Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1
Reactant: CN1CCNCC1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Solvent: CN(C)C=O
Product: CN1CCN(C(c2ccc(Cl)cc2)c2ccc(-n3ncc(=O)[nH]c3=O)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 17.8 %

Procedure:
A mixture of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol) and 1-methylpiperazine (0.04 mol) in DMF (100 ml) was stirred for 24 hours at 80° C. The solvent was evaporated. MIK was added and azeotroped on the rotary evaporator. The residue was stirred in water, then extracted with CH2Cl2. The separated organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/THF 90/5/5 and CH2Cl2/CH3OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue was stirred overnight in DIPE, then the solvent was evaporated. The residue was crystallized from EtOAc. The precipitate was filtered off, washed with EtOAc, DIPE, then dried, yielding 1.19 g (±)-2-[3-chloro-4-[(4-chlorophenyl)(4-methyl-1-piperazinyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 118).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:17][C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[CH3:1][C:2]([CH3:24])([CH2:17][C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-:33])=[CH:8][C:7]=2[N:6]=[CH:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(Cn1cnc2cnc3ccccc3c21)CC1(C)OCCO1
Product: CC(C)(Cn1cnc2c[n+]([O-])c3ccccc3c21)CC1(C)OCCO1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-[2,2-dimethyl-3-(2-methyl[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinoline (8.8 g, 27 mmol) by reaction with m-CPBA (11.8 g) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-5-oxido-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (9.1 g, 48 mmol) and ammonium hydroxide solution (100 mL) to provide 1-[2,2-dimethyl-3-(2-methyl[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine as a light brown solid after chromatography on silica gel (elution with a solution of 7% methanol in dichloromethane that contained about 5 mL of ammonium hydroxide solution per liter of eluent) and recrystallization from aqueous methanol, mp 153-155° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([N:14]([CH2:21][CH2:22][CH3:23])C(=O)C(F)(F)F)[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]>CO.[OH-].[Na+]>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:14][CH2:21][CH2:22][CH3:23])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(OCC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNC1CCc2ccc(OCC)cc2C1

Procedure:
A solution of N-(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-2,2,2-trifluoro-N-propyl-acetamide (660 mg, 2.0 mmol) in methanol (30 mL) and 1 N NaOH (30 mL) was stirred at room temperature for 30 h. The reaction was concentrated and the residue partitioned between EtOAc (40 mL) and water (40 mL). The aqueous layer was extracted twice more with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), and concentrated to afford (7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1>[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: Cc1ccc(SSN(C)C(=O)F)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(SSN(C)C(=O)ON=C2SC(C)(C)C(=O)N2C)cc1

