Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[N:10]1([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(F)nc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=Cc1ccc(N2CCCC2)nc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
6-Fluoro-3-pyridinecarboxaldehyde (152 mg, 1.22=01) was dissolved in tetrahydrofuran (3.0 mL). To this, pyrrolidine (507 μL, 6.08 mmol) was added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 2 hours and successively at 60° C. for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 6-(pyrrolidin-1-yl)-3-pyridinecarboxaldehyde (181 mg, yield: 84%).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]>CN(C)C=O.CO.[Cu]>[Cl:17][C:12]1[CH:13]=[CH:14][C:15]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:16][CH:11]=1
Reactant: Clc1ccccc1Br
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(Cl)cc2)cn1
Reaction time: 18 h

Procedure:
7.35 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 20 ml of dimethylformamide, and 9.6 g of bromochlorobenzene and 800 mg of a copper powder were added to the suspension. The reaction was effected at a temperature of 120° C. for a period of 18 hours in a nitrogen stream while stirring. After allowing the reaction mixture to cool, the reaction mixture was diluted with 50 ml of methanol and then filtered. The filtrate was immediately concentrated to dryness, and 200 ml of chloroform and 100 ml of water were added to the dried material, and the mixture adjusted to a pH of 9 with 5 N sodium hydroxide. The insoluble matter was again separated by filtration. The resulting chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 8.2 g of oily 5-(p-chlorophenoxy)-2-methylpyridine. Gas chromatography revealed that the thus-obtained product contained no 5-(p-bromophenoxy)-2-methylpyridine.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=3)[CH:17]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.[CH3:36][C:37]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[C:38]=1[C:39](O)=[O:40]>CS(C)=O>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][CH2:18][C:16]2[CH:17]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:2]([NH:1][C:39](=[O:40])[C:38]4[C:42]([CH3:47])=[CH:43][C:44]([CH3:46])=[CH:45][C:37]=4[CH3:36])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=3)[O:14][CH:15]=2)[CH:25]=1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: Cc1ccnc(NCc2coc(-c3ccc(CC(N)C(=O)O)cc3)c2)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(NCc2coc(-c3ccc(CC(NC(=O)c4c(C)cc(C)cc4C)C(=O)O)cc3)c2)c1
Reaction time: 12 h

Procedure:
50 mg of (11) as 2HCl salt and 1201l of DIPEA were dissolved in 1 ml of DMSO. 29 mg of the OAT ester of 2,4,6-trimethylbenzoic acid were added. The solution was stirred for 12 h and the product was purified by HPLC to give 10.8 mg of (12) as TFA salt.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C@@H:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1C=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
Sodium hydride (60% dispersion in oil, 7.2 mg, 0.18 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (47 mg, 0.19 mmol) in THF (1 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude, prepared in accordance with Example 29, step 5, ˜0.20 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 17 h at rt, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 59 mg (90%) of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][C:13](OC(C)(C)C)=[O:14])[C:5]=2[CH2:4][O:3]1.[Li+].[BH4-].CO>C1COCC1>[CH3:1][C:2]1([CH3:20])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH2:13][OH:14])[C:5]=2[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)Cc1cccc2c1COC(C)(C)O2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)OCc2c(CCO)cccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)acetate (2.6 g, 80% pure, 9.34 mmol, 1 eq.) in THF (20 mL) were added LiBH4 (7.0 mL, 14.01 mmol, 1.5 eq.) and MeOH (1.0 mL) at rt. The mixture was stirred at rt for 30 min, added MeOH (20 mL), concentrated to dryness, added MeOH (20 mL) and silica gel, and concentrated to dryness again. The mixture was loaded directly on silica gel for purification using a mixture of EtOAc and hexanes as eluent to give 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethanol (1.1 g, 71%) as a pale brown oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (t, J=7.9 Hz, 1H), 6.92 (d, J=7.4 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.02 (s, 2H), 3.99 (q, J=6.4 Hz, 2H), 2.86 (t, J=6.6 Hz, 2H), 1.68 (s, 6H), 1.57 (t, J=5.5 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([O:19][CH3:20])=[C:13]([O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:12]=2)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[NH4+]>ClCCl>[Cl:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:7]
Reactant: COc1cc2c(Cl)c(NC(=O)OC(C)(C)C)cnc2cc1OCCCN1CCCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Cl)c(N)cnc2cc1OCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
[4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-yl]-carbamic acid tert-butylester (1.8 g) was dissolved in dichloromethane and added trifluoroacetic acid (2 ml) and stirred at room temperature for 2 h. This was carefully basified with ammonium hydroxide solution and extracted the desired amino product with ethyl acetate. The solvent was evaporated to give 4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-ylamine (0.500 g). MS(ES) 350 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.N>Cl.C1COCC1>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)OCC1CCNCC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of intermediate 10 (18 g) in HCl (25 ml) and THF (250 ml) was stirred for 30 minutes at 70° C. The reaction mixture was cooled, alkalized with aqueous ammonia and the layers were separated. The aqueous layer was extracted twice with THF. The combined organic layers were dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue (10 g) was dissolved in CHCl3, washed with aqueous ammonia, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried, yielding 8.5 g (65%) 4-piperidinylmethyl 4-amino-5-chloro-2-methoxybenzoate (intermediate 11).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:18])[CH3:17]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Sc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.5 %

