Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1.O>O1CCCC1>[CH2:1]([O:5][C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-butyn-1-ol (530 mg, 7.5 mmol) and sodiumhydride (180 mg, 7.5 mmol) dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]=[O:12])(=[O:5])=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=2)=[CH:17][CH:16]=1>>[CH3:1][N:2]([CH3:13])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=2)=[CH:17][CH:16]=1)[OH:12])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1C=O
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Product: CN(C)S(=O)(=O)n1ccnc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Yield: 40.3 %

Procedure:
Similar to Production Example 164, 4.54 g of N,N-dimethyl-2-formylimidazole-1-sulfonamide was treated with 7.0 g of 2-(4-bromophenyl)-4,4-dimethyl-2-oxazoline to thereby give 3.41 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[S:32][C:33]([Cl:38])=[C:34]([CH2:36]Br)[CH:35]=2)[O:11][C@@H:10]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:48][C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[S:32][C:33]([Cl:38])=[C:34]([CH2:36][C:52]3[CH:53]=[CH:54][C:49]([CH3:48])=[CH:50][CH:51]=3)[CH:35]=2)[O:11][C@@H:10]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1sc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)sc2Cl)cc1
Temperature: 120 °C
Yield: 70.7 %

Procedure:
To a solution of bromide 38 (850 mg, 1.16 mmol) in toluene/EtOH (18 mL/2 mL) were added 4-methylphenylboronic acid (200 mg, 1.39 mmol), tetrakis(triphenylphosphin)palladium (70 mg, 0.058 mmol) and Cs2CO3 (770 mg, 2.32 mmol) at room temperature. The mixture was stirred at 120° C. The mixture was cooled to room temperature and filtered off thorough silica gel to remove insoluble materials. The filtrate was ure was extracted with EtOAc/H2O (100 mL/150 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 39 (611 mg, 71%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH:16][C:17](=O)[CH2:18][NH:19][CH2:20][CH2:21][C:22]2[N:23](CCO)[CH2:24][N:25]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(P(CCCC)CCCC)CCC.[CH3:63][C:64]([O:67]C(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH3:1][S:2]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[N:16]2[CH2:17][CH2:18][N:19]([CH2:20][CH2:21][C:22]3[N:23]=[CH:24][N:25]([C:27]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:26]=3)[CH2:63][C:64]2=[O:67])=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CNCCC3=CN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CN3CCO)c2c1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc2cccc(N3CCN(CCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)CC3=O)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.2 %

Procedure:
To a solution of the product from Step F (60.5 mmol) in 500 mL of tetrahydrofuran was added tributylphosphine (25 mL, 100 mmol). After cooling to 0° C., di-tert-butylazodicarboxylate (23 g, 100 mmol) was added, and the reaction was allowed to come to room temperature for 2 hours. The solution was concentrated in vacuo, partitioned between EtOAc and water, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product (45.0 g). The crude product was purified by silica gel chromatography (5% MeOH/CHCl3) to provide the pure titled product along with impure fractions.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]1[O:20][C@H:19]1[CH2:21][OH:22]>CC(C)=O>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][C@@H:19]([OH:20])[CH2:21][OH:22])=[CH:7][CH:6]=1
Reactant: OC[C@H]1CO1
Reactant: OCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCc1ccc(OC[C@@H](O)CO)cc1
Temperature: 25 °C

