Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:21]([O:23][C:24](=[O:36])[CH2:25][NH:26][S:27]([C:30]1[S:31][C:32](Br)=[CH:33][CH:34]=1)(=[O:29])=[O:28])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl>[CH2:21]([O:23][C:24](=[O:36])[CH2:25][NH:26][S:27]([C:30]1[S:31][C:32]([C:19]#[C:18][C:16]2[CH:15]=[N:14][C:12]3[N:13]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[N:9]=[C:10]([OH:20])[C:11]=3[CH:17]=2)=[CH:33][CH:34]=1)(=[O:29])=[O:28])[CH3:22]
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CNS(=O)(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)s1
Yield: 93.2 %

Procedure:
A mixture of 436 mg (1.27 mmol) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 415 mg of N-(5-bromothien-2-ylsulfonyl)glycine ethyl ester, 20 mg of palladium chloride, 54 mg of triphenylphosphine, 10 mg of cuprous iodide, and 0.4 mL of triethylamine in 7 mL of acetonitrile was heated to reflux under nitrogen for 1 hour. The resulting reaction mixture was then concentrated in vacuo and the residue flash chromatographed with 4% CH3 OH/chloroform to give 610 mg of N-[5-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)thien-2-ylsulfonyl]glycine ethyl ester as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ1.13 (t, J=7 Hz, 3H), 1.25, (s, 9H), 3.79 (d, J=5.8 Hz, 2H), 3.99 (q, J=7 Hz, 2H), 7.48 (d, J=3.6 Hz, 1H), 7.56 (d, J=3.6 Hz, 1H), 8.51 (s, 1H), 8.65 (t, J=5.8 Hz, 1H), 8.99 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18]N1C(=O)CCC1=O>C(#N)C.[Fe](Cl)(Cl)Cl>[Cl:18][C:13]1[C:12]([OH:17])=[CH:11][CH:10]=[C:9]2[C:14]=1[CH2:15][CH2:16][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:8]2
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: Oc1ccc2c(c1Cl)CCC(c1ccccc1)O2
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a suspension of 200 mg of 2-phenyl-chroman-6-ol (0.88 mmol) and 142 mg of iron(III) chloride (0.88 mmol) in 15 ml of acetonitrile at room temperature 118 mg of N-chlorosuccinimide (0.88 mmol) were added in one portion and stirring was continued for 16 h. The volatile components were removed under reduced pressure. The resulting residue was purified by reversed phase HPLC. 127 mg of the title compound were obtained as a pale yellow solid (55%).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41].[CH2:43](I)[CH3:44]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:43][CH3:44])[C:31](=[O:42])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: COc1ccccc1COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1OC)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-methoxybenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (66 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (84 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (63 mg, yield 93%).
Reaction SMILES: [OH-:1].[Na+:2].Cl[C:4]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13]>O>[Cl:18][C:14]1[C:5]2[CH:6]=[C:7]([C:8]([O-:1])=[O:13])[S:11][C:4]=2[CH:17]=[CH:16][CH:15]=1.[Na+:2]
Reactant: [OH-]
Reactant: O=C1NC(=S)SC1=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: O
Product: O=C([O-])c1cc2c(Cl)cccc2s1
Temperature: 25 °C

Procedure:
After sodium hydroxide (4.55 g) was dissolved in water (50 ml), 2,6-dichlorobenzylidenerhodanine (10.00 g) was added. The mixture was stirred under reflux for 5 hours, and then cooled to room temperature. The precipitated crystals were collected by filtration and washed with cold water to obtain sodium 4-chlorobenzo[b]thiophen-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH:12]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[CH:16]=1)([CH3:14])[CH3:13].CCN(CC)CC>O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:20]2[C:15]([CH:12]([CH3:13])[CH3:14])=[CH:16][C:17]([CH:24]([CH3:26])[CH3:25])=[CH:18][C:19]=2[CH:21]([CH3:23])[CH3:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)cc1
Yield: 88.3 %

