([O:30][CH3:31])[C:23]=1[O:28][CH3:29]
Reactant: C=CCC(C(=O)Cc1cc(OC)c(OC)c(OC)c1)c1cc(OC)c(OC)c(OC)c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc(CC(=O)C(CCO)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 27.5 g of the compound prepared in (d) above in 640 ml of a mixture of tetrahydrofuran and water (in a 2:1 ratio) was added 9 ml of a 2.5% solution of osmium tetraoxide in tert.-butanol. The reaction mixture was then allowed to stir at room temperature until it darkened to a black opaque mixture, after which time 82.07 g of sodium metaperiodate was added. The resultant mixture was then stirred at room temperature for 20 hours, after which time it was filtered and the solvent was removed by evaporation to yield a residue that was extracted with a mixture of ethyl acetate and water. The organic layer was evaporated and the resultant residue was chromatographed on silica gel employing a mixture of methylene chloride and ethyl acetate in a ratio of 8:1 as the eluent to yield a solid.
Reaction SMILES: [S:1]1[C:5]([C:6]([Cl:8])=[O:7])=[CH:4][N:3]=[CH:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:5]3[S:1][CH:2]=[N:3][CH:4]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)c1cncs1
Product: COc1cc2nc(N3CCN(C(=O)c4cncs4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared from thiazole-5-carbonyl chloride (0.77 g.) and 4-amino-6,7dimethoxy-2-(1-piperazinyl)quinazoline (1.51 g.) following previously described procedures. The product had a m.p. of 280°-281° C. with decomposition.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[N:18]=[C:19]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)[CH2:37][CH2:36]3)=[C:31]([CH3:48])[CH:30]=2)[C:20]([C:25]([NH2:27])=[O:26])=[N:21][C:22]=1[CH2:23][CH3:24]>CN(C)C=O>[C:25]([C:20]1[N:21]=[C:22]([CH2:23][CH3:24])[C:17]([O:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:18][C:19]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][CH:38]([N:41]3[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]3)[CH2:37][CH2:36]2)=[C:31]([CH3:48])[CH:30]=1)(=[O:26])[NH2:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
To a mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (860 mg) and N,N-dimethylformamide (30 mL) was added 55% oily sodium hydride (200 mg) under ice-cooling. After stirring for 30 minutes under ice-cooling, 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (1 g) was added thereto, followed by further stirring for 1 hour under ice-cooling. 55% oily sodium hydride (100 mg) was added thereto, followed by stirring at room temperature for 4 hours, and then 55% oily sodium hydride (100 mg) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-ethyl-6-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (284 mg).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH2:6]Br)[CH2:3]Br.[NH2:8][C@@H:9]([CH3:12])[CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C@H:2]1[CH2:5][CH2:6][N:8]([C@@H:9]([CH3:12])[CH2:10][OH:11])[CH2:3]1
Reactant: C[C@H](CBr)CCBr
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C

Procedure:
A solution of 2-(S)-methyl-1,4-dibromobutane (2.70 g, 0.012 moles) in anhydrous acetonitrile (8 mL) was added to a mixture of of (S)-(+)-2-amino-1-propanol (0.882 g, 0.012 moles, Aldrich) and potassium carbonate (3.25 g, 0.024 moles) in anhydrous acetonitrile (92 mL). The resulting mixture was refluxed for 22 hours then cooled to room temperature and concentrated under vacuum to an oily white solid. Dichloromethane (50 mL) and saturated aqueous potassium carbonate (10 mL) were added followed by just enough water to dissolve all solid. The layers (upper layer organic, lower layer aqueous) were separated and the aqueous layer was saturated with sodium chloride and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over magnesium sulfate and potassium carbonate, filtered and evaporated to a light yellow liquid. This crude product was purified by column chromatography on silica gel eluted with 10:7:2:1 ethyl acetate:hexane:methanol:triethylamine to afford the title compound as a light yellow liquid. NMR: (CDCl3, 600 MHz) δ 3.52 & 3.32 (2H, 2 dd, J=5, 10 Hz, H1), 3.36 (1H, br s, OH), 2.79 (1H, t, J=8 Hz, H2′a), 2.54–2.58 (1H, m, H2), 2.66–2.72 & 2.56–2.62 (4H, 2m, H5′), 2.13–2.21 (1H, m, H3′), 2.08 (1H, td, J=8 Hz, H2′b), 1.92–2.00 & 1.25–1.33 (4H, 2m, & H4′), 1.00 (3H, d, J=7 Hz, H3′Me), 0.99 (3H, d, J=7 Hz, H3); MS (electrospray): m/e 144 (M+H), 126 (M−OH). [α]D+3.4°.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][N:3]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[C:6]2[C:7]([O:11][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1noc2cccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc2cccc(Oc3ccc([N+](=O)[O-])cc3)c12
Temperature: 110 °C
Yield: 40.3 %

