Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.[Br:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21](Br)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Oc1cc(Br)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(O)cc(Br)c2)cn1
Temperature: 800 °C
Yield: 37 %

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (750 mg; 3.6 mmol; 1.0 eq.), 3,5-Dibromo-phenol (4.54 g; 18.0 mmol; 5.0 eq.), bis(triphenylphosphine)palladium(II) chloride (253 mg; 0.36 mmol; 0.1 eq.) and potassium carbonate (2.49 g; 18.02 mmol; 5 eq.) were suspended in DMF (80 mL) and water (1 mL). The reaction mixture was then heated at 800° C. for 16 h in a sealed tube. It was filtered through Celite and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (n-heptane:EtOAc, gradient from 95:5 to 10:90) afforded the title compound as a clear oil (337 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 10.01 (brs, 1H), 8.14 (s, 1H), 7.83 (d, J=0.7 Hz, 1H), 6.96 (d, J=1.7 Hz, 1H), 6.92 (dd, J=2.1, 1.5 Hz, 1H), 6.76 (t, J=2.0 Hz, 1H), 3.84 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[F:25][C:23]([F:24])([F:26])[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=2)=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
{2-[4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2200 mg, 1.135 mmol, 1 eq) was dissolved in dichloromethane (4 ml) and stirred at 0° C. for 5 min. TFA (3084 ml, 40.273 mmol, 7 eq) was added and stirring was continued at rt overnight. Reaction mixture was diluted with NaHCO3 (sat.) and extracted with DCM (3×). Organic layers were combined and evaporated to give 2-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethylamine as white solid (1.6 g, yield=99%, purity 99%). [M+H]+=283.26 1H NMR (DMSO-d6, 300 MHz): 2.83-2.91 (m, 2H), 3.03-3.13 (m, 2H), 7.13-7.19 (d, 2H), 7.20-7.24 (d, 1H), 7.30-7.36 (d, 2H), 7.86 (bs, 2H), 8.19-8.25 (m, 1H), 8.53 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9]Cl.[Na+].[I-:13]>CC#N>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][I:13]
Reactant: Nc1ccccc1C(=O)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ccccc1C(=O)CI
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
To a solution of 33.11 g (195.21 mM) of 2'-amino-2-chloroacetophenone in 680 ml of CH3CN is added 87.8 g (585.63 mM) of NaI, and the mixture is stirred at room temperature for 45 minutes and concentrated under reduced pressure. The residue is dissolved in ethyl acetate, and the organic layer is washed with aqueous Na2S2O3, and brine in order, dried and concentrated to give 46.1 g (Yield: 90.5%) of 2'-amino-2-iodoacetophenone as crystals.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8][C@@H:7](Br)[C@H:6]1[O:33][C:34](=[O:36])[CH3:35])(=[O:3])[CH3:2].[CH3:37][OH:38]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8][C@H:7]([O:38][CH3:37])[C@H:6]1[O:33][C:34](=[O:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@@H](Br)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Temperature: 70 °C
Yield: 78 %

Procedure:
Crude bromide from step B (8.4 g, 14.4 mmol) and ZnO (1.2 g, 14.4 mmol) were dissolved in MeOH (144 ml) and heated at 70° C. for 1 hour. The reaction was cooled to room temperature, filtered through celite with EtOAc, and concentrated under vacuum. The residue was recrystallized from MeOH in two batches to give acetic acid (2S,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-methoxy-tetrahydro-pyran-3-yl ester (5.98 g, 11.2 mmol, 78%) as the pure β-anomer.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[C:8]([Cl:30])[CH:7]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:23]2[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=2)=[CH:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:31])=[O:3])=[CH:7][C:8]=2[Cl:30])=[CH:21][CH:20]=1
Reactant: CCOC(=O)Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of {4-[3,3-bis-(4-bromo-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid ethyl ester (example 9) (1.0 g, 1.8 mmol) in THF (8 ml) and ethanol (5 ml) was added 1N NaOH (4.0 ml) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo. The residue was suspended in water and 817 mg (82%) of the title compound was isolated by filtration as the sodium salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccc(Cl)c2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A for Example 13i, and 3-chlorobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 585 (M+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[O:51][C:52]([F:55])([F:54])[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[O:51][C:52]([F:55])([F:54])[F:53])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3OC(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethoxy)benzene and isolated as light-yellow gum (7.3 mg, 39%). MS (m/e): 457.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].ON1C2C=CC=CC=2N=N1.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][NH:28][CH3:29].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][N:28]([CH3:29])[C:11]([C@H:8]1[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1)=[O:13]
Reactant: CNCCN(C)C
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N(C)CCN(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (8.84 g) obtained in Reference Example 1(2) is dissolved in chloroform (100 ml), and thereto are added 1-hydroxybenzotriazole (7.14 g), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (10.00 g) and N,N,N′-trimethylethylenediamine (5.33 g) under ice-cooling. The mixture is then stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform/methanol/28% ammonia water=200/10/1) to give methyl trans-4-{[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}cyclohexane-carboxylate (11.98 g). APCI-MS M/Z:271[M+H]+
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=1.Cl.[NH+]1C=CC=CC=1>Cl>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[CH:12][C:3]([OH:2])=[CH:4]3)=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc3ccc(OC)cc3c2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc(-c2ccc3ccc(O)cc3c2)cc1
Temperature: 190 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
2-Methoxy-7-(4-methoxy-phenyl)naphthalene (1.02 g, 3.86 mmol) was added to of pyridinium HCl (10 g) at 190° C. The solution was stirred for 3 hr at 190° C. and cooled to room temperature and stirred with 200 mL of 1 N HCl. The resulting suspension was filtered and dissolved ethyl acetate (500 mL). The combined organic layers were washed with water (200 mL), dried over magnesium sulfate, filtered, the solvent removed under vacuum, and the product purified by silica chromatography (40% ethyl acetate-hexanes to yield 0.36 g (39%) of a white solid: mp 210° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.58 Hz), 7.05 (1H, dd, J=2.42 Hz, J=8.77 Hz), 7.17 (1H, d, J=2.24 Hz), 7.52 (1H, dd, J=1.68 Hz, J=8.40 Hz), 7.61 (2H, d, J=8.58 Hz), 7.74 (1H, d, J=8.58 Hz), 7.79 (1H, d, J=8.58 Hz), 7.86 (1H, d, J=1.12 Hz), 9.60 (1H, bs), 9.72 (1H, bs); MS (ESI) m/z 235 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[OH-].[Na+]>O.CCO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:19])[O:18][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][C:8]2=[O:17]
Reactant: O=C(C=Cc1ccccc1)c1cc(Br)c(F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccccc2)Oc2cc(F)c(Br)cc21
Reaction time: 8 h
Yield: 53.5 %

