Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[N:28][C:5]2S[CH2:7][CH2:8][N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[F:20])[N:13]=[C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:11]=3[CH3:27])[C:4]=2[CH:3]=1.O.OO.[OH:33][S:34]([O-:36])=O.[Na+]>CCOC(C)=O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:29]=[N:28][C:5]2[S:34](=[O:36])(=[O:33])[CH2:7][CH2:8][N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[F:20])[N:13]=[C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:11]=3[CH3:27])[C:4]=2[CH:3]=1
Reactant: O=S([O-])O
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCSc2ncc(Cl)cc21
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCS(=O)(=O)c2ncc(Cl)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-chloro-1-(5-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine (30 mg, 0.071 mmol) in EtOAc (2.5 mL) was added disodium tungstate (2.08 mg, 7.09 μmol) and water (0.2 mL). The reaction was cooled at 0° C. and then H2O2 (36.2 μL, 0.355 mmol, 30%) was added. The reaction was allowed to warm to rt for 1 h. After this time more disodium tungstate (5 mg) was added followed by H2O2 (0.3 mL) and the reaction was stirred at rt overnight. After this time the reaction was diluted with EtOAc (50 mL) and treated with a saturated aqueous solution of NaHSO3 (10 mL). The separated organic layer was washed with brine (10 mL), dried over MgSO4, filtered and evaporated in vacuo to give 7-chloro-1-(5-fluoro-3-methyl-2-pyridin-2-ylquinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide. Mass Spectrum (ESI) m/e=455.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:39]2[CH2:40][CH2:41][N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)[CH2:37][CH2:38]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(c4ccccn4)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-(pyridin-2-yl)piperazine (0.030 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(pyridin-2-yl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([CH:16]([C:20]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[C:21]=2[C:22]([OH:24])=O)[C:17](=O)[CH3:18])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:20]3[C:21](=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=3)[C:22](=[O:24])[N:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:17]=2[CH3:18])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1cccnc1
Reactant: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CCC1)c1cc(F)cc(F)c1C(=O)O
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cc(F)cc(F)c2c(=O)n1-c1cccnc1

Procedure:
The title compound was prepared analogously from 2-(1-{[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-2-oxo-propyl)-4,6-difluoro-benzoic acid and 3-aminopyridine (acetonitrile 90° C., 16 hours). LC-MS (m/z) 478.1 (MH+); tR=1.27.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=3[F:30])[CH:12]=2)[CH:8]=[CH:7][C:6]1=[O:31].[BH4-].[Na+]>CO.C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][N:14]=[C:13]3[CH:12]=[C:11]([C:9]4[CH:8]=[CH:7][C:6](=[O:31])[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:32])[CH:10]=4)[S:19][C:18]=23)=[C:22]([F:30])[CH:23]=1
Reactant: CN(C)CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)ccc1=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCn1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)ccc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 27 %

Procedure:
To a solution of the nitro compound 421 (0.103 g, 0.227 mmol) in methanol (2 mL) and THF (2 ml) at 0° C. was added nickel chloride hexahydrate (0.162 g, 0.681 mmol) followed by sodium borohydride (28 mg, 0.749 mmol). After one hour of stirring at 0° C. another portion of nickel chloride hexahydrate (0.108 g, 0.458 mmol) and sodium borohydride (19 mg, 0.50 mmol) were added. The reaction mixture was then stirred at room temperature for 5 hours before it was concentrated and treated with 1N HCl(aq) and dichloromethane. The mixture was stirred for 10 minutes and then basified to pH 10 by the addition of NH4OH. The basified solution was then extracted with dichloromethane. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (eluent a gradient of 10 to 100% methanol in ethyl acetate) to give the title compound 422 as yellow solid (26 mg, 27% yield). MS (m/z): 425.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:19][CH2:20][O:21][CH2:22][CH3:23]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[CH3:7])=[CH:4][CH:3]=1
Reactant: CCOCCBr
Reactant: CNc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCN(C)c1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 96 h

