Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)(=O)=O)=CC=1.[C-]#[N:29].[Na+].[Na+].[Cl-]>CS(C)=O>[C:12]([CH2:13][CH:14]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)#[N:29]
Reactant: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2ccsc2)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC(CC#N)c1ccsc1
Temperature: 90 °C

Procedure:
To 3-(tert-butoxycarbonylamino)-3-(thiophen-3-yl)propyl 4-methylbenzenesulfonate (E73B) in DMSO is added NaCN, and the solution is heated to 90° C. for 2 hours. The reaction is cooled, poured into NaCl (sat), and extracted with EtOAc. The organics are dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 25% EtOAc/Hexanes) gives pure tert-butyl 2-cyano-1-(thiophen-3-yl)ethylcarbamate (E73C).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH:12]=[CH:13][C:4]=2[NH:3][C:2]1=[O:14].[H-].[Na+].Br[CH2:18][CH3:19]>>[CH2:18]([N:3]1[C:4]2[CH:13]=[CH:12][C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[NH:1][C:2]1=[O:14])[CH3:19]
Reactant: CCBr
Reactant: O=c1[nH]c2ccc3ncccc3c2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)[nH]c2c3cccnc3ccc21

Procedure:
3-Ethyl-quinolino[5,6-d]imidazolinone (1f) was prepared analogously by treatment of quinolino[5,6-d]imidazolinone with sodium hydride (1.1 eq.) and bromoethane (1.1 eq.), successively. Yield after column-chromatographic workup: 12%. Mp. 258-259° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Na+].C(=O)(O)[O-].[Na+]>CCOCC.CO.C(Cl)Cl>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1
Reactant: C1=COCCC1
Reactant: CCOC(=O)CCCCCCC1=CC(O)CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCCCCCC1=CC(OC2CCCCO2)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 674 mg. (2.64 mmoles) of 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 1302) and 2.22 g. (26.4 mmoles) of dihydropyran in 2.6 ml. of methylene chloride is added 5.0 mg. (0.026 mmoles) of p-toluenesulfonic acid monohydrate. After stirring for 20 minutes at room temperature the solution is diluted with ether and poured into saturated sodium chloride solution containing a little sodium bicarbonate. The organic phase is separated and washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate, and volatile matter is evaporated at reduced pressure to give an oil, λmax.MeOH =224 mμ(7950); max. = 1735 (ester carbonyl group), 1710 (ketone carbonyl group), and 1030 cm-1 (tetrahydropyran-yloxy group).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[N:3]=[C:4]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=[N+]([O-])c1cccc(Oc2nc(Cl)nc3ccsc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
The compound (2.9 g, 14.2 mmol) obtained in Step 2 was dissolved in N,N-dimethylsulfoneamide (70 mL), and 3-nitrophenol (1.9 g, 14.2 mmol) and cesium carbonate (9.2 g, 28.4 mmol) were added thereto, followed by stirring room temperature for 1 hour. After the reaction was complete, distilled water was added to the reaction mixture, and the resulting solid was filtered under a reduced pressure with washing with distilled water. The resulting solid was dried under a reduced pressure to obtain the title compound (yield: 4.0 g, 91.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>>[CH3:29][N:30]([CH:32]=[C:13]1[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:31]
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O

Procedure:
A mixture of 1.35 g of 1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 15 ml of tert-butoxy-bis(dimethylamino)methane is heated for on a steam bath for 2 hours. The volatiles are evaporated in vacuo to a residue which is stirred with ether and filtered. The cake is washed with ether and the combined filtrates evaporated in vacuo to a residue which is dissolved in 30% ethyl acetate in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is dissolved in 30% ethyl acetate in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue to give 1.60 g of yellow crystalline product, m.p. 180°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]2[O:19][C:18]3[C:9](=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=[CH:16][CH:17]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(O)c1NC(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc2oc(-c3ccc(F)cc3)nc12
Yield: 55 %