Procedure:
Dissolve 4-bromo-benzenethiol (2.6 g, 13.2 mmol) in 150 mL acetone, add potassium carbonate (2.0 g, 14.5 mmol) and 2-bromo-propane (1.8 g, 14.5 mmol) and stir 2 days at r.t. Evaporate the solvent under vacuum, add water and extract with dichloromethane. Filter through a hydrophobic filter paper and concentrate. Purify the resulting material via column chromatography on silica gel, eluting with hexane:ethyl acetate 98:2 to afford the title compound as a yellow oil (2.06 g). MS (m/e): 231 [(79Br)M], 233 [(81Br)M].
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1.[Cl:12]([O-])(=O)=O.[K+]>O>[Cl:12][C:8]1[C:3]([OH:2])=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=1
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 53 °C

Procedure:
Concentrated hydrochloric acid (239 g) was added to 2-hydroxy-5-nitropyridine (40.0 g). The resulting slurry was heated to 53° C., and stirred until all the solids dissolved. To this was slowly added a solution of potassium chlorate (14.0 g) in water (250 g), while maintaining the temperature between 55° C. and 59° C. The resulting mixture was stirred at 58-62° C. for about 1 hour. The reaction was then cooled to room temperature, stirred for 12 hours and then filtered. After washing the wet cake with water, the product was dried in a vacuum oven. 1H NMR (400 MHz/DMSO-d6) δ 8.64 (d, J=2.9 Hz, 1H), 8.35 (d, J=2.9 Hz, 1H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C1COCC1.[CH2:14](Br)[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CBr
Reactant: O=C(O)c1cccs1
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(=O)O)s1
Temperature: -78 °C
Reaction time: 5 h
Yield: 28.2 %

