Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH3:10][I:11]>C(#N)C>[I-:11].[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][N+:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: COCc1ccncc1
Reactant: CI
Solvent: CC#N
Product: COCc1cc[n+](C)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
A solution of 4.8 g (0.039 mol) of 4-methoxymethyl-pyridine in 25 ml of acetonitrile is mixed with 6.6 g (0.047 mol) of methyl iodide and stirred for 5 hours at ambient temperature. Then the partially precipitated quaternary salt is precipitated by the addition of ethyl acetate. 9.1 g (88% of theory) of 4-methoxymethyl-1-methyl-pyridinium iodide are obtained, m.p. 105°-108° C.
Reaction SMILES: Br[C:2]([F:17])([F:16])[S:3][C:4]1[N:8]=[CH:7][N:6]([C:9](=[O:15])[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[N:5]=1.C([O-])=O.[NH4+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>CN(C)C=O.O>[CH2:13]([N:10]([CH2:11][CH3:12])[C:9]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH:2]([F:16])[F:17])=[N:5]1)=[O:15])[CH3:14]
Reactant: CCN(CC)C(=O)n1cnc(SC(F)(F)Br)n1
Agent: O=C[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)n1cnc(SC(F)F)n1
Temperature: 50 °C
Yield: 87.2 %

Procedure:
To a stirred solution of 10.7 g (0.033 mol) 3-(bromodifluoromethylthio)-1-(N,N-diethylcarbamoyl)-1,2,4-triazole, prepared as in Example 1, step (c), in 25 ml N,N-dimethylformamide, was added 4.11 g (0.065 mol) ammonium formate and 2.24 g (0.01 mol) ammonium persulfate and the mixture was heated at 50° C. for 2.5 h. The reaction mixture was then diluted with 100 ml water and extracted with ether (3×100 ml). The combined resulting organic layers were washed with water, dried over MgSO4 and evaporated to give 7.2 g (88% yield) of the desired 1-(N,N-diethylcarbamoyl)-3-(difluoromethylthio)-1,2,4-triazole as a colorless oil.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[CH2:11]([O:18][CH2:19][C:20]([O:22]CC)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br.[OH:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][N:33]=[C:32]1[NH2:36]>>[CH2:11]([O:18][C:19]1[C:20](=[O:22])[N:33]2[CH2:34][CH2:35][N:31]([CH2:30][CH2:29][OH:28])[C:32]2=[N:36][C:2]=1[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)COCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC1=NCCN1CCO
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2CCO
Yield: 9.4 %

Procedure:
Reaction of the adduct of diethyl oxalate (14.61 g, 0.10 mol), ethyl benzyloxyacetate (19.42 g, 0.10 mol) and sodium hydride (4.40 g of a 60% dispersion in mineral oil, 0.11 mol) with 1-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide (21.0 g, 0.10 mol) as described for intermediate 1 gave 3.37 g (9% yield) of the title ester as white crystals; mp 104-106° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH3), 3.53 (2H, m, CH2), 3.83 (2H, t, J=8.9 Hz, CH2), 3.90 (2H, m, CH2), 4.19 (2H, t, J=8.9 Hz, CH2), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.11 (2H, s, OCH2), 7.35-7.40 (3H, m, aromatics), 7.51 (2H, m, aromatics). Anal. Calcd for C18H21N3O5: C, 60.16; H, 5.89, N 11.69. Found: C, 60.24; H, 5.89; N, 11.77.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](SC)[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4].O[O:20][S:21]([O-:23])=O.[K+].[CH3:25]O>O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([S:21]([CH3:25])(=[O:23])=[O:20])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4]
Reactant: COC(=O)c1nc(SC)[nH]c1-c1ccc(F)cc1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: COC(=O)c1nc(S(C)(=O)=O)[nH]c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a stirred solution of compound 8 (19.3 g, 72.5 mmol) in MeOH (500 mL) was added a solution of OXONE (133 g) in water (500 mL) dropwise at rt in 1 h. The resulting mixture was stirred at rt for 4 h and then concentrated under reduced pressure. The slurry aqueous mixture was extracted with DCM (200 mL×4). The combined extracts were washed with brine (100 mL×2), dried over anhydrous MgSO4, filtered, and evaporated to afford sulfone 10 (19.8 g, 92%) as a white solid. ESI MS m/z 299.2 (M+H)+.
Reaction SMILES: [O:1]([C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][CH2:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C(#N)C>[Cl-:16].[O:1]([C:8]([O:10][CH2:11][CH2:12][N+:13]([CH2:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])([CH3:15])[CH3:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCOC(=O)Oc1ccccc1
Reactant: O=C(CCl)Oc1ccccc1
Solvent: CC#N
Product: C[N+](C)(CCOC(=O)Oc1ccccc1)CC(=O)Oc1ccccc1
Product: [Cl-]

