Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][O:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51]C)=[O:50])=[CH:47][CH:46]=2)[CH:5]=[CH:6][CH:7]=1.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][O:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([OH:51])=[O:50])=[CH:47][CH:46]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCOc2c(-c3cccc(Cl)c3)cc(C(=O)NCCCCCCCCn3ccc4ccccc43)cc2-c2cccc(Cl)c2)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)c1ccc(OCCOc2c(-c3cccc(Cl)c3)cc(C(=O)NCCCCCCCCn3ccc4ccccc43)cc2-c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared as a light green solid (0.073 g, 62%) from 4-{2-[3,3″-Dichloro-5′-(8-indol-1-yl-octylcarbamoyl)-[1,1′:3′,1″]terphenyl-2′-yloxy]-ethoxy}benzoic acid, methyl ester using a procedure similar to step 4 of example 165; dec. >65° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.16–1.30 (m, 8H), 1.44–1.53 (m, 2H), 1.67–1.76 (m, 2H), 3.20–3.26 (m, 2H), 3.56–3.60 (m, 2H), 3.72–3.76 (m, 2H), 4.12 (t, J=7.0 Hz, 2H), 6.37 (dd, J=0.66, 3.1 Hz, 1H), 6.66–6.70 (m, 2H), 6.94–6.99 (m, 1H), 7.06–7.10 (m, 1H), 7.32 (d, J=3.1 Hz, 1H), 7.38–7.52 (m, 6H), 7.57–7.60 (m, 2H), 7.67 (t, J=1.8 Hz, 2H), 7.76–7.80 (m, 2H), 7.88 (s, 2H), 8.55 (t, J=5.7 Hz, 1H), 12.54 (broad s, 1H); IR (KBr) 3420, 2920, 1680, 1600, 1260, 1160 cm−1; mass spectrum [(−)APCI], m/z 747 (M−H)−; Anal. Calcd. for C44H42Cl2N2O5: C, 70.49; H, 5.65; N, 3.74. Found: C, 70.12; H, 6.01; N, 3.44.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([NH:24][CH3:25])[CH:16]=2)[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Zn]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:26])=[CH:16][C:17]=1[NH:24][CH3:25]
Reactant: CNc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CNc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Zinc (9.49 g) was added to a solution of 4-(benzyloxy)-1-(3-(methylamino)-4-nitrophenyl)pyridin-2(1H)-one (5.1 g) in AcOH (120 ml) at room temperature. The mixture was stirred at room temperature for 2 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The mixture was neutralized with saturated NaHCO3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with IPE and dried to give the title compound (3.5 g) as a brown solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.Cl[S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[N:17][CH:18]=1)(=[O:12])=[O:11].Cl.[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:8][C:5]1[S:4][C:3]([NH:2][S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=2)(=[O:11])=[O:12])=[N:7][CH:6]=1
Reactant: Nc1ncc(Cl)s1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cn1
Temperature: 25 °C
Yield: 7.4 %

Procedure:
2-Amino-5-chlorothiazole hydrochloride (2.63 g, 15.4 mmol, 3.96 eq) was dissolved in pyridine (10 ml) and stirred at room temperature for 10 minutes before the addition of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate (Preparation 16, 915 mg, 3.8 mmol, 1 eq) portionwise and the resulting reaction mixture stirred at room temperature for a further hour. The mixture was dropped slowly into 6M HCl (20 ml), extracted into ethyl acetate (15 ml), washed with saturated sodium hydrogen carbonate (15 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was suspended in dioxane (5 ml), a solution of sodium hydroxide (300 mg, 7.5 mmol, 1.9 eq) in water (2 ml) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was washed with ethyl acetate (10 ml). The remaining aqueous phase diluted with brine (10 ml), acidified to pH 1, extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound as an orange solid (90 mg, 0.28 mmol, 7%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][C@@H:21]([C:23]2[CH:34]=[CH:33][C:26]3[O:27][C:28]([CH3:32])([CH3:31])[O:29][CH2:30][C:25]=3[CH:24]=2)[O:20][C:19]1=[O:35])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:31][C:28]1([CH3:32])[O:27][C:26]2[CH:33]=[CH:34][C:23]([C@H:21]3[O:20][C:19](=[O:35])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][OH:8])[CH2:22]3)=[CH:24][C:25]=2[CH2:30][O:29]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO[Si](C)(C)C(C)(C)C)C(=O)O3)ccc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 2.75 h
Yield: 91.5 %