Procedure:
2-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example I, by reacting 5.0 g (0.0287 m) of 3,5,5-trimethyl-2-oximino thiazolidin-4-one, 6.64 g (0.028 m) of N-methyl-N-(4-methylphenylthiosulfenyl)carbamoyl fluoride and 2.9 g (0.0287 m) of triethylamine in 50 ml of dioxane. 2-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was crystallized from ethylacetate-hexane to yield 8.0 g of solid, m.p. 116°-118° C. It was then recrystallized from ethyl acetate isopropyl ether, to yield a solid, m.p. 123°-125° C.
Reaction SMILES: N.[K].[C:3]1([CH3:11])[C:4]([C:9]#[N:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>O.O1CCCC1>[NH2:10][C:9]1[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1ccccc1C#N
Agent: N
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-c2ccccn2)cc2ccccc12
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To 250 ml. of liquid ammonia under a nitrogen atmosphere are added 7.5 g. (0.19 gram atom) of potassium in small portions and a few crystals of ferric nitrate. When all the potassium has been converted into the amide (i.e. when the blue color disappears), 11.1 g. (0.095 mole) of o-toluonitrile in 30 ml. of anhydrous tetrahydrofuran are added, upon which the solution immediately takes on a red color. 19.8 g. (0.19 mole) of 2-cyanopyridine in 100 ml. of anhydrous tetrahydrofuran are then added. The mixture is left standing overnight and then decomposed with water. The tetrahydrofuran is evaporated and the residue is extracted with chloroform. The extract is washed with water, dried with magnesium sulphate and the solvent is removed by evaporation. The residue is purified by sublimation. 5.2 g. of 1-amino-3-(2-pyridyl)isoquinoline are obtained. Yield 24.8%, m.p. 152°-153° C. The base is dissolved in diethyl ether and an etheral hydrogen chloride solution is added. The precipitate formed is filtered off and crystallised from ethanol (96%) to yield the monohydrochloride, m.p. 266° C., (with decomposition). 0.95 g. (4.30 mmol) of the base and 2.44 g. (17.2 mmol) of methyl iodide, dissolved in 20 ml of acetone are heated at 43° C under a nitrogen atmosphere for 4 days. The solvent is distilled off and the residue is crystallised from methanol. 1-Amino-3-(2-pyridyl)isoquinoline methyliodide is obtained. Melting point 206° C with decomposition.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[NH2:25][CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:25][CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:23])=[CH:19][CH:20]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCNS(C)(=O)=O)cc1
Yield: 90.1 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (30 mg, 0.093 mmol), N-(2-aminoethyl)methylsulphonamide (12.9 mg, 0.093 mmol), HATU (35.5 mg, 0.093 mmol), HOBT (12.6 mg, 0.093 mmol) and DIPEA (481 μl, 0.28 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum gave N-[6-methyl-4′-({[2-(methylsulphonylamino)ethyl]amino}carbonyl)-1,1′-biphenyl-3-yl]-3-furamide (37 mg, 90%). NMR; δH [2H6]—DMSO 9.91,(1H, s), 8.59,(1H, t), 8.35,(1H, s), 7.92,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.59,(1H, d), 7.45,(2H, d), 7.27,(1H, d), 7.17,(1H, t), 6.98,(1H, m), 3.40,(2H, q), 3.13,(2H, q), 2.91,(3H, s), 2.19,(3H, s). LCMS: retention time 2.82 min, MH+442.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:9][CH2:10]P(OCC)(=O)OCC.[CH3:25][CH:26]([CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH:27]=O.O>O1CCCC1.CCOCC>[CH3:25][CH:26]([CH:27]=[CH:10][CH:9]=[C:8]([CH3:7])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]
Reactant: CCOP(=O)(CC=C(C)CCC=C(C)C)OCC
Reactant: CCOC(OCC)C(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)C(C)C=CC=C(C)CCC=C(C)C
Temperature: -27.5 °C
Yield: 66.3 %

Procedure:
To a 500 mL three-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a solution of 2.4 g potassium tert-butoxide (0.11 mol) in 60 mL of anhydrous tetrahydrofuran was added. Then 29.2 g of diethyl 3,7-dimethyl-2,6-octadienyl-phosphonate (3B) (0.10 mol) was added dropwise over 30 min under mechanical stirring by use of an external cold bath to maintain the internal temperature of approximately −30 to −25° C., and the reaction mixture was subsequently stirred in the cold for 60 min to ensure the formation of carbanion thoroughly. Then 16 g of 2-methyl-3,3-diethoxy-1-propanal (4B) (0.10 mol)) was added dropwise at −30˜−25° C. over 1 h and the reaction mixture was subsequently stirred for 30 min at this temperature until the reaction completed according to GC. Followed by the addition of 50 mL water and 100 mL ether and stirring for 10 min, after stratification, the organic layer was washed with 5% aqueous sodium chloride (3×25 mL), then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents in vacuo, the residue subsequently was fractional distillated to afford 19.7 g of (5-E and 5-Z)-2,6,10-trimethyl-1,1-diethoxy-3,5,9-undecatriene (2D) of 99-103° C./1 mmHg, as a colorless liquid with GC content of 94.2% (total content of cis and trans) and the yield of 66.3%. There are 2 peaks according to GC and GC-MS. ascertained is the same with that of Example IV
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1.CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[NH2:14][C:3]1[N:4]=[CH:5][C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:13]2)=[N:7][C:2]=1[Br:1]
Reactant: COC(=O)Cl
Reactant: Nc1ncc(C2CCNCC2)nc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine (60 mg, 0.233 mmol) in DCM (2 mL) in ice bath was added DIEA (408 μl, 2.333 mmol) and methyl chloroformate (18.07 μl, 0.233 mmol). The reaction mixture was stirred under ice bath for 30 min. The reaction mixture was partitioned between DCM and water. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered off, and evaporated in vacuo. The crude methyl 4-(5-amino-6-bromopyrazin-2-yl)piperidine-1-carboxylate was used for next step. LCMS (m/z): 315.0/317.0 (MH+), 0.647 min.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23]N[CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1>>[C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Solvent: C1CCNC1
Product: O=c1c2c[nH]c3ccc(N4CCCC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using pyrrolidine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.99 (4H, br), 3.49 (4H, br), 6.77 (1H, d, J=9.06 Hz), 7.05 (1H, tt, J=7.41, 0.89 Hz), 7.37 (2H, m), 7.77 (1H, d, J=9.07 Hz), 8.28 (2H, dd, J=7.70, 1.09 Hz), 8.34 (1H, s). m/z 332.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]([F:44])([F:43])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]2)=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:43][C:26]([F:25])([F:44])[C:27]1[CH:28]=[CH:29][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:41])[CH2:36][CH2:35]2)=[CH:31][CH:32]=1
Reactant: O=C(Cl)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@](O)(COC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (1.54 g, 7.01 mmol), N,N-diisopropylethylamine (1.63 ml, 9.34 mmol) and 4-dimethylaminopyridine (0.11 g, 0.93 mmol) were added to a suspension of 4-(4-trifluoromethylphenylamino)piperidine-1-carbonylchloride (1.43 g, 4.67 mmol) in toluene (30 ml) followed by stirring at 100° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenylamino)piperidine-1-carboxylate (1.44 g, yield 61%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=O)[C:8]2[CH:7]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:4][C:3]1=2.[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC.O>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[CH3:16][O:15][C:13]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:17])([CH3:1])[CH2:11][CH:10]=[C:9]([S:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:7]=1)=[O:14]
Reactant: Sc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)=CCC2(C)C

