Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:28])[C:6]([C@H:17]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]2[O:12][S:13]([CH3:16])(=[O:15])=[O:14].[CH3:29]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO>[C:24]([O:23][C@@H:17]([C:6]1[C:5]([CH3:28])=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:29])[C:7]=1[O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:26])([CH3:27])[CH3:25]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(Br)cccc2c1OS(C)(=O)=O
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(C)cccc2c1OS(C)(=O)=O
Temperature: 125 °C

Procedure:
A solution of (S)-ethyl 2-(5-bromo-3-methyl-1-(methylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (0.47 g, 0.99 mmol) in toluene/EtOH (6 mL/2.5 mL) was treated with trimethylboroxine (0.42 mL, 3 mmol), PdCl2dppf (0.036 g, 0.05 mmol) and K2CO3 (2M, 1.5 mL, 3 mmol). The vessel was sealed and sparged with Ar for 20 minutes prior to heating in a microwave reactor at 125° C. for 90 minutes. The reaction mixture was loaded directly onto silica gel and purified via Yamazen column chromatography to afford (S)-ethyl 2-tert-butoxy-2-(3,5-dimethyl-1-(methylsulfonyloxy)naphthalen-2-yl)acetate that was approximately an 85:15 mixture with an inseparable, uncharacterized side product. 1H-NMR: 400 MHz, (CDCl3) δ: 8.09 (br d, J=8.4 Hz, 1H); 7.77 (s, 1H); 7.44 (dd, J=8.4, 7.2 Hz, 1H); 7.35 (d, J=7.2 Hz, 1H); 5.77 (s, 1H); 4.27-4.09 (m, 2H); 3.43 (s, 3H); 2.68 (s, 3H); 2.63 (s, 3H); 1.24 (s, 9H); 1.20 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH2:25][CH2:26][CH3:27])=[C:8]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)[CH:9]=1.[CH2:28]([OH:30])[CH3:29]>>[CH2:28]([O:30][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH2:25][CH2:26][CH3:27])=[C:8]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)[CH:9]=1)[CH3:29]
Reactant: CCO
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Na]
Product: CCCOc1ccc(COCC)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1

Procedure:
Sodium (0.15 g, 0.0013 mol) was added portionwise to ethanol (40 ml) over 1 hour. 5-(5-Chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.5 g, 0.0013 mol) was then added to the solution and, after 3 days at room temperature, the solvent was removed by evaporation under vacuum. The residual solid was suspended in water (50 ml) and the suspension extracted with ethyl acetate (3×30 ml). The extracts were then combined, dried (Na2SO4) and evaporated under vacuum to give a green solid. Chromatography on silica gel (6 g) using a methanol in dichloromethane elution gradient gave, after crystallisation of the required product from a hexane-ethyl acetate mixture, the title compound as a white solid (0.2 g, 39%) m.p. 89°-90° C. Found: C,65.87; H,7.57; N,14.66. C21H28N4O3 requires C,65.60; H,7.34; N,14.57%.
Reaction SMILES: [C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:3][CH2:2][C:1]([N:5]([CH3:15])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: C=CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Product: CN(C(=O)CCN1CCCCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from N-acryloyl-N-methyl-4-nitro-aniline and piperidine
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[CH3:18]I>C1COCC1>[CH3:18][O:3][CH2:4][CH:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of sodium hydride (0.10 g, 2.6 mmol, 60% in mineral oil) in THF (6.0 mL) at 0° C., was treated with a solution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (0.56 g, 2.6 mmol, racemic, AstaTech) in THF (6.0 mL). After 15 min, methyl iodide (0.16 mL, 2.6 mmol) was added. The mixture was allowed to warm to RT and stir for 1.5 h. The reaction was then quenched with water, and extracted with four portions of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated. Flash chromatography using a 40 g silica gel cartridge, eluting with a gradient from 0-15% MeOH in DCM afforded the purified desired product, as the second product to elute (60 mg, 10%). 1H NMR (500 MHz, CDCl3): δ 3.90 (br s, 2H), 3.37 (dd, 1H), 3.34 (s, 3H), 3.25 (dd, 1H), 2.99-2.92 (m, 1H), 2.90-2.79 (m, 2H), 2.72 (td, 1H), 2.57 (br s, 1H), 2.15 (br s, 1H), 1.45 (s, 9H); LCMS (M+H)+: 231.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:17][C:16]=1[Cl:27]>O>[Cl:27][C:16]1[C:15]([CH2:14][OH:13])=[CH:20][CH:19]=[C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:17]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)nc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccc2)nc1Cl
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To the mixture of lithium aluminum hydride (120 mg, 2.5 mmol) and tetrahydrofuran (10 ml), a mixture of 2-chloro-6-phenyl-nicotinic acid methyl ester (620 mg, 2.5 mmol) synthesized in Example 24 and tetrahydrofuran (2.4 ml) was gradually added under nitrogen atmosphere at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at the same temperature for 30 minutes. Water was gradually added dropwise thereto at the same temperature, and the obtained reaction mixture was stirred at room temperature for 1 hour. Impurities were removed by filtration with Celite, and the solvents were evaporated under reduced pressure from the filtrate. The obtained residue was purified with silica gel column chromatography (heptane:ethyl acetate=2:1), thereby obtaining the entitled compound (470 mg, 86%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12]>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:9]([O:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]([I:1])=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOc1ncccc1C(=O)O
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1ncc(I)cc1C(=O)O
Yield: 67.9 %