Procedure:
A solution of (5R)-3-[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.79 g) in THF (30 ml) was treated with tetrabutylammonium fluoride on silica gel (3.08 g) and the mixture stirred under nitrogen at 20° C. for 2.75 h. The reaction mixture was filtered and the filtrate evaporated in vacuo to give a residue which was purified by SPE on silica. Elution with dichloromethane, then EtOAc followed by solvent evaporation in vacuo gave the title compound (0.56 g). LCMS RT=3.05 min, ES+ve 394 (MH)+.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10].COCCO.C(=O)([O-])[O-].[Na+].[Na+]>O.N1C=CC=CC=1>[CH2:9]([N:11]1[C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:3]2[C:2]1=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:10]
Reactant: O=C1CCCCC1Cl
Reactant: CCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: COCCO
Solvent: O
Product: CCn1c2c(c3ccccc31)CCCC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
132.5 g of 2-chloro-cyclohexanone was added to 123.42 g of N-ethyl aniline, 500 ml of methyl cellosolve, 127 g of dry sodium carbonate and 7.9 g of pyridine at 30-40° C. over a period of 1 hour. Reaction mass was heated to 100° C. and stirred for 2 hours. Reaction temperature was further raised to 130° C. and held at this temperature till no more water get distilled. Reaction mass was then worked up to get 48.2 g of crude 9-ethyl-tetrahydrocarbazole of 96.3% GC purity.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24][C:25](=O)[CH:26](Br)[CH2:27]C)C.COCCCC.C[O-].[Na+]>O.C(O)(=O)C>[CH2:26]([C:25]([CH2:15][C:14]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(Br)CC
Reactant: COc1ccc(C=O)cc1OCCOCc1ccccc1
Agent: CCCCOC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)Cc1ccc(OC)c(OCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
24 g of the product of step (ii) 21.5 g bromobutyric acid ethyl ester and 30 ml t.butyl methyl ether are added dropwise over 50 mins. at 5° C. to a pre-prepared suspension of sodium methylate in 25 ml t.butyl methyl ether. The reaction mixture is stirred for 45 mins. at ca. 5° C. and then stirred for 12 hrs. at room temperature. The pH is adjusted to 5 by addition of glacial acetic acid and the obtained suspension diluted with H2O and extracted 3× with t.butyl methyl ether. The organic phase is extracted with NaHCO3 (1×) and brine (1×), and evaporated to ca. 100 ml. 13.5 ml 50% aqueous NaOH are added drop-wise and the whole stirred for 2 hrs. at 40° C., diluted with 50 ml. H2O and stirred for a further 30 mins. at room temperature. The organic phase is separated and the aqueous phase adjusted to pH 1 at max. 40° C. with 15 ml conc. HCl. The reaction mixture is stirred at 40° C. for a further 1.5 hrs., cooled to room temperature and extracted with toluene. The organic phase is washed with NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to yield the title compound as an oil.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[F:6][C:7]([F:14])([F:13])[C:8](OCC)=[O:9]>O1CCOCC1>[F:6][C:7]([F:14])([F:13])[C:8](=[O:9])[CH2:4][C:3]#[N:5]
Reactant: CC#N
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CCC(=O)C(F)(F)F
Temperature: 100 °C
Yield: 98.5 %

Procedure:
To a stirred suspension of 60% NaH (33.80 g, 1.408 mol, 2 eq) in dioxane (700 mL) was added acetonitrile (44.3 mL, 0.845 mol, 1.2 eq.) at 0° C. over a period of 30 min followed ethyl trifluoroacetate (83.70 mL, 0.704 mol, 1.0 eq). The reaction mixture was slowly and carefully heated to 100° C. for 3 h. The dioxane was evaporated under reduced pressure and pH was adjusted to ˜6 with 1N HCl and extracted with ether (200 mL×4), dried (MgSO4) and evaporated under vacuum to get 4,4,4-trifluoro-3-oxobutanenitrile (95 g, crude, brown oil). The compound was confirmed by matching with the TLC of reference compound.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([OH:22])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:22][CH2:1][CH3:2])[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCI
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(OCc2ccccc2)ccc1C(=O)OC