Procedure:
To a 250 ml three-necked round-bottomed flask fitted with a reflux condenser, magnetic stirrer, internal thermometer, addition funnel, and argon inlet are added N-[2-((phenoxycarbonyl)oxy)ethyl]-N,N-dimethylamine (25.00 g, 0.120 mol), acetonitrile (100 ml), and phenyl chloroacetate (20.38 g, 0.120 mol) over 5 min. After addition is complete, the mixture is heated to reflux for 3 h. The cooled mixture is triturated with ether (500 ml). A white solid, 23.15 g (51%) is isolated to give 9.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=2)[CH2:12]1>C1COCC1>[CH3:22][O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:23][CH3:24])[CH2:12][N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:20][CH2:19]2
Reactant: C=C1CC(=O)O1
Reactant: COc1cc2c(cc1OC)CN(CCCN)CC2
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CN(CCCNC(=O)CC(C)=O)CC2
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
Diketene (1.41 mL, 18.3 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 2-(3-aminopropyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (3.05 g, 12.2 mmol, 1.00 equiv) in anhydrous THF (30 mL) under argon, and stirring was continued at room temperature for 1.5 hours. The mixture was concentrated and the residual oil washed with hexane (2×100 mL) to give 4.07 g (100%) of brown oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10](C2CCC(CC(OCC)=O)CC2)[CH:9]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C([CH:66]2[CH2:71][CH2:70][CH2:69][CH:68]([CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:67]2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:47][Si:2]([CH3:1])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:70]2[CH2:71][CH2:66][CH2:67][CH:68]([CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:69]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)C1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Product: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)C1

Procedure:
Ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]([CH:13]=[O:14])[CH3:12])[CH:7]=[CH:6][C:5]=1[N+:15]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]([CH:13]=[O:14])[CH3:12])[CH:7]=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(CN(C)C=O)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(CN(C)C=O)ccc1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
There was dissolved, in 34 mL of methanol, 4.47 g of the crude product of 5-(N-formyl-N-methylamino-methyl)-2-nitrobenzoic acid methyl ester, prepare in the step 1, 5% Pd/C (wet product) was added to the solution in an argon gas atmosphere and then hydrogen gas was introduced into the reaction container. The reaction system was stirred at a reaction temperature of 40° C. for 8 hours, the hydrogen gas was replaced with argon gas, 14 mL of methanol was then added to the reaction system and the temperature thereof was raised up to 55° C. The Pd/C catalyst was removed through filtration under reduced pressure, the catalyst was washed with 25 mL of methanol and the resulting filtrate and the wash liquid were maintained at a temperature of 40° C. Water (31 mL) was dropwise added thereto thus separate out solid and the resulting slurry was stirred at 10° C. overnight. The resulting solid was separated from the slurry through filtration under reduced pressure, washed with 7 mL of water and then dried under reduced pressure at 70° C. for 5 hours to give 2.53 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.C1C=CC2N(O)N=[N:34]C=2C=1.CCN=C=NCCCN(C)C>>[F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:34])=[O:19])=[CH:13][CH:12]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccc(-c2cnccc2Oc2ccc([N+](=O)[O-])cc2F)cc1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)Cc1ccc(-c2cnccc2Oc2ccc([N+](=O)[O-])cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A 25 mL round bottom flask was charged with 2-(4-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid (50 mg, 0.136 mmol), HOBT (46 mg, 0.34 mmol), and EDCI (65 mg, 0.34 mmol). The flask was flushed with nitrogen and then DMF was added (1 mL). After stirring at rt for 1 h, the solution was cooled to 0° C. and then charged with ammonium hydroxide (0.5 mL). The reaction was stirred at 0° C. for 1 h and was then diluted with brine (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% MeOH/EtOAc) to give the title compound (33 mg, 66%) as a colorless oil. 1H NMR (CD3OD) δ 8.49 (s, 1H), 8.38 (d, 1H, J=5.6 Hz), 8.10 (dd, 1H, J=10.4, 2.4 Hz), 7.99 (m, 1H), 7.45 (d, 2H, J=8.2 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.28 (m, 1H), 6.93 (d, 1H, J=5.6 Hz), 3.44 (s, 2H); MS(ESI+) m/z 368.18 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[C:24]2[C:15](=[N:16][C:17]3[C:22]([C:23]=2[C:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][CH:12]=1.[S:28]([F:33])([O:31]C)(=[O:30])=[O:29].CCOCC>ClCCl>[F:33][S:28]([O-:31])(=[O:30])=[O:29].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[C:24]2[C:15](=[NH+:16][C:17]3[C:22]([C:23]=2[C:25]([OH:27])=[O:26])=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(OC)c1-c1cccc2nc3ccccc3c(C(=O)[O-])c12
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(OC)c1-c1cccc2[nH+]c3ccccc3c(C(=O)O)c12
Product: O=S(=O)([O-])F
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
The compound (2,6-dimethoxy)phenyl-acridine-9-carboxylate (13) (2.01 g, 5.6 mmole) was dissolved in dichloromethane (110 ml, anhydrous) in a 250 ml round bottom flask. Methyl fluorosulfate (4.60 ml, 6.48 g, 56 mmoles) was added and the mixture was stirred at room temperature for 15 hours. Anhydrous ether (100 ml) was added and the precipitated bright yellow solids were filtered after stirring the suspension for 0.5 hours. The solid was washed well with ether (about 100 ml) and then with pentane (50 ml). The acridinium was recrystallized from acetonitrile to provide pure 2,6-dimethoxy-phenyl-acridinium-9-carboxylate fluorosulfonate (14) (yield=81%). The same results may be achieved by crystallization from acetonitrile by the addition of ethyl acetate. Other useful solvent combinations include alcohol and ether, such as methanol, ethanol or propanol and diethyl ether (ether is the precipitating solvent).
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:5]=2[O:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: BrCCCCBr
Reactant: CC1=COc2cc(C)ccc2C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=COc2cc(C)ccc2C(=O)N1CCCCBr
Yield: 68 %

