Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][O:35][CH3:36])=[C:28]4[O:37][CH2:38][O:39][C:27]=34)=[C:18]([C:23]#[N:24])[CH:19]=[N:20]2)=[CH:15][C:14]=1[O:40][CH3:41].[I-].[Na+].[ClH:44]>C(OCC)(=O)C.C(OCC)C>[ClH:6].[ClH:44].[C:23]([C:18]1[CH:19]=[N:20][C:21]2[C:16]([C:17]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][O:35][CH3:36])=[C:28]3[O:37][CH2:38][O:39][C:27]=13)=[CH:15][C:14]([O:40][CH3:41])=[C:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:22]=2)#[N:24]
Reactant: C1CCNC1
Reactant: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCOCCCl)c(OC)cc23)c2c1OCO2
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCOCCN4CCCC4)c(OC)cc23)c2c1OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyrrolidine (10 ml) was added to a mixture of 7-[2-(2-chloroethoxy)ethoxy]-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline (0.225 g) and sodium iodide (0.133 g) and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was evaporated and the residue was triturated under methylene chloride. The resultant solid was washed with water and dried. The material so obtained was dissolved in the minimum quantity of ethyl acetate and a solution of hydrogen chloride in diethyl ether (1M) was added. The resultant solid was isolated, washed with diethyl ether and dried. There was thus obtained the title compound as a solid (0.145 g); NMR Spectrum: (DMSOd6 and CD3CO2D at 100° C.) 1.84–1.89 (m, 4H), 3.29–3.39 (m, 9H), 3.88 (m, 2H), 3.94 (m, 2H), 3.96 (s, 3H), 4.3 (s, 2H), 4.36 (m, 2H), 6.04 (s, 2H), 6.84 (d, 1H), 6.94 (d, 1H), 7.46 (s, 1H), 7.87 (s, 1H), 8.56 (s, 1H); Mass Spectrum: M+H+ 545.
Reaction SMILES: [CH3:1][Li].[C:3]([CH2:6][N:7]1[C:11]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[N:8]1)([OH:5])=O>C(OCC)C.O1CCCC1>[C:3]([CH2:6][N:7]1[C:11]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[N:8]1)(=[O:5])[CH3:1]
Reactant: O=C(O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of methyllithium in diethyl ether (250 ml) was added to a solution of 1-carboxymethyl-5-triphenylmethylaminopyrazole (25.95 g) in tetrahydrofuran (400 ml) under ice-cooling and the mixture was stirred for hours at ambient temperature. The reaction mixture was added to a mixture of ice-cold water (500 ml) and diethyl ether (500 ml). The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-acetylmethyl-5-triphenylmethylaminopyrazole.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CC(C)=O.C(=O)=O.[C:13]([C:15]1(O)[CH2:21][CH:20]2[N:22]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:17]([CH2:18][CH2:19]2)[CH2:16]1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:13]([C:15]1[CH2:16][CH:17]2[N:22]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:20]([CH2:19][CH2:18]2)[CH:21]=1)#[N:14]
Reactant: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=CC2CCC(C1)N2CC(F)(F)F
Temperature: 20 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
An oven-dried 25 ml 3-necked round bottom flask was fitted with a reflux condenser, thermometer and magnetic stirrer and the apparatus filled with nitrogen. Phosphorous oxychloride (1.41 g, 9.1 mmol) and pyridine (6.53 g) were charged to the flask and the mixture then cooled to −10° C. in an acetone/Drikold™ bath. 3-Cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (0.97 g, 4.1 mmol—assumed, prepared in Step 1) was added in one portion and the resultant exotherm raised the reaction mass temperature to 20° C. The mixture was then heated to 80° C. and held at this temperature for 24 hours, after which the reaction mixture was cooled and stirred at ambient for 18 hours. The reaction mass was poured onto ice/water (50 ml) and solid sodium carbonate was added portionwise until the mixture was adjusted to pH8. The mixture was extracted with ethyl acetate (3×30 ml), the combined extracts were dried (Na2SO4), filtered and concentrated in vacuo to give 3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene (0.51 g, 51% yield from 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one; 60:40 exo:endo cyano).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: Cc1cccc(COc2ccc([N+](=O)[O-])cc2Cl)n1
Agent: [Pt]
Solvent: CO
Product: Cc1cccc(COc2ccc(N)cc2Cl)n1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
2.79 g of compound 9.1 (10 mmol) was suspended in MeOH (50 ml) and treated wet 5% Pt/C (Degussa type, Aldrich, 1.5 g). The flask is flushed with hydrogen gas from a balloon and the reaction mixture was stirred under hydrogen balloon for 2 hours. The reaction mixture was filtered through a Celite plug and the solvent is removed under reduced pressure to yield 2.2 g of the desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:3]=1)=[O:15]
Reactant: C1CCNCC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCCCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C

