Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S([O-])([O-])(=O)=O.[Mg+2]>[Pt].C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCOCCO
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: Nc1cnc2ccccc2c1NCCOCCO
Yield: 72.8 %

Procedure:
A mixture of 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethanol (66.2 g, 239 mmol) and 5% platinum on carbon (7.5 g) in ethanol (250 mL) was hydrogenated at approximately 30 psi (2.1×105 Pa) on a Parr apparatus overnight. Magnesium sulfate was added to the mixture, which was then filtered through CELITE filter agent. The filtrate was concentrated under reduced pressure to provide 43.0 g of crude 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethanol as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([C:20]=1[Cl:21])=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:16]=1[Cl:22])[CH:11]=2)[CH3:2].S(=O)(=O)(O)O.[N+:38]([O-])([O-:40])=[O:39].[K+].[OH-].[Na+]>>[CH2:27]([N:26]([CH2:29][CH3:30])[CH2:25][CH2:24][O:23][C:15]1[C:14]([N+:38]([O-:40])=[O:39])=[CH:13][C:12]2[C:17]([C:16]=1[Cl:22])=[N:18][C:19]1[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:31][CH3:32])[C:20]=1[Cl:21])[CH:11]=2)[CH3:28]
Reactant: O=[N+]([O-])[O-]
Reactant: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(Cl)c3nc2c1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: CCN(CC)CCOc1ccc2cc3cc([N+](=O)[O-])c(OCCN(CC)CC)c(Cl)c3nc2c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 119.5 mg. portion of 3,6-bis(2-diethylaminoethoxy)-4,5-dichloroacridine is dissolved in one ml. of concentrated sulfuric acid. The solution is cooled in an ice bath and 60 mg. of potassium nitrate are added. The mixture is stirred at 0° C. for one hour, then at room temperature for 20 hours, poured into 20 ml. of ice water and the pH adjusted to 11.5 with 5 N sodium hydroxide. The mixture is then extracted three times with dichloromethane. The extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a black gum. This gum is slurried in 25 ml. of boiling hexane and filtered. The filtrate is concentrated to 10 ml. and cooled in an ice bath. The crystals are collected and dried in vacuo, giving 54 mg. of the desired product, m.p. 100°-102° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[C:7]([CH2:19][O:20][CH3:21])[CH:6]=1)=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39]CC2C=CC=CC=2)=[CH:26][CH:25]=1>C1COCC1.C(O)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([CH2:2][NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)[OH:4])=[CH:6][C:7]=1[CH2:19][O:20][CH3:21]
Reactant: COc1ccc(CCOCCCCCCNCc2ccccc2)cc1
Reactant: COCc1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1cc(C(O)CNCCCCCCOCCc2ccc(OC)cc2)ccc1O
Reaction time: 20 h
Yield: 48.1 %

Procedure:
A solution of 2-bromo-1-[3-(methoxymethyl)-4-(phenylmethoxy)phenyl]ethanone (1.38 g), N-[6-[2-(4-methoxyphenyl)ethoxy]hexyl]benzenemethanamine (1.35 g) and DEA (1.02 g) in THF (21 ml) was allowed to stand under nitrogen for 20 h. The mixture was filtered and the filtrate evaporated in vacuo to give an oil, a solution of which in ethanol (35 ml) was hydrogenated over pre-reduced 10% PdO-C (50% aqueous, 500 mg) and 5% PtO-C (400 mg). The mixture was filtered through hyflo and evaporated in vacuo to give an oil. Purification by FCC eluting with System B (900:100:5) gave the title compound as a cream solid (0.82 g) m.p. 97.5°-98.5°.