Procedure:
To a solution of 2-thiophene-carboxylic acid (4.16 g, 32.1 mmol) in THF (200 mL) tert. butyllithium (49 mL, 1.7 M solution in pentane, 83.6 mmol) is slowly added at −78° C. The mixture is stirred at −78° C. for 30 min before isobutylbromide (22.7 g, 160.7 mmol) is carefully added. The mixture is stirred at −78° C. for 5 h, then at rt for 16 h. The reaction is quenched by the addition of water (400 mL). The mixture is acidified and extracted with EA. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on reverse phase silica gel to give the title compound (1.67 g) as a brownish oil; LC-MS: tR=0.91 min, 1H NMR (CDCl3): δ 0.96 (d, J=6.7 Hz, 6H), 1.94 (hept, J=6.7 Hz, 1H), 2.72 (d, J=7.0 Hz, 2H), 6.80 (d, J=3.8 Hz, 1H), 7.73 (d, J=3.8 Hz, 1H).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27]>C1COCC1.CCOC(C)=O>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:25]([C:26](=[O:27])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCCBr)C(=O)O
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCCBr)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDCI (2.10 g, 11.1 mmol) and aniline (0.68 ml, 7.5 mmol) were added to a solution of 7.4 mmol of (S)-7-bromo-2-tert-butoxycarbonylamino-heptanoic acid (Gupta P. K., et al., Bioorg. Med. Chem. Lett., 2010, 20, 23, 7067) in THF (70 ml) and the reaction mixture was stirred overnight at RT. The solvent was removed under reduced pressure and the crude reaction mixture was diluted with AcOEt, washed with water and then with 10% aqueous citric acid and finally with saturated NaHCO3. After removal of the solvent under reduced pressure and purification on silica gel (n-hexane/AcOEt: 1/9) the desired adduct was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].C(N(CC)CC)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[CH3:19][N:20]([CH3:25])[S:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([O:5][CH2:6][C:7]#[N:8])[CH:3]=1)(=[O:23])=[O:22]
Reactant: N#CCOc1cccc(N)c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-aminophenoxy)-acetonitrile (1.5 g, from Example 1), triethylamine (3.22 mL) in THF (35 mL) was added dimethylsulfamoyl chloride (4.2 mL) dropwise over 10 min. After stirring at room temperature for 1 hr, the solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with 5% HCl solution and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel eluting with ethyl acetate:dichloromethane (10:90) to give N,N-dimethyl-N'-(3-cyanomethoxyphenyl)-sulfamide (1.11 g).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:20][C:21]1([F:29])[CH2:25][NH:24][C@@H:23]([C:26]([NH2:28])=[O:27])[CH2:22]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([N:24]3[CH2:25][C:21]([F:29])([F:20])[CH2:22][C@@H:23]3[C:26]([NH2:28])=[O:27])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@H]1CC(F)(F)CN1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Agent: Cl
Product: NC(=O)[C@H]1CC(F)(F)CN1C(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (R)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 1315304-75-6) as starting materials and isolated (20 mg, 32%); MS (ESI, m/z): 394.5 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[C@@H:7]([CH3:19])[CH2:8][N:9]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)C.Cl>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[N:6]([C:20]([CH:22]1[CH2:23][CH2:24]1)=[O:21])[C@@H:7]([CH3:19])[CH2:8][NH:9]2
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1C(=O)C1CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C1CC1
Temperature: 50 °C
Yield: 93.3 %

Procedure:
A 200-mL round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and condenser was charged with (S)-tert-butyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (5.74 g, 14.52 mmol), ethanol (100 mL), water (25 mL), and 6 M hydrochloric acid solution (2.66 mL, 15.97 mmol). The reaction mixture was heated to 50° C. for 24 h and then cooled to room temperature. The ethanol was removed under reduced pressure, the residue was extracted into dichloromethane (100 mL), and the extract was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with 3:2 hexanes-ethyl acetate) to afford (S)-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(cyclopropyl)methanone (4.00 g, 93%) as an off-white solid. MS (ESI, pos. ion) m/z 295, 297 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[CH:9]([CH3:12])[CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S([Cl:38])(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]([CH:9]([CH3:12])[CH2:10][Cl:38])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CO)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CCl)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Reaction time: 12 h

Procedure:
2-[benzyl(3-chloro-4-fluorophenyl)amino]propan-1-ol (1-6, 0.060 g, 0.204 mmol) in CH2Cl2 was treated with triethylamine (0.028 mL, 0.204 mmol) and TsCl (0.042 g, 0.204 mmol). The resulting solution was allowed to stir 12 h. Additional TsCl (0.084 g, 0.408 mmol) was added and allowed to stir until complete. Upon completion, the reaction mixture was partitioned between NaHCO3 (sat. aq) and CH2Cl2 (3×2 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated to yield N-benzyl-3-chloro-N-(2-chloro-1-methylethyl)-4-fluoroaniline.
Reaction SMILES: S([O-])([O:4][CH2:5][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:7])(=O)=O.[Na+].[OH2:24]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:7])[C:5]([O:24][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O
Reactant: CCCCCCOC(C)(COS(=O)(=O)[O-])OCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Yield: 84 %

Procedure:
To a solution of methyl pyruvate 1 (10.0 g, 98.0 mmol) in toluene (100 mL) is added 1-hexanol 2 (40.1 g, 392 mmol) and p-TsOH (186 mg, 0.98 mmol). The mixture is heated to reflux for 10 hours with azeotropic removal of water from the reaction mixture. The reaction is quenched with saturated NaHCO3 (100 mL), and the reaction mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give hexyl 2,2-bis(hexyloxy)propanoate 3 (29.5 g, 84%) as a colorless oil: Rf (15% EtOAc/hexane)=0.53; IR (thin film, cm−1) 2956, 2930, 2860, 1746 (C═O), 1467, 1280, 1137, 1062. 1H NMR (600 MHz, CDCl3) δ 4.14 (t, J=7.2 Hz, 2H), 3.48 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.35 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.65-1.63 (m, 2H), 1.59-1.54 (m, 4H), 1.49 (s, 3H), 1.35-1.24 (m, 18H), 0.86 (t, J=7.2 Hz, 9H); 13C NMR (150 MHz, CDCl3) δ 170.2, 99.5, 65.4, 62.6, 31.7, 31.3, 29.7, 28.5, 25.8, 25.5, 22.6, 22.5, 21.9, 14.0, 13.9.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1.[I-:14].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: ClCCc1ccc2c(c1)OCCO2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCc1ccc2c(c1)OCCO2
Yield: 77.8 %