Procedure:
Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate 9dd (7.4 mmol, 1.2 g crude) and 1.3 g (7.5 mmol) of p-toluenesulfonic acid was refluxed in 10 mL of xylene overnight. After cooling saturated NaHCO3 was added and the resulting mixture was extracted with EtOAc. The organic solvent was evaporated to give 1.1 g (55%) of methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate, 9ee. MS m/z (M+H+) 272.0.
Reaction SMILES: Cl.CO[CH:4](OC)[CH2:5][N:6]([CH3:18])[C:7](=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1>CC(O)=O.ClCCl>[CH3:16][O:15][C:11]1[CH:12]=[CH:13][C:14]2[CH:4]=[CH:5][N:6]([CH3:18])[C:7](=[O:17])[CH2:8][C:9]=2[CH:10]=1
Reactant: COc1cccc(CC(=O)N(C)CC(OC)OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(=O)N(C)C=C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Add concentrated HCl (3.5 L) to a solution of N-(2,2-dimethoxyethyl)-2-(3-methoxyphenyl)-N-methylacetamide (790 g, 2.709 mol, 1.0 eq) dissolved in HOAc (3.5 L). Stir the mixture for 16 hours at room temperature. Dilute the reaction mixture with 4 L of dichloromethane and then quench slowly with 50% NaOH (4.0 L) over 2 hours. Separate the two layers. Collect the organic layer, dry over sodium sulfate and concentrate under vacuum to yield an off-white solid. The solid is put through a silica plug (1/1 hexanes/ethyl acetate) to obtain the product (Cmpd N, 460 g, 84% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(OCC)(=[O:28])C>CS(C)=O.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:28])[CH2:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1C(O)CC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccccc1CC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving 1.63 g of 2-(1-benzylpiperidin-4-yl)-1-(2-methoxyphenyl)ethanol in 5 ml of dimethylsulfoxide, 4.2 ml of triethylamine was added, a solution of 2.39 g of sulfur trioxide-pyridine complex in dimethylsulfoxide (15 ml) was added dropwise and the mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain 1.38 g of 1-(1-benzylpiperidin-4-yl)-2-(2-methoxyphenyl)ethanone. After dissolving this in 12 ml of 1,2-dichloroethane, 0.55 ml of 1-chloroethyl chloroformate was added while stirring on ice, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, 10 ml of methanol was added to the residue and heating to reflux was continued for 30 minutes. The solvent was distilled off under reduced pressure. A 1N sodium hydroxide solution was added to the residue and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (750 mg, 64% yield).
Reaction SMILES: [ClH:1].C(OC([NH:9][C:10]1[CH:11]=[CH:12][C:13]([P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])=[C:14]([CH:25]=1)[CH2:15][N:16](C)[C:17](=O)OC(C)(C)C)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH2:32]([O:31][P:26]([C:13]1[CH:12]=[CH:11][C:10]([NH2:9])=[CH:25][C:14]=1[CH2:15][NH:16][CH3:17])(=[O:27])[O:28][CH2:29][CH3:30])[CH3:33]
Reactant: CCOP(=O)(OCC)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)c1ccc(N)cc1CNC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
HCl in dioxane (4.0 M, 1 mL) was added to 12C (100 mg, 0.212 mmol) and stirred at rt for 1 h. The reaction mixture was concentrated to yield 12D (70 mg, 0.203 mmol, 96% yield) as a yellow solid.
Reaction SMILES: C([O:8]P(=O)(O)OCC1C=CC=CC=1)C1C=CC=CC=1.[CH:20]1([N:26]=[C:27]=[N:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>C1COCC1>[C:27]([NH:26][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)([NH:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=P(O)(OCc1ccccc1)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
A flask fitted with a nitrogen inlet, overhead stirrer, teflon-coated thermocouple probe, and pressure-equalizing addition funnel was charged with 350 milliliters of dry (water content ≤50 μg/mL), peroxide-free tetrahydrofuran, followed by 50.0 grams (174 millimoles) of dibenzylphosphoric acid (DBP), and the resulting mixture was stirred until the solid dissolved (about 10-15 minutes). A solution of 18.9 grams (91.6 millimoles) of dicyclohexylcarbodiimide (DCC) in 215 milliliters of THF was added from the addition funnel to a stirred, cooled (water-bath) solution of DBP at a rate to maintain the temperature at about 20°-25° C. The reaction is slightly exothermic and the addition took about 30 minutes. Within minutes, a precipitate of dicyclohexylurea formed in the mixture. Stirring was continued for about 2 hours at 20°-25° C. The reaction was monitored by HPLC assay using VYDAC C-18 (300A, 4.6×250 mm) column with water (0.02M KH2PO4) acetonitrile as eluent. The reaction was complete in about 1 hour (assay showing <2 percent unreacted DBP). The mixture was then filtered while excluding moisture to remove dicyclohexylurea. The filter cake was washed with two 25 milliliter portions of THF. The solution when assayed by HPLC showed 45.9 grams (98 percent) yield of tetrabenzyl pyrophosphate (TBPP) in 620 milliliters of THF (0.137M). The filtrate was then stored at 0° C. with exclusion of moisture until the next step.
Reaction SMILES: C([N:9]1[CH2:18][CH2:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH:20]=[C:21](C4C=CC=CC=4F)[N:22]=[C:12]3[C:11]=2[CH2:10]1)(=O)C1C=CC=NC=1.B.Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[N:22]1[CH:21]=[CH:20][N:13]2[C:12]=1[C:11]1[CH2:10][NH:9][CH2:18][CH2:17][C:16]=1[NH:15][C:14]2=[O:19]
Reactant: O=C(c1cccnc1)N1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1[nH]c2c(c3nccn13)CNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 9-(Nicotinoyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (128 mg, 0.33 mmol), methylene chloride (3 mL) and 1M borane in THF (3.3 mL) was stirred at room temperature for 16 h. The reaction mixture was carefully acidified with 5 mL of 6N HCl and heated at reflux for 15 min. The reaction mixture was made alkaline with 10% NaOH and the product was extracted with 10% methanol in ethyl acetate. After drying over magnesium sulfate the solvent was removed in vacuo to afford a yellow solid which was recrystallized from ethanol to afford 9-(3-Pyridylmethyl)-2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 52) as a pale yellow solid, m.p. 290°-292° C.
Reaction SMILES: [Si](Cl)(C)(C)C.BrCCBr.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](I)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl:24][C:25]1[N:33]=[C:32]2[C:28]([N:29]=[C:30](I)[N:31]2[CH3:34])=[C:27]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:26]=1>CC(N(C)C)=O.[Zn].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].[Cu]I.C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:30]2[N:31]([CH3:34])[C:32]3[C:28]([N:29]=2)=[C:27]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:26]=[C:25]([Cl:24])[N:33]=3)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Reactant: Cn1c(I)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
To a suspension of zinc powder (320 mg, 4.92 mmol) and Celpure P65 in anhydrous DMA (3 mL) was added a 7:5 (v:v) mixture of TMS—Cl: 1,2-dibromoethane (65 μL) drop wise. The reaction mixture was stirred at room temperature for 15 min. A solution of 4-iodopiperidine-1-carboxylic acid tert-butyl ester (1.22 g, 3.95 mmol) in anhydrous DMA (2 mL) was added dropwise to the mixture described above and the reaction mixture was stirred for 30 minutes at room temperature. The zincate mixture was quickly filtered through a grade-3 sintered funnel and added onto a mixture of 2-Chloro-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine (1.0 g, 2.63 mmol), Pd(dppf)Cl2.DCM (107 mg, 0.13 mmol) and CuI (50 mg, 0.26 mmol). The vessel was then evacuated and back-filled with nitrogen. The resulting reaction mixture was stirred at 85° C. for 18 hours, after 3 hours additional Pd(dppf)Cl2.DCM and CuI was added. The mixture was cooled to room temperature and partitioned between EtOAc and sat. aqueous solution of ammonium chloride. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (cyclohexane:EtOAc, 20-70%) affording 4-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-piperidine-1-carboxylic acid tert-butyl ester as a solid (375 mg, 33%). LCMS (Method H): RT 4.57 min, [M+H]+ 437.46 1H NMR (400 MHz, CDCl3): δ 4.40-4.15 (m, 6 H); 3.81 (t, J=12.1 Hz, 4 H); 3.71 (s, 3); 2.99-2.87 (m, 3 H); 1.94-1.85 (m, 4 H); 1.71-1.59 (m, 1 H); 1.48 (s, 9 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O.C(Cl)(Cl)Cl.[IH:19]>>[IH:19].[I:19][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: NCCCCCCCCCCCCO
Agent: I
Solvent: ClC(Cl)Cl
Product: NCCCCCCCCCCCCI

