Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][N:12]([CH2:17][CH2:18][N:19]([CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][N:19]([CH2:18][CH2:17][N:12]2[CH2:13][CH:14]3[O:16][CH:10]([CH2:9][NH:8][CH2:15]3)[CH2:11]2)[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:28][CH:29]=1)#[N:34]
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCN(CCCc3ccc(C#N)cc3)S(C)(=O)=O)CC(C1)O2
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CCCc1ccc(C#N)cc1)CCN1CC2CNCC(C1)O2

Procedure:
7-(2-{[3-(4-cyanophenyl)propyl]methanesulfonylamino}ethyl)-9-oxa-3,7-di-azabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (3.8 g, 0.0095 mol; see step (i) above) was added to a saturated solution of HCl(g) in ethyl acetate (50 mL) and the resultant mixture was then stirred overnight. On completion of the reaction (as determined by TLC), ethyl acetate was decanted and the product was dried under high vacuum to give the title compound. Yield: 1.5 g (54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH:13]=[O:14])=[CH:6]2.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13][OH:14])=[CH:6]2
Reactant: COc1ccc2ncc(C=O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ncc(CO)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a stirred solution of 6-methoxyquinoline-3-carbaldehyde (1.00 g, 5.3 mmol) in THF (50 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (0.20 g, 5.3 mmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (12 mL). After stirring for 15 min at RT, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave (6-methoxyquinolin-3-yl)methanol SLA 47088A as a yellow solid (0.49 g, 49% yield).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH2:19]([O:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:2]2[N:3]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:20]
Reactant: CCOc1cccc(CCc2nc3ccccc3[nH]2)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(CCc2nc3ccccc3n2CC(C)C)c1
Temperature: 90 °C
Yield: 69.3 %

Procedure:
A 50 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with benzimidazole 70 (800 mg, 3.00 mmol) and K2CO3 (829 mg, 6.00 mmol). DMF (10 mL) was added followed by 1-bromo-2-methylpropane (617 mg, 0.489 mL, 4.50 mmol). The mixture was heated in a 90° C. bath overnight. Another 0.5 mL of 1-bromo-2-methylpropane and 300 mg of K2CO3 were added, and the mixture was heated overnight again. A third addition of 0.5 mL of 1-bromo-2-methylpropane and 300 mg of K2CO3 were added. The mixture was heated another 4 hr until complete as monitored by HPLC. The suspension was cooled, and the solids were filtered off and rinsed with EtOAc (60 mL). The filtrate was washed with saturated aqueous NH4Cl (2×50 mL), H2O (2×50 mL), and brine (30 mL), filtered through phase separation paper, and concentrated in vacuo to an orange-brown oil. The crude oil was filtered through a plug of silica gel with CH2Cl2 (2×100 mL) and 5% EtOAc in CH2Cl2 (3×100 mL). The EtOAc/CH2Cl2 filtrates were concentrated to give 670 mg of Compound #16 as a yellow oil (69%). 1H NMR (300 MHz, CDCl3): δ 7.78 (m, 1H), 7.34-7.19 (m, 4H), 6.87-6.76 (m, 3H), 3.98 (qt, 2H), 3.81 (d, 2H), 3.32-3.22 (m, 2H), 3.21-3.11 (m, 2H), 2.17 (nonet, 1H), 1.40 (t, 3H), 0.93 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 99% with a retention time of 5.1 min.
Reaction SMILES: N1C2C(=CC=CC=2)C([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=C1.[NH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](C)=[CH:17]1>>[NH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[C:17]1[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: Cc1c[nH]c2ccccc12
Product: O=C(O)CCCc1cc2ccccc2[nH]1
Reaction time: 3 h

