Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:15][C:16]1[C:50]([CH:51]=[O:52])=[CH:49][CH:48]=[CH:47][C:17]=1[C:18]([O:20][C@H:21]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)[CH2:22][C:23]1[C:28]([Cl:29])=[CH:27][N+:26]([O-:30])=[CH:25][C:24]=1[Cl:31])=[O:19])C1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:51]([C:50]1[C:16]([OH:15])=[C:17]([CH:47]=[CH:48][CH:49]=1)[C:18]([O:20][C@H:21]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:40])[F:41])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)[CH2:22][C:23]1[C:24]([Cl:31])=[CH:25][N+:26]([O-:30])=[CH:27][C:28]=1[Cl:29])=[O:19])=[O:52]
Reactant: O=Cc1cccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=Cc1cccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1O
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
TFA (0.4 mL) was carefully added to a solution of [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-benzyloxy-3-formyl-benzoate (116 mg, 0.18 mmol) in toluene (0.8 mL) at 0° C. The resulting mixture was stirred at 0° C. for 50 minutes. The solution was diluted with DCM (20 mL) and sat. NaHCO3 (20 mL). The layers were separated over a hydrophobit fit and the organic phase concentrated in vacuo, the residue azeotroped with toluene to dryness. The yellow gum (120 mg) was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]2[CH3:1])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129 %

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (10.0 g, 49.9 mmol, supplier Aldrich) in pyridine (30 ml) was added 4-chlorobenzenesulfonyl chloride (12.7 g, 59.9 mmol) portionwise. The reaction was stirred at room temperature under an argon atmosphere for 2 hours. The reaction was then evaporated, partitioned between 2N aq. HCl (70 ml) and DCM (80 ml). The aqueous was further extracted with DCM (2×80 ml) and the combined DCM layers were passed through a hydrophobic frit and evaporated. The product was dried under vacuum at 40° C. for 18 hours to yield the title compound as an orange solid (24.14 g).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:15]2[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:19][C:20]([O:22]C)=[O:21])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>C(O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([C:15]2[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:19][C:20]([OH:22])=[O:21])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(-c2cccc(C=CC(=O)OC)c2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCc1cc(-c2cccc(C=CC(=O)O)c2)ccc1OC
Yield: 59.1 %

Procedure:
Methyl 3-(3-hexyl-4-methoxyphenyl)cinnamate (80 mg, 0.29 mmol), ethanol (1 ml) and a 1N aqueous sodium hydroxide solution (1 ml) were mixed, and this solution was refluxed under heating for 1.5 hours. Ethanol was evaporated under reduced pressure, and conc. hydrochloric acid was added to make the solution acidic. Ethyl acetate (5 ml) was added to dissolve the precipitated crystals. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (5 ml). The organic layers were combined, washed 3 times with saturated brine (8 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give 3-(3-hexyl-4-methoxyphenyl)cinnamic acid (58 mg, 76%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:26])=[O:25])=[CH:20][CH:19]=1.[H-].[Li+]>O1CCCC1.C(OC)(C)(C)C>[F:1][C:2]([F:15])([F:16])[C:3]([OH:4])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=1)[CH2:26][C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)=[O:25]
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1ccc(C(=O)CC(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Yield: 97.2 %

Procedure:
A solution of 2,2,2-trifluoro-1-[3-(trifluoromethyl)-phenyl]ethanone (3.0 g), 4-methylacetophenone (1.1 g) and lithium hydride (0.13 g) in tetrahydrofuran (30 mL) was stirred for 3 hours at 60° C. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 4,4,4-trifluoro-3-hydroxy-1-(4-methylphenyl)-3-[3-(trifluoromethyl)phenyl]butan-1-one (3.0 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:11])[CH:4]([CH3:10])[O:5][CH:6](OC)[CH:7]=1.C(O)(=[O:14])C>>[CH3:10][C:4]1[O:5][CH:6]=[CH:7][C:2](=[O:14])[C:3]=1[OH:11]
Reactant: CC(=O)O
Reactant: COC1C=C(Cl)C(=O)C(C)O1
Product: Cc1occc(=O)c1O
Yield: 65 %