Procedure:
An aqueous solution of 100 mg of 12-aminododecanol in 57% hydriodic acid was heated under reflux for one hour. To the reaction solution was added chloroform and the mixture was washed successively with water, a 10% aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue thus obtained was chromatographed over a silica gel column to afford 171 mg of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH:3]=[CH:4][CH2:5]Br.[K].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>CN(C=O)C>[Br:1][CH2:2][CH:3]=[CH:4][CH2:5][N:12]1[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]2[C:8]1=[O:18]
Reactant: BrCC=CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC=CCBr
Temperature: 40 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To a solution of 1,4-dibromo-2-butene (5 g, 23.37 mmol) in 4 mL DMF was added phthalimide potassium salt (433 mg, 2.34 mmol). The reaction mixture was stirred at 40° C. for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo to provide the product (250 mg). 1H NMR (CDCl3) δ3.92 (d, 2H); 4.32 (d, 2H); 5.90 (m, 2H); 7.74 (m, 2H); 7.87 (m, 2H).
Reaction SMILES: C[C:2]1[C:10]([CH3:12])(C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC1S[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.IC>>[CH:21]1[CH:20]=[CH:19][C:17]([N:18]=[CH:12][CH2:10][CH:2]=[N:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:22]=1
Reactant: CC1=Nc2ccccc2C1(C)C
Reactant: Cc1nc2ccccc2s1
Solvent: CI
Product: C(CC=Nc1ccccc1)=Nc1ccccc1