Procedure:
To a solution of methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (Compound E2, 835.0 mg, 3.60 mmol) in 25.0 mL of THF at room temperature was added TiCl4 (670.0 mg, 3.55 mmol). Thereafter a solution of thiophenol (430.0 mg, 3.90 mmol) and Et3N (730.0 mg, 7.20 mmol) in 10 mL THF was added. The resulting brown mixture was stirred for 6 h before H2O was carefully added to quench the reaction. The pruduct was extracted into Et2O and the combined organic layers washed with saturated aqueous NaCl and dried over MgSO4. Removal of the solvents under reduced pressure afforded a solid from which the title compound was isolated as a yellow solid by column chromatography (5% EtOAc-hexanes).
Reaction SMILES: [N:1]1([CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:22]([O:27]C)([O:25][CH3:26])(=[O:24])=[O:23].[CH3:29]OS([O-])(=O)=O>>[CH3:26][O:25][S:22]([O-:27])(=[O:24])=[O:23].[C:7]([CH:6]([N+:1]1([CH3:29])[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)#[N:8]
Reactant: N#CC(c1cccc(Oc2ccccc2)c1)N1CCCC1
Reactant: COS(=O)(=O)OC
Agent: COS(=O)(=O)[O-]
Product: C[N+]1(C(C#N)c2cccc(Oc3ccccc3)c2)CCCC1

Procedure:
N-(α-Cyano-3-phenoxybenzyl)-N-methylpyrrolidinium methylsulfate (5) was prepared from α-(1-pyrrolidinyl)-3-phenoxybenzeneacetonitrile (Example 3) and dimethyl sulfate following essentially the same procedure as that described in Example 2. The product was obtained as a yellow oil. Proton magnetic resonance spectrum (CDCl3 ; ε in ppm): 2.4 (4H, m, pyrrolidine ring β-protons); 3.2 (4H, m, pyrrolidine ring α-protons); 3.2-3.8 (6H, m, N--CH3 and CH3SO4); 6.8 (1H, s, CH); 7.0-7.7 (9H, m, aromatic protons).
Reaction SMILES: [C:1]([C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[C:9](N(C)OC)=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][Mg]Cl)=[CH:22][CH:21]=1>C1COCC1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][C:9]([C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:10])=[CH:22][CH:21]=1
Reactant: Fc1ccc(C[Mg]Cl)cc1
Reactant: CCCCC#Cc1ccccc1C(=O)N(C)OC
Solvent: C1CCOC1
Product: CCCCC#Cc1ccccc1C(=O)Cc1ccc(F)cc1
Yield: 61 %

Procedure:
2-(1-Hexyn-1-yl)-N-methyl-N-(methyloxy)benzamide (158) (0.50 g, 2.04 mmol) was treated with 4-fluorobenzylmagnesium chloride in THF at room temperature to give 0.37 g (61%) of compound (165) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (t, J=7.2 Hz, 3H), 1.40-1.53 (m, 2H), 1.56-1.65 (m, 2H), 2.45 (t, J=7.1 Hz, 2H), 4.40 (s, 2H), 6.99 (t, J=8.6 Hz, 2H), 7.16-7.22 (m, 2H), 7.26-7.32 (m, 1H), 7.35-7.41 (m, 1H), 7.45-7.52 (m, 2H).
Reaction SMILES: BrC1C=CC=CC=1.[Li].O1CCCCC1[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.CN(C)[CH:30]=[O:31]>CCOCC>[OH:15][C:16]1[C:17]([CH:30]=[O:31])=[C:18]([O:26][CH3:27])[C:19]([O:22][CH2:23][CH2:24][CH3:25])=[CH:20][CH:21]=1
Reactant: CN(C)C=O
Reactant: CCCOc1ccc(OC2CCCCO2)cc1OC
Agent: [Li]
Solvent: CCOCC
Solvent: Brc1ccccc1
Product: CCCOc1ccc(O)c(C=O)c1OC
Temperature: 25 °C