Procedure:
3-methyl-1,2-benzisoxazol-4-ol (Intermediate 10, 137 mg) was stirred with 1-fluoro-4-nitrobenzene (130 mg, 0.92 mmol) in DMF (3.0 ml) with potassium carbonate (381 mg, 2.8 mmol). The reaction mixture was heated at 110° C. for 1 hour under microwave irradiation After removal of the volatiles, the residue was purified by silica gel chromatography eluting with CyHex/EtOAc (100%/0% to 0%/100%) to afford the title compound (100 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:6][CH:7]=1.C(N(CC)CC)C.C(O)=O>C1(C)C=CC=CC=1>[CH:11]1([C:9]([NH:8][C:5]2[C:4]([N+:14]([O-:16])=[O:15])=[C:3]([CH3:17])[CH:2]=[CH:7][N:6]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1c(Br)cnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: Cc1ccnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Yield: 72.3 %

Procedure:
Toluene (60 ml) was added to 3.0 g (10.0 mmol) of 5-bromo-2-cyclopropanecarboxamido-4-methyl-3-nitropyridine, 10% Pd--C (100 mg) and 2.9 g (28.6 mmol) of triethylamine, followed by stirring and heating under reflux. 1.9 g (41.3 mmol) of formic acid was dropwise added to this solution, followed by stirring for 5 hours. The reaction liquid was brought to room temperature and filtered to remove the catalyst. The filtrate was subjected to vacuum concentration. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) once. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.6 g of the title compound (yield 72%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:28][C:29]([OH:31])=O)([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:19])[C:9]1=[O:32])C1C=CC=CC=1.ON1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:64][C:65]1[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=1>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:28][C:29]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)=[O:31])([NH:17][C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:19])[C:9]1=[O:32])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(N)cc1
Reactant: Cc1ccc(NC(=O)NC2(CC(=O)O)C(=O)N(Cc3ccccc3)c3ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(Cc3ccccc3)c3ccccc32)cc1
Reaction time: 6 h
Yield: 57 %

Procedure:
(RS)-1-Benzyl-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one was dissolved in 15 ml of dry N,N-dimethylformamide, and 0.080 g of 1-hydroxybenzotriazole, 0.1 ml of diisopropylethylamine, 0.111 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 0.065 g of p-toluidine were successively added to the solution. The mixture was stirred for 6 hours and concentrated. The concentrate was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (chloroform/ethyl acetate=4/1) to give 0.350 g (57%) of the title compound as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[S:10][C:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])=[O:15])=[CH:12][N:13]=2)[CH2:3][CH2:2]1.Cl.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30].CCN(CC)CC>C(Cl)Cl.CO>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[S:10][C:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])=[O:15])=[CH:12][N:13]=2)[CH2:3][CH2:2]1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1ccccc1C(=O)c1cnc(NCC2CCNCC2)s1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1cnc(NCC2CCN(S(=O)(=O)c3cccs3)CC2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 35.2 mg (0.1 mmol) {2-[(piperidin-4-ylmethyl)-amino]-thiazol-5-yl}-o-tolyl-methanone; hydrochloride, 21.9 mg (0.12 mmol) thiophene-2-sulfonyl chloride (commercially available) and 44.6 ul (0.32 mmol) NEt3 in a mixture of DCM/MeOH 3/1 was stirred at 60° C. for 16 h. After cooling to room temperature the mixture was concentrated and MeOH (1 ml) and formic acid (0.5 ml) was added and the mixture was subjected to reversed phase HPLC purification eluting with a gradient of acetonitrile/water. After evaporation of the product fractions 22 mg (48%) of the title compound was obtained.
Reaction SMILES: C(N(CC)CC)C.S(O)(O)(=O)=O.[CH:13]1[C:29]2[CH2:28][C@H:27]3[N:30]([CH2:32][CH2:33][C@@:19]45[C@H:26]3[CH:25]=[CH:24][C@H:22]([OH:23])[C@@H:20]4[O:21][C:17]([C:18]=25)=[C:15]([OH:16])[CH:14]=1)[CH3:31].[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1.CC[OH:43].O>CN(C=O)C>[CH:13]1[C:29]2[CH2:28][C@H:27]3[N:30]([CH2:32][CH2:33][C@@:19]45[C@H:26]3[CH:25]=[CH:24][C@H:22]([OH:23])[C@@H:20]4[O:21][C:17]([C:18]=25)=[C:15]([OH:16])[CH:14]=1)[CH3:31].[C:34]([O-:39])(=[O:40])[CH2:35][CH2:36][C:37]([O-:43])=[O:38]
Reactant: CCO
Reactant: O=C1CCC(=O)O1
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C([O-])CCC(=O)[O-]
Reaction time: 36 h