Procedure:
A solution of (a) (0.22 g) in acetone (10 ml) was treated with sodium iodide (0.6 g) and heated to reflux overnight. The mixture was filtered and evaporated. The residue was partitioned between dichloromethane and dilute aqueous sodium sulphite solution. The organic extract was dried and evaporated to give a brown oil (0.25 g).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C.[F:20][C:21]([F:38])([F:37])[CH:22]1[CH2:24][N:23]1[S:25]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])(=[O:27])=[O:26]>COC(C)(C)C.CCOCC.[Cu]I>[CH3:36][C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[C:33]([CH3:34])[C:28]=1[S:25]([NH:23][CH:22]([CH2:24][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][CH:10]=1)[C:21]([F:38])([F:20])[F:37])(=[O:26])=[O:27]
Reactant: c1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Agent: [Cu]I
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3cccc(-c4ccccc4)c23)C(F)(F)F)c(C)c1
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a stirred solution of 115 mg (0.60 mmol) of 4-phenylindole in 2 mL of tert-butyl methyl ether at room temperature was added 0.25 mL (0.75 mmol) of a 3 M solution of ethyl magnesium bromide in ether. The mixture stirred for 30 minutes and then 22.8 mg (0.12 mmol) of copper (I) iodide was added. After 30 minutes, a solution of 87.9 mg (0.30 mmol) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine in 1 mL of tert-butyl methyl ether was added. After 18 hours, the reaction was quenched with 1 mL of ice-cold water. After 10 minutes, the reaction mixture was diluted with dichloromethane, filtered through CELITE® filter aid, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (12 g) eluting with ethyl acetate-hexanes (0-30% gradient) to afford an off-white solid. A second chromatography by preparative TLC eluting with ethyl acetate-hexanes (3:7) afforded 65 mg (22%) of the title compound as an off-white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:16])[CH2:14][CH3:15].Br[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>C1COCC1>[Cl:24][C:23]1[C:18]([CH:14]([CH3:15])[C:13]#[N:16])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccnc1Br
Reactant: CCC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C#N)c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a −78° C. solution of diisopropylamine (3.04 g, 4.28 mL, 30 mmol) was added n-butyl lithium (13.2 mL, 2.5M in hexane, 33 mmol). The reaction mixture was stirred for 20 minutes at −78° C., followed by the addition of propionitrile (1.65 g, 2.15 mL, 30 mmol). The reaction mixture was stirred for an additional 50 minutes, followed by the slow addition of 2-bromo-3-chloropyridine (1.92 g, 10 mmol) in THF (10 mL). The reaction was then allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with water and extracted with two portions of diethyl ether. The combined organic phases were washed with brine, concentrated, and the residue chromatographed on silica gel eluting with 30% ethyl acetate-hexane to obtain the title compound (1.52 g, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (dd, J=1.5, 4.7, 1H), 8.02 (dd, J=1.5, 8.1, 1H), 7.48 (dd, J=4.7, 8.1, 1H), 4.73 (q, J=7.1, 1H), 1.59 (d, J=7.1, 3H). MS (DCI) m/z 167 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([C@H:29]([NH2:33])[C:30]([OH:32])=[O:31])[CH2:15][C:16]([NH:18][C@H:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH2:20][SH:21])=[O:17]>>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[S:21][CH2:20][C@@H:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[NH:18][C:16](=[O:17])[CH2:15][CH2:14][C@@H:29]([C:30]([OH:32])=[O:31])[NH2:33])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Product: N[C@@H](CCC(=O)N[C@@H](CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)NCC(=O)O)C(=O)O

Procedure:
DNP-GS was synthesized from 1-chloro-2,4-dinitrobenzene and GSH by a modification of the enzymatic procedure of Kunst et al., (1989, Biochim. Biophys. Acta 983:123; Li et al., 1995, supra).