Procedure:
To a round bottom flask equipped with a stirring bar and a condenser was added 4-chloro-6-methoxy-2-methyl-2H-pyran-3(6H)-one and acetic acid and the reaction mixture heated to reflux for an hour. Maltol (65%) was obtained on cooling.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[S:27])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccccc1F
Solvent: Cc1ccccc1
Product: Fc1ccccc1C(=S)Nc1ccc(Br)cc1
Temperature: 25 °C
Yield: 178.3 %

Procedure:
A mixture of N1-(4-bromophenyl)-2-fluorobenzamide (3.3 g, 0.0112 mol) and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.27 g, 0.00561 mol) was heated in toluene at reflux under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:6) as mobile phase to yield N1-(4-bromophenyl)-2-fluoro-1-benzenecarbothioamide (3.1 g, 0.010 mol) as a yellow solid.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:7](=[O:9])[C@:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)([OH:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCN(C(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (1.0 g, 4.54 mmol) in DCM (50 mL) was added t-butoxycarbonyl-4-aminopiperidine (0.9 g, 4.5 mmol). DIPEA (2.4 mL, 1.4 mmol) and HOBt (1.0 g, 6.8 mmol) were added to the mixture, followed by EDCI (1.0 g, 5.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then washed with 1N NaOH (50 mL), 1N HCl (50 mL), and then saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed by rotary evaporation. To the crude material was added a solution of 20% TFA/DCM and the reaction was stirred for 2 hours at room temperature. The solvent was removed by rotary evaporation. DCM (50 mL) was added and the mixture was then washed with saturated sodium bicarbonate (50 mL). The organic layer was removed, dried over MgSO4 and filtered. The crude material was purified by silica gel chromatography (10% MeOH/DCM with 1% NH3 (aq)) to afford the title compound as a white powder (920 mg, 3.0 mmol).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[OH-].[Na+].[CH2:9]([C:11]1([CH2:15]OS(C)(=O)=O)[CH2:14][O:13][CH2:12]1)[CH3:10]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.O.C1(C)C=CC=CC=1>[CH2:9]([C:11]1([CH2:15][O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:14][O:13][CH2:12]1)[CH3:10]
Reactant: OCCCCO
Reactant: CCC1(COS(C)(=O)=O)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(COCCCCO)COC1
Temperature: 60 °C
Yield: 69.5 %

Procedure:
After adding 721 g (8.0 mol) of 1,4-butanediol and 350 ml of toluene in a glass flask having an internal volume of 2000 ml equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser and heating up to 60° C. while stirring, 38.7 g (0.12 mol) of tetrabutylammonium bromide and 184 g (4.4 mol) of 96 mass % sodium hydroxide were added and heated up to 75° C. while stirring. Then, 777 g (3.8 mol) of 3-ethyl-3-methanesulfonyloxymethyloxetane with a purity of 95 mass % synthesized in (1) above was gently dropped while keeping the liquid temperature from 75° C. to 85° C. to carry out a reaction at the same temperature range for two hours. After completing the reaction, 800 ml of water was added to the reaction solution [a bisoxetane ether compound was generated as little as 7% (value analyzed by gas chromatography)] to separate into a water layer and an organic layer. The organic layer thus obtained was added with 800 ml of toluene and 400 ml of water, and by adding acetic acid while stirring, the pH was adjusted to 9.5. Then, after separating into a water layer and an organic layer, the water layer was extracted twice with 400 ml of toluene, the extract (toluene liquid) was mixed with the previous organic layer and concentrated under reduced pressure. By distilling the concentrate thus obtained under reduced pressure (from 157° C. to 159° C., 1.9 kPa), 497 g of 3-ethyl-3-(4-hydroxybutyl)oxymethyloxetane with a purity of 96% (value analyzed by gas chromatography) as a colorless liquid was obtained (isolated yield based on 3-ethyl-3-methanesulfonyloxymethyloxetane=67%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[C:37]([NH:56][CH2:57][CH2:58][NH:59][CH2:60][CH2:61][NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:59]([CH2:60][CH2:61][NH:62][C:63](=[O:69])[O:64][C:65]([CH3:66])([CH3:68])[CH3:67])[CH2:58][CH2:57][NH:56][C:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1ncc(NC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 92.9 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)pyrazol-4-yl]carbamate (712 mg) and tert-butyl 2-{[2-(tritylamino)ethyl]amino}ethylcarbamate (668 mg) in dehydrated chloroform (4 ml) was added N-ethyldiisopropylamine (0.257 ml), and the mixture was stirred under reflux for 16 hours. To the reaction mixture was added ethyl acetate, and the solution was washed successively with water, 5% aqueous citric acid solution, 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% methanol/methylene chloride to give tert-butyl (2-{N-({[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}carbonyl)-N-[2-(tritylamino)ethyl]amino}ethyl)carbamate (1.15 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)CCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 22.8 %