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[NH2:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][C:24]=2[O:33][CH3:34])=[C:13]([CH3:35])[N:12]=1.C(O)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[NH2:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([CH2:27][OH:28])=[CH:25][C:24]=2[O:33][CH3:34])=[C:13]([CH3:35])[N:12]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of DIBAL-H (80 ml, 1M in hexanes) was added portion wise over 20 min to a stirred solution of the product from step (ii) (3.8 g) in THF (25 mL) at 0° C. The mixture was allowed to warm to rt, stirred for 2 h, then cooled to 0° C. Isopropanol (2 mL) was added, stirred for 10 min and then added to a saturated solution of sodium sulfate (50 mL). The mixture was diluted with DCM (100 mL) and then stirred for 1 h. The organic phase was separated and the aqueous was extracted with DCM. The combined organic extracts were dried and filtered. The crude product was purified via silica chromatography (10% MeOHIDCM) to give the subtitle compound as a cream solid, 2.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(C)(C)C(Cl)=O.[CH3:42][O:43][CH2:44][CH2:45][NH2:46].C(N(CC)CC)C>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:33])([F:34])[F:32])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][C:28]([NH:46][CH2:45][CH2:44][O:43][CH3:42])=[O:29])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: COCCN
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCNC(=O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N—[[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine (i.e. the title product of Step B) (100 mg) and pyridine (0.019 mL) in dichloromethane (3 mL) was added trimethylacetyl chloride (0.029 mL). The reaction mixture was stirred at room temperature for 2 h, and then 2-methoxyethylamine (0.11 mL) and triethylamine (0.68 mL, 5.0 mmol) were added. The reaction mixture was stirred at room temperature overnight, quenched with water, extracted with dichloromethane, washed with brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate (3:2 to 1:4) as eluent to afford the title compound, a compound of the present invention, as a white solid (71 mg, 0.13 mmol, 65% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH:9]1[N:14]2[CH:15]=[C:16]([CH3:18])[CH:17]=[C:13]2[CH:12]([C:19]([O:21]C(C)C)=[O:20])[CH2:11][CH2:10]1)=[O:8].CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH:9]1[N:14]2[CH:15]=[C:16]([CH3:18])[CH:17]=[C:13]2[CH:12]([C:19]([OH:21])=[O:20])[CH2:11][CH2:10]1)=[O:8]
Reactant: Cc1cc2n(c1)C(C(=O)c1cccn1C)CCC2C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc2n(c1)C(C(=O)c1cccn1C)CCC2C(=O)O

Procedure:
A solution of 328 mg. of isopropyl 5-(N-methyl-2-pyrroyl)-2-methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 5 ml. of methanol is treated with a solution of 0.28 g. of potassium carbonate in 5 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 3 hours, cooled, and evaporated to dryness. The residue is taken up in 50 ml. of water, cooled to 0°, made acidic with 10% hydrochloric acid and the resultant mixture extracted with ethyl acetate (3×50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 5-(N-methyl-2-pyrroyl)-2-methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid (XIVa, R and Q=CH3, n-1).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C@H:3]([NH:34][C:35](=[O:38])[O:36][CH3:37])[C:4](=[O:33])[N:5]1[C@H:10]([C:11]2[NH:15][C:14]3[C:16]4[C:21]([CH:22]=[CH:23][C:13]=3[N:12]=2)=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=4)[CH2:9][C@@H:8]2[C@H:6]1[CH2:7]2.Br[C:41]1[CH:42]=[C:43]2[C:66](=[CH:67][CH:68]=1)[C:47]1[NH:48][C:49]([C@@H:51]3[CH2:55][C@H:54]([CH2:56][O:57][CH3:58])[CH2:53][N:52]3[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[N:50][C:46]=1[CH:45]=[CH:44]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][O:36][C:35]([NH:34][C@@H:3]([CH:2]([CH3:1])[CH3:39])[C:4]([N:5]1[C@H:10]([C:11]2[NH:15][C:14]3[C:16]4[C:21]([CH:22]=[CH:23][C:13]=3[N:12]=2)=[CH:20][C:19]([C:41]2[CH:42]=[C:43]3[C:66](=[CH:67][CH:68]=2)[C:47]2[NH:48][C:49]([C@@H:51]5[CH2:55][C@H:54]([CH2:56][O:57][CH3:58])[CH2:53][N:52]5[C:59]([O:61][C:62]([CH3:65])([CH3:63])[CH3:64])=[O:60])=[N:50][C:46]=2[CH:45]=[CH:44]3)=[CH:18][CH:17]=4)[CH2:9][C@@H:8]2[C@H:6]1[CH2:7]2)=[O:33])=[O:38]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(Br)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H]9C[C@H]9N8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 