Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[CH3:4][N:5]([C+:7]([N:9]([CH3:11])[CH3:10])Cl)[CH3:6].[CH3:12][N-:13][CH3:14].[Li+]>C(#N)C>[S-:1][C:2]#[N:3].[CH3:4][N:5]([CH3:6])[C:7](=[N+:13]([CH3:14])[CH3:12])[N:9]([CH3:11])[CH3:10]
Reactant: CN(C)[C+](Cl)N(C)C
Reactant: C[N-]C
Agent: N#C[S-]
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C(N(C)C)=[N+](C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
1.00 g (5.16 mmol) of bis(dimethylamino)chlorocarbenium thiocyanate and 0.26 g (5.10 mmol) of lithium dimethylamide are dissolved in 10 ml of acetonitrile under a protective-gas atmosphere (argon). The reaction mixture is stirred for 5 hours at room temperature, and LiCl is subsequently filtered off. The salt LiCl is washed with 2 ml of acetonitrile, and the organic phases are combined. The solvent is distilled off, and the residue is dried under reduced pressure at 7 Pa and 50° C., giving 0.99 g of hexamethylguanidinium thiocyanate as an oil, corresponding to a yield of 94.8%.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][C:4]([CH3:14])([CH3:13])[CH2:5][NH:6][C:7](=[O:12])[CH2:8][CH2:9]OC.[OH-].[Na+]>>[CH3:15][N:2]([CH3:1])[CH2:3][C:4]([CH3:14])([CH3:13])[CH2:5][NH:6][C:7](=[O:12])[CH:8]=[CH2:9]
Reactant: COCCC(=O)NCC(C)(C)CN(C)C
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCC(C)(C)CN(C)C
Temperature: 300 °C

Procedure:
A total of 820 g (3.8 moles) N-(N',N',2,2-tetramethyl-3-aminopropyl)-3-methoxypropionamide was fed continuously to an evaporator flask heated to 170° to 180° C., and the vapors were conducted under a vacuum of 14 millibars to a reaction tube 1 meter long and 3 cm in diameter which was heated externally, by means of a strip heater, to 300° C. and was filled with alumina beads impregnated with 10% sodium hydroxide. With a head temperature ranging from 150° to 220° C., about 475 g of a yellow oil was collected over a period of 2 hours, which for further purification was distilled once more in a high vacuum. 383 g (2.1 moles=52% of theory, based on 3-methoxypropionamide) of a product having a boiling point 0.2 of 98° to 102° C. was obtained.
Reaction SMILES: C([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[CH:11]=[CH:10][CH:9]=2)(=O)C.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]=[C:25]=[O:26])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C1COCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][NH:24][C:25]([NH:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:5]([OH:4])[N:6]=[CH:7]3)=[O:26])=[CH:21][CH:22]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: CC(=O)Oc1cc2c(N)cccc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2cnc(O)cc12
Reaction time: 1 h

Procedure:
5-Amino-3-isoquinolinyl acetate in toluene:THF (5:1, 5 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (105 mg). After stirring for 1 hour, the mixture was concentrated under reduced pressure and the residue dissolved in MeOH (20 mL) and treated with K2CO3 (4 eq) and stirred for 16 hours. The mixture was concentrated under reduced pressure and partitioned between CH2Cl2 and water. The aqueous phase was separated and the pH was adjusted to approximately 6 with HCl. The acidified solution was filtered, and the filter cake was dried. The solid was purified by reverse-phase chromatography (using TFA as eluent) to provide the title compound. MS (ESI+) m/z 374, 372 (M+H)+; MS (ESI−) m/z 372, 370 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 4.33 (d, J 5.8, 2H), 7.06 (m, 1H), 7.29 (m, 3H), 7.57 (m, 3H), 8.07 (d, J 7.8, 1H), 8.48 (s, 1H), 8.80 (s, 1H), 8.87 (s, 1H); Anal. Calcd for C17H14BrN3O2+0.2 TFA: C, 53.08; H, 3.42; N, 10.43. Found: C, 52.91; H, 3.62; N, 10.43.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]1([CH:18]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)C)C=CC=CC=1.[C:25]1([CH2:31][N:32]2[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O>[C:8]1([CH2:12][CH2:18][N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[C:35]2([OH:38])[CH2:36][CH2:37][N:32]([CH2:31][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:33][CH2:34]2)[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(c1ccccc1)n1ccnc1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2nccn2CCc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: -70 °C
Yield: 75 %