Procedure:
To a 10 mL reaction vial containing stir bar were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.060 g, 0.160 mmol), ethanol (1.5 mL), and then piperidine (0.318 mL, 3.21 mmol) via syringe at once. The contents were capped, placed into a heat block, and heated at 120° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL), adjusted to pH 6-7, and stirred for 15 min. The contents were filtered and washed with water. The product was dried in vacuum oven at 50° C. for 5 hr. The product was obtained as 57 mg (82%). LCMS E-S (M+H)=422.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J=6.82 Hz, 6 H), 1.53-1.67 (m, 6 H), 2.12 (s, 3 H), 2.20 (s, 3 H), 3.61-3.73 (m, 4 H), 4.34 (d, J=5.05 Hz, 2 H), 4.91-5.04 (m, 1 H), 5.89 (s, 1 H), 7.10 (s, 1 H), 7.97 (s, 1 H), 8.65 (t, J=4.93 Hz, 1 H), 11.51 (br. s., 1 H).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:9]1[C:16](Cl)=[N:15][C:13](Cl)=[N:12][C:10]=1Cl>N1C=CC=CC=1>[C:1]1(=[N:7][O:8][C:10]2[N:12]=[C:13]([O:8][N:7]=[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:15]=[C:16]([O:8][N:7]=[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=C1CCCCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: c1ccncc1
Product: C1CCC(=NOc2nc(ON=C3CCCCC3)nc(ON=C3CCCCC3)n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.1 %

Procedure:
To a cold (0° C.) solution of cyclohexanone oxime (4.53 g, 0.04 mol) in dry pyridine (20 ml) is added cyanuric chloride (1.84 g, 0.01 mol). An exothermic reaction occurs and the temperature rises to 22° C. The solution is then stirred 15 h at room temperature and then poured into 200 ml of ice-cold water. The precipitated solid is filtered off, dried and recrystallized from dichloromethane-hexane to afford 3.57 g of the title compound as a white solid. The compound decomposes without melting above 120° C. (DSC data).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([N:20]=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C1COCC1.[BH4-].[Na+]>CO>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: C[C@]1(CN2CCN(N=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]1(CN2CCN(NCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a mixture of (S)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethylbenzylidene)amine prepared in Example 504 (100 mg, 0.23 mmol) and THF (4 ml), sodium borohydride (13 mg, 0.34 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 30 minutes. To the reaction mixture, methanol (1 ml) was added, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethylbenzyl)amine (32 mg, yield 31%) as a light yellow powder.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCO)cc1
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
To a chilled (0° C.) solution of hexaethylene glycol (5.41 g, 19.2 mmol) in DCM (191 mL) were added TsCl (4.02 g, 21.1 mmol), Ag2O (6.67 g, 28.8 mmol), and KI (0.64 g, 3.84 mmol). After stirring for 20 min the reaction mixture was filtered through a 4 cm pad of celite and flushed with EtOAc. The resulted filtrate was concentrated under reduced pressure to give a yellow oil. The crude product was purified via silica flash chromatography using 3:2 DCM/Acetone as an eluent, providing 33 (6.24 g, 75%): 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 4.23-4.07 (m, 2H), 3.82-3.51 (m, 22H), 2.55 (d, J=6.0 Hz, 1H), 2.44 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[N:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C(#N)C>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[N:26][C:21]([C:20]([F:31])([F:19])[F:30])=[CH:22][CH:23]=4)[CH3:28])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Reactant: C[C@H](N)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1CN(c1ccc(Cl)cn1)CC2)c1ccc(C(F)(F)F)nc1
Yield: 55.6 %

