Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C.[Mg].C(Br)C.C1(C#C[Mg]Br)C=CC=CC=1.[C:27]1([C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[C:27]1([C:33]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: Br[Mg]C#Cc1ccccc1
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: CCOCC
Solvent: CCBr
Product: CCOC(=O)C(O)(C#Cc1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of phenylacetylene (11.2 g., 0.1 mole) in 25 ml. of anhydrous ether was added over a 45 minute period to a suspension of ethylmagnesium bromide (0.1 mole) prepared from magnesium (2.4 g., 0.1 g. atom) and ethyl bromide (10.9 g., 0.1 mole) in 100 ml. of ether. The mixture was stirred overnight. The resultant phenylethynylmagnesium bromide suspension was subsequently added dropwise through a stop-cock at the base of the flask to a solution of ethyl phenylglyoxylate (17.8 g., 0.1 mole) in 100 ml. of dry ether at 0°-5° over a two hour period. The cooling bath was removed and the mixture stirred for five hours. The reaction mixture was kept overnight, then poured on a slurry of ice and concentrated hydrochloric acid and extracted with ether. The ether extracts were dried and the solvent distilled in vacuo. The resultant oil was distilled to give 14.5 g. (52%) of product, b.p. 170°-82° (0.25 mm.). An analytical sample distilled at 156°-58° (0.08 mm.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14](=[O:16])[CH3:15])[CH2:7]2)([O-])=O.[C:17](OC(=O)C)(=[O:19])[CH3:18].[H][H]>O1CCCC1.[Ni]>[C:17]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14](=[O:16])[CH3:15])[CH2:7]2)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Reactant: CC(=O)NC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)CC(NC(C)=O)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
The mixture of N-(5-nitro-indan-2-yl)-acetamide (20.5 g, 93 mmol) in tetrahydrofuran (200 mL) was combined with acetic anhydride (10 mL) and Raney nickel (5 g) and stirred under an atmosphere of hydrogen gas (in a balloon) at room temperature for 24 h. Additional Raney nickel was added and the balloon recharged with hydrogen gas and stirred an additional 24 h. After removing the Raney nickel by filtration through a celite pad and washing with methanol several times, the filtrate was evaporated to a syrup. The residue was triturated with ether/water and the resulting white solid collected by filtration (9.2 g, 52% yield overall from 2-aminoindan, prepared in Example 20).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][C:15]([OH:17])=[O:16]>O.CO.[Ni]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: NCC(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Solvent: O
Solvent: CO
Product: O=C(O)CNCC(O)C(O)C(O)C(O)CO
Yield: 73.2 %

Procedure:
A solution of 39.6 gm of D-glucose in 200 ml of water and 150 ml of methanol was added to a solution of 15 gm (0.2 mol) of glycine in 200 ml of water and 100 ml of methanol in an autoclave. Then, after the addition of 18.0 gm of Raney nickel, a hydrogenation was carried out in the autoclave with stirring at a pressure of 180 to 200 kg/cm2. The autoclave was heated in a progressive manner first for 2 hours to 50° C., subsequently for 2 hours to 70° C. and finally for 2 hours to 90° C. After separation of the catalyst by filtration and evaporation of the reaction solution in vacuum, the highly viscous residue obtained was allowed to stand for a few days. After crystallization had commenced the same was completed by crystallization from 100 ml of boiling methanol. 35 gm (73% of theory) of N-(2,3,4,5,6-pentahydroxy-hexyl)-glycine having a melting point of 172° to 177° C. (decomposition) were obtained. An analytically pure sample recrystallized from water/ 2-propanol melted at 175° to 180° C. with decomposition.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[BH4-].[Na+].[Cl-].[Na+]>C(O)C.C(Cl)Cl.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(-c2ccco2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: OCc1cccc(-c2ccco2)c1
Yield: 101.3 %

Procedure:
A solution of 3.0 g (0.017 mol) of 3-(2-furanyl)benzaldehyde and 0.66 g (0.017 mol) of sodium borohydride in 30 mL of ethanol was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give a residual oil. The oil was dissolved in a mixture of methylene chloride and water, and was saturated with solid sodium chloride, then extracted with three portions of 100 mL each of methylene chloride. The combined extracts were dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 3.0 g of 3-(2-furanyl)-phenylmethanol.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[BH4-].[Na+]>>[O:32]1[CH2:33][CH2:34][N:29]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:28][CH:27]=2)[CH2:30][CH2:31]1.[OH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([CH:13]2[NH:12][C:7]3[C:6]4[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:14]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: C1COCCN1
Agent: [BH4-]
Agent: [Na+]
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCOCC3)cc1)C2c1ccccc1
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CO)cc1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %
Yield: 12 %

Procedure:
4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (59 mg, 0.16 mmol) and morpholine (42 mg) were added and the mixture was stirred at room temperature for 2 h. Then 20 mg of sodium borohydride was added and stirred for another 2 h. The resulting mixture was evaporated under reduced pressure and purified by prep-HPLC to give 8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (8 mg, yield 11%) and 8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (7 mg, yield 12%). 8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one: 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.31 (s, 4H), 3.36 (s, 4H), 3.61-3.63 (m, 4H), 4.15-4.17 (d, J=10 Hz, 1H), 4.58-4.61 (d, J=10 Hz, 1H), 4.79 (s, 1H), 6.94-7.19 (m, 10H), 7.51-7.55 (m, 1H), 7.68-7.70 (m, 1H), 7.63 (s, 1H). LC-MS (ESI) m/z: 439 (M+1)+. 8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one: 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.21-4.25 (m, 1H), 4.63-4.70 (m, 1H), 4.86 (s, 1 H), 6.97-7.06 (m, 3H), 7.11-7.26 (m, 7 H), 7.58-7.62 (m, 1H), 7.75-7.77 (m, 1H). LC-MS (ESI) m/z: 370 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:25]3[C:33]4[CH2:32][CH2:31][C:30]([CH3:35])([CH3:34])[CH2:29][C:28]=4[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=3)[N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)=[O:7])[CH3:4].N1C=CN=C1.[Si:49](Cl)([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.O>CN(C)C=O.C(OCC)(=O)C>[Si:49]([O:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:25]3[C:33]4[CH2:32][CH2:31][C:30]([CH3:35])([CH3:34])[CH2:29][C:28]=4[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[N:26]=3)[N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)=[O:7])[CH3:4])([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(CO)NC(=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid (2-hydroxy-1-methylethyl)amide (265 mg, 0.42 mmol) in N,N-dimethylformamide (2.7 ml) were added imidazole (35 mg, 0.51 mmol) and tert-butyldiphenylsilyl chloride (132 μl, 0.51 mmol) under ice-cooling, and the mixture was stirred at room temperature for 8 hr. Then, to the reaction mixture were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (341 mg, yield 93%).
Reaction SMILES: C=[CH:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2(C)[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2(C)[C:11](=CC(=O)[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:31]([O:34]C(=O)C)(=[O:33])[CH3:32]>C(OCC)(=O)C>[C:31]([O:34][C:19]1[CH:20]=[CH:21][C:7]2[C@@H:6]3[C:11]([C@H:16]4[C@@:3]([CH2:4][CH2:5]3)([CH3:24])[CH:2]=[CH:14][CH2:15]4)=[CH:10][CH2:9][C:8]=2[CH:18]=1)(=[O:33])[CH3:32]
Reactant: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)CC=C1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Yield: 35.1 %

Procedure:
A solution of estra- 1,3,5(10),7,16-pentaen-3-ol (5, 192.1 mg, 0.7612 mmol) in anh. pyridine (2.6 ml, 32 mmol) and acetic anhydride (0.36 ml, 3.8 mmol) was stirred 6 h, after which 30 ml of ethyl acetate were added. The mixture was washed with three 10 ml portions of 1 N hydrochloric acid+10 ml of saturated sodium bicarbonate+10 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Example 15. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC (5% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) and recrystallization from aqueous ethanol gave fine white needles (78.6 mg, 0.267 mmol, 35%), m.p. 77-80° C. TLC (4% ethyl acetate/hexanes on silica gel) showed 2 spots at Rf 0.21 and 0.24.