Procedure:
1 ml of bromobenzene (11.88 ml) was added to a mixture of lithium chips (1.63 g) and anhydrous ether (90 ml) under nitrogen. When the reaction had commenced the remainder of the bromobenzene was added dropwise to the stirred mixture at such a rate as to cause gentle refluxing. After the addition was complete the mixture was stirred and refluxed (1 hr) and then cooled to room temperature. 3-Methoxy-4-n-propoxyphenol tetrahydropyranyl ether (30.03 g, 0.113 M) was added dropwise to the stirred mixture and then stirred at room temperature (3 days). A solution of anhydrous dimethyl formamide (8.5 ml) in anhydrous ether (8.5 ml) was added dropwise to the stirred mixture at such a rate as to cause gentle refluxing, and then stirred for an extra hour. The reaction mixture was poured into 2 N sulphuric acid/ice (200 ml) and extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The residue was dissolved in 95% ethanol (175 ml) and 2 N hydrochloric acid (210 ml) was added. After stirring at room temperature (2 hr) the mixture was diluted with water (500 ml) and extracted with ethyl acetate/ether (1:1). The combined extracts were extracted with 2 N sodium hydroxide solution, the combined aqueous phases acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The residue was chromatographed on silica (MFC) eluting with chloroform-methanol (98:2) to give 6-hydroxy-2-methoxy-3-n-propoxybenzaldahyde as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])=[CH:7][C:6]=2[CH:18]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.C(O)C.CO.CS(C)=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>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:18][C:6]=2[CH:7]=1
Reactant: Cc1ccccc1B(O)O
Reactant: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2o1
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: c1ccccc1
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1ccccc1-c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Temperature: 75 °C

Procedure:
A portion (˜330 μL) of a solution of the product from Example 115A (650 mg, 2.1 mmol) and tetrakis(triphenylphosphine)palladium (125 mg, 0.11 mmol) in benzene (6.2 mL) was added to a mixture of (2-methylphenyl)boronic acid (˜24 mg, ˜0.18 mmol) in ethanol (150 μL). The mixture was treated with 2.0 M aqueous Na2CO3 (200 μL, 0.4 mmol), and the reaction vial was sealed, placed on a heater-stirrer apparatus, and heated at 75° C. for four days. The mixture was cooled to room temperature, diluted with 1:1 MeOH/DMSO (1 mL), filtered, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL/min.] to provide the title compound. MS (APCI) m/z 320 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[NH:21][C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1.[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:31])[C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (160 g, 0.369 mol), potassium carbonate (76.6 g, 0.554 mol) and iodomethane (34.5 mL, 0.554 mol) in N,N-dimethylformamide is stirred at room temperature for 4 hours, and poured onto ice. The resultant aqueous mixture is extracted with methylene chloride. The organic extract is diluted with hexanes, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacua to obtain the title product as an orange foam (163 g, 98.8%) which is identified by NMR spectral analyses.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[S:5]1(=[O:15])=[O:14])[CH:2]=[CH2:3].[CH2:16]([O:18][CH:19]=[CH2:20])[CH3:17]>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([N:4]1[CH2:9][CH:8]([O:10][CH2:17][CH2:16][O:18][CH2:19][CH3:20])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[S:5]1(=[O:15])=[O:14])[CH:2]=[CH2:3]
Reactant: C=COCC
Reactant: C=CCN1CC(O)c2ccsc2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN1CC(OCCOCC)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
The product from Step A (4.2 g, 17.1 mmol) was dissolved in tetrahydrofuran (75 mL) and cooled to 0° C. at which point p-toluenesulfonic acid (163 mg, 0.6 mmol) was added followed by ethylvinyl ether (3.3 mL, 34.3 mmol). This mixture was stirred at 0° C. for 2 h, diluted with cold ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (70 mL) and brine (70 mL). The organic layer was dried (MgSO4) and evaporated to provide 5.2 g of crude product which was used in the next step without further purification.