Procedure:
4-Methoxyphenylboronic acid (152 mg, 1.00 mmol), and Pd(dtbpf)Cl2 (6 mg, 0.01 mmol) were added to a reaction tube equipped with a magnetic stir bar. Under a positive flow of argon while stirring, surfactant solution (1.0 mL, 2 wt % TPGS-M-PEG-750 in water), 2,4,6-triisopropylbenzene (126 μL, 0.50 mmol), and Et3N (0.21 mL, 1.5 mmol) were added by syringe and stirred vigorously for 24 h. The reaction mixture was then diluted with brine and extracted with EtOAc. The solution obtained was dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by flash column chromatography eluting with 5% CH2Cl2/hexanes to afford the product (137 mg, 88%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:25](O)[CH2:26][CH2:27][CH:28]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[OH:29])[CH:10]=[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:26][CH2:27][C@H:28]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:29]2)[CH:10]=[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Reaction time: 1 h

Procedure:
A solution of 1-[3-(2-hydroxyethylsulfonyl)-4-n-propoxy-5-benzyloxyphenyl]-4-(3,4,5-trimethoxyphenyl)butan-1,4-diol (from previous experiment) in chloroform (20 mL) was treated with 10% trifluroacetic acid (20 mL). The reaction was monitored by TLC. After 1 h, anhydrous sodium carbonate was added, and the solid was filtered off and washed with chloroform. The solvent was evaporated and the residue was passed through a flash column of silica gel (hexane-ethyl acetate; 2:1, v/v). The cis- and trans-isomers were then separated by HPLC (hexane-ethyl acetate; 1:1, v/v). Rf 0.33 (hexane-ethyl acetate; 1:1, v/v); NMR (CDCl3) δ 0.98 (t, J=7.5 Hz, CH2CH2CH3), 1.83 (m, CH2CH2CH3), 2.85 (t, J=6.5 Hz, OH), 3.67 (q, SO2CH2), 3.98 (q, SO2CH2CH2), 4.17 (t, CH2CH2CH3), 5.18 (s, CH2C6H5), 6.63 (s, 2 H, C5ArH).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[OH:21][CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([OH:30])[C:26]([CH3:31])=[CH:25][N:24]=1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([OH:5])([C:7]([F:9])([F:10])[F:8])[CH2:6][N:24]3[CH:25]=[C:26]([CH3:31])[C:27](=[O:30])[C:28]([CH3:29])=[C:23]3[CH2:22][OH:21])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: Cc1cnc(CO)c(C)c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cn(CC(O)(CC(C)(C)c2cccc3c2OCC3)C(F)(F)F)c(CO)c(C)c1=O
Temperature: 85 °C
Yield: 22.6 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (30.0 mg) and 2-hydroxymethyl-3,5-dimethylpyridin-4-ol (32.2 mg) in anhydrous ethanol (0.25 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 39.0 μL). After heating at 85° C. for 18 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 4% to 7% methanol-methylene chloride) to give the title compound as a white solid (10.4 mg), m.p. 160° C.-162° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Cl)[CH:20]=1.CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: ClCc1cccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OCc3cccnc3)c12
Yield: 90 %

Procedure:
To a round bottom flask with stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmol), 3-picolyl chloride (1.1 equiv.) potassium carbonate (5 equiv.) and 10 mL DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 mL) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 mL), brine (20 mL), dried over magenesium sulfate. Filtration and evaporation of solvent afforded 3-methyl-4-(pyridin-3-ylmethoxy)-benzofuran-2-carboxylic acid t-butyl ester as a thick oil in 90% yield.
Reaction SMILES: O.[ClH:2].[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH3:11][O:12][NH2:13].C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)C>[ClH:2].[CH3:11][O:12][N:13]=[C:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=C1CCNCC1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CON=C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Piperidinone hydrochloride monohydrate (5 g, 32.5 mmol), methoxyamine hydrochloride (4.18 g, 50 mmol) and potassium carbonate (13.82 g, 100 mmol) were taken into 100 mL of ethanol and stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate evaporated to afford a white solid. The crude solid was dissolved in water, made basic with solid potassium carbonate, and extracted with dichloromethane (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to afford a clear, colorless liquid. It was converted to its hydrochloride salt by treating with ethereal hydrogen chloride to give 233 g, m.p. 140°-141° C. C6H12N2O·HCl: Calc.: C, 43.77; H, 7.96; N, 17.02. Found: C, 43.78; H, 7.96; N, 17.08.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)(=O)=O)=CC=1.FC(F)(F)C(O)=O.[NH2:30][C:31]1[C:36]([C:37]([NH:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)/C=C\C(O)=O>C(#N)C>[NH2:30][C:31]1[C:36]([C:37]([NH:39][CH2:40][CH:41]2[CH2:46][CH2:45][N:44]([CH2:11][CH:12]3[O:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[O:14][CH2:13]3)[CH2:43][CH2:42]2)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Reactant: Nc1ncccc1C(=O)NCC1CCNCC1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1C(=O)NCC1CCN(CC2COc3ccccc3O2)CC1