Reaction SMILES: [CH2:1]=[O:2].[C:3]12[CH2:9][C:6]([CH2:7][CH2:8]1)=[CH:5]C=2.[CH:10]([OH:12])=[O:11]>OS(O)(=O)=O>[CH:10]([OH:12])=[O:11].[CH:10]([OH:12])=[O:11].[CH:6]12[CH2:7][CH:8]3[CH:1]([OH:2])[CH:5]1[CH:9]2[CH2:3]3
Reactant: C=O
Reactant: C1=C2CCC(=C1)C2
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: OC1C2CC3C(C2)C13
Yield: 84 %

Procedure:
To a stirred solution of 39.9 g paraformaldehyde in formic acid (800 ml) and conc. H2SO4 (15 ml) under nitrogen and at 20°C was added dropwise 132 g norbornadiene while keeping the temperature between 20°-25°C. After 1.5 hr the reaction was quenched by adding to 800 ml of ice-water. Extraction with ether (3 × 750 ml), washing the organic layer with water (1 × 250 ml), brine (3 × 250 ml) and drying (Na2SO4) afforded the crude 3-hydroymethyl tricyclo [2.2.1.02,6 ]heptan-5-ol bisformate (1') as an oil. Distillation, after a forerum of bp. 40°C/15mm, gave 235 g pure tricyclenebisformate, bp. 104°C/0.3 mm (84% yield).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[C:9]([O:13][C:14](=[O:21])[NH:15][C:16]1([CH:19]=[CH2:20])[CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C1COCC1.[OH2:27]>[Os](=O)(=O)(=O)=O>[OH:27][CH:19]([C:16]1([NH:15][C:14](=[O:21])[O:13][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:17][CH2:18]1)[CH2:20][OH:5]
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC1(NC(=O)OC(C)(C)C)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(O)CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A catalytic amount of osmium tetroxide (<1 mg) and 4-methylmorpholine N-oxide (70 mg, 0.6 mmol) were added to a solution of tert-butyl(1-ethenylcyclopropyl)carbamate (0.10 g, 0.55 mmol) in THF/water (5 mL/5 mL). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (methanol/dichloromethane) to give tert-butyl [1-(1,2-dihydroxyethyl)cyclopropyl]carbamate. 1H NMR (400 MHz, CD3OD): δ 3.63-3.60 (m, 1H), 3.52-3.48 (m, 1H), 3.21-3.18 (m, 1H), 1.43 (s, 9H), 0.91-0.89 (m, 1H), 0.80-0.75 (m, 2H), 0.68-0.67 (m, 1H).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:28])[CH:13]([N:15]2[CH2:20][CH2:19][C:18]([OH:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH3:14])=[CH:8][CH:7]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:28])[CH:13]([N:15]2[CH2:16][CH2:17][C:18]([OH:27])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CC(C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)N1CCC(O)(c2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C(=O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 112.3 %

Procedure:
1-(4-(Triisopropylsilyloxy)phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanone (International Application Publication Number: WO 90/14088, Example 36 at page 41; 22.0 g, 45.7 mmol) was dissolved in dry tetrahydrofuran (500 mL). Tetrabutylammonium fluoride (55 ml, 55 mmol, 1N in tetrahydrofuran) was added dropwise to the stirred solution over 3 minutes. After stirring for 1 hour, the reaction mixture was concentrated and the concentrate flash chromatographed on silica gel (3×6 inches). The column was gradiently eluted with ethyl acetate/hexane, then sequentially with 100% ethyl acetate, 1:9 methanol:ethyl acetate and finally with 1:5 methanol:ethyl acetate. Product-containing fractions were stripped to yield 16.7 g (100%) of title product as a light yellow solid which was triturated with hexane; m.p. 95-97 C; 1H-NMR (CDCl3) delta (ppm) 8.08 (d, J=8.5 Hz, 2H), 7.48 (d, J=8 Hz, 2H), 7.34 (t, J=8 Hz, 2H), 7.28-7.25 (m, 1H partially obscured by CHCl3 from NMR solvent), 6.89 (d, J=8.5 Hz, 2H), 4.15 (q, J=7 Hz, 1H), 3.0-2.65 (m, 4H), 2.25-2.10 (m, 2H), 1.85-1.77 (m, 2H), 1.35 (d, J=7 Hz, 3H).
