Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:4]=2[CH2:3]1.[Li+].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43]([C:48]([NH:50][C@@H:51]1[CH2:54][CH2:53][C@@H:52]1[NH2:55])=[O:49])=[CH:42]2>CN(C)C=O>[ClH:38].[Cl:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43]([C:48]([NH:50][C@@H:51]1[CH2:54][CH2:53][C@@H:52]1[NH:55][C:11]([C:9]1[S:10][C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][C:5]=3[N:8]=1)=[O:13])=[O:49])=[CH:42]2
Reactant: N[C@H]1CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2nc(C(=O)N[C@H]3CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
Lithium 5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate (136 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (255 mg) and 1-hydroxybenzotriazole monohydrate (90 mg) were added to a solution with (±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclobutanediamine (117 mg) dissolved in N,N-dimethylformamide (5 ml), and the mixture was stirred overnight at room temperature. The solvent was then distilled off under reduced pressure using a vacuum pump, and dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to conduct liquid separation. The resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography on silica gel (methanol:dichloromethane=7:93). After ethyl acetate and a 1N ethanol solution of hydrochloric acid were added to the thus-obtained compound to acidify it, and the solvent was distilled off under reduced pressure. Ethyl acetate was added again, and precipitate formed was collected by filtration and dried to obtain the title compound (56 mg) as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:22]3[CH2:23][C:9]4([CH2:13][N:12]([CH2:14][CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[CH2:11][CH:10]4[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=43)[C:8]=2[CH:28]=1)(=O)[CH3:2].Cl.[NH2:30][OH:31].[OH-].[Na+].C(Cl)Cl>C(O)C.O>[C:1](=[N:30][OH:31])([C:4]1[CH:5]=[CH:6][C:7]2[CH:22]3[CH2:23][C:9]4([CH2:13][N:12]([CH2:14][CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[CH2:11][CH:10]4[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=43)[C:8]=2[CH:28]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(=NO)c1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Yield: 24.7 %

Procedure:
To a stirred mixture of 5.0 g (13.6 mmoles) of 5-acetyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, (Example 66), and 1.5 g (21.3 mmoles) of hydroxylamine hydrochloride in 25 ml of ethanol and 5.0 ml of water was added portionwise 2.8 g (70 mmoles) of powdered sodium hydroxide. The reaction mixture was then heated at reflux for 5 minutes, cooled, and distributed between water and methylene chloride. The organic layer was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel CC No. 7 with 5% methanol in chloroform to give 1.3 g of 5-acetyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole oxime as an oil; nmr spectrum: δ 1.0-4.0 (m, 19); 2.2 (s, 2); 6.8-7.4 (m, 7); 7.5 (s, 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])N.N([O-])=O.[Na+].[CH2:14]([N:16]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])[CH3:15].C(=O)(O)[O-].[Na+]>Cl.O.CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[C:17](=[O:22])[N:16]([CH2:14][CH3:15])[C:20](=[O:21])[CH:19]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCN1C(=O)C=CC1=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Solvent: CC(C)=O
Product: CCN1C(=O)C=C(c2ccc(Cl)c(Cl)c2)C1=O
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
A 260 g portion of 3,4-dichloroaniline was dissolved in a mixture of 400 ml of concentrated hydrochloric acid and 1.5 liters of water, cooled to 15° C. in an ice-salt bath. A solution of 111 g of sodium nitrite in 250 ml of water was added dropwise, with stirring, over a 90 minute period. Then 40 g of cupric chloride dihydrate was added followed by 200 g of N-ethylmaleimide in one liter of warm acetone. The reaction mixture was cooled to 10° C. and sodium bicarbonate was added in portions over 2 hours to adjust the pH to 3.5. The mixture was allowed to stand for 48 hours. The precipitate formed was collected, air dried, and taken up in 2.5 liters of isopropanol, then 185 ml of 2,6-lutidine was added and the mixture was heated to boiling, then poured into water and allowed to stand. The solid was collected and dried. Recrystallization from acetone gave 187.1 g of 3-(3,4-dichlorophenyl)-1-ethyl-1H-pyrrole-2,5-dione as a yellow solid, mp 138°-141° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])(C)(C)C>O1CCOCC1.Cl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][CH2:16][O:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[NH2:7]
Reactant: Cc1ccc(OCCCN(C)C)c(NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(OCCCN(C)C)c(N)c1
Reaction time: 12 h