Procedure:
Microtiter plates (Nunc, Sweden) coated with anti-indoleacetic acid polyclonal antibodies (described above) were used. A mixture of 100 μl of the enzyme conjugate (Indole-3-butyric acid-AP conjugate, prepared as described above, and diluted 1:10,000 in TBS) and 100 μl of skatole solution (either in TBS or in 10% porcine serum solution) of a number of dilutions was added to wells in duplicate. The mixture was incubated for 3 hrs. at 4° C. and then washed with saline-Tween solution 3 times (200 μl volume). 200 μl of the substrate solution (1mg/ml in TBS) was added per well and incubated at 37° C. for an hour. The wells were then treated with approximately 50.0 μl of 1N NaOH/well to stop the reaction. Final absorbances were measured.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:7]=[C:8]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:15][C:14]3[CH:26]=[CH:27][CH:28]=[N:29][C:13]2=3)[CH:9]=[CH:10][CH:11]=1)C(=O)C.C(=O)(O)[O-].[Na+]>Cl>[CH3:1][NH:2][C:6]1[CH:7]=[C:8]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:15][C:14]3[CH:26]=[CH:27][CH:28]=[N:29][C:13]2=3)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)N(C)c1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Temperature: 0 °C
Yield: 58.9 %

Procedure:
A solution of 4-[3-(N-methyl-N-acetylamino)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (2.02 g) in 3N hydrochloric acid (20 ml) was stirred under reflux for 2 hours. Then the mixture was poured into ice-water and alkalinized with sodium bicarbonate. The resultant solid was collected and washed with water and recrystallized from ethanol to give 4-[3-(methylamino)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.06 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[C:25]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([N:39]5[CH2:43][CH2:42][CH2:41][CH:40]5[CH3:44])[N:34]=4)[C:26]4[N:27]([CH:29]=[CH:30][N:31]=4)[N:28]=3)[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:45]CCl>>[ClH:45].[CH3:44][CH:40]1[CH2:41][CH2:42][CH2:43][N:39]1[C:35]1[N:34]=[C:33]([NH:32][C:25]2[C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[N:28]=[C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: ClCCl
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCN(C(=O)OC(C)(C)C)CC4)c3)nn3ccnc23)n1
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCNCC4)c3)nn3ccnc23)n1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
tert-butyl-4-(2-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate (25 mg, 0.042 mmol) was dissolved in dichloromethane (5 mL) that had been saturated by bubbling HCl gas. The solution was stirred at room temperature for 2 h. The solvent was concentrated in vacuo. The residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 10% acetonitrile/90% water (0.1% TFA, v/v) initially, proceeding to 60% acetonitrile/40% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-(piperazin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (15 mg, 71%) as a yellow solid. 1H NMR (300 MHz, DMSO+D2O): δ 9.12 (s, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 7.58-7.52 (m, 4 h), 7.27-7.26 (m, 1H), 6.66 (d, 1H, J=7.8 Hz), 6.19 (d, 1H, J=8.4 Hz), 4.51 (brs, 2H), 4.25 (brs, 1H), 3.69-3.37 (m, 12H), 2.08-1.99 (m, 3H), 1.72 (brs, 1H), 1.12 (d, 3H, J=6.3 Hz). LC/MS: 499 [M+H]+, tR=1.08 min. HPLC: 99.25% at 214 nm, 99.12% at 254 nm, tR=4.99 min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCc2ccccc2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 2-bromoethylbenzene (0.10 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (117 mg, yield 63%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:26]N1C(=O)CCC1=O>C(#N)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[C:21]=2[I:26])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC1CC1
Solvent: CC#N
Solvent: O
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of Step 3 intermediate (3.89 g, 10.72 mmol) was added N-iodosuccinimide (2.69 g, 11.79 mmol) in acetonitrile at room temperature. The reaction temperature was then raised to 60° C. and stirred for 4 h. The reaction mixture was then cooled to room temperature, diluted with water and stirred for 20 min. The filtered solid was washed with water and dried to afford 5.19 g of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.33 (m, 2H), 0.54-0.56 (d, J=7.2 Hz, 2H), 1.22 (br s, 1H), 3.77-3.81 (m, 5H), 7.06-7.14 (m, 2H), 7.27-7.29 (d, J=7.2 Hz, 1H), 7.49-7.52 (m, 1H), 7.57 (s, 1H), 7.96 (d, J=3.9 Hz, 1H), 8.18 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 481.45 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCOCC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
0.20 g (2.2 mmol) of morpholine was added to a solution of 0.25 g (0.85 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 l of DMF and stirred at 60° for 1 hr. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 25:1) and crystallization from EtOH yielded 0.20 g (70%) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 206-208°.
Reaction SMILES: C([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:14]=[N:13][C:12]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:25][CH2:24]3)[C:12](=[O:23])[NH:13][CH2:14]2)=[CH:17][CH:18]=1
Reactant: O=C1N=CN(c2ccc(F)cc2)C12CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 81 g 8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one in 960 ml methanol and 24 ml acetic acid were added 21.2 g 10% Pd on charcoal and stirred for 16 h under a hydrogen atmosphere at ambient temperature. The reaction mixture was filtered, concentrated, diluted with 100 ml water, made alkaline with sat NaHCO3 solution and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The residue, 23 g crude product, was crystallised from AcOEt: 6.6 g 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one as colorless crystals: MS (ISP): 250.2 MH+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1>C(Cl)Cl>[NH:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[CH:10]3)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]ncc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2[nH]ncc2cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
Trifluoroacetic acid (0.20 ml, 2.60 mmol) was added to a solution of tert-butyl 4-(1H-indazol-5-yloxy)-1-piperidinecarboxylate (70 mg, 0.221 mmol) in methylene chloride (5 ml) at room temperature and stirred overnight at room temperature. Then, the solvent of the reaction solution was distilled off under reduced pressure and the resulting residue was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5-(4-piperidinyloxy)-1H-indazole (25 mg, 52%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.ClCCCl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O>[C:19]([O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(OC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (3.0 g) was mixed with DCE (30 ml), and TEA (3.0 ml) and benzoyl chloride (2.4 g) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with DCE (30 ml), and TFA (10 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain piperidin-4-yl benzoate (3.1 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[O:19]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:29]3[CH:30]=[CH:31][C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][CH:28]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1cc[n+]([O-])cc1
Yield: 87.5 %