Procedure:
1-(5-Bromo-4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (10.8 g, 33.75 mmol) was dissolved in H2O (252 mL) and EtOH (84 mL). Then NaOH (1.35 g, 33.75 mmol) was added. The mixture was stirred overnight and filtered. The cake was dissolved in EtOAc and washed with H2O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-7-fluoro-2-phenylchroman-4-one (5.8 g, 54%). 1H-NMR (CDCl3): 2.85 (m, 1H), 3.04 (m, 1H), 5.43 (m, 1H), 6.78 (m, 1H), 7.37 (m, 5H), 8.07 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=1
Reactant: O=Cc1cccn1-c1ncccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 1.5 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine in 20 ml of N,N-dimethylformamide, 1.3 g of N-bromosuccinimide was added. The mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.9 g of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:19](=[S:20])[N:18]([CH3:22])[CH3:17])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CN(C)C(=S)Cl
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C(=S)Oc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
8.13 g of 5-bromosalicylaldehyde was dissolved in 100 ml of acetone, followed by the addition of 6.7 g of anhydrous potassium carbonate. With stirring at room temperature, 5.0 g of N,N-dimethylthiocarbamoyl chloride was added to the above solution, and the stirring was continued for two hours. The resulting reaction solution was poured into ice water, and crystals thus precipitated were collected by filtration, and dried to obtain 9.2 g of 5-bromo-2-[(N,N-dimethylthiocarbamoyl)oxy]benzaldehyde.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:20]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:18][CH3:19])=[CH:17][CH:16]=3)=[CH:37][CH:38]=2)[CH2:29][CH2:30]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC[C@H](C)CCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(O)cc2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(OC(=O)c3ccc(OCCCCC[C@@H](C)CC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (S)-4-(6-methyloctyloxy)benzoyl chloride obtained was dissolved in 20 ml of toluene and then added dropwise to a solution of 0.26 g of 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol in 2 ml of pyridine. The reaction mixture was stirred at room temperature overnight, then poured into ice-water and extracted with diethyl ether. The extract was washed four times with 25 ml of 3 N hydrochloric acid each time, then washed with 25 ml of 2 N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Chromatography of the residual oil on silica gel with toluene gave 0.2 g of (S)-4-(6-methyloctyloxy)benzoic acid 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenyl ester. The product was recrystallized several times from ethanol until the phase transition temperatures were constant. M.p. (C-S) 58°, transition S-S*C 58.5° C., transition S*C -Ch 93° C., cl.p. (Ch-I) 140° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2ccco2)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl)amine 17 (99 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CH2Cl2 was added 2-furoyl chloride (95%, 56.0 mg, 1.2 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 20 (80 mg, 61%). LRMS 286 (M−100)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1.[C-:15]#[N:16].[K+].O>CS(C)=O>[CH3:8][C:7]1[C:3]([CH2:2][C:15]#[N:16])=[N:4][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1
Reactant: [C-]#N
Reactant: Cc1cn(-c2ccccc2)nc1CBr
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2ccccc2)nc1CC#N
Temperature: 60 °C
Yield: 113.2 %

