Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[H-].[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>C1(C)C(C)=CC=CC=1>[CH3:45][O:44][C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([O:32][CH3:31])[C:41]=1[O:42][CH3:43])[C:36]([O:1][CH:2]([CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)=[O:37]
Reactant: O=C1CCc2c(cccc2OCC(O)CN2CCN(c3ccccc3)CC2)N1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cc(C(=O)OC(COc2cccc3c2CCC(=O)N3)CN2CCN(c3ccccc3)CC2)cc(OC)c1OC

Procedure:
1.9 Grams of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril and 0.24 g of sodium hydride are dispersed in 40 ml of xylene and heated for 1 hour under refluxing conditions. Then the temperature of the bath is lowered to 130° C. and 1.40 g of 3,4,5-trimethoxybenzoyl chloride are added gradually and heated for 8 hours under refluxing condition. Xylene is removed from the reaction mixture by distillation, then the residue is poured into 80 ml of water and extracted with chloroform. The chloroform layer is washed with water, dried and chloroform is removed by distillation. The residue is recrystallized from ethanol to obtain 1.5 g of 5-[2-(3,4,5-trimethoxybenzoyloxy)-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless crystals with a melting point of 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][NH:16][CH3:17].ClC(OCC1C=CC=CC=1)=O>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:15])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CNC
Agent: O=C(Cl)OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1cccnc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
A mixture of 2-chloronicotinic acid (1 kg, 6.35 mmol) and thionyl chloride (575 mL, 7.88 mmol) 30 mL of DMF and 3.2L of toluene was warmed slowly to 70° C. and heated at 70° C. for 30 minutes. The mixture was allowed to cool to approximately 40° C. and then added to a 40% solution of aqueous dimethylamine (3.2L, 25.5 mmol) at 10° C. such that the reaction mixture did not exceed 28° C. An additional 30 minutes was allowed and then the aqueous layer was separated and extracted with toluene (2×1L). Combined organic layers were dried (Na2 SO4), filtered and concentrated under reduced pressure. The residue was dissolved in 2L of ethyl acetate and 4L of hexanes were added slowly to give a precipitate. The mixture was aged for 16 hours and then an additional 1L of hexanes was added. The mixture was cooled in an ice bath for 2 hours and filtered. The filtered residue was washed with 20% ethyl acetate/hexanes (1×1L) and dried under a stream of air to give 2-chloro-N,N-dimethyl-nicotinamide (924.5 g, 5.01 mmol), m.p. 66°-67° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:11]=2[CH2:12][N:13]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[N:15]=[N:16][N:17]([CH3:19])[N:18]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.BrC[CH2:56][O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]>CC1CCCO1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([C:10]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][C:11]=2[CH2:12][N:13]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[N:15]=[N:16][N:17]([CH2:19][CH2:56][O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[N:18]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCO[Si](C)(C)C(C)(C)C)n2)CCCCCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a solution of N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (51 mg; 0.086 mmol) in 2-methyltetrahydrofuran (1.0 mL) was added sodium carbonate (38 mg; 0.358 mmol), N,N-dimethylformamide (0.4 mL) and (2-bromoethoxy)-tert-butyldimethylsilane (100 mg; 0.418 mmol). Reaction was stirred for 16 hours at 60° C. The reaction was diluted with ethyl acetate, washed twice with water and then brine. The organic was dried over sodium sulfate and concentrated in vacuo. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-35% ethyl acetate in heptane) to give 45 mg (70% yield) of a colorless gum. 1H NMR (400 MHz CDCl3) δ ppm 7.77 (s, 1H), 7.73 (s, 2H), 7.47 (d, J=9.96 Hz, 2H), 7.41 (d, J=8.30 Hz, 1H), 5.11 (s, 2H), 4.80 (s, 2H), 4.55 (t, J=5.39 Hz 2H), 4.08 (t, J=5.39 Hz, 2H), 2.94 (s, 3H), 2.12 (m, 2H), 1.98 (m, 2H), 1.8-1.45 (m, 8H), 0.82 (s, 9H), −0.07 (s, 6H).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:31])[CH:4]=[CH:5]2.[CH3:32][I:33]>C(#N)C>[I-:33].[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N+:18]([CH3:32])([CH3:19])[C@@H:8]([C@:9]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:31])[CH:4]=[CH:5]2
Reactant: CI
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Solvent: CC#N
Product: C[N+]1(C)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Product: [I-]
Reaction time: 72 h

Procedure:
A solution of 4,5α-epoxy-3-hydroxy-17-methyl-14β-[(3-phenylpropyl)oxy]morphinan-6-one (oil, 257 mg, 0.61 mmol) and methyl iodide (0.38 ml, 6.11 mmol) in acetonitrile (10 ml) was stirred for 2 days at 50° C. (bath temperature) under N2. A DC examination showed that the reaction was not concluded. Therefore further methyl iodide (0.38 ml, 6.11 mmol) was added and the solution stirred further for 3 days under the same conditions. Then the solvent was evaporated off and the evaporation residue (367 mg of yellow foamy resin) was purified using column chromatography (silica gel; CH2Cl2/MeOH (10:1)). Evaporation residue 240 mg (71%) amorphous compound 38. Fp. 164-170° C.; IR (KBr): 1723 (C═O) cm−1; 1H-NMR (DMSO-d6): δ 9.57 (s, C3-OH), 7.3-7.16 (m, 5 arom. H), 6.67 (s, 2 arom. H, C1—H, C2—H), 4.88 (s, C5—H), 3.56 (s, N+CH3, axial), 3.21 (s, +NCH3, equatorial); MS (CI): m/z 434 (M+).
Reaction SMILES: C([Mg]Br)C.[CH2:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2)[CH3:6].[C:16](Cl)(=O)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+].CC[O:31]CC>C1C=CC=CC=1>[CH2:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C:17](=[O:31])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:6]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCc1cccc2cc[nH]c12
Reactant: CCOCC
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCc1cccc2c(CC(=O)Cc3ccccc3)c[nH]c12
Temperature: -10 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a vigorously stirred solution of ethyl magnesium bromide (2.85M in ether, 0.07 mol, 24.6 mL) in anhydrous ether (50 mL), was added a solution of 7-ethyl-1H-indole (7.25 g, 0.05 mol) in benzene (25 mL), dropwise over the course of 10 minutes. The resulting pale green mixture was heated at reflux for 2 hours, and then cooled to -10° C. with a dry ice/methanol bath. A solution of hydrocinnamoyl chloride (8.43 g, 0.05 mol) in benzene (20 mL) was added dropwise (45 minutes). The reaction mixture was allowed to warm to room temperature; after an additional 2 hours, no starting material was detected by TLC analysis. Aqueous ammonium chloride (10%, 30 mL) was added to the reaction mixture and a white precipitate formed, which was collected by filtration, washed with ether, and dried in vacuo to yield 7.78 g (56%) of the desired ketone, m.p. 140°-141.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nccc3ccccc23)cc1
Reaction time: 8 h
Yield: 51.1 %

Procedure:
In a 200 ml-three-necked flask, 3.40 g (25.0 mmole) of 4-methylphenyl-boronic acid (made by Aldrich Co.), 4.09 g (25.0 mmole) of 1-chloroisoquinoline, 25 ml of toluene, 12.5 ml of ethanol and 25 mol of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.98 g (0.85 mmole) of tetrakis(triphenylphosphine)palladium (0) was added thereto. Thereafter, reflux under stirring was performed for 8 hours under nitrogen stream. After completion of the reaction, the reaction product was cooled and extracted by addition of cold water and toluene. The organic layer was washed with saline water and dried on magnesium sulfate, followed by removal of the solvent under a reduced pressure to provide dry solid. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2.80 g (yield=51.1%) of 1-(4-methylphenyl)isoquinoline.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:12][CH:13]([CH3:15])[CH3:14])=[C:5]([CH:9]=[CH:10][CH:11]=1)C(O)=O)#[N:2].C(Cl)(=O)[C:17](Cl)=[O:18].[Br:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[C:25]([CH3:33])[CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:11]=[C:10]([C:17]([NH:30][NH:29][C:27](=[O:28])[C:26]2[CH:31]=[CH:32][C:23]([Br:22])=[CH:24][C:25]=2[CH3:33])=[O:18])[CH:9]=[CH:5][C:4]=1[O:12][CH:13]([CH3:14])[CH3:15])#[N:2]
Reactant: Cc1cc(Br)ccc1C(=O)NN
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Oc1c(C#N)cccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)NNC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 170 mg (0.83 mmol) of 3-cyanoisopropyloxybenzoic acid in 10 mL of anhydrous CH2Cl2 and 10 μL of DMF was treated with 1.0 mL of oxalyl chloride. The reaction mixture was heated to 50° C. for 10 minutes, cooled to rt and the solvents were removed under reduced pressure. The resulting crude material was dissolved in 10 mL of EtOAc and added in one portion to a vigorously stirring biphasic mixture of 209 mg of 4-bromo-2-methylbenzhydrazide (0.91 mmol), 20 mL of EtOAc, and 20 mL of saturated aqueous solution of sodium bicarbonate. After 30 minutes, the precipitate was collected by filtration and rinsed with 2×10 mL of water and dried in a desiccator overnight. Product (299 mg) was found to be >95% pure by 1H NMR and used in subsequent cyclization step without further purification: 1H NMR (500 MHZ, temp.=50° C., CDCl3) δ 1.55 (d, J=6.5, 6H), 2.51 (s, 3H), 4.78 (sep, J=6.5, 1H), 7.04 (d, J=9.0, 1H), 7.42 (s, 2H), 7.48 (s, 1H), 8.02 (dd, J=9.0, 2.0, 1H), 8.10 (d, J=2.0, 1H), 8.66 (d, J=2.0, 1H), 9.18 (d, J=2.0, 1H).
Reaction SMILES: CO.C([O:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][C:30](=[O:32])[CH3:31])[CH:14]=1)=[O:12])C1C=CC=CC=1.[H][H]>O.[C].[Pd]>[C:30]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:15]1[CH:14]=[C:13]([C:11]([OH:12])=[O:10])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Oc1ccccc1-c1cc(C(=O)OCc2ccccc2)c2ccccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(=O)Oc1ccccc1-c1cc(C(=O)O)c2ccccc2n1
Yield: 85 %

Procedure:
A suspension of 50% hydrated 10% palladium-carbon (180 mg) in water (1 mL) was added to a methanol (10 mL) solution of 2-(2-acetoxyphenyl)-4-quinolinecarboxylic acid benzyl ester (940 mg, 2.34 mmol) obtained above, and the mixture was stirred for 7 hours in a hydrogen atmosphere. The catalyst was filtered off through celite, and then, the solvent was distilled off to obtain the title compound (610 mg, 1.99 mmol).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH:14]([O-])([O-])[O:15]C.[CH3:19]O>>[CH3:19][O:9][CH:8]([O:15][CH3:14])[C:7]1[C:2]([Br:1])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=1
Reactant: COC([O-])[O-]
Reactant: CO
Reactant: COc1cc(Br)c(C=O)cc1OC
Product: COc1cc(Br)c(C(OC)OC)cc1OC
Temperature: 25 °C
Yield: 93.9 %

Procedure:
6-Bromo-3,4-dimethoxybenzaldehyde (470 g) is suspended in methanol (600 ml), and thereto are added methyl ortho-formate (1025 ml) and IRA-120 (H+-type) (10 g), and the mixture is refluxed for one hour. The mixture is cooled to room temperature, and the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure, and the resulting residue is dissolved in diethyl ether. The mixture is washed, dried, and evaporated to remove the diethyl ether. The resulting residue is distilled under reduced pressure to give 6-bromo-3,4-dimethoxybenzaldehyde dimethylacetal (522 g) as main distillate (133°-138° C./1Torr).