Procedure:
To a stirred solution of [2-(3-dimethylamino-propoxy)-5-methyl-phenyl]-carbamic acid tert-butyl ester (617 mg, 2.0 mmol) in 5 mL of dioxane was added hydrochloric acid (2 mL; 4N in dioxane). After stirring for 12 hours, the reaction was diluted with 20 ml of 1N hydrochloric acid and washed with ethyl acetate (2×30 mL). The aqueous layer was basified with 10% aqueous sodium carbonate (50 mL) and extracted with ethyl acetate (3×50 mL). The ethyl acetate was washed with brine (1×30 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced to yield the corresponding aniline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]([Mg]Br)=[CH2:16].C1COCC1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH:15]=[CH2:16])([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 12.5 mmol) was dissolved in 25 ml of diethylether and cooled to 0° C. A 1M solution of vinylmagnesiumbromide in THF (16.3 ml, 16.31 mmol) was added dropwise at 0° C. After 90 min stirring at 0° C., the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was further purified by flash chromatography (silicagel, cyclohexane/ethylacetate 4:1).
Reaction SMILES: [C:1]([C:3]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[N:2].CC([O-])(C)C.[K+].[Cl:36][CH:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39].C1CCC(N=C=NC2CCCCC2)CC1>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOCC>[Cl:36][CH:37]([CH:41]([CH3:43])[CH3:42])[C:38]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH:6]3[CH2:7][CH2:8][C:3]([C:1]#[N:2])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)=[O:39]
Reactant: CC(C)C(Cl)C(=O)O
Reactant: CCCCCCCCC1(C#N)CCC(c2ccc(-c3ccc(O)cc3)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCC1(C#N)CCC(c2ccc(-c3ccc(OC(=O)C(Cl)C(C)C)cc3)cc2)CC1
Reaction time: 12 h

Procedure:
A mixture of 5.3 g of p-[p-(4-cyano-4-octylcyclohexyl)phenyl]phenol (obtainable by alkaline ether splitting from r-1-cyano-cis-4-(4'-propyloxybiphenyl-4-yl)-1-octylcyclohexane with potassium tert-butylate in NMP at 180°), 1.9 g of optically active 2-chloro-3-methylbutyric acid and 170 g of DMAP are suspended in 40 ml of CH2Cl2. 3.1 g of DCC in 5 ml of CH2Cl2 are then added dropwise at 0° and stirring is carried out for 12 hours at room temperature. After separating off the dicyclohexylurea and the usual working up, optically active 4'-(4-cyano-4-octylcyclohexyl)-biphenyl-4-yl 2-chloro-3-methylbutyrate is obtained, K 81 SA 138 I.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.CC1C=CC(S(O[CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])(=O)=O)=CC=1>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: Cc1ccc(S(=O)(=O)OCCS(C)(=O)=O)cc1
Product: CS(=O)(=O)CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 40.6 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2-(methylsulfonyl)ethyl 4-methylbenzenesulfonate, 157 was obtained as a white solid (50 mg, 40.6%) over two steps. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.16 (s, 1H), 8.58 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.02 (s, 1H), 7.76-7.79 (t, J=16 Hz, 1H), 7.23-7.24 (d, J=7.5 Hz, 1H), 6.71-6.73 (d, J=8.5 Hz, 1H), 4.64-4.67 (t, J=13.5 Hz, 2H), 4.01-4.03 (t, J=9.5 Hz, 2H), 3.89-3.87 (t, J=11.5 Hz, 2H), 3.76-3.79 (t, J=14 Hz, 2H), 3.32 (s, 2H), 3.17-3.20 (t, J=10.5 Hz, 2H), 2.94 (s, 3H), 2.13-2.14 (d, J=4.5 Hz, 2H); MS (ESI) m/z: 467 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[CH3:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[NH:18][C:19](=[O:35])[CH2:20][NH:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:8].CCN(CC)CC>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:4])[N:21]([CH2:20][C:19]([NH:18][C:10]1[C:9]([CH:7]([CH3:6])[CH3:8])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:15]([CH3:17])[CH3:16])=[O:35])[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N(CC(=O)Nc1c(C(C)C)cccc1C(C)C)C(c1ccccc1)c1ccccc1
Reaction time: 120 h