Procedure:
A suspension of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (0.140 g, 0.00040 mol) in dimethoxyethane (7 mL) and water (15 mL) was reacted with 4-phenoxyphenylboronic acid (0.093 g, 0.00043 mol), sodium carbonate (0.105 g, 0.00099 mol) and tetrakis(triphenylphosphine)palladium (O) (0.046 g, 0.00004 mol) at 80° C. for 18 hours. The solid was filtered to give 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.138 g, 0.00035 mol) as a brown solid. A portion (0.040 g, 0.00010 mol) was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 40% isocratic for five minutes, then 40%-100% acetonitrile-0.1M ammonium acetate over 30 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give the product 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate as a white solid (0.013 g, 0.00003 mol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([N-:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:20])#[N:17]>>[C:25]1([CH2:24][CH2:23][CH2:22][NH:21][C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=2)/[C:16]#[N:17])=[O:20])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#CCC(=O)[N-]CCCc1ccccc1
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCCCc2ccccc2)cc(OC)c1O
Yield: 90.2 %

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4 hydroxycinnamaldehyde (0.10 g, 0.48 mmol) to N-(cyanoacetyl)phenylpropylamide (Example 19, 0.097 g, 0.48 mmol). After refluxing for 3 h the residue was purified by silica gel chromatography (CHCl3-hexane, 1:1) to give a brown solid (0.17 g, 90% yield). The product gave the following analytical data:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]([C:49]1[CH:57]=[CH:56][C:52]([CH2:53][CH2:54]O)=[CH:51][CH:50]=1)#[N:48]>ClCCl.CCCCCCC>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:54][CH2:53][C:52]2[CH:56]=[CH:57][C:49]([C:47]#[N:48])=[CH:50][CH:51]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: N#Cc1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.1 %