Procedure:
N-Iodosuccinimide (6.0 g, 26.7 mmol) was added to a solution of 2-n-butoxypyridine-3-carboxylic acid (Preparation 4; 3.46 g, 17.7 mmol) in trifluoroacetic acid (28 mL) and trifluoroacetic anhydride (7 mL) and the reaction heated under reflux in the absence of light, for 3 hours. The cooled reaction mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate. This solution was washed sequentially with water (2×), aqueous sodium thiosulfate solution, aqueous sodium citrate solution, 2 N hydrochloric acid, and brine, then dried (MgSO4) and evaporated under reduced pressure. The solid was triturated with pentane, filtered, washed with additional pentane and dried, to give the title compound as a white solid (3.86 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:38][C:39]([F:44])([F:43])[CH:40]1[CH2:42][O:41]1.O>CN(C=O)C>[F:38][C:39]([F:44])([F:43])[CH:40]([OH:41])[CH2:42][N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[CH:7]=3)[CH:21]=[N:22]2)[CH2:27][CH2:28]1
Reactant: FC(F)(F)C1CO1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCN(CC(O)C(F)(F)F)CC3)c2)c2ccc(F)cc21
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 111 mg; 0.25 mmol), K2CO3 (35 mg; 0.25 mmol) and 2-(trifluoromethyl)oxirane (142 mg; 1.27 mmol) in DMF (10 mL) was stirred overnight under nitrogen. The reaction mixture was added water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse phase flash chromatograph to afford 65 mg (47%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.ClCCl>[CH2:17]([O:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc(CO)c(=O)c(OCc2ccccc2)c1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
A solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.15 g, 5.92 mmol) in dimethylformamide (5 ml) was stirred while 60% oily sodium hydride (260 mg, 6.50 mmol) was gradually added thereto. Subsequently, benzyl chloride (1 ml, 8.41 mmol) was added, then the reaction solution was heated at 80° C. for 4 hours. The reaction solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (1:1)] to give 729 mg of 2-benzyloxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (yield: 43%) as a pale yellowish brown oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1cccs1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1csc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.13 g, 0.42 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 2-thiophenecarbaldehyde (0.05 g, 0.45 mmol) was added followed by oxone (0.17 g, 0.28 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.10 g/15 mL) was added to the reaction solution. This was extracted with ethyl acetate, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (60 mg, 36% yield) as light brown crystals.
Reaction SMILES: [CH2:1]([P:8](=[O:15])([O:12]CC)[O:9]CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl>[CH2:1]([P:8](=[O:9])([OH:15])[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: Cl
Solvent: CO
Product: O=P(O)(O)Cc1ccccc1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A solution of diethyl benzylphosphonate (25 g) in methanol (10 ml) and concentrated hydrochloric acid (500 ml) solution was refluxed for 4 days. The mixture was cooled to room temperature, and precipitatedcrystal was collected by filtration to give benzylphosphonic acid (11.17 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](O)([C:20]([F:23])([F:22])[F:21])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH:17]1[CH2:19][CH2:18]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=[C:6]1[CH:17]1[CH2:18][CH2:19]1)[C:20]([F:22])([F:23])[F:21]
Reactant: COC(=O)C(O)(c1c(C2CC2)[nH]n(-c2ccccc2)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2ccccc2)N=C1C1CC1)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 3-cyclopropyl-α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (178 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (169 mg).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH:33][CH3:34].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O>[CH3:32][N:33]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH3:34]
Reactant: CNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(C)C)c4)cc23)CC1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (45 mg, 0.10 mmol) in DMSO (2 mL) was added 2 M dimethylamine in THF (500 μL, 1.0 mmol). The reaction mixture was stirred at room temperature for h before addition of sodium triacetoxyborohydride (220 mg, 1.04 mmol). The reaction was then stirred overnight. Compound was purified by Gilson Preparatory HPLC to give 9.0 mg of the title compound (19.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14]C(=O)C2CCC3C(=CC=CC=3)N2)[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]([N:34]1[CH:38]=[CH:37]N=[CH:35]1)(N1C=CN=C1)=[O:28].[BH4-].[Na+]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:27]([N:34]2[C:35]3[C:6](=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH2:5][CH2:37][CH2:38]2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(CC(=O)C1CCc2ccccc2N1)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 166.8 %