Procedure:
Several milliliters of methylchloroformate was added to the product from Example 4 (0.60 g) in a mixture of excess NEt3 and EtOAc at room temperature. Vigorous outgassing occurred with the formation of a precipitate. The solution was stripped to dryness and the residue taken up in a mixture of 50 mL THF and 50 mL saturated NaHCO3 solution. Excess methyl chloroformate was added at room temperature. This solution was allowed to sit 5 days at room temperature. The reaction mixture was diluted with EtOAc and washed with aqueous K2CO3 solution and aqueous NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated to a white solid. The solid was slurried in hexane/EtOAc 9/1 and collected by filtration. 0.55 g (80%). NMR (CDCl3) δ 1.06 (12H, d), δ 2.56 (2H, m), δ 3.84 (3H, s), δ 4.20 (2H, s), δ 6.80 (1H, bs), δ 7.0-7.5 (13H, m). IR (KBr) 3443, 2963, 1705, 1685, 699 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[OH-:13].[Na+]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)(=[O:13])[NH2:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Yield: 76 %

Procedure:
A solution of 5-cyanooxindole (1.2 g, 7.6 mmol), (Tet. Let., 1987, 28, 4027), in 85% sulphuric acid (8 ml) was heated at 80° C. for 6 hours. The mixture was allowed to cool, poured into ice/water and the mixture was adjusted to pH5 with 2M sodium hydroxide solution. The solid product was collected by filtration, washed with water, and dried under vacuum at 60° C. over phosphorus pentoxide to give 5-carbamoyloxindole (1.02 g, 76%).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([O:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C@H:4]1[C@@H:8]([O:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5]1
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.7 %

Procedure:
(+/−)-Cis-benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate (5.43 g, 19.65 mmol) was dissolved in THF (50 mL) and added triphenylphosphine (5.41 g, 20.64 mmol) and stirred at RT overnight. Added water (6 mL) and warmed to 60 deg. C. for ˜6 hrs. THF was removed in vacuo and the aqueous portion was diluted with 1N HCl (50 mL) and extracted 5× with EA (20 mL) to remove all of triphenylphosphine and triphenylphosphine oxide. The aq. portion was cooled to ˜5 deg. C. and adjusted to pH of 10 by dropwise addition of 1N NaOH. Extracted with DCM (5×) and the organic extractions were combined, dried (Na2SO4) and concentrated. This material was combined with another similar reaction performed on 22.8 mmol scale to afford a total of 8.0 g (75%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.36 (5 H, m), 5.34 (2 H, m), 3.45-3.73 (5 H, m), 3.42 (3 H, s), 3.13-3.22 (1 H, d, m), 1.28-1.31 (2 H, br s). LCMS: M+1=251, Rt=1.54 min.
Reaction SMILES: [CH2:1]([OH:3])C.[Na].[C:5]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)=O>C1(C)C=CC=CC=1.O>[CH:1]([CH:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([O:14][CH2:15][CH3:16])=[O:13])=[O:3]
Reactant: CCO
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCOC=O
Solvent: O
Product: CCOC(=O)CC(C=O)C(=O)OCC
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Ethanol (20 cm3) was added portionwise to a suspension of finely divided sodium (10.0 g) in dry toluene (100 cm3). On completion of the addition the mixture was heated for 3.5 hours at 80° C. To the resulting yellow suspension, cooled to 20° C., was added dropwise, over a period of 1 hour, a mixture of diethyl succinate (70.0 g) and ethyl formate (35.0 g), whilst the temperature of the mixture was maintained in the range 20° to 30° C. The mixture was kept at the ambient temperature for 16 hours after which water (100 cm3) was added carefully.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13]C)=[O:11].C([O-])([O-])=O.[K+].[K+].CCOCC.CCCCCCC>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Solvent: CO
Product: COC(=O)c1cc2ccccc2[nH]1
Temperature: 55 °C