Procedure:
2.84 g of 4,5-dihydro-3,8-dimethyl-1,4-benzoxazepin-5-one was dissolved in 75 ml of acetone, 12.9 g (4 equivalents) of 1,4-dibromobutane and 6.22 g (3 equivalents) of potassium carbonate were added, then the resultant mixture was heated and refluxed for 12 hours. This was allowed to cool, then was filtered, the filtrate was concentrated, and the residue was refined by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the above-referenced compound in an amount of 3.3 g (yield of 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.[I:28]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(Cl)Cl>CC#N.[Cl-].[Na+].O.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:14])[CH3:15])[N:5]2[N:25]=[CH:26][C:27]([I:28])=[C:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (7.9 g) in CH3CN (100 mL) was added N-iodosuccinimide (4.3 g, 19.2 mmol) and the resulting mixture was stirred at room temperature for 30 min, at which time LC/MS confirmed full conversion of starting material to product. Saturated sodium thiosulfate solution (˜20 mL) was added and stirring continued for 5 minutes before the reaction mixture was transferred to a separatory funnel using CH2Cl2 (30 mL) and H2O (30 mL). Brine (50 mL) was added and organics were extracted with CH2Cl2 (4×40 mL), dried (Na2SO4) and concentrated in vacuo to give crude 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine as a light brown liquid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Br:10])=[N:8][C:7]([Br:11])=[CH:6][N:5]=1.[H][H].[CH3:14][N:15]([CH3:30])[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[S:26](Cl)(=[O:28])=[O:27]>CN(C)C=O>[CH3:14][N:15]([CH3:30])[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[S:26]([NH:3][C:4]1[C:9]([Br:10])=[N:8][C:7]([Br:11])=[CH:6][N:5]=1)(=[O:28])=[O:27]
Reactant: [H][H]
Reactant: Nc1ncc(Br)nc1Br
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ncc(Br)nc3Br)cccc12
Temperature: 95 °C
Yield: 5.3 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.16 g) was added to a solution of 2-amino-3,5-dibromopyrazine (0.506 g) in N,N-dimethylformamide (30 ml). When evolution of hydrogen ceased, 5-dimethylamino-1-naphthalenesulphonyl chloride (0.54 g) was added and the solution was heated at 95° C. for 18 hours. Volatile material was removed by evaporation and water (50 ml) was added to the residue. The mixture was extracted with ethyl acetate (20 ml), and the aqueous layer was neutralised with 0.05M aqueous acetic acid (40 ml) and extracted with ethyl acetate (3×25 ml). The extracts were washed with water (20 ml) and saturated sodium chloride solution (20 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by elution with dichloromethane through a silica gel mega Bond Elut column. The resulting foam was triturated with ether/hexane (1:1 v/v) to give 5-(dimethylamino)-N-(3,5-dibromo-2-pyrazinyl)-1-naphthalenesulphonamide, (0.052 g), m.p. 178° C.; mass spectrum (+ve FAB, methanol/NBA): 485 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2].I[CH2:40][CH3:41].[H-].[Na+]>CN(C)C=O.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][O:29][CH2:40][CH3:41])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)c1
Reaction time: 5 h
Yield: 52.7 %