Procedure:
2,3,3-Trimethyl indolenine, methylbenzothiazole, iodomethane, and diidopropane were purchased from Aldrich and used without further purification. Malonaldehyde dianil was synthesized according to literature reports (Glauert, R. H. and Mann, F. G. J. Chem. Soc. (1952) 5012, by the method of Claisen Ber. (1903) 36, 3668). Dry nitrobenzene was freshly distilled from CaH2. Dry triethylamine was distilled from Na°. DMF was predried with MgSO4, fractionally distilled and stored over molecular sieves. All dry solvents were stored under N2. All reactions were run under anhydrous conditions under N2. Reactions were monitored by TLC (silica gel 60, A260, Fisher) and visualized with short and long wavelength UV irradiation. Flash column chromatography was performed on silica gel 60 (200-440 mesh Fluka).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 45 %

Procedure:
To a stirring mixture of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.28 mmol) in DMF (0.47 mL) at 20° C. was added 1-bromo-3-methylbutane (40 mg, 0.28 mmol). The resulting reaction mixture was heated at 80° C. for 60 min. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (27 mg, 0.063 mmol) as a yellow oil. MS: [M+H]+=426.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#N)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1CC(O)=[O:37].O>[Ni]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=[O:37])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Reactant: O=C(O)Cc1ccccn1
Agent: [Ni]
Solvent: O
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Yield: 45 %

Procedure:
(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile (Example 1, 0.4 g, 1.1 mmol) was dissolved in the mixture pyridine-acetic acid-water (1:1:1, 18 ml total volume) at room temperature, to which was added Raney nickel (0.09 g, 1.1 mmol). The reaction was purged with nitrogen, evacuated, and then placed under hydrogen filled balloon for 18 hours. The reaction mixture was flushed with nitrogen, and filtered to remove the catalyst, which was washed with MeOH (30 ml). The filtrate was then extracted with DCM (5×50 ml), washed with aq. NaHCO3, and purified by reverse phase column chromatography (5-30% ACN) to give the title compound (0.18 g, 45%). 1H NMR (400 MHz, CD3OD) δ 9.40 (s, 1H), 7.45 (d, J=10.4 Hz, 1H), 7.34-7.31 (m, 2H), 7.05-7.01 (m, 2H), 6.11 (s, 1H), 5.26 (s, 1H), 1.92-1.86 (m, 1H), 1.55 (d, J=7.0 Hz, 3H), 1.00-0.98 (m, 2H), 0.71-0.64 (m, 2H). MS: Calcd.: 383. Found: [M+H]+ 384.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24]I)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.CNCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH:23]=[CH2:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Agent: CNCCN(C)C
Solvent: ClCCl
Product: C=Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.8 %

Procedure:
A solution of 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (53 mg, 0.11 mmol) in CH2Cl2 (1.5 ml) was added to trimethylethylene diamine (97 mg, 0.95 mmol) and the mixture stirred at ambient temperature for 3 days. The solvent was removed in vacuo and the crude purified by chromatography (silica gel, gradient 5 to 100% ethyl acetate/isohexane) to give Compound 82 as a yellow solid (12 mg).