Procedure:
4-Bromo-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (25 mg, 0.077 mmol), (S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (73.0 mg, 0.384 mmol), N,N-diisopropylethylamine (40.1 μL, 0.230 mmol), and acetonitrile (1.0 mL) were added to a 0.5 to 2 mL microwave vial. The mixture was reacted in the microwave reactor for 2.5 hrs at 200° C. The resulting mixture was treated with CH2Cl2 and washed with 1 M NaH2PO4, dried (Na2SO4), and evaporated. The residue was purified by silica gel column to obtain a light yellow solid (18.6 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH:31]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:32][NH:33]C(OC(C)(C)C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[NH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][CH:27]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCC(Nc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCC(Nc1cccc(-c2n[nH]c3nc(NC4CCC(N)CC4)ncc23)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of (4-{3-[6-(2-tert-Butoxycarbonylamino-1-phenyl-ethylamino)-pyridin-2-yl]-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (103 mg, 0.116 mmol) in C2H5OH (8 mL) was added conc. HCl (8 mL) at room temperature. The mixture was stirred at room temperature for 15 hour. The solvent was removed under reduced pressure. The residue was washed with dichloromethane (10 mL) to get the crude compound which was purified by prep-HPLC to give N-{3-[6-(2-amino-1-phenyl-ethylamino)-pyridin-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride as a yellow solid. (Yield 14 mg).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21].C(ON=O)(C)(C)C>O1CCCC1>[C:19]([C:4]1[C:3]([I:21])=[CH:2][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reaction time: 3 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (90 g) in tetrahydrofuran (720 ml) heated to 65° C. was added t-butylnitrite (144 ml) over a period of 0.5 hours. Stirring and heating were continued for 3 hours. The cooled reaction mixture was evaporated and the residue recrystallised from propan-2-ol to give the title compound as a white solid, m.p.83-4° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:23][Li]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CSc1ccc2cnnc(-c3ccc(NC(C)=O)cc3)c2c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(c1ccc(NC(C)=O)cc1)=NNC2C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the phthalazine 7 (1.2 g, 3.88 mmol) in THF (150 mL) was added methyl lithium (1.4 M, 11 mL) at 0° C. The resulting dark brown solution was stirred 2 hours. Ice water was added to quench the reaction. The aqueous phase was extracted with DCM three times. The combined organic phase was dried over Na2SO4. Removal of the solvent afforded the crude product, which was used directly for the next step.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][CH2:11][C:12]2([CH2:15][C:16]#[N:17])[CH2:14][CH2:13]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)(=O)C.C(O)C>[NH2:1][C:4]1[C:5]([O:10][CH2:11][C:12]2([CH2:15][C:16]#[N:17])[CH2:14][CH2:13]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CCC1(COc2ncccc2[N+](=O)[O-])CC1
Solvent: CCO
Solvent: CC(=O)O
Product: N#CCC1(COc2ncccc2N)CC1
Temperature: 100 °C

Procedure:
2-(1-((3-Nitropyridin-2-yloxy)methyl)cyclopropyl)acetonitrile (466 mg) was dissolved in a mixture of glacial acetic acid (4 ml) and ethanol (8 ml). Ferrum (1.1 g) was added and the reaction mixture was heated to 100° C. for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane, extracted with an aqueous solution of K2CO3 (2M) and concentrated in vacuo
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[CH:10]1[CH:15]=[N+:14]([C@@H:16]2[O:20][C@H:19]([CH2:21][O:22][P:23]([O:26][P:27]([O:30][CH2:31][C@H:32]3[O:36][C@@H:35]([N:37]4[C:41]5[N:42]=[CH:43][N:44]=[C:45]([NH2:46])[C:40]=5[N:39]=[CH:38]4)[C@H:34]([O:47][P:48]([OH:51])([OH:50])=[O:49])[C@@H:33]3[OH:52])([OH:29])=[O:28])([OH:25])=[O:24])[C@@H:18]([OH:53])[C@H:17]2[OH:54])[CH:13]=[C:12]([C:55]([NH2:57])=[O:56])[CH:11]=1>C(O)(C)C>[CH:43]1[N:44]=[C:45]([NH2:46])[C:40]2[N:39]=[CH:38][N:37]([C@@H:35]3[O:36][C@H:32]([CH2:31][O:30][P:27]([O:26][P:23]([O:22][CH2:21][C@H:19]4[O:20][C@@H:16]([N:14]5[CH:13]=[C:12]([C:55]([NH2:57])=[O:56])[CH2:11][CH:10]=[CH:15]5)[C@H:17]([OH:54])[C@@H:18]4[OH:53])([OH:25])=[O:24])([OH:29])=[O:28])[C@@H:33]([OH:52])[C@H:34]3[O:47][P:48]([OH:51])([OH:50])=[O:49])[C:41]=2[N:42]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CC(C)O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Temperature: 45 °C