Procedure:
To a solution of 4-bromo-N-methylaniline (18.18 g) in DMF (150 ml) were added at room temperature potassium carbonate (25.8 g), sodium iodide (28.0 g) and 2-bromoethylethyl ether (21 ml), and the mixture was stirred at 90° C. for 4 days. To the mixture were added 2-bromoethylethyl ether (10.0 ml), potassium carbonate (20.0 g) and sodium iodide (13.3 g), and the mixture was stirred for 2 days. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brined and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:19) and distilled under reduced pressure (0.7 mmHg, 131° C.) to give yellow oil of 4-bromo-N-(2-ethoxyethyl)-N-methylaniline (17.63 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.P(Br)(Br)([Br:23])=O.O>CC1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][Br:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](CO)COCc1ccccc1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@H](CBr)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
Dissolve (R)-2-(benzyloxy-methyl)-3-methyl butanol (15.6 g, 75 mmol) and N,N-dimethyl formamide (0.6 g, 8.25 mmol) in methyl benzene (351 ml), add phosphorus oxybromide (25.8 g, 90 mmol) in droplets slowly, and control the temperature below 60° C. in that process; then, let them to react at 80° C. for 2 hours; cool down to room temperature, add water (702 ml), stir for 20 minutes, and separate the layers; extract the aqueous layer with petroleum ether for three cycles, combine the organic layers and wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively; dry the organic layer with anhydrous sodium sulfate, filter, and condense the filtrate so as to obtain 17.5 g of oily matter; treat the oil matter by reduced pressure distillation to obtain 16.1 g of colorless transparent liquid; the yield is 79.2%, and the chiral purity is ≧99.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18][CH:19]=[CH2:20])[CH:12]=1.[Cl-].[NH4+]>CO.[Zn]>[NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18][CH:19]=[CH2:20])[CH:12]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc([N+](=O)[O-])cc2N)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(N)cc2N)ccn1
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a clear, orange solution of 1D (2.9 g, 7.54 mmol) in methanol (75 mL) was added sequentially zinc dust (4.93 g, 75 mmol) and ammonium chloride (4.04 g, 75 mmol). The resulting suspension was stirred vigorously for 4 h. The reaction was yellow filtrate. Concentration of the filtrate gave a yellow-black residue. The residue was partitioned between EtOAc and 0.25 M HCl (50 mL) and the layers were separated. The organic layer was extracted with 0.25 M HCl (1×50 mL). The combined aqueous layers were basified with 1.5M K2HPO4 and then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 1E (2.63 g, 98%) as a brown foam. MS (ESI) m/z: 355.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[N:4]=[C:5]([S:41][CH3:42])[C:6](=[N:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[C:27]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:26]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([O:15][Si](C(C)(C)C)(C)C)[C:8]=1[F:23].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[CH3:1][O:2][C:3](=[O:43])[N:4]=[C:5]([S:41][CH3:42])[C:6](=[N:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[C:27]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH:26]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([OH:15])[C:8]=1[F:23]
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(=Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(O)c(F)c(C(=Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a mixture of {2-[4-bromo-3-(t-butoxycarbonylaminomethyl)phenylimino)-2-[3-(t-butyldimethylsilanyloxy)-5-ethyl-2-fluorophenyl]-1-methylsulfanylethylidene}carbamic acid methyl ester (686 mg) and THF (25 mL) there was added a 1M THF solution (1.18 mL) of tetrabutylammonium fluoride at 0° C., under a nitrogen atmosphere. The mixture was stirred at 0° C. for 2 hours, and then ethyl acetate (200 mL) and water (100 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed twice with water (100 mL) and then with saturated aqueous sodium chloride (100 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (542 mg) as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS([O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47]C[CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:45][CH2:44][N:43]4[CH2:42][CH2:41][O:40][CH2:47][CH2:48]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCOCC4)c3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 40 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-morpholinoethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.65 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.59-7.54 (m, 3H), 7.45-7.40 (m, 2H), 7.04-7.02 (m, 2H), 6.22 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=7.8 Hz), 4.25-4.20 (m, 3H), 3.79-3.76 (m, 4 h), 3.68 (brs, 1H), 3.51-3.48 (m, 1H), 2.87 (t, 2H, J=5.7 Hz), 2.64 (brs, 4 h), 2.14-2.06 (m, 3H), 1.78 (brs, 1H), 1.67-1.62 (m, 4 h), 1.50-1.48 (m, 2H), 1.25 (d, 3H, J=6.3 Hz). LC/MS: 500 [M+H]+, tR=1.13 min. HPLC: 95.85% at 214 nm, 95.41% at 254 nm, tR=5.12 min.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][OH:8])[CH2:4][CH2:3][CH2:2]1.[C:9]([C@H:13]1[C:40](=[O:41])[N:39]2[CH2:42][C@@H:36]([CH2:37][C@H:38]2[C:43]([NH:45][C@:46]2([C:51](=[O:60])[NH:52][S:53]([C:56]3([CH3:59])[CH2:58][CH2:57]3)(=[O:55])=[O:54])[CH2:48][C@H:47]2[CH:49]=[CH2:50])=[O:44])[O:35][C:25]2=[N:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33](O)=[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[CH2:61][C@H:17]2[O:16][C:15](=[O:62])[NH:14]1)([CH3:12])([CH3:11])[CH3:10]>>[N:1]1([CH2:5][CH2:6][CH2:7][O:8][C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25]3[O:35][C@H:36]4[CH2:42][N:39]([C:40](=[O:41])[C@H:13]([C:9]([CH3:11])([CH3:10])[CH3:12])[NH:14][C:15](=[O:62])[O:16][C@@H:17]5[CH2:61][C@H:18]5[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]=23)[C@H:38]([C:43]([NH:45][C@:46]2([C:51](=[O:60])[NH:52][S:53]([C:56]3([CH3:59])[CH2:57][CH2:58]3)(=[O:55])=[O:54])[CH2:48][C@H:47]2[CH:49]=[CH2:50])=[O:44])[CH2:37]4)[CH2:4][CH2:3][CH2:2]1
Reactant: OCCCN1CCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1(C)CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OCCCN1CCC1)O2)C(=O)NS(=O)(=O)C1(C)CC1