Procedure:
Ethyl iodide (0.137 mL) was added to a suspension of methyl 4-benzyloxy-2-hydroxybenzoate (0.296 g) and potassium carbonate (0.317 g) in N,N-dimethylformamide (2.9 mL) at room temperature with stirring. The mixture was stirred at that temperature for 1.6 hrs and at 50° C. for 1.4 hrs. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.293 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:21][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccccc1Br
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(Br)cc2)cn1
Yield: 41 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 2-bromophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (78 mg, 41%) which was obtained as a white solid. MS (ESI): m/e=379.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].[CH2:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([N:23]([CH2:21][CH3:22])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(=O)CC1)C2
Reactant: CCNc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)N1C2CCC1CC(N1CCC(N(CC)c3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(4-Oxo-piperidin-1-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester 2 (200.000 mg; 0.713 mmol; 1.000 eq.) was dissolved in DCE (4 mL) and treated with TEA (87.821 uL; 63.758 mg; 0.631 mmol; 1.000 eq.) and ethylaniline (91.79 mg; 0.856 mmol; 1.200 eq.), followed by NaBH(OAc)3 (453.569 mg; 2.140 mmol; 3.000 eq.) and AcOH (40.870 uL; 42.873 mg; 0.713 mmol; 1.000 eq.). The reaction was allowed to stir at room temperature for 48 hr and was quenched with MeOH (3 mL). The quenched mixture was allowed to stir at room temperature for 2 hrs, and the resulting suspension was filtered through a syringe filter. A 1 mL aliquot of the filtrate was purified by LC/MS (1 mL injection, 10-99 CH3CN gradient with 0.03% TFA, 15 minute run) to provide a pure sample of the desired product. LC/MS M/Z 372.2, retention time=1.82 minutes, 10-99% CH3CN/H2O gradient with 0.05% TFA.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[CH:5]2.[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[N:7][CH:6]=[CH:5]3)=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Reactant: Brc1ccc2nnccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cc(-c2ccc3nnccc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Yield: 5.2 %

Procedure:
(Some starting materials may be obtained from Inogent Laboratories Private Lmited, Begumpet Hyerabad, India) A glass microwave reaction vessel was charged with 6-bromocinnoline (150 mg, 0.7 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (296 mg, 0.7 mmol), anhydrous sodium carbonate (228 mg, 2.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (37 mg, 0.05 mmol) and dioxane-H2O (2:1, 3 mL). The reaction vessel was sealed and the mixture was stirred and heated at 100° C. for 1 h. Water was added in, and the suspension was filtered, the solid was air-dried. The crude was purified through a Redi-Sep® (Teledyne ISCO, Lincoln, Nebr.) pre-packed silica gel column (40 g), eluting with a gradient of 2% to 5% MeOH in CH2Cl2 to provide N-(2-chloro-5-(cinnolin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (15 mg, 5.0% yield) as a yellow solid. MS (ESI pos. ion) m/z: calc'd for C19H12ClFN4O2S:414.8.0; found: 415.0 (MH+). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.44(t, J=8.78 Hz, 2 H) 7.83 (dd, J=8.78, 5.27 Hz, 2 H) 8.24 (s, 1 H) 8.28-8.31 (m, 2 H) 8.46 (s, 1 H) 8.60 (d, J=9.03 Hz, 1 H) 8.79 (s, 1 H) 9.46 (d, J=5.52 Hz, 1 H) 10.60 (s, 1 H).
Reaction SMILES: C(N(CC)CC)C.Cl.O(N)C.ClC[C:14]1[N:15](CC(O)(C)C)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=1.O>CN(C=O)C>[NH:15]1[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=[CH:14]1
Reactant: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Agent: CON
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1nc2ccccc2c2[nH]cnc12
Temperature: 50 °C
Reaction time: 17 h

Procedure:
Triethylamine (1.49 g, 2.1 mL, 14.8 mmol) and methoxylamine hydrochloride (0.822 g, 9.84 mmol) were added to a stirring suspension of 2-chloromethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 4.92 mmol) in DMF (10 mL). The resulting suspension was heated to 50° C. and stirred for 17 hours. The reaction mixture was cooled to room temperature and poured into water (20 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL) and dichloromethane (3×50 mL). A significant amount of the desired product remained in the aqueous layer thus the organic fractions were combined with the aqueous fraction and concentrated under reduced pressure. The residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 10-25% methanol in dichloromethane) and triturated with dichloromethane to provide 760 mg of 1-(2-Hydroxy-2-methylpropyl)-2-{[methoxylamino]methyl)}-1H-imidazo[4,5-c]quinolin-4-amine; hydrochloride as a tan solid, mp 255-257° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O=S(Cl)Cl.[CH3:16]O>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:16])=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccccc1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2-hydroxyphenyl)acetic acid (11 g, 72.3 mmol) in 100 mL of MeOH was added SOCl2 (17.2 g, 144.7 mmol) at 0° C. The mixture was stirred at 50° C. overnight. The reaction was concentrated. The residue was purified column chromatography to give methyl (2-hydroxyphenyl)acetate (14 g).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH2:6][CH:5]1[CH:4]([C:9]([OH:11])=O)[CH2:3][CH:2]2[C:12]([OH:14])=O.C(OC(=O)C)(=O)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:29][CH2:28]1>O>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[N:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[C:12](=[O:14])[CH:2]3[CH2:3][CH:4]([CH:5]4[CH2:6][CH2:7][CH2:8][CH:1]43)[C:9]2=[O:11])[CH2:28][CH2:29]1
Reactant: O=C(O)C1CC(C(=O)O)C2CCCC12
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1C2CC(C(=O)N1CCCCN1CCN(c3ncccn3)CC1)C1CCCC21