Procedure:
Beta-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-delta-oxo-quinolinepentanoic acid (14.3 g) in EtOAc (300 mL) was treated with carbonyldiimidazole (7.42 g) and N,N-dimethylaminopyridine (450 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (5.5 g) in H2O (100 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (500 mL) and washed with 1N HCl (1×200 mL), sat. NaHCO3 (1×200 mL) and water (1×200 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (11.5 g). Mass spectrum (CI): 378.
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]=[C:9]([C:14]([O:17]S(F)(=O)=O)([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].O>CO>[F:15][C:14]([F:16])([O:17][CH3:1])[C:9]([C:10]([F:13])([F:12])[F:11])=[CH2:8]
Reactant: CCN(CC)CC
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Solvent: O
Solvent: CO
Product: C=C(C(F)(F)F)C(F)(F)OC
Yield: 51.1 %

Procedure:
Triethylamine (2.5 g, 0.02 mole) is added gradually to CH2═C(CF3)CF2OSO2F (5 g, 0.02 mole) in dry methanol (10 ml) at 10° C. After 20 minutes the reaction mixture is poured into water. The organic layer is separated, washed in turn in dilute aqueous HCl, water, sodium bicarbonate solution, and water, and then dried over MgSO4. Distillation of the dried mixture gives 3,3-difluoro-3-methoxy-2-trifluoromethylpropene (1.8 g, 50% yield). The isomer 1,1-difluoro-2-trifluoromethyl-3-methoxypropene (about 1%) and CH2═C(CF3)COOCH3 (about 3%) are also detected by gas chromatography-mass spectrometry (GC-MS).
Reaction SMILES: [Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([N+:26]([O-:28])=[O:27])[C:7](OS(C3C(C)=CC(C)=CC=3C)(=O)=O)=[CH:8][CH:9]=2)[O:4][C:3]=1[CH:29]([CH3:31])[CH3:30].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([N+:26]([O-:28])=[O:27])[C:7]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[CH:8][CH:9]=2)[O:4][C:3]=1[CH:29]([CH3:30])[CH3:31]
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2ccc3c(=O)c(Br)c(C(C)C)oc3c2[N+](=O)[O-])c(C)c1
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CNc2ccc3c(=O)c(Br)c(C(C)C)oc3c2[N+](=O)[O-])cc1
Temperature: 130 °C

Procedure:
To a solution of 2,4,6-trimethyl-benzenesulfonic acid 3-bromo-2-isopropyl-8-nitro-4-oxo-4H-chromen-7-yl ester (1.906 g, 3.5 mmol) in dry toluene (18 ml) in a 20 ml capacity microwave tube is added p-methoxybenzylamine (0.69 ml, 5.26 mmol). The mixture is heated at 130° C. under microwave irradiation for 90 minutes and then at 140° C. under microwave irradiation for a further 30 minutes. Water (40 ml) is added, and the mixture is extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts are combined, washed with saturated brine (50 ml), dried (MgSO4), filtered and evaporated. The crude product is purified by chromatography on silica gel using cyclohexane-ethyl acetate (8:1) as eluant. The product-containing fractions are evaporated under reduced pressure, and the residue is triturated with diethyl ether to give a pale yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH2:18]Cl)[CH3:5])[CH:2]=[CH2:3].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CC(N(C)C)=O>[CH2:1]([N:4]([CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH2:18][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])[CH3:5])[CH:2]=[CH2:3]
Reactant: CCNCC
Reactant: C=CCN(C)Cc1cc([N+](=O)[O-])ccc1OCCCl
Solvent: CC(=O)N(C)C
Product: C=CCN(C)Cc1cc([N+](=O)[O-])ccc1OCCN(CC)CC
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of (xxiv) (1 g, 3.68 mmol) in DMA (10 mL) was added diethylamine (7.36 mmol) and the resulting mixture was stirred overnight at 60° C. The reaction mixture was quenched with water. The product was extracted with CH2Cl2 thrice and the combined organic extracts were washed with H2O followed by brine, dried over Na2SO4 and concentrated under reduced pressure to furnish without purification 750 mg of compound (xxv) in 70% yield. MS (m/z) 322 [M+H]+.
Reaction SMILES: COC1C=C2C(C(NCC3N4N=[C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:22]=[N:23][C:18]4=NN=3)=CC=N2)=NC=1.CN1C[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([CH2:49]NC(=O)OC(C)(C)C)=[N:47][N:48]=4)[N:45]=3)[CH:37]=2)C1=O.[ClH:59]>>[ClH:59].[C:36]1([C:40]2[CH:41]=[CH:42][C:43]3[N:44]([C:46]([CH2:49][C:26]4[CH:25]=[C:24]5[C:29](=[CH:28][CH:27]=4)[CH:18]=[N:23][CH:22]=[CH:21]5)=[N:47][N:48]=3)[N:45]=2)[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=1
Reactant: COc1cnc2c(NCc3nnc4ncc(-c5ccccc5)nn34)ccnc2c1
Reactant: CN1Cc2cc(-c3ccc4nnc(CNC(=O)OC(C)(C)C)n4n3)ccc2C1=O
Agent: Cl
Product: c1ccc(-c2ccc3nnc(Cc4ccc5cnccc5c4)n3n2)cc1
Reaction time: 0.25 h