Procedure:
Triethylamine (9.584 ml, 69.45 mmol) was added dropwise to a suspension of morphine sulphate (9.286 g, 27.78 mmol) in dry DMF (140 ml) at 0° C. under nitrogen. After stirring for ten minutes, succinic anhydride (2.781 g, 27.78 mmol) was added portionwise to the reaction. The reaction was monitored by TLC (50% EtOH/H2O) and by analytical HPLC (RtI of Mor-Suc was 5.06′). The reaction was complete in 24 to 48 h and the product precipitated out. The precipitate was filtered and washed with a small volume of cold DMF and THF. Both 1H NMR and HPLC indicated that the product was of sufficient purity for the next reaction (Mor-Suc 6.11 g; 57% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:17])[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][C:4]2[C:5]3[CH2:12][CH2:11][CH2:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Nc1nc(O)c2c(n1)-c1ccccc1CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1

Procedure:
The product from Example 59B (1.37 g, 6 mmol) was suspended in CH2Cl2 (100 mL), treated with TsCl (2.28 g, 12 mmol), treated with 4-dimethylaminopyridine (100 mg, 0.82 mmol), treated with triethylamine (2.2 mL. 16 mmol), and heated at reflux for 4 hours. The mixture was washed with H2O, dried (MgSO4), concentrated under reduced pressure and chromatographed on silica gel eluting with EtOAc:hexanes (25:75) to provide the title compound. 1H NMR (DMSO-d6) δ 1.99 (t, J=6.95 Hz, 2H), 2.23 (t, J=6.95 Hz, 2H), 2.45 (s, 3H), 2.47 (m, 2H), 6.91 (bs, 2H), 7.31 (m, 1H), 7.4 (m, 2H), 7.55 (dd, J=7.29, 1.87 Hz, 1H), 7.5 (d, J=8.48 Hz, 2H), 8.03 (d, J=8.14 Hz, 2H). MS (M+H)+ m/z 382.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12](O)=O)[C:8]([F:15])=[C:7]([F:16])[C:3]=1[C:4](O)=O.B>C1COCC1>[F:1][C:2]1[C:10]([F:11])=[C:9]([CH3:12])[C:8]([F:15])=[C:7]([F:16])[C:3]=1[CH3:4]
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: B
Solvent: C1CCOC1
Product: Cc1c(F)c(F)c(C)c(F)c1F

Procedure:
To a stirred solution of perfluoroterephthalic acid (1.0 g, 4.2 mmol) in anhydrous THF (10 ml) under an atmosphere of dry argon was added Borane. THF complex (1.0M solution in THF, 10 equivalents, 42 ml) dropwise, and the mixture stirred at room temperature overnight. The solution was evaporated under reduced pressure to give a colourless oil and the excess Borane destroyed by addition of anhydrous methanol (40 ml) and evaporation (repeated three times). The residue was treated with 5% aqueous hydrocMoric acid then the pH of the mixture was adjusted to pH9 with 1N aqueous sodium hydroxide solution and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 2,3,5,6-tetrafluoro-p-xylene-.varies.,.varies.'-diol (0.75 g, 86%) as a white solid. This was used without further purification.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[Br:15][C:16]1[CH:17]=[C:18]([C:19]([N:6]2[CH:7]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][CH:26]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:20])[CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)c1cccc(Br)c1
Product: O=C(c1cccc(Br)c1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
(3-Bromo-phenyl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 3-bromobenzoyl chloride, and indole according to GP 2. Yield, 22%. 1H-NMR (DMSO-d6): δ=6.22 (d, J=1.9 Hz, 1H), 6.41 (s, br., 1H), 6.86 (t, J=7.5 Hz, 1H), 6.99-7.28 (m, 7H), 7.40-7.48 (m, 2H), 7.51-7.60 (m, 3H), 7.84 (“d”, J=7 Hz, 1H), 7.98 (dd, J=7.9 Hz, J=1.1 Hz, 1H), 8.12 (d, J=7.5 Hz, 1H), 10.71 (s, 1H); (+)-ESI-MS: m/z=479 [M(79Br)+H]+, 362[M(79Br)-indole+H]+.