Procedure:
Bicyclo[3.3.0]-octane-2,4-dicarboxylic acid (1.6 g., 8.1 mmole) was converted to the anhydride by refluxing for three hours in 100 ml. of acetic anhydride. The excess reagent was removed in vacuo. Two hundred fifty (250) ml. of xylene was added along with 1.9 g. (8.1 mmole) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine. The mixture was refluxed under nitrogen for 48 hours with water removal via a Dean-Stark trap. The solvent was then removed in vacuo and the residue filtered through 75 g. of silica gel with 2% ethanol/chloroform as eluent. Removal of solvent and recrystallization of the residue from isopropanol with the addition of 4N isopropanolic HCl, followed by a second recrystallization from isopropanol, gave 750 mg. of white solid title compound as hydrochloride, one quarter hydrate, m.p. 188°-189° C.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23](OCC)=[O:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].ClCCl.CO.[CH3:33][NH2:34]>[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23]([NH:34][CH3:33])=[O:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCOC(=O)C1CCCN(Cc2ccc3c(c2)c2ccccc2n3CC)C1
Reactant: CN
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: CCn1c2ccccc2c2cc(CN3CCCC(C(=O)NC)C3)ccc21
Temperature: 140 °C
Reaction time: 24 h
Yield: 6 %

Procedure:
A 50-mL seal tube charge with a solution of ethyl 1-((9-ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carboxylate (500 mg, 1.37 mmol, 1.00 equiv) in CH3NH2 (25 mL). To the mixture was added CuSO4 (100 mg, 0.51 mmol, 0.37 equiv). The resulting solution was stirred at 140° C. for 24 hours in an oil bath. The progress was monitored by TLC (dichloromethane/methanol=5:1). Upon completion, the solids were filtered out. The resulting solution was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with dichloromethane/methanol (30:1) affording 1-((9-ethyl-9H-carbazol-3-yl)methyl)-N-methylpiperidine-3-carboxamide as white solid (28 mg, 6%). LCMS: [M+H]+: 350. 1H NMR (CDCl3, 300 MHz) δ 8.10 (d, 1H), 8.01 (s, 1H), 7.53-7.39 (m, 4H), 7.29-7.24 (m, 1H), 4.44-4.37 (q, 2H), 3.85-3.81 (d, 1H), 3.69-3.65 (d, 1H), 2.89 (m, 2H), 2.80-2.78 (d, 3H), 2.59 (br, 1H), 2.45 (br, 2H), 1.91 (m, 1H), 1.73-1.73 (m, 3H), 1.47 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCCC.C1(C)C=CC=CC=1>[CH3:41][C:37]1[CH:36]=[C:35]([NH:34][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]4[C:20]3=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1cccc(N)c1
Reactant: Cc1cccc(C2(c3cccc(Br)c3)c3ccccc3-c3ccccc32)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cccc(Nc2cccc(C3(c4cccc(C)c4)c4ccccc4-c4ccccc43)c2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
In a 200 mL three-neck flask were put 3.0 g (7.3 mmol) of 9-(3-bromophenyl)-9-(3-methylphenyl)-fluorene and 2.1 g (22.0 mmol) of sodium tert-butoxide. The air in the flask was replaced with nitrogen. To this mixture were added 37.0 mL of toluene, 0.8 mL (7.4 mmol) of m-toluidine, and 0.2 mL of a 10% hexane solution of tri(tert-butyl)phosphine. The temperature of this mixture was set to 85° C., and 29.8 mg (0.1 mmol) of bis(dibenzylideneacetone)palladium(0) was added to the mixture. The temperature of the mixture was raised to 90° C., followed by stirring for 4.0 hours. After the stirring, the mixture was suction-filtered through Florisil, Celite, and alumina to give a filtrate. The filtrate was concentrated to give an oily substance, which was then purified by silica gel column chromatography (the developing solvent has a 2:1 ratio of hexane to toluene). Accordingly, 3.1 g of a compound was obtained in 98% yield, which was the substance to be produced. The synthesis scheme of this Step 1 is shown in the following (E14-1).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:28])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[C:11]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[OH-:29].[Na+].OO>CN(C)C=O>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:28])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[C:11]([C:12]3[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:29])=[CH:14][CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(-c3ccc(C#N)cc3)c(-c3ccc(OC)cc3)c(C)nn12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3ccc(C(N)=O)cc3)c(-c3ccc(OC)cc3)c(C)nn12
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (22 mg) in N,N-dimethylformamide (1 mL) were added 1N sodium hydroxide (0.12 mL) and 30% hydrogen peroxide (0.07 mL) at ambient temperature. After 1 hour stirring, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel column chromatography (silica gel, 30 mL) eluting with hexane-ethyl acetate=5-1 and 0-1 to give 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzamide (18 mg, 78.0%) as an yellow solid.