Procedure:
A mixture of DIPA (1.4 mol) in THF (3000 ml) was stirred at −70° C. under N2 flow. Butyllithium 2.5 M/hexane (1.3 mol) was added portionwise at a temperature below −40° C. The mixture was stirred at −70° C. for 15 min. 1-phenylethyl-1H-imidazole (1 mol) dissolved in THF was added dropwise at a temperature below −55° C. The mixture was stirred at −70° C. for 1 hour. 1-(phenylmethyl)-4-piperidinone (1.2 mol) dissolved in THF was added dropwise at a temperature below −55° C. The mixture was stirred at −70° C. for 1 hour, then brought to room temperature, stirred at room temperature overnight and decomposed with H2O. The organic solvent was evaporated. The aqueous concentrate was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from DIPE (1100 ml). The precipitate was filtered off, washed with DIPE and dried, yielding 271 g of 4-[1-(2-phenylethyl)-1H-imidazol-2-yl]-1-(phenylmethyl)-4-piperidinol (75%) (interm. 1).
Reaction SMILES: [CH:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]3[CH2:16][CH:15]3[C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)C=C(C#N)C=C4)[CH:12]=2)[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.[C:34]([BH3-])#[N:35].[Na+].O>CO>[CH:29]1([CH2:32][N:5]2[CH2:6][CH2:7][C:8]3[C:13](=[CH:12][C:11]([CH:14]4[CH2:16][CH:15]4[C:17]4[C:18]5[C:19](=[CH:2][CH:1]=[CH:4][CH:13]=5)[CH:24]=[CH:25][C:26]=4[C:34]#[N:35])=[CH:10][CH:9]=3)[CH:4]2[CH:1]([CH3:2])[CH3:3])[CH2:31][CH2:30]1
Reactant: O=CC1CC1
Reactant: CC(C)C1NCCc2ccc(C3CC3c3ccc4cc(C#N)ccc4c3)cc21
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)C1c2cc(C3CC3c3c(C#N)ccc4ccccc34)ccc2CCN1CC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 20A (0.25 g, 0.95 mmol), cyclopropanecarboxaldehyde (71 mL, 0.95 mmol), and sodium cyanoborohydride (119 mg, 1.86 mmol), in methanol (3.5 mL) was heated to 50° C., stirred for 2 hours, cooled to room temperature, and treated with water. The resulting precipitate was collected by filtration, dried, and purified by flash column chromatography with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1)[CH3:2].[Br:12]Br>C(O)C.O>[Br:12][C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cn2ccccc2n1
Reactant: BrBr
Solvent: CCO
Solvent: O
Product: CCc1nc2ccccn2c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of 2-ethyl-imidazo[1,2-a]pyridine (2.17 g, 14.9 mmol) in ethanol (25 mL) was added bromine (2.0 g, 12.5 mmol) in water (5 mL) dropwise at rt. After stirring at rt for 4 h, ethanol was evaporated under reduced pressure. The residue was basified with aqueous sodium bicarbonate and extracted with methylene chloride (3×). The organic phase was washed with brine and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography eluting with 20% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes afforded the title compound (1.88 g) as a viscous oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:28][C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[O:17][CH2:16][CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[N:23]=1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(OCCN3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Temperature: 70 °C

Procedure:
tert-Butyl piperazine-1-carboxylate (1.4 g, 7.52 mmol) was added to a mixture of 5-(2-bromoethoxy)-2-methylquinoline (2 g, 7.52 mmol) and potassium carbonate (4.16 g, 30.1 mmol) in N,N-dimethylformamide (20 mL). The reactants were heated at 70° C. for 16 h under an atmosphere of argon. The reaction mixture was poured into water (200 mL) and extracted into ethyl acetate (3×200 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography, eluting with 30% ethyl acetate in hexane affording the title compound as a tan solid (1.04 g, 37%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][S:19](=[O:23])(=[O:22])[NH:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])C.Cl>>[OH2:3].[O:23]=[S:19]1(=[O:22])[CH2:20][CH2:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)=[CH:15][CH:14]=2)[CH2:17][NH:18]1.[O:23]=[S:19]1(=[O:22])[CH2:20][CH2:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)=[CH:15][CH:14]=2)[CH2:17][NH:18]1
Reactant: CC(=O)N1CCN(c2ccc(C3CCS(=O)(=O)NC3)cc2)CC1
Agent: Cl
Product: O
Product: O=S1(=O)CCC(c2ccc(N3CCNCC3)cc2)CN1
Yield: 51.9 %