Procedure:
A mixture of 4-chlorobenzenesulphonamide (4.5 g), ethyl 8-bromo-2,2-dimethyloctanoate (3.3 g) and potassium carbonate (9.3 g) in dry methylethylketone (140 ml) was refluxed for 9 hours. The inorganic residues were removed by filtration and the filtrate was evaporated to dryness to give an oil. Chromatography on silica gel eluted with chloroform-petroleum ether 15:1 gave the title compound (1.05 g) as an oil.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:20]([Cl:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=3[Cl:25])[CH:11]=[CH:10][C:9]=2[OH:26])(=[O:7])=[O:6])[CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:22][C:18]1[CH:17]=[C:16]([Cl:25])[C:15]([O:14][C:12]2[CH:11]=[CH:10][C:9]([OH:26])=[C:8]([S:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)(=[O:7])=[O:6])[CH:13]=2)=[C:20]([Cl:21])[CH:19]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC3CC3)c2)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC3CC3)c2)c(Cl)c1
Reaction time: 12 h
Yield: 61.5 %

Procedure:
To a solution of 2-cyclopropylmethanesulfonyl-4-(2,6-dichloro-4-nitro-phenoxy)-phenol (76 mg, 0.18 mmol) in ethanol (2 mL) was added catalyst 10% Pd/C (27 mg). The mixture was hydrogenated under 45 psi at RT for 12 h. The mixture was filtered through Celite and concentrated to give the title compound of Step E (43 mg) as a solid. The title product of Step E was used in the next step without further purification. MS (APCl−) Calc.: 387.0. Found: 386.2 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].Cl.C(=O)(O)[O-].[Na+].[CH3:33][C:34]([CH3:36])=O>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][N:13]([CH:34]([CH3:36])[CH3:33])[CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: CC(C)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (89 mg) and sodium cyanoborohydride (63 mg) in methanol (1 ml) was added acetone (0.1 ml) with ice cooling. The pH of the mixture was adjusted to 3 to 4 with 1N hydrochloric acid and the solution was stirred at 4° C. for 30 minutes. Then, the solution was neutralized with an aqueous saturated sodium bicarbonate solution and poured into cold water. The separated oil was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated in vacuo. The residue was crystallized from diethyl ether to give 7-(4-fluorophenyl)-2-isopropyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (75 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>O1CCOCC1.Cl.CN(C)CC(O)=O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1ccc(Br)cc1
Agent: CN(C)CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 114.8 %