Procedure:
p-Hydroxybenzaldehyde (24.9 g; 203.8 mmole) was dissolved in dichloromethane (dry). ADDP (47.2 g; 187 mmole) was added followed by addition of triphenylphosphine (49 g; 187 mmole). The reaction mixture was stirred at room temperature for 45 minutes and then p-cyanophenethyl alcohol (25 g; 110 mmole) dissolved in a small amount of dichloromethane (dry) was added in portions during one hour. The reaction mixture was stirred at room temperature over night, filtered and evaporated. Chromatography of the residue on silica gel using ethyl acetate:heptane as eluant gave 9.7 g (22.7% yield) of 4-[2-(4-formylphenoxy)ethyl]benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19]CC4C=CC=CC=4)=[O:18])[CH2:12]3)=[C:8]([C:27](=[O:29])[NH2:28])[CH:7]=[N:6][N:5]2[CH:30]=1.BrC1C=C2[C:39](Cl)=[C:38]([C:41](N)=O)[CH:37]=NN2C=1.N[C@H]1[C@@H](C)CN(C(OCC2C=CC=CC=2)=O)C1.I[Si](C)(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:38]([CH3:41])([CH3:39])[CH3:37])=[O:18])[CH2:12]3)=[C:8]([C:27](=[O:29])[NH2:28])[CH:7]=[N:6][N:5]2[CH:30]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Agent: C[Si](C)(C)I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A suspension of 5.8 g (12.28 mmol) of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (prepared by coupling Intermediate 2 and enantiopure intermediate 5 as described in Step 1 of Example 52) in acetonitrile (75 mL) was cooled to 0° C. in an ice-water bath. Iodotrimethylsilane (6.99 mL, 49.1 mmol) was then added dropwise and the reaction mixture was stirred while the ice bath was allowed to slowly warm to room temperature. After 90 minutes, the deprotection step is complete. The reaction mixture was recooled to 0° C. and was quenched by slowly adding 35 mL MeOH. After stirring 45 minutes to ensure that the quench was complete, the volatiles were removed in vacuo to afford a solid. After drying for 1 hour under high vacuum, di-t-butyldicarbonate (4.02 g, 18.42 mmol) was weighed into the flask containing the solid. DCM (100 mL) and N,N-Di-iso-propylethylamine (10.69 mL, 61.4 mmol) were then added and the solution was stirred at room temperature. Within 15 minutes the reaction is complete and the product began to precipitate out of solution. The reaction mixture was diluted with 150 mL DCM and the resulting suspension was filtered. The filter cake was washed with 1:1 hexanes:ethyl ether and dried to afford 3.44 gm of title compound as a white solid. The DCM mother liquor was washed 2× with water and 1× brine. After drying over sodium sulfate and concentration, the residue was loaded onto a 120 gm ISCO column for purification by flash chromatography, eluting with 0-10% MeOH in DCM. Concentration of the pure fractions afforded an additional 1.13 gm of the titile compound as a light yellow solid. Concentration gave (3S,4S)-tert-butyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (4.57 gm; 9.90 mmol; 81% yield). MS (ES+) m/z: 438.0, 440.0 (M+H); LC retention time: 3.103 min (analytical HPLC Method O).
Reaction SMILES: [CH2:1]([C:8]1(Br)[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:22])[C:16]=3[Cl:21])[NH:11][C:10]=2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Br-]>CN(C=O)C.O>[CH2:1]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:22])[C:16]=3[Cl:21])[NH:11][C:10]=2[C:9]=1[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2[nH]c3ccc(Cl)c(Cl)c3c2CCC1(Br)Cc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1c(Cc2ccccc2)ccc2c1[nH]c1ccc(Cl)c(Cl)c12
Temperature: 90 °C
Yield: 55.1 %

Procedure:
2-Benzyl-2-bromo-5,6-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.48 g, 1.14 mmol) was dissolved in DMF (4 mL) and LiBr (0.1 g, 1.25 mmol) followed by Li2CO3 (0.09 g, 1.25 mmol) were added. The reaction mixture was heated to 90° C. for 1 h, then cooled to room temperature, diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography [EtOAc-hexane (3:17) as eluant] to provide the title compound as a light green solid (0.215 g, 56%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.31 (s, 1H), 9.22 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.52 (s, 2H), 7.26-7.23 (m, 4H), 7.18-7.20 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.14 (s, 2H).