Procedure:
A stirred mixture of 1,4-benzodioxan-2-ylmethyl toluene4-sulphonate (0.82 g), 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide trifluoroacetate (0.905 g; prepared in a similar manner to that described in Example 2) and potassium carbonate (1.4 g) in acetonitrile (50 ml) was heated under reflux for 6 hours. After cooling, the solvent was removed in vacuo, water (60 ml) was added to the residue, and the product was extracted with dichloromethane (2×30 ml). The extracts were dried over magnesium sulphate and the solvent was removed in vacuo to give an oil. The oil was purified by flash chromatography on silica eluting with a 9:1 then 1:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvents removed in vacuo to give an oil. Ethereal maleic acid (20 ml) was added to yield a white solid. The solid was collected by filtration, washed with ether and the solvent removed in vacuo to yield 2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide 0.5 maleate (95 mg) m.p. 104-106° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].I[CH3:17]>CN(C=O)C>[Br:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:17]
Reactant: CI
Reactant: CC(C)c1ccc2[nH]ncc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c(cnn2C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A solution of 4-bromo-5-isopropylindazole (27) (488 mg, 2.04 mmol) in 5 ml of anhydrous DMF is added to a suspension of sodium hydride (122 mg, 60% in mineral oil, 3.06 mmol, 1.5 eq.) in 5 ml of DMF under nitrogen at 0° C. The resulting mixture is stirred at 0° C. for 30 minutes, then warmed to room temperature. After stirring at room temperature for an additional 2 hours, the reaction mixture is cooled to 0° C., and iodomethane (318 mg, 2.24 mmol, 1.1 eq.) is added dropwise, the mixture is stirred at 0° C. for 2 hours, then warmed to room temperature, and stirred overnight. The reaction mixture is poured into 30 ml of ice-water, extracted with ethyl acetate (30 ml×3), washed with water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated and the product is purified via flash chromatography to give 340 mg of 4-bromo-5-isopropyl-1-methylindazole 1H NMR (400 MHz, CDCl3) 7.95 (1H, s), 7.31 (2H, S), 4.05 (3H, S), 3.55 (1H, m), 1.27 (6H, d, J=6.8 Hz). MS (+VE) m/z 253 (M+). 165 mg of 4-bromo-5-isopropyl-2-methylindazole (28). 1H NMR (400 MHz, CDCl3) δ 7.82 (1H, s), 7.59 (1H, d, J=9.2 Hz), 7.21 (1H, d, J=8.8 Hz), 4.16 (3H, s), 3.50 (1H, m), 1.21 (6H, d, J=6.8 Hz). MS (+VE) m/z 253 (M+).
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(CCOCCOCCOCCI)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCOCCOCCOCCN=[N+]=[N-])OCC
Temperature: 50 °C

Procedure:
To a solution of diethyl 2-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)ethylphosphonate (1 eq) in DMF (0.5 M) was added sodium azide (3 eq). The reaction mixture was heated at 50° C. overnight. The mixture was then concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the product as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:22])[C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O)(=O)C>ClCCCl>[CH3:7][N:8]([CH3:22])[C:9]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH:12]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:14]1
Reactant: C1CCNCC1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperidine (400 μl, 4 mmole) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmole) were dissolved in dry 1,2-dichloroethane (10 ml). Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg, 2.8 mmole) were added to this mixture and the whole was stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and the mixture was adjusted to pH 11 with 5M NaOH. The alkaline phase was diluted with water (10 ml) and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. Dimethyl-(1-phenyl-4-piperidine-1-ylcyclohexyl)-amine was purified by chromatography with ethanol. The non-polar diastereoisomer (15 mg) still contained impurities, which also could not be removed by further purification attempts. The polar diastereoisomer was obtained as a colourless oil in a yield of 92 mg (16%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[OH:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 3 g (0.1 mole) of sodium hydride (80% in oil) and 50 ml of dimethylformamide (DMF), there are slowly added 15.4 g (0.1 mole) of 2,4-dihydroxybenzoic acid dissolved in 50 ml of DMF. The mixture is stirred at ambient temperature until the cessation of gaseous emission. There are then added 13.1 ml (0.1 mole) of benzyl bromide and the mixture is stirred at ambient temperature until solubilization of the reaction medium. The reaction mixture is poured into water, and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The residue is purified by chromatography on a silica column by eluting with dichloromethane. 19.7 g (81% yield) of the expected ester having a melting point of 94°-95° C. are recovered.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl.[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH2:29]>C(OCC)(=O)C>[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Temperature: 45 °C
Reaction time: 25 h