Reaction SMILES: [O:1]=O.[C:3]1([C:9]([C:11]2[CH:12]=[C:13]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.[Co+2].C(O)(=O)C>[C:9]([C:11]1[CH:12]=[C:13]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=O
Reactant: C=C(c1ccccc1)c1cccc(C(C)C(=O)O)c1
Agent: [Co+2]
Agent: O=C([O-])c1ccc2ccccc2c1
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
To a 300 ml reaction vessel with a stirrer were fed 15 g of α-(3-(1-phenylethenyl)phenyl)propionic acid obtained in Example 2, 0.03 g of cobalt naphthenate and 100 ml of acetic acid as a solvent and 150 ml/min of pure oxygen was fed into the vessel for 16 hours at a reaction temperature of 120° C. After the reaction, the solvent was removed by reduced-pressure distillation to obtain a solid substance. The solid substance was washed five times with 500 ml of water and it was dissolved in 500 ml of ether and washed three times again with water. After that, the ether was removed by reduced-pressure distillation and the product was finally recrystallized with benzene/petroleum ether mixture to obtain 9.8 g of α-(3-benzoylphenyl)propionic acid (ketoprofen). The properties such as melting point and the spectrum of the final product were the same as those of an authentic sample.
Reaction SMILES: FC(F)(F)C(O)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:13]>N1C(C)=CC=CC=1C>[CH2:17]([O:16][C:14]([C:12]1[NH:13][N:10]=[N:9][N:8]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nnn[nH]1
Temperature: 0 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
Trifluoroacetic acid (24.47 g, 0.21M) was added dropwise over 0.5 hr under nitrogen to a stirred suspension of sodium azide (12.59 g, 0.19M) in 2,6lutidine (100 ml) at 8° to 12°. After stirring for 7 minutes ethyl cyanoformate (20.4 g, 0.20M) was added in one portion. The mixture was heated and stirred at 75° for 6 hours and then, after cooling, stirred at 20° for 16 hr. After cooling to 10° the mixture was added to ice (250 g) and 11 molar hydrochloric add (100 ml) keeping the temperature below 20°. The product was extracted into ethyl acetate (1×250, 1×200, 2×100 ml) and the combined extracts dried over magnesium sulphate. After evaporation of the solvent under reduced pressure the oily product (38.22 g) was taken up in ether (50 ml) and hexane (25 ml) added. Storage at 4° for 2-3 days produced crystalline ethyl-1H-tetrazole-5-carboxylate that was filtered off, washed with chilled ether, and air dried, 14.12 g (52.6% yield), m.p. 88°-93°.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.[C-:27]#[N:28].[K+]>O>[NH:16]([C:2]1([C:27]#[N:28])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 102 parts of 4-oxo-1-(2-phenyl-ethyl)-piperidine, 47 parts of aniline and 350 parts of acetic acid is added dropwise a solution of 36 parts of potassium cyanide in 100 parts of water, at a temperature between 35°-45° C (exothermic reaction). After the addition is complete, the cooling-bath is removed and the whole is stirred for 20 hours at room temperature. The reaction mixture is poured into 650 parts of ammonium hydroxide and 500 parts of crushed ice are added. The mixture is extracted with chloroform. The organic extract is dried over potassium carbonate, filtered and evaporated. The residue (solid) is triturated in diisopropylether. After keeping at room temperature, 4-anilino-4-cyano-1-(2-phenylethyl)-piperidine is obtained; mp. 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:17])[C@@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[NH2:16])=[CH:4][CH:3]=1.[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:17])[C@@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[NH:16][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CN(CCc1ccc(Cl)cc1)[C@@H]1CCC[C@H]1N