Procedure:
The gel was used to prepare a sepharose-alcohol dehydrogenase column (0.4×4.0 cm) which was then immersed in a water bath maintained at 45° C. A 0.01 M Tris-HCl solution (pH 9.0) containing 2.5 mg/ml NADP and 0.25 v/v isopropanol was applied to the column at a rate of 0.25 ml/min.; the treated solution was collected in a cooled ethanol precipitation vessel. Several milliliters of petroleum ether were added to 20 ml of the eluted solution and the precipitate was collected by centrifugation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:10](=[O:27])[N:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:12]=[CH:13][C:14]=2[N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1.C[Sn](C)(C)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:11]2[C:10](=[O:27])[C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[C:14]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:13]=[N:12]2)=[CH:21][CH:22]=1
Reactant: C[Sn](C)(C)c1ccncc1
Reactant: O=c1c(Oc2ccc(Br)cc2)c(-n2ccnc2)cnn1-c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(Oc2ccc(-c3ccncc3)cc2)c(-n2ccnc2)cnn1-c1ccc(Cl)cc1

Procedure:
1.5 mmol of 4-(4-bromophenyl)oxy-2-(4-chlorophenyl)-5-(1H-imidazol-1-yl)-3(2H)-pyridazinone, 2.1 mmol of 4-trimethylstannylpyridine, 0.1 mmol of bis(triphenyl-phosphine)palladium dichloride and 1.3 mmol of ethyldiisopropylamine in 5 ml of dimethylformamide are heated at 100° C. for 5 hours. The solvent is removed in a rotary evaporator, and the residue is purified by chromatography on silica gel (elution with ethyl, acetate/methanol mixtures). 0.3 g (45% of theory) is obtained of m.p. 188° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][CH:6]=[CH:5]2.C(OC(=O)C)(=[O:15])C>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:15])[CH:6]=[CH:5]2
Reactant: [O-][n+]1cccc2cc(F)ccc21
Reactant: CC(=O)OC(C)=O
Product: O=c1ccc2cc(F)ccc2[nH]1
Reaction time: 8 h

Procedure:
A solution of 6-fluoroquinoline 1-oxide from Step B (5.0 g, 30.65 mmol) in acetic anhydride (30 mL) is heated at 110° C. for 6.5 hours. The reaction is allowed to stand at room temperature overnight. The solid (1.1 g) is collected and recrystallized from anhydrous ethanol (75 mL). The reddish crystals are collected by filtration and dried under high vacuum to give the title compound (0.653 g), m.p. dec. 269–270° C.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[N:34][N:35]=2)[N:32]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C(O)CCC>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[N:34][N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ccc2nncn2n1
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: c1ccc(C(OC2CCN(CCCCNc3ccc4nncn4n3)CC2)c2ccccc2)cc1
Yield: 39.4 %

Procedure:
1.15 g of 4-(diphenylmethoxy)-1-piperidinebutanamine and 578 mg of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine were dissolved in 20 ml of 1-butanol; 1.17 ml of N-ethyldiisopropylamine was added, followed by refluxing under heating for 14 hours. After cooling, ethyl acetate was added; the reaction mixture was washed with aqueous sodium bicarbonate and saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized from ethyl acetate and dried to yield 611 mg of the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[I:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]1[CH2:36][CH2:37][CH:32]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3I)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(2-iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 533.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:24][C@H:23]([CH2:25][O:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:13]([O:14]C(=O)C2C=CC=CC=2)[C@@H:12]1[F:46].[NH3:47]>>[C:27]([O:26][CH2:25][C@H:23]1[O:24][C@@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH2:47])[C@@H:12]([F:46])[C@@H:13]1[OH:14])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O[C@H]1[C@H](F)[C@H](n2cnc3c(Cl)ncnc32)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: N
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@@H]1F
Reaction time: 48 h
Yield: 73 %

Procedure:
6-Chloro-9-(5-O-trityl-3-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9-H-purine (3.15 g, 4.98 mmol) was dissolved in 100 ml methanolic ammonia (saturated at 0° C.) and left in a sealed tube at 100° C. for 2 days. After cooling, the solvent was carefully distilled off, and the residues were dissolved in 100 ml chloroform. The insolubles were filtered off and the solution was applied to a silica gel column (3.5×50 cm) and eluted with 3 to 10% ethanol/methylene chloride solution (4000 ml). Product fractions were collected, and the solution was concentrated to give white crystals (1.87 g, 3.66 mmol, 73%)