Procedure:
To a solution of 4-[3-[6-(3-bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.0 g, 1.68 mmol) in N,N-dimethylformamide (10 mL) was added iodoethane (403 μL, 5.04 mmol) and sodium hydride, 60% dispersion in mineral oil (202 mg. 5.04 mmol) at room temperature. The resulting suspension was stirred for 5 h. Then, the reaction mixture was diluted with water and brine. The organic compound was extracted into ethyl acetate and the combined organic extracts were washed with brine solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (Isco™ 40 g) with 0-30% ethyl acetate/hexanes as eluting solvents to afford the title compound (550 mg, 53%) as a colorless oil.
Reaction SMILES: C([CH:3]([C:34]([OH:36])=[O:35])[N:4]([CH2:15][P:16]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[C:38](O)(=O)C>>[CH2:5]([N:4]([CH2:15][P:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=[S:17])[CH2:3][C:34]([OH:36])=[O:35])[CH3:38]
Reactant: CCC(C(=O)O)N(CP(=S)(Oc1cccc(Cl)c1)Oc1cccc(Cl)c1)C(=O)OCc1ccccc1
Reactant: CC(=O)O
Agent: Br
Product: CCN(CC(=O)O)CP(=S)(Oc1cccc(Cl)c1)Oc1cccc(Cl)c1

Procedure:
Ethyl-N-[bis(metachlorophenoxy)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (1.0 g.) was dissolved in 15 ml. of 35% hydrobromic acid in acetic acid and was stirred for one hour. The reaction mixture was concentrated under vacuum and the residue triturated thoroughly with ether three times, dissolved in benzene and treated with excess propylene oxide. The resultant solution was concentrated in vacuo and the residue chromatographed on silica gel using diethyl ether as an eluant to yield ethyl-N-[bis(metachlorophenoxy)phosphinothioylmethyl]glycine as an oil, ND25 =1.5371, which gave the following analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([O:20]C)=[O:19])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.CO.O.[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([OH:20])=[O:19])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: COC(=O)c1nn(C)c(=O)cc1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1nc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
Methyl 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (84.9 mg, 0.211 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (2.5 mL) and water (2.5 mL). Aqueous 2 M lithium hydroxide (200 μL) was added at room temperature. After 10 minutes, the reaction mixture was heated to 50° C. for 30 minutes and continued to stir at room temperature for 16 hours at which time the solvents were evaporated. The residue was made acidic with 2 M aqueous hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic layer separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (54.0 mg, 66% yield). MS (EI) for C12H9N3O3FI: 390 (MH+).
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([S:23]([CH:26]=[CH2:27])(=[O:25])=[O:24])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.[CH3:41][NH:42][CH3:43]>C1COCC1.O>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:18][CH2:19][N:20]([S:23]([CH2:26][CH2:27][N:42]([CH3:43])[CH3:41])(=[O:24])=[O:25])[CH2:21][CH2:22]4)[N:15]=[CH:16][C:11]3=[C:10]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCC(n2ncc3c(N4CCOCC4)nc(-n4c(C(F)F)nc5c(OC)cccc54)nc32)CC1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCN(S(=O)(=O)CCN(C)C)CC3)c2n1
Reaction time: 0.17 h
Yield: 93 %

Procedure:
A suspension of the above vinylsulfonamide (140 mg, 0.243 mmol) in 100 mL THF was treated with 10 mL of 40% aq. dimethylamine to give a clear solution. After 10 min, the mixture was diluted with water and the THF was removed under vacuum to give 140 mg (93% yield) of N-[2-({4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine as a white solid: 1H NMR (CDCl3) δ 7.99 (s, 1H), 7.82 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.85 (tt, J=11.1, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m, 4H), 4.02 (m, 1H), 3.98 (m, 1H), 3.91 (m, 4H), 3.18-3.07 (m, 4H), 2.80 (dd, J=8.3, 6.4 Hz, 2H), 2.41 (dq, J=11.7, 4.2 Hz, 2H), 2.29 (s, 6H), 2.14 (dd, J=12.5, 2.5 Hz, 2H).