Procedure:
Following the general procedure for Example 12 (step 1), N,N-dimethylglycine hydrochloride (0.04 g, 0.26 mmol), cesium carbonate (1.85 g, 5.68 mmol), and Cu(I) iodide (0.02 g, 0.11 mmol) were added to a solution of 4-bromochlorobenzene (0.82 g, 4.28 mmol) and 4-methoxyphenol (0.35 g, 2.82 mmol) in dioxane (10 mL) to afford the title compound (0.76 g, 100%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[N+:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][S:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)(=[O:31])=[O:32])[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol), was mixed with 3-nitrobenzenesulfonyl chloride (0.466 g, 2.0 mmol) and pyridine (9 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (15 mL) was added and the mixture allowed to stand 1.5 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL), and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a yellow solid. The solid was triturated with hexanes/ethyl acetate, 1/1, dried in vacuo, taken up in tetrahydrofuran, concentrated to dryness, triturated with hexanes/ethyl acetate, 4/1, v/v and was collected by filtration (0.488 g), mp 228-230° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[N:31][N:30]=[N:29]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH:32]=[N:31][N:30]=[N:29]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: c1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3cnnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=444.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1.[H-].[Na+]>CN(C=O)C>[Cl:27][C:25]1[CH:26]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:8]2=[O:12])[CH:22]=[N:23][CH:24]=1
Reactant: Clc1cncc(OCCCCCCBr)c1
Reactant: O=C1NCCN1c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCOc2cncc(Cl)c2)CCN1c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-pyridyl)-2-imidazolidinone (100 mg, 0.61 mmol) and 3-[(6-bromohexyl)oxy]-5-chloropyridine (269 mg, 0.92 mmol) in DMF (5 mL) was added sodium hydride (39 mg, 1.23 mmol, 75% in mineral oil) in an ice bath. The mixture was stirred at room temperature overnight. After removing the solvent under reduced pressure, the crude residue was purified by column chromatography eluted with 15% methanol in ethyl acetate to afford the product (i.e., Compound 11) as a light yellow solid (0.17 g, 75%).
Reaction SMILES: Cl[P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4](Cl)[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]=1[OH:37])([CH3:22])([CH3:21])[CH3:20]>C(N(CC)CC)C>[C:19]([C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]=1[O:37][P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4]([O:37][C:24]2[C:25]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:26][C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:28][C:23]=2[C:19]([CH3:22])([CH3:21])[CH3:20])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: ClP1N(c2ccccc2)P(Cl)N1c1ccccc1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP2N(c3ccccc3)P(Oc3c(C(C)(C)C)cc(C(C)(C)C)cc3C(C)(C)C)N2c2ccccc2)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-diphenyl-1,3,2,4-diazadiphosphetidine, 2,4,6-tri-tert-butylphenol and triethylamine to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:21])[C:16]2([CH3:20])[CH:17]([OH:19])[CH2:18][CH:13]1[CH2:14][CH2:15]2.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[C:16]12([CH3:20])[C:12]([CH3:21])([CH3:11])[CH:13]([CH2:14][CH2:15]1)[CH2:18][C:17]2=[O:19]
Reactant: CC1(C)C2CCC1(C)C(O)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC12CCC(CC1=O)C2(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.3 %

Procedure:
To a well-stirred solution of anhydrous CH2Cl2 (5 mL) under an argon atmosphere at −30° C. was added oxalyl chloride (0.14 mL, 1.6 mmol). Fluorous DMSO (1.0 g, 3.2 mmol) then was added dropwise, and the reaction mixture stirred for an additional 20 minutes. Isoborneol (0.153 g, 1 mmol) dissolved in CH2Cl2 (5 mL) then was added to this solution, followed, after an additional 40 min to 1 hour, by diisopropylethylamine (0.88 mL, 5 mmol). The reaction mixture then was warmed to room temperature and stirred for 30 minutes before quenching with water, washing with ammonium chloride (5 mL), extracting with CH2Cl2 (10 mL), and careful concentration under aspirator vacuum in a cold water bath. The reaction mixture then was dissolved in toluene (6 mL) and extracted continuously, with FC72 (15 mL) in a cooled continuous extractor for 4 hours (see, D. Crich et al., “Design, Synthesis, Application and Recovery of a Minimally Fluorous Diaryl Diselenide for the Catalysis of Stannane-Mediated Radical Chain Reactions,” Tetrahedron, 55 , pp. 14261-14268 (1999)). After decantation, concentration of the toluene layer and chromatography on silica gel yielded camphor (0.142 g, 94%). The FC72 phase, containing a mixture of fluorous. DMS and fluorous DMSO, then was stirred with methanol (3 mL) and hydrogen peroxide (0.23 mL of 30 %, 2 mmol) for 1 hour followed by dilution with water (5 mL), and extraction with CH2Cl2 (10 mL) in a three phase system. Concentration of the CH2Cl2 layer gave recovered crystalline fluorous DMSO (0.9 g, 90%).