Procedure:
Add to ethyl indole-2-carboxylate 1 (42.3 mmol) in MeOH (50 mL), K2CO3 (1.20 equiv., 50.7 mmol) and stir the suspension with heating to 55° C. for 1 h. Monitor the reaction by tlc (ether/heptane) and when complete concentrate the reaction in vacuo, dilute with H2O and stir for 15 min. Collect the solid by filtration and dry under vacuum at 65° C. for 3 h to afford methyl indole-2-carboxylate 2.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>CCO.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1OCCC1Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(OC2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 3-(4-nitrophenoxy)-dihydrofuran-2-one (47 mg, 0.21 mmol) in EtOH (3 mL) was added palladium hydroxide (<1 mg). The reaction flask was evacuated and purged with H2 and then stirred at room temperature under a H2 atmosphere for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to provide the desired product (40 mg, 99%).
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]1([C:67]2[CH:68]=[C:69]([CH:73]=[CH:74][CH:75]=2)[C:70](O)=[O:71])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:70]([C:69]1[CH:68]=[C:67]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:75]=[CH:74][CH:73]=1)=[O:71]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 70.6 %

Procedure:
DIPEA (78 mg, 0.61 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (104 mg, 0.24 mmol) in DMF (1 mL). HOBT (33 mg, 0.24 mmol) and EDCI.HCl (46 mg, 0.24 mmol) were then added at room temperature. After 2 minutes, 3-phenyl benzoic acid (40 mg, 0.20 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 70 mg (70% yield) of biphenyl-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.7%, 1H NMR (DMSO-d6): δ 8.8 (t, 1H), 8.2 (s, 1H), 7.9-7.8 (m, 3H), 7.8-7.6 (m, 4H), 7.6-7.4 (m, 4H), 7.4 (m, 1H), 4.2 (m, 2H), 3.8-3.6 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3.0 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13](N)=[O:14])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)(O)(O)O.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cc(-c2ccccc2)ccn1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1cc(-c2ccccc2)ccn1
Yield: 71 %

Procedure:
The procedure of Example 1 was used except that the catholyte was prepared from the following weight parts: 4-phenylpicolinamide (0.3), phosphoric acid (0.9), water (2.0), and toluene (0.8). The reduction was carried out similarly to Example 1 to give a 71% yield of 4-phenyl-2-pyridylcarbinol at 5.8 F/mole charge passage. Repeating the reduction with no toluene added gave a 49% yield of carbinol at 6 F/mole charge passage. Addition of a titanium salt to the catholyte containing added toluene resulted in a 55% yield of 4-phenyl-2-picolylamine by HPLC analysis. Other cathode materials than lead were also used successfully such as cadmium or zinc with similar results.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.1 %

Procedure:
A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (170 mg, 0.38 mmol), 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (100 mg, 0.34 mmol), and 2-aminopyridine (36 mg, 0.38 mmol) in N,N-dimethylformamide (1.75 mL) was treated with N,N-diisopropylethylamine (0.12 mL, 0.73 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a 1N aqueous hydrochloric acid solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide (127 mg, 53.3%) as a white gum: EI-HRMS m/e calcd for C20H21F3N2O (M+) 362.1605, found 362.1592.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[N:25]1[C:33]([SH:34])=[C:32]2[C:28]([N:29]=[CH:30][NH:31]2)=[N:27][CH:26]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:34][C:33]3[N:25]=[CH:26][N:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[N:29]4)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ncnc2nc[nH]c12
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ncnc4nc[nH]c34)s2)c(C(=O)C2CCCC2)c1
Yield: 25.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(7H-purin-6-ylsulfanyl)-thiazol-2-yl]-urea (124 mg, 28%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 7H-purine-6-thiol (304 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13].[C:14](Cl)(=[O:16])[CH3:15].Cl>CCOC(C)=O>[Br:5][C:6]1[C:7]([F:13])=[CH:8][C:9]([F:12])=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Br)c(F)cc1F
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A mixture of AlCl3 (1040 g, 7878.7 mmol) in 1-bromo-2,4-difluorobenzene ([CAS 348-57-2], 600 g, 3108.9 mmol) was stirred for 10 min at 60° C. Acetyl chloride [CAS 75-36-5], 366 g, 4662.4 mmol) was added dropwise in the reaction mixture for 4 h at 60° C. The mixture was stirred an additional 6 h at 95° C. The reaction mixture was cooled to −10° C. Ice (2450 g) was added for 1.5 h. HCl (12 N, 1500 mL) was added and the mixture was stirred for 1 h. EtOAc (9000 mL) was added and the organic layer was washed with water, dried over Na2SO4 and filtered. After concentration, the residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc, 50/1) to yield I-18 (300 g, 41%).