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)(=[O:29])=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:29])[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNS(=O)(=O)c1cccs1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNS(=O)(=O)c3cccs3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.105 g, 0.379 mmol) was reacted with N-(2-azidoethyl)thiophene-2-sulfonamide (0.099 g, 0.379 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(thiophene-2-sulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.49 (s, 3H), δ 7.39 (S, 1H), δ 6.99 (s, 1H), δ 6.41 (bm, 3H), δ 4.43 (s, 2H), δ 3.42 (s, 2H), δ 2.54 (s, 2H), δ 2.09 (s, 2H), δ 1.51 (m, 13H), δ 1.19 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 150.8, 149.4, 148.1, 141.1, 138.3, 132.2, 132.1, 127.7, 122.6, 85.2, 53.8, 50.2, 43.2, 31.2, 29.9, 29.2, 28.8, 28.1, 25.5 ppm; HRMS (ESI) calcd for C21H31N7O4S2 (M+) 509.1879. Found 509.1879, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)thiophene-2-sulfonamide hydrochloride (0.098 g, 58% yield). 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), δ 7.76 (s, 1H), δ 7.57 (s, 1H), δ 7.11 (s, 1H), δ 6.46 (s, 1H), δ 4.79 (s, 2H), δ 3.55 (s, 2H), δ 2.50 (s, 2H), δ 1.66-1.18 (bm, 8H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.6, 155.6, 147.2, 140.9, 132.7, 132.3, 127.8, 127.7, 108.8, 53.1, 42.2, 36.8, 28.1, 27.8, 27.5, 24.9, 24.3, 23.8 ppm; HRMS (ESI) calcd for C16H23N7O2S2(M+) 409.1355. Found 409.1354.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15](O)[CH2:16][CH2:17][C:13]=3[N:12]=[C:11]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:22]([O:24][C:25]([CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])[CH3:23].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:25]([O:24][CH2:22][CH3:23])=[O:26])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16][CH2:17][C:13]=3[N:12]=[C:11]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)C)n(Cc3ccc(Cl)c(Cl)c3)c21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 22 (660 mg) and triethylmethanetricarboxylate (0.86 ml) in toluene (1.5 ml) and tetrahydrofuran (1.5 ml), stirred at RT under an inert atmosphere of nitrogen, was added dropwise trimethylphosphine, 1M in toluene (4.06 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.799 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 2 hours. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere for 30 mins. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (40 ml) and washed with water (40 mL). The 2 phases were separated; the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (750 mg). LC/MS MH+ 539, 541, Rt 2.19 min (5 minute run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[I-].[K+].C(=O)(O)[O-].[K+].C[O:23][C:24](OC)([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH2:27]Cl>C1(C)C=CC=CC=1.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:27][CH2:26][CH2:25][C:24]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[O:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: COC(CCCCl)(OC)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
4.87 Parts of 4-(4-chlorophenyl)piperidin-4-ol, 1.91 parts of potassium iodide and 25 parts of deionized water is stirred together and gently warmed under a nitrogen atmosphere. Then, 2.75 parts of potassium bicarbonate and 6.17 parts of 1,1-dimethoxy-1-(4-fluorophenyl)-4-chlorobutane is added and the mixture is heated to reflux. After heating for 4.5 hours, the reaction mixture is allowed to cool to room temperature and 55 parts of toluene is added. The aqueous and organic layers are separated, and the aqueous layer discarded. 