Procedure:
A mixture of 3-(bromomethyl)-4-methyl-1-phenyl-1H-pyrazole (112 mg, 446 μmol) and potassium cyanide (33.3 mg, 491 μmol) in DMSO (2 mL) was heated to 60° C. for 2 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic phases were washed with water (3×25 mL) and brine 1×25 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 99.6 mg crude material. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow oil (58 mg, 294 μmol, 65.9%).
Reaction SMILES: OC1C([NH2:11])=CC=CC=1C(O)=O.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[NH2:11]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1cccc(C(=O)O)c1O
Product: NC(=O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 3-amino benzoic acid (300 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane (0.287 g. 41%). EI-MS m/z 351 (M+H)+
Reaction SMILES: [CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-])=O.[OH-].[K+]>>[CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([NH2:17])=[CH:21][CH:22]=2)[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCCCC1Cc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(CC2CCCCCC(Cc3ccccc3)C2=O)cc1

Procedure:
This example illustrates the preparation of benzylcyclooctanones wherein the aromatic ring is substituted with an amino group. 2-Benzylcyclooctanone is allowed to react with equimolar amounts of p-nitrobenzaldehyde in refluxing methanolic potassium hydroxide for 3 hours. The 2-benzyl-8-(p-nitrobenzylidene)cyclooctanone which forms is removed by filtration and subjected to hydrogenation at 50 p.s.i.g. in the presence of 10 percent palladium on carbon using a solvent system comprising equal portions of ethyl acetate and acetic acid. The 2-benzyl-8-(p-aminobenzyl)cyclooctanone which is obtained from the hydrogenation is purified by converting it to the hydrochloride salt by means of hydrogen chloride introduced into an ethereal solution of the crude product. The melting point of the crude 2-benzyl8-(p-aminobenzyl)cyclooctanone hydrochloride is 175°-195° C.
Reaction SMILES: [C:1]1([CH:7]([NH2:11])[CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C>ClCCl>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]#[CH:10])=[O:17]
Reactant: O=C=NCCCl
Reactant: C#CCC(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCC(NC(=O)NCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 187 mg of 1-phenylbut-3-yn-1-amine (Formula 17) in 5 mL of dichloromethane was added 0.16 mL of 2-chloroethyl isocyanate and 0.26 mL of triethylamine. The mixture was stirred at room temperature for 2 hours. Then, dichloromethane was removed. Column chromatography (3% methanol/dichloromethane) followed by recrystallization from chloroform to give 25 mg of 1-(2-chloroethyl)-3-(1-phenylbut-3-ynyl)urea (Formula 18) as a white solid and 200 mg of impure material which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 2.02-2.04 (m, 1H), 2.64-2.82 (m, 2H), 3.49-3.61 (m, 4H), 4.80 (br, 1H), 4.92-5.05 (m, 2H), 7.26-7.37 (m, 5H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][Si](C(C)C)(C(C)C)C(C)C)[CH3:8])([CH3:4])([CH3:3])[CH3:2].F.F.F.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[SH:18])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Sc1ccc(F)cc1CCN(C)C(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCc1cc(F)ccc1S)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 69.7 %

Procedure:
[2-(5-Fluoro-2-triisopropylsilanylsulfanyl-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (1.60 g, 3.62 mmol) is dissolved in dry THF (12 mL) and triethylamine trihydrofluoride (0.59 g, 3.66 mmol) is added. The resulting mixture is heated at 60° C. for 5 minutes, then cooled and concentrated in vacuo. The product is purified by eluting through a plug of silica with ethyl acetate-heptane (1:4) to give 0.72 g (72%) of the title compound as an oil.
Reaction SMILES: [H-].[Na+].C(NC([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)=O)(C)(C)C.[CH2:16]([O:20][C:21]1[C:25](S(C)(=O)=O)=[N:24][S:23][N:22]=1)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([O:20][C:21]1[C:25]([O:15][CH:12]2[CH2:13][CH2:14][NH:10][CH2:11]2)=[N:24][S:23][N:22]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CC(C)(C)NC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC1CCNC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of NaH (0.066 g, 0.0028 mol) in THF (25 mL) was treated with 1-t-butylcarbamoyl-3-hydroxypyrrolidine (Ref. Syn. Commun. 15, 587) (0.5 g, 0.0027 mol) and the reaction warmed to 50° C. for 30 min. After cooling to ambient temperature, 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (0.55 g, 0.0027 mol) in THF (5 mL) was added and the reaction heated to reflux for 2.5 h. The solvent was evaporated, the residue treated with ice-water, and the mixture extracted with ether. The extracts were washed with brine, dried, and the solvent evaporated. The residue was dissolved in ether (50 mL) and treated with a slow stream of HCl for 5 min. After stirring overnight, the reaction was extracted with cold water. The aqueous was washed with ether, made basic, and extracted with EtOAc. The extracts were washed with brine, dried, and the solvent evaporated to give a clear oil. The HCl salt (0.42 g) crystallized from EtOAc, m.p. 127°-128° C. (Compound 27).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.Cl.[NH2:16][OH:17]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: O=C1CCN(Cc2ccncc2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(Cc2ccncc2)CC1

Procedure:
1-(4-Pyridinylmethyl)-4-piperidone oxime is prepared from 1-(4-pyridinylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.