Procedure:
To 3-(4-hydroxyphenyl)-1-propanol (10 g, 66 mmol) and potassium carbonate (13.5 g, 100 mmol) in acetone (200 ml) is added (S)-glycidol (6.5 ml, 100 mmol). The mixture is heated at reflux for 18 hours. After cooling to room temperature the solvent is removed in vacuo and the residue partitioned between EtOAc and water. The aqueous layer is further extracted twice with EtOAc and the combined organic portions are washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified by flash column chromatography on silica eluting with 1:1 EtOAc/iso-hexane to afford (S)-3-[4-(3-Hydroxy-propyl)-phenoxy]-propane-1,2-diol as a white solid; 1H NMR (CDCl3): 1.20 (1H, br), 1.85 (2H, pent, J=6.8 Hz), 1.98 (1H, br), 2.58 (1H, br), 2.65 (2H, tr, J=6.9 Hz), 3.56 (2H, tr, J=6.8 Hz), 3.72 (1H, m), 3.83 (1H, m), 4.00 (2H, dd, J=2.1 Hz, J=6.5 Hz), 4.09 (1H, br), 6.82 (2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz).
Reaction SMILES: [CH:1]1([CH:7]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)[C:8]2[CH:12]=[C:11]([CH:13]=[O:14])[S:10][C:9]=2[CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]([Mg]Br)([CH3:30])[CH3:29].O1CCCC1.[Cl-].[NH4+].[OH-].[Na+]>O1CCCC1.C(O)C>[CH:1]1([CH:7]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[C:8]2[CH:12]=[C:11]([CH:13]([OH:14])[CH:28]([CH3:30])[CH3:29])[S:10][C:9]=2[CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C=O)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Reactant: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1sc(C(O)C(C)C)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of methyl 4-{[cyclohexyl(2-ethyl-5-formylthiophen-3-yl)methyl]amino}benzoate (540 mg) synthesized in Example 287 (6) in tetrahydrofuran (10 mL) was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (3.50 mL) at −45° C., and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred with heated under reflux for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (350 mg, 60%) as a pale-yellow solid. The obtained resultant product was a mixture of two diastereomers (about 2:3).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[O:12]>>[NH2:1][CH:2]([CH:11]([OH:12])[C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: NCC(=O)O
Reactant: O=Cc1ccco1
Product: NC(C(=O)O)C(O)c1ccco1

Procedure:
The substrate solution was prepared by dissolving glycine (14.0 mg, 0.186 mmol) and furaldehyde (15.5 μL, 0.187 mmol) in buffer (10.0 mL). When 360 μL of this was added to the enzyme solution (0.2 mg SHMT in 40 μL), the concentration of each substrate was 17 mM.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1ccc(OCCN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
Methyl 4-(2-aminoethoxy)benzoate (5.86 g) and 4.08 g of p-methylbenzoic acid were dissolved in 100 ml of N,N-dimethylformamide and then 6.19 g of N,N'-dicyclohexylcarbodiimide was gradually added thereto with stirring at room temperature.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:21](=[O:23])[NH2:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].[Na+].[Cl-]>CN(C=O)C.CCOC(C)=O.O>[CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:20][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:21](=[O:23])[NH2:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2CC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 9-[(cyclopentyl)methyl]-4-hydroxy-5-carbamoyl carbazole (45 mg, 0.146 mmol) and Cs2CO3 (120 mg; 0.365 mmol) in 2 mL of DMF was treated with methyl bromoacetate (0.018 mL; 0.19 mmol). The reaction was stirred for 2 hours at ambient temperature, then it was diluted with EtOAc and H2O (10 mL each). The aqueous layer was saturated with solid NaCl extracted with EtOAc (2×10 mL). The combined organic layers were washed with H2O (2×25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (elution with a gradient of 0% to 100% EtOAc/hexanes) followed by trituration with Et2O/EtOAc afforded 26 mg (0.0683 mmol; 47%) of title compound as a tan solid. MS (ES) m/e 381 (M+1), 364 (M+H—NH3), 439 (M+AcO−).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:11]2[CH:10]=[C:9]([C:12](=O)[CH:13]=[CH:14][C:15]3[CH:29]=[CH:28][C:18]([C:19]([O:21]CC[Si](C)(C)C)=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:4][CH2:3]1.Cl.[NH2:40][OH:41].N1C=CC=CC=1.[F-]>CCO.CS(C)=O.O>[CH3:1][C:2]1([CH3:38])[C:11]2[CH:10]=[C:9]([C:12](=[N:40][OH:41])[CH:13]=[CH:14][C:15]3[CH:29]=[CH:28][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:4][CH2:3]1
Reactant: NO
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)OCC[Si](C)(C)C)cc4)ccc32)cc1
Agent: Cl
Agent: [F-]
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(C=Cc4ccc(C(=O)O)cc4)=NO)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 2-trimethylsilanyl-ethyl 4-[3-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-naphthalen-2-yl)-3-oxo-propenyl]-benzoate (Compound 6, 240 mg, 0.46 mmol) in 5 mL of EtOH was added hydroxylamine hydrochloride (64 mg, 0.92 mmol) and pyridine (77 mg, 0.97 mmol). The reaction mixture was then heated at reflux for 6 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was taken up in water. The aqueous layer was adjusted to pH=4-5 with 1 N HCl and extracted with ethyl acetate (3×10 mL). The organic layers were combined and washed with water (2×10 mL) and brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure to obtain a yellow crude oil. This crude product was then dissolved in 2 mL of dimethylsulfoxide (DMSO) and tetraethylammomium fluoride (TEAF) (137 g, 0.92 mmol) was added. After stirring at room temperature for 0.5 h, the mixture was diluted with water (10 mL), extracted with ethyl acetate (3×5 mL), washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by recrystallization with acetonitrile yielded Substance 7c, (a mixture of E/Z isomers, 84 mg, 42% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: COc1cccc(Cl)c1B(O)O
Reactant: Cc1ccccc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(Cl)c1-c1ccccc1C
Temperature: 82 °C
Yield: 62.5 %