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN(CCc1ccc(Cl)cc1)[C@@H]1CCC[C@H]1NC(=O)c1ccc(S(C)(=O)=O)cc1
Product: Cl

Procedure:
Using General Procedure D, as described in Example 2, Step A, the title compound was prepared from (±)-trans-N-[2-(4-chlorophenyl)ethyl]-N-methylcyclopentane-1,2-diamine and 4-methylsulfonylbenzoic acid MS m/z 435 (M+1)+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([Si:14]([CH3:54])([CH3:53])[O:15][CH:16]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]2[N:21]=[C:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:19]([CH:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)O)=[C:18]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[C:47]([F:52])[CH:46]=3)[C:17]1=2)([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[Si:14]([O:15][CH:16]1[CH2:25][C:24]([CH3:26])([CH3:27])[CH2:23][C:22]2[N:21]=[C:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:19]([CH:33]([F:7])[C:35]3[CH:36]=[CH:37][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:39][CH:40]=3)=[C:18]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[C:47]([F:52])[CH:46]=3)[C:17]1=2)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:54])[CH3:53]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
At −5° C., 0.06 ml of diethylaminosulphur trifluoride, dissolved in 10.15 ml of toluene, was added dropwise to 200 mg (0.3 mmol) of [5-(tertbutyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol dissolved in 2 ml of toluene. After 60 minutes, the reaction was quenched with saturated aqueous sodium bicarbonate solution, toluene was added and the organic phase was washed once more with saturated aqueous sodium bicarbonate solution and dried. The solvent was distilled off under reduced pressure and the residue was then purified over a silica gel column This gave a total of 190 mg of a colourless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:6])[C:3]([NH2:5])=[O:4].[BH3-]C#N.[Na+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.[CH3:30][S:31]([OH:34])(=[O:33])=[O:32]>CO>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:1][C@@H:2]([CH3:6])[C:3]([NH2:5])=[O:4])=[CH:24][CH:23]=1.[CH3:30][S:31]([O-:34])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)O
Reactant: C[C@H](N)C(N)=O
Reactant: O=Cc1ccc(OCCCc2ccccc2F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)[O-]
Product: C[C@H](NCc1ccc(OCCCc2ccccc2F)cc1)C(N)=O
Reaction time: 0.17 h

Procedure:
To a solution of (S)-(+)-2-aminopropanamide (1.93 g; 0170 mol) in anhydrousmethanol (60 ml), under stirring and nitrogen, 2.0 g of 4 Å molecular sieves were added and then, in a single portion, NaBH3CN (0.78 g; 0.0124 mol); after 10 minutes, 4 g (0.0155 mol) of 4-(3-(2-fluorophenyl)propyl) oxybenzaldehyde were added, in 20 ml of anhydrous methanol. After 3 hours, the reaction was completed, the mixturewas filtered, the filtrates washed with methanol, the residue was directly flash-chromatographed on silica gel (eluant: CH2Cl2 195: CH3OH 5: 30% NH4OH 0.5) to give a white solid (2.7 g; 53%). The free base thus obtained was treated with a stoichiometric amount of methanesulfonic acid to yield (S)-(+) 2-{4-[3-(2-fluorophenyl)propyl)oxybenzyl}aminopropanamide, methanesulfonate; m.p. 172°-177° C.; [α]25 +10.4 (C=1.06, AcOH).