100.5 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (0.60 g, 1.1 mmol) and (2S,4S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (0.46 g, 1.0 mmol) in DME (5 mL) was added Pd(PPh3)4 (0.08 g, 0.07 mmol) and K3PO4 (2M aqueous, 1.5 mL, 3.0 mmol). The resulting solution was degassed with argon for 5 min and heated to 80° C. (external temperature, oil bath) for 18 h. The reaction mixture was then cooled to room temperature and diluted with MeOH and CH2Cl2. The solution was washed with H2O and brine, and the aqueous layers were back extracted with CH2Cl2 and MeOH (˜10:1). The organic layers were combined and dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (30 to 100% EtOAc (10% MeOH)/Hexanes to 80% MeOH/EtOAc) to provide (2S,4S)-tert-butyl 2-(2′-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (0.79 g, 71%). LCMS-ESI+: calc'd for C45H51N7O6: 785.39 (M+); Found: 786.61 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17](=O)[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].Cl.ClC1C=CC=C2C=1C(=O)OC(C1C=CC(OC3C=CC=CC=3)=CC=1)=C2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:31]([CH2:30][C:29]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:28]=3[F:27])[C:17](=[O:16])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1F
Reactant: O=c1oc(-c2ccc(OCc3ccccc3)cc2)cc2cccc(Cl)c12
Agent: Cl
Agent: O=c1oc(-c2ccc(Oc3ccccc3)cc2)cc2cccc(Cl)c12
Solvent: Cc1ccccc1
Product: O=c1c2c(Cl)cccc2cc(-c2ccc(OCc3ccccc3)cc2)n1Cc1ccc(F)cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 3-(4-benzyloxyphenyl)-8-chloro-isochromen-1-one (1.7 g, 4.7 mmol) and 2,4-difluorobenzylamine (0.75 mL, 6.3 mmol) was prepared in toluene (25 mL) in a 100 mL round-bottomed flask under nitrogen. To the resulting suspension was added a solution of methyl aluminoxane (5.0 mL, of a 1.5 M solution in toluene, 7.5 mmol). Gas evolution was observed as the aluminoxane solution was added. The resulting suspension was then heated to reflux. As the solution came to reflux the solids dissolved to afford a brown solution. After stirring at reflux for 16 hours, an aliquot of the reaction was worked up with aqueous HCl, and analyzed by TLC. There was no visible 8-chloro-3-(4-phenoxyphenyl)-isochromen-1-one, and there were two product spots visible. Heating was discontinued and the reaction was allowed to cool to ambient temperature. The reaction was then quenched by the addition of 1N HCl (aq.) (50 mL), and diluted with EtOAc (100 mL). The layers were separated and the acidic aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (50 mL), saturated aqueous NaHCO3 (30 mL), then brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white foam. The crude foam was purified by silica gel column chromatography eluting with a gradient from 0% to 30% EtOAc/hexane. Two product peaks were collected from the column: The first peak that eluted was concentrated to afford 3-(4-benzyloxyphenyl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one, a compound of formula (Id), (1.68 g, 73% yield); 1H-NMR (400 MHz, CDCl3): δ 7.51-7.48 (2H, m), 7.46-7.33 (6H, m), 7.11-7.07 (2H, m), 7.04-6.96 (1H, m), 6.95-6.91 (2H, m), 6.78-6.71 (1H, m), 6.66-6.59 (1H, m), 6.39 (1H, s), 5.17 (2H, s), 5.10 (2H, s); and the second peak that eluted was concentrated to afford 2-[2-(4-benzyloxyphenyl)-2-oxoethyl]-6-chloro-N-(2,4-difluorobenzyl)benzamide, a compound of formula (W) (533 mg, 22% yield); 1H-NMR (400 MHz, CDCl3): δ 7.78 (2H, d, J=8.8 Hz), 7.45-7.30 (5H, m), 7.26-7.14 (3H, m), 7.00-6.93 (3H, m), 6.71 (1H, t, J=6.3 Hz), 6.56-6.49 (1H, m), 6.45-6.37 (1H, m), 5.12 (2H, s), 4.40 (2H, d, J=6.3 Hz), 4.16 (2H, s).