Procedure:
4′-Bromomethyl-2-cyanobiphenyl (15 g, 0.0551 moles) was added to a mixture of potassium carbonate (19.05 g), DM water (45 ml), ethyl acetate (60 ml) and L-valine methyl ester hydrochloride (11.09 g, 0.066 moles) at 20-30° C. The reaction mixture was heated to 40-50° C. and stirred for 25 h. After completion of the reaction, the ethyl acetate layer was separated at 20-30° C., concentrated under reduced pressure and dissolved in o-xylene (90 ml)
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([Mg]Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(Cl)Cl>CCOCC>[C:20]1([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:18][CH3:19])=[C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1c(Cc2ccccc2)ccc2ccccc12
Reactant: Cl[Mg]c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1c(Cc2ccccc2)cc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of the compound of Example 94 Part B (5.00 g, 15.3 mmole) and bis-(1,3-diphenylphosphino)-propane nickel(II) chloride (0.40 g, 0.74 mmole) in dry ether was stirred at 0°. Phenylmagnesium chloride (2.0M in ether; 9.5 mL, 19.0 mmole) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The mixture was then poured into 1.0N hydrochloric acid, and the crude product was isolated by extraction with methylene chloride. This was chromatographed to provide the title product (4.26 g, 86%) as a white solid. A small sample recrystallized from hexane melted at 103°-105°.
Reaction SMILES: [F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8][OH:9])[C:4]#[N:5].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8][O:9][S:28]([CH3:27])(=[O:30])=[O:29])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCO)N1C(=O)c2ccccc2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 2-fluoromethyl-2-phthalimido-5-hydroxypentanenitrile (42.8 g), dry pyridine (170 ml), and dry dichloromethane (350 ml) is stirred and cooled with ice/salt mixture. Freshly distilled methanesulfonylchloride (15.7 g) in dichloromethane (200 ml) is slowly added, and stirring is continued at room temperature overnight. The mixture is then poured onto ice/2N HCl, and the organic phase is extracted subsequently with 1N HCl, water, 10 % sodium bicarbonate, and water (3×). Drying (MgSO4), treatment with charcoal (room temperature), and evaporation gives 2-fluoromethyl-2-phthalimido-5-methanesulfonyloxypentanenitrile as a brown oil (42 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(O)C>ClCCl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(COC(=O)c2ccc(O)cc2)cc1

Procedure:
4-Hydroxybenzoic acid (1.38 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a. The title compound (2.06 g) was obtained after silica gel column chromatography (0, 1, 2, 3% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.40.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[N:7]([CH3:18])[C:8](=[O:13])[C:9]([F:10])([F:12])[F:11]
Reactant: O=C(Nc1cc(Cl)ccc1[N+](=O)[O-])C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CN(C(=O)C(F)(F)F)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
5-Chloro-2-nitro-N-trifluoroacetylaniline (38 g) from Example 8 was dissolved in acetone (300 ml), followed by addition of potassium carbonate (19.5 g). To the mixture was added dropwise dimethyl sulfate (13.4 ml) for subsequent stirring for 1.5 hours. After filtering off insoluble inorganic materials, the resulting material was washed with ethyl acetate. Removal of the solvent under reduced pressure, hexane was added to the residue under stirring, to separate the crystal by filtration. By washing the crystal further with ether-hexane mixture solution, the title compound was given (33 g; 83.5%).