5.1 Parts of methanol is added to the organic layer. Then, 2.5 parts of concentrated hydrochloric acid is added with vigorous stirring. The resulting precipitate is cooled to about 25° C., filtered, washed twice with 22 parts by volume portions of a 10:9:1 mixture of acetone-toluene-methanol, and twice with 20 parts by volume portions of a 10:1 mixture of acetone-methanol. After air-drying, the product, 4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-4' -fluorobutyrophenone hydrochloride, melts at about 227°-229° C. and is obtained in 80.1% yield. This compound is the hydrochloride salt of the product of Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC1(C)C(C)(C)OB([C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH2:28][CH2:29][N:30]([S:36]([NH:39][C:40]2[S:44][N:43]=[CH:42][N:41]=2)(=[O:38])=[O:37])[CH2:31]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[O:15]1[CH2:16][CH2:17][N:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH2:28][CH2:29][N:30]([S:36]([NH:39][C:40]2[S:44][N:43]=[CH:42][N:41]=2)(=[O:37])=[O:38])[CH2:31]3)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(c2cccc3c2CCN(S(=O)(=O)Nc2ncns2)C3)OC1(C)C
Reactant: FC(F)(F)c1ccc(Br)c(N2CCOCC2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2N2CCOCC2)C1
Temperature: 25 °C
Yield: 9.1 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.023 g, 0.033 mmol), 4-(2-bromo-5-(trifluoromethyl)phenyl)morpholine (Intermediate G, 0.154 g, 0.497 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (Intermediate F, 0.140 g, 0.331 mmol), and potassium phosphate (0.281 g, 1.326 mmol) in 2.5 mL dioxane and 1 mL water was heated to 100° C. 2 hours. The reaction mixture was cooled to rt, diluted with EtOAc and washed with 1 N citric acid solution. The organic layers were dried over MgSO4 and concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C-18 50 g, 5 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 5-(2-morpholino-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.016 g, 0.030 mmol). [M+H]+=525.8 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.23 (s, 1H), 7.38-7.44 (m, 1H), 7.26-7.36 (m, 3H), 7.14-7.22 (m, 2H), 4.35-4.40 (m, 2H), 3.39-3.49 (m, 3H), 3.28-3.38 (m, 2H), 2.86-2.96 (m, 2H), 2.73-2.81 (m, 2H), 2.47-2.60 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10][Br:11]>>[Br-:11].[CH3:1][C:2]1[O:3][CH2:4][CH2:5][N+:6]=1[CH2:10][CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: CC1=NCCO1
Reactant: CC(C)=CCBr
Product: CC(C)=CC[N+]1=C(C)OCC1
Product: [Br-]

Procedure:
8.5 g (0.1 mol) of 2-methyloxazoline and 14.9 g (0.1 mol) of 3-methyl-2-butenyl bromide (prenyl bromide) were stirred at 20°-25° C. for 2 hours, crystalline, hygroscopic 2-methyl-3-(3-methyl-2-butenyl)-2-oxazolinium bromide being formed in an exothermic reaction.
Reaction SMILES: [C:1]1([C@H:7]2[O:12][C@@H:11](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O-:27])(=[S:26])[CH3:25].[Na+].C1C=CC=CC=1>CN(C)C=O>[C:24]([S:26][C@@H:11]1[CH2:10][CH2:9][O:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:12]1)(=[O:27])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCO[C@@H](c3ccccc3)O2)cc1
Reactant: CC([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)S[C@@H]1CCO[C@@H](c2ccccc2)O1
Temperature: 117.5 °C
Yield: 43.5 %

Procedure:
In 200 ml of dimethylformamide were dissolved 29.0 g (86.8 mmol) of cis-2-phenyl-4-(p-toluenesulfonyloxy)-1,3-dioxane and 17.0 g (149 mmol) of sodium thioacetate, and the solution was heated at 115 to 120° C. under a nitrogen atmosphere for 1 hour. After cooling, benzene was added to the reaction mixture and the mixture was washed with water, followed by evaporation of the solvent. The thus obtained brown residue was subjected to column chromatography using silica gel and the fractions eluted with a mixed solvent of benzene-hexane (2:1) were collected, followed by recrystallization from a mixed solvent of benzene-hexane to obtain 8.99 g (yield: 43%) of the title compound having a melting point of 95 to 96° C.