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:17]1[C:22](=[O:23])[N:21]([O:24][C:25](ON2C(=O)CCC2=O)=[O:26])[C:19](=[O:20])[CH2:18]1>C(#N)C>[C:25](=[O:26])([O:24][N:21]1[C:22](=[O:23])[CH2:17][CH2:18][C:19]1=[O:20])[O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: OC1CCC=CCCC1
Agent: O=C(OC1CC/C=C/CCC1)ON1C(=O)CCC1=O
Agent: OC1CC/C=C/CCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(OC1CCC=CCCC1)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
50 mg of (E)-cyclooct-4-enol (major isomer) and 0.2 mL triethylamine were added to 3 mL anhydrous acetonitrile. To this solution was slowly added 250 mg of N,N-disuccinimidyl carbonate. The reaction mixture was stirred at room temperature until thin layer chromatography revealed that the reaction was complete (approximately 48 hours). The acetonitrile was removed by rotary evaporation and the remaining residue was suspended in ether, washed with 0.1M HCl followed by brine, and dried with magnesium sulfate. The ether was evaporated and the resulting oil was purified by column chromatography (1:1 Ethyl Acetate:Hexane) yielding 80 mg (75% yield) of the title compound. 1H NMR (400 MHz CDCl3): δ 5.65-5.54 (m, 1H), 5.5-5.4 (m, 1H), 4.5-4.4 (m, 1H), 2.88-2.78 (s, 4H), 2.45-2.3 (m, 2H), 2.2-1.5 (m, 8H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1)(O)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:43]1([NH2:50])[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH2:49]>C1COCC1.O>[NH2:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[NH:50][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1)=[O:2]
Reactant: CCOC(=O)CC1=Cc2ccc(CCCC(=O)O)cc2Cc2ccccc21
Reactant: Nc1ccccc1N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC1=Cc2ccc(CCCC(=O)Nc3ccccc3N)cc2Cc2ccccc21
Temperature: 0 °C
Yield: 88.5 %

Procedure:
A solution of ethyl (±)-3-[3-carboxy-1-propyl]-5H-dibenzo[a,d]cycloheptene-10-acetate (233.7 mg, 0.64 mmole) in dry THF (6.4 mL) was cooled to 0° C. under argon, and 4-methylmorpholine (0.14 mL, 1.28 mmole) was added. The solution was stirred at 0° C. for several min, then isobutyl chloroformate (0.11 mL, 0.83 mmole) was added dropwise. The cloudy reaction was stirred at 0° C. for 0.5 hr, then a solution of 1,2-phenylenediamine (138 mg, 1.28 mmole) in dry THF (0.6 mL) was added rapidly. The reaction was warmed to RT and stirred for 3 hr, then was diluted with H2O (2 mL) and extracted with EtOAc. Drying (MgSO4), concentration, and silica gel chromatography (3:2 EtOAc/hexanes) gave the title compound (257.6 mg, 88%) as a light yellow foam: TLC (3:2 EtOAc/hexanes) Rf 0.40; 1H NMR (250 MHz, CDCl3) δ 6.90-7.23 (m, 10 H), 6.72-6.80 (m, 2 H), 4.33 (d, J=15.0 Hz, 1 H), 4.10-4.25 (m, 2 H), 3.71-3.91 (m, 4 H), 3.32 (dd, J=15.1, 4.0 Hz, 1 H), 2.95 (dd, J=15.1, 9.5 Hz, 1 H), 2.59-2.72 (m, 3 H), 2.54 (dd, J=15.6,9.5 Hz, 1 H), 2.34 (t, J=7.4 Hz, 2 H), 1.98-2.09 (m, 2 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 457 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:24]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[N:22]O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:35][CH3:36].C(O)=O.[OH-].[Na+]>C(O)C.O.CO.[Zn]>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:24]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH2:22])=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:35][CH3:36]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=NO)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: O=CO