Procedure:
To a solution of 2-bromotoluene (13.8 g, 80.6 mmol) and sodium carbonate (9.0 g, 84.9 mmol) in DME-water (5:1, 250 mL) was added 2-chloro-6-methoxybenzene boronic acid (5.0 g, 26.8 mmol) at 82° C., followed by tetrakis(triphenylphosphine)-palladium (0) (1.5 g, 1.4 mmol). The reaction mixture was heated at 82° C. overnight and cooled to room temperature. The resulting mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4) and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 5% ethyl acetate in hexanes provided 3.9 g (62%) of 2-chloro-6-methoxy-2′-methylbiphenyl as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])OC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C1(C)C(C)=CC=CC=1>[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:14])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
9.81 g (50 mmoles) of methyl N-(4-nitrophenyl)carbamate, 6.9 g (50 mmoles) of 4-nitroaniline, 140 ml of xylene and 11.8 g (about 50 mmoles) of Genamin CS 302 D (a mixture of N,N-dimethyl-C10-18 alkylamines sold by the firm Hoechst AG) are introduced into a flask equipped with a reflux condenser, and the mixture is boiled. The yellow crystals of the end-product appear already in the 3rd minute of boiling, and the amount of the crystalline precipitate rapidly increases. After 0.5 hours of boiling the thick, orange crystal suspension is filtered in vacuo when hot, the filter cake is washed twich with 20 ml of hot xylene, each, and then with acetone, finally the product is dried in vacuo. 12.78 g (85.2%) of N,N'-bis(4-nitrophenyl)-urea are obtained. The product is uniform when examined by layer chromatography utilizing a 3:1 mixture of n-hexane and acetone as solvent, and the chromatographic appearance of the product is identical with that of the authentic sample.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=3)=[N:7][C:6]=12.[C:26]([C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1)#[CH:27]>>[CH3:25][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:5]3[N:4]=[CH:3][C:2]([C:27]#[C:26][C:28]4[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=4)=[C:6]3[N:7]=2)[CH:20]=[CH:19][C:18]=1[C:21]([F:24])([F:23])[F:22]
Reactant: C#Cc1ccc(N)nc1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(N)nc4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 3-iodo-5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.32) (236 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (59 mg, 0.5 mmol) according to general procedure II. Obtained as a red solid (165 mg, 71%). MS (EI) 461.1 [(M)+]; mp 201° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9]([N:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:12][CH3:13])[CH3:10].[OH-].[Na+]>CO>[CH2:9]([N:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4](=[CH:18][C:17]3[CH:20]=[CH:21][C:14]([N:11]([CH2:9][CH3:10])[CH2:12][CH3:13])=[CH:15][CH:16]=3)[C:5]2=[O:8])=[CH:16][CH:15]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CN1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)c1ccc(C=C2CN(C)CC(=Cc3ccc(N(CC)CC)cc3)C2=O)cc1