Procedure:
A 10 mL, CEM microwave vessel was charged with 3 (0.1040 g, 0.427 mmol), 1-(5-phenylpyridin-2-yl)hydrazine (4, 0.119 g, 0.641 mmol), a stirbar and 1 mL concentrated HCl. The vessel was sealed, and fitted with an 18-gauge needle and an Argon inlet. The slurry was placed in a heating block at 115° C. for 15 minutes with stirring. A volatile substance evolved during this time. The vessel was briefly cooled, and the seal was replaced. The vessel was irradiated on a CEM Explorer using the following parameters: ramp time 20 s, hold time 10 min, hold temperature 150° C., powermax=on, 75 W max. The resultant turbid aqueous solution was filtered and concentrated in vacuo. The solids were suspended in 3 mL hot EtOH, and cooled. The precipitate was isolated by filtration and washed with EtOH (3×3 mL). The solids were taken up in 2 mL H2O, and filtered through a 0.1 μm PVDF Ultra-free-CL centrifugal filter (Millipore Corp, PN UFC40W00, 2000 g for 5 minutes). The aqueous filtrate was lyophilized to afford 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)isoquinoline hydrochloride. Anal. Calcd for C21H15N5.HCl. 1.7 H2O: C, 62.36; H, 4.83; N, 17.31. Found: C, 62.39±0.08; H, 4.48±0.02; N, 17.28±0.03.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:17][CH3:19])[CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(F)c21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of ethyl-2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.25 g, 1.0 mmol) in DMF (5 mL) was added potassium carbonate (0.14 g, 1.0 mmol), followed by iodomethane (0.42 g, 3.0 mmol). The reaction mixture was stirred at room temperature overnight and quenched by addition of brine (20 mL). The resulting mixture was extracted with EtOAc (25 mL×2) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/4) on silica gel to give the title compound as a white solid. (253 mg, Yield: 94%). MS (ESI) m/z=269 [M+H]+.
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:10]([NH2:13])(=[S:12])[CH3:11]>N1C=CC=CC=1>[CH3:11][C:10]1[S:12][C:2]2[C:3](=[O:9])[CH2:4][CH2:5][CH2:6][C:7]=2[N:13]=1
Reactant: CC(N)=S
Reactant: O=C1CCCC(=O)C1Br
Solvent: c1ccncc1
Product: Cc1nc2c(s1)C(=O)CCC2
Temperature: 100 °C
Yield: 42.7 %

Procedure:
To a stirred solution of 2-bromocyclohexane-1,3-dione (8 g, 42 mmol) in pyridine (50 mL), was added thioacetamide (3.2 g, 42.5 mmol). The reaction mixture was heated at 100° C. for 16 hours. The solvent was then removed under reduced pressure the residue poured in water (250 mL). The reaction mixture was extracted with dichloromethane (3×100 mL). The organic extract was dried using anhydrous sodium sulfate, concentrated under reduced pressure. The crude product was purified by flash column chromatography (Silica gel, gradient from 100% dichloromethane to 2% methanol in dichloromethane) to give the pure desired product (3 g, 42%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 3.01 (t, J=6.0 Hz, 2H), 2.74 (s, 3H), 2.60 (t, J=4 Hz, 2H), 2.20 (quintet, J=4 Hz, 2H); LCMS [M+H]: 168.