Procedure:
The title compound was prepared using the same method as described in Example 75, using the 3-(azetidin-1-yl)propan-1-ol and (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-17-hydroxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxamide (Example 120). LRMS (ES+) m/z 863.50 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.I[CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH2:4][CH2:3][CH2:2][CH3:14])[CH2:10][CH2:9][CH2:8][CH3:7])=[CH:10][C:11]=3[C:12]2([CH2:13][CH2:5][CH2:6][CH3:11])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: Nc1ccc2c(c1)Cc1cc(Br)ccc1-2
Product: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(Br)ccc1-2

Procedure:
As shown in Scheme 2, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21). Then, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a). Finally, in acetonitrile, 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-Cyano-3-[5-(9,9-dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (23a).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]([C:9]([O:11]C)=O)=[CH:6][S:7][CH:8]=1)=O.C([O-])=O.[NH4+:16].O>C(N)=O>[N:3]1[C:4]2=[CH:8][S:7][CH:6]=[C:5]2[C:9](=[O:11])[NH:16][CH:1]=1
Reactant: COC(=O)c1cscc1NC=O
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: NC=O
Solvent: O
Product: O=c1[nH]cnc2cscc12
Temperature: 140 °C

Procedure:
A stirred mixture of methyl 4-formamido-3-thenoate (see below) (3.39 g) and ammonium formate (3,4 g) in formamide (5 ml) was heated at 140° C. for 7 hours. On cooling, the mixture was poured into water, and the mixture filtered to give a solid which was washed with water followed by light petroleum (b.p. 60-80° C.) and air dried to give the title product, m.p. 275-278° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH:32]([CH3:34])[CH3:33])[NH:5][C:6](=[O:31])[C@H:7]([CH:28]([CH3:30])[CH3:29])[NH:8][C:9](=[O:27])[CH2:10][CH:11]1[CH2:17][CH2:16][C:15]([CH3:18])=[CH:14][CH:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]1=[O:26].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH:32]([CH3:34])[CH3:33])[NH:5][C:6](=[O:31])[C@H:7]([CH:28]([CH3:30])[CH3:29])[NH:8][C:9](=[O:27])[CH2:10][CH:11]1[CH2:17][CH2:16][C:15]([CH3:18])=[CH:14][CH:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]1[OH:26]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC(C)=CC(Cc2ccccc2)C1=O)C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC(C)=CC(Cc2ccccc2)C1O)C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To the above keto-peptide (24) (0.44 g) in ethanol (20 mL) with stirring at room temperature was added NaBH4 (69 mg) in one portion. After stirring for 30 min the reaction was quenched by the addition of aqueous 1N HCl (50 mL). The reaction was extracted with ethyl acetate, washed with saturated NaCl, dried over MgSO4 and evaporated to dryness. The title compound was obtained as a mixture of diastereomers by flash chromatography on silica gel eluted with 60% ethyl acetate in n-hexane then by gravity chromatography in the same system. TLC Rf 0.31 and 0.36 (60% ethyl acetate, n-hexane); MS (DCI/NH3) (M+H)+ =487; 1H NMR (CDCl3)δ0.8-1.0(12H, m) Val γ(CH3)2's, 1.7 (3H, s) allylic CH3, 3.72 (3H, s) CO2CH3, 5.18m and 5.08(1H, br s) vinylic CH, 7.30(5H, s) phenyl.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([NH2:16])=[O:15])[CH:10]=[CH:11][CH:12]=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][C:14]1[O:15][C:2](=[O:3])[S:4][N:16]=1
Reactant: NC(=O)Cc1cccc(Cl)c1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: O=c1oc(Cc2cccc(Cl)c2)ns1