Procedure:
Two grams (17.7 mmoles) of N-methyl-4-piperidone and 6.26 g (35.4 mmoles) of p-N,N-diethylaminobenzaldehyde were introduced into a 100 ml eggplant type flask, to which was added a solution of 0.5 g of sodium hydroxide in 50 ml methanol. The contents of the flask equipped with a reflux condenser were heated under reflux for about one hour with stirring by means of a magnetic stirrer. After allowing the reaction mixture to cool, the deposited organge-colored crystalline product was collected by filtration and thoroughly washed with methanol. Then, it was purified by recrystallization from benzene/chloroform.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.C([O:14][C:15](=O)[CH:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:17])C.OS(O)(=O)=O>O>[CH2:19]([O:18][CH:16]([CH3:17])[CH2:15][OH:14])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCOC(C)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCOC(C)CO
Reaction time: 3 h

Procedure:
2.0 g of LiAlH4 was added to 62 ml of ether and the mixture was stirred for 3 hours. To the mixture was added dropwise 14.6 g of (-)-ethyl-2-heptyloxypropionate in the same manner as in Example 2, and the mixture was stirred for 15 minutes. Then, a small amount of water and then 50 ml of 10% H2SO4 aqueous solution were added thereto. The ether layer was separated, dried with MgSO4 and filtrated. Ether was distilled off to obtain the objective product at an yield of 9.0 g. The optical rotation [α]D25° was +17.4°
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([CH2:21][CH:22]=[CH2:23])=[C:9]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[C:7]1[CH:8]=[C:9]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]([CH2:21][CH:22]2[CH2:23][O:41]2)=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(OCc2ccccc2)cc(C(=O)OC(C)(C)C)cc1OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2CO2)c(OCc2ccccc2)c1
Yield: 57.9 %

Procedure:
To a solution of 4-allyl-3,5-bis-benzyloxy-benzoic acid tert-butyl ester (200d) (125 g, 0.29 mol) in CH2Cl2 was added m-CPBA (100 g, 0.58 mol) in several portions. The mixture was refluxed overnight. The solid was filtered and washed with CH2Cl2. The combined filtrates were washed with saturated aqueous Na2S2O4 (250 mL) and brine (250 mL). The organic layer was dried over Na2SO4 and concentrated to give a yellow oil. The crude oil was purified by flash column chromatography (EtOAc/petroleum ether=1/20) to give the title compound (75 g, 57.8%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 12H), 5.09 (s, 4H), 3.53 (dd, 1H), 3.17 (m, 1H), 2.80 (dd, H), 2.63 (t, 1H), 2.51 (dd, 1H), 1.60 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].O.[OH-].[Li+:30]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O-:9])=[O:8].[Li+:30]
Reactant: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 123.1 %

Procedure:
To a mixture of methyl 5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinate (D91) (220 mg, 0.548 mmol) in a mixture 1,4-dioxane/water (2 ml/1 ml), lithium hydroxide monohydrate (34.55 mg, 0.823 mmol) was added and the resulting mixture was stirred at 150° C. under microwave irradiation for 10 min (2 cycles of 5 min each). Solvents were evaporated in vacuo to afford the title compound (D136) 265 mg
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C@@H:18]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>>[C@@H:18]1([NH:27][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: CC1(C)COC2(CCC(O)(CCN[C@H]3CCc4ccccc43)CC2)OC1
Yield: 26 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-indan-1-ylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 26% of theory; LC (method 6): tR=1.11 min; Mass spectrum (ESI+): m/z=360 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16][NH2:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CCOC(C)=O.[Cu]I.CS(C)=O>[C:18]1([CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:15][CH2:16][NH:17][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Ic1cccnc1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: c1ccc(C(CCNc2cccnc2)c2ccccc2)cc1
Temperature: 75 °C

Procedure:
To a mixture of 3-iodopyridine (1.12 g, 5.46 mmol) and 3,3-diphenylpropan-1-amine (1.72 g, 8.14 mmol) was added potassium carbonate (1.49 g, 10.8 mmol), copper(I) iodide (0.126 g, 0.662 mmol), (S)-pyrrolidine-2-carboxylic acid (0.154 g, 1.34 mmol), and DMSO (3.5 mL). The reaction mixture was heated to 75° C. for 18 h and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 30% to 80% EtOAc in hexanes) gave N-(3,3-diphenylpropyl)pyridin-3-amine.