Product: COc1cc2c(nc1OC)c(-c1cc3c(CN)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a solution of 0.5 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde oxime in 30 cm3 of ethanol and 25 cm3 of water, at a temperature in the region of 20° C., are added 0.65 g of zinc and 17.5 cm3 of concentrated formic acid. The reaction medium is stirred at room temperature for 8 days. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in methanol, basified with sodium hydroxide (30%) to pH=9-10 and then filtered through Celite. The filtrate is concentrated under reduced pressure and the residue obtained is purified by flash-pack chromatography (SiO2, dichloromethane/methanol 95/05 by volume as eluents). 0.1 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methylamine is obtained with the following characteristics:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:12]#[N:13].Cl.Cl[CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[NH:26]1[CH:27]=[C:23]([CH2:22][C:11]([C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]#[N:13])[N:24]=[CH:25]1
Reactant: N#CC(c1ccccc1)c1ccc(Cl)cc1Cl
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 64 h

Procedure:
According to the scheme of Example 1, 2.04 g. of 50% sodium hydride, 11.64 g. of 2-(2,4-dichlorophenyl)-2-phenylacetonitrile, and 3.06 g. of 4-chloromethylimidazole hydrochloride were reacted at about 60° C. for 2 hours. The reaction mixture was then allowed to cool to ambient temperature and was stirred for 64 hours. The solvent was then evaporated and the reaction mixture was worked up as described in Example 1. The product was converted to the hydrochloride salt, and crystallized from ethyl acetate/diethyl ether to obtain 6.86 g. of the hydrochloride salt of the product named in the heading above, m.p. 215°-218° C.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=C.[O:26]=[O+][O-]>CO>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][C:10]2=[C:5]3[C:4]=1[CH2:1][CH:2]([OH:26])[N:18]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:6]3=[N:7][CH:8]=[N:9]2
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Reactant: O=[O+][O-]
Solvent: CO
Product: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine (0.14 g, 0.39 mmol) (from Example 16, Step E, supra), in methanol (50 mL) at −78° C. was passed a continuous stream of O3 until the color of the solution became blue. The reaction solution was then purged with argon, and methyl sulfide (5 mL) (Aldrich) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. The solution was concentrated, the residue was dried in vacuo to give the desired 7,8-dimethoxy-4-(4-chloro-phenyl)-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol as a crude yellow solid. (Yield 0.14 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH2:15][CH2:14][N:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12](=[O:22])[CH:11]=1.[H-].[Na+].Br[CH:26]([CH3:41])[C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([O:38][CH2:39][CH3:40])[CH3:37])=[CH:31][CH:30]=1)=[O:28]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH2:15][CH2:14][N:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12](=[O:22])[C:11]=1[CH:26]([CH3:41])[C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([O:38][CH2:39][CH3:40])[CH3:37])=[CH:31][CH:30]=1)=[O:28]
Reactant: CCOC(C)Oc1ccc(C(=O)C(C)Br)cc1
Reactant: O=C1C=C(Nc2ccc(Cl)cc2Cl)CCN1N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(C)Oc1ccc(C(=O)C(C)C2=C(Nc3ccc(Cl)cc3Cl)CCN(N3CCCCC3)C2=O)cc1
Reaction time: 8 h
Yield: 138.9 %

Procedure:
4-[(2,4-dichlorophenyl)amino]-1-piperidin-1-yl-5,6-dihydropyridin-2(1H)-one (450 mg, 1.323 mmol) suspended in THF (7 ml) was added during 15 min to NaH (67 mg, 2.645 mmol) suspended in THF (5 ml) at 5° C. under nitrogen. After the resulting mixture had been stirred at 0° C. for 1 h tetrabutylammonium iodide (49 mg, 0.132 mmol) was added followed by dropwise addition of 2-bromo-1-[4-(1-ethoxyethoxy)phenyl]propan-1-one (597 mg, 1.984 mmol) dissolved in THF (5 ml) during 15 min. After the addition the cooling bath was removed and the reaction was continued at rt overnight. Water was added and the solvent was removed by evaporation. The residue was partitioned between DCM and water. The organic phase was dried (MgSO4), filtered and evaporated to yield an orange oil (1.030 g, 90%).