Procedure:
7.32 g (55.9 mmol) of chlorocarbonylsulphenyl chloride and 7.90 g (46.6 mmol) of 2-(3-chlorophenyl)acetamide are stirred in 50 ml of toluene at 80° C. for 3 h. The crude product is reacted further without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.CN(CCN(C)C)C.C([Li])CCC.[C:24](OCC)(=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:24](=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1cccc(OC)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 28 g of 1,3-dimethoxybenzene and 24.3 g of TMEDA in 400 ml of hexane is cooled to a temperature below 10° C., 132 ml of a 1.6 M solution of n-butyllithium in hexane are added dropwise and the mixture is left stirring for 30 minutes. The reaction mixture is cooled to 0° C., 140 ml of diethyl oxalate are added over 15 minutes and the mixture is left stirring for 1 hour at RT. The reaction mixture is poured into a mixture of concentrated HCl solution and ice and is extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The excess diethyl oxalate is removed by distillation under vacuum (b.p.=90° C. at 2 400 Pa). The resulting crude product is chromatographed on silica gel, eluting with heptane and then with DCM. 34.5 g of the expected product are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[F:31])C1C=CC=CC=1>C1COCC1.[Pd]>[F:31][C:24]1[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:23]=1[C:10]1[C:9]([OH:8])=[CH:14][C:13]([OH:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(F)c(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 161.4 %

Procedure:
To a solution of 2,4-bis(benzyloxy)-2′-fluoro-5′-methoxy-1,1′-biphenyl (23.9 g) in THF (300 mL) was added 10% palladium-activated carbon (9.60 g) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (21.8 g) as a colorless crude oil. This compound was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:7]([CH2:19][CH2:20][CH3:21])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:4][CH:3]=1.[CH:27](OC(=O)C)=[O:28]>ClCCl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH:27]=[O:28])[CH:10]=2)[C:6]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:7]1[CH2:19][CH2:20][CH3:21]
Reactant: CC(=O)OC=O
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(N)cc2n1Cc1ccccc1Cl
Solvent: ClCCl
Product: CCCc1c(C(=O)C(C)C)c2ccc(NC=O)cc2n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 6-amino-1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole (147 mg) in dichloromethane (2 ml) was added acetic formic anhydride (0.5 ml) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, then diluted with dichloromethane. The organic phase was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:2) to give crystals which were recrystallized from a mixture of ethyl acetate and hexane to give 1-(2-chlorobenzyl)-6-formamido-3-isobutyryl-2-propylindole (85 mg) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]([OH:16])=O)[C:8]=2[Cl:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:22]([CH2:26][CH2:27][NH2:28])[N+:23]([O-:25])=[O:24].C(OC(C)C)(C)C>>[O:22]([CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][O:12][C:9]1[C:8]([Cl:17])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)[N+:23]([O-:25])=[O:24]
Reactant: O=C(O)COc1noc(-c2ccccc2)c1Cl
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(COc1noc(-c2ccccc2)c1Cl)NCCO[N+](=O)[O-]
Yield: 45.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.70 g of 5-phenyl-4-chloro-3-isoxazolyloxyacetic acid and 0.46 g of nitroxyethylamine nitrate, 0.42 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).