Procedure:
A mixture of the product of part (ii) (1.3 g, 3.8 mmole) and 5N hydrochloric acid (15 ml) was heated under reflux for 2 hous. The resulting mixture was concentrated under reduced pressure, the residue diluted with water (10 ml), neutralised with aqueous sodium bicarbonate and extracted into methylene chloride. After drying over magnesium sulphate, the organic phase was concentrated under reduced pressure to yield the title compound as a white solid, (0.6 g, 53%), m.p. 172°-173°.
Reaction SMILES: [C:1]([C:9]1[C:16]([Cl:17])=[CH:15][C:12]([CH2:13]Br)=[CH:11][C:10]=1[Cl:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>C(O)C>[C:1]([C:9]1[C:16]([Cl:17])=[CH:15][C:12]([CH2:13][N:19]=[N+:20]=[N-:21])=[CH:11][C:10]=1[Cl:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccccc1)c1c(Cl)cc(CBr)cc1Cl
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccccc2)c(Cl)c1
Yield: 212.3 %

Procedure:
A mixture of 4-benzoyl-3,5-dichlorobenzyl bromide (2.37 g, 6.89 mmol) and sodium azide (1.32 g, 20:3 mmol) in absolute ethanol (31 ml) was refluxed 5 hours, cooled, and evaporated. The residue was dissolved in diethyl ether and filtered. The filtrate was evaporated to provide 1.95 g (92%) 4-benzoyl-3,5-dichorobenzyl azide, IR (neat): 2090, 1670 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:30]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:30])[CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc4c(N)ncnn34)cc2)CC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(Br)c4c(N)ncnn34)cc2)CC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 4-[4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylate (1.20 g, 3.04 mmol) in tetrahydrofuran (15 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (435 mg, 1.21 mmol) in four portions over 15 min. The mixture stirred at −20° C. for 3 h. Saturated, aqueous Na2SO3 (20 mL) was added and the mixture was allowed to warm to rt. The mixture was extracted with ethyl acetate (2×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 25 to 75% ethyl acetate in hexanes. 1H-NMR indicated the presence of residual hydantoin side product, thus the material was partitioned between ethyl acetate (50 mL) and 5% aqueous K2CO3 (50 mL). The layers were separated and the organic layer was further washed with 5% aqueous K2CO3 (2×25 mL). The combined aqueous layer was extracted with ethyl acetate (2×25 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford 340 mg (23%) of the desired product as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.91-7.83 (m, 3 H), 7.09 (s, 1 H), 7.00 (d, 2 H), 3.50-3.42 (m, 4 H), 3.20-3.14 (m, 4 H), 1.42 (s, 9 H); ES-MS m/z 473.0 [M+H]+, HPLC RT (min) 3.25.
Reaction SMILES: C(N=[C:4]([C:9]1C=NC=CC=1)[O:5][CH:6](C)[CH3:7])#[N:2].[NH2:15][C:16]1C=C[C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>CO>[CH3:4][OH:5].[N:24]1[CH:23]=[CH:22][CH:19]=[CH:18][C:17]=1[C:16](=[NH:2])[NH2:15].[CH2:4]([O:5][CH2:6][CH3:7])[CH3:9]
Reactant: NCCc1ccc(N)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: CCOCC
Product: N=C(N)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (1.0 g, 5.3 mmol) was dissolved in methanol (15 ml), and 2-(4-aminophenyl)ethylamine (0.80 g, 5.8 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether pyridinecarboximidamide (0.88 g, 3.3 mmol, yield: 63%) as colorless needles.
Reaction SMILES: C(N1CCC[C@H]1C(O)=O)(OCC1C=CC=CC=1)=O.ClC(OCC(C)C)=O.CN1CCOCC1.NC(CO)C(C)C.[C:41]([N:51]1[CH2:64][CH2:63][CH2:62][C@H:52]1[C:53]([NH:55][C@H:56]([CH2:60][OH:61])[CH:57]([CH3:59])[CH3:58])=[O:54])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>C(OCC)(=O)C.CCCCCC>[C:41]([N:51]1[CH2:64][CH2:63][CH2:62][C@H:52]1[C:53]([NH:55][CH:56]([CH2:60][OH:61])[CH:57]([CH3:59])[CH3:58])=[O:54])([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42].[C:41]([N:51]1[CH2:64][CH2:63][CH2:62][C@H:52]1[C:53]([NH:55][C@@H:56]([CH2:60][OH:61])[CH:57]([CH3:59])[CH3:58])=[O:54])([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]
Reactant: CC(C)[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C(N)CO
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CCCCCC
Product: CC(C)C(CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Product: CC(C)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
N-Carbobenzoxy-L-prolyl-DL-valinol was prepared by reacting 9.97 g (40 mmol) N-carbobenzoxy-L-proline, 5.46 g (40 mmol) isobutyl chloroformate, 4.05 g (40 mmol) N-methylmorpholine, and 4.13 g (40 mmol) DL-valinol substantially according to the mixed anhydride procedure described in Example 1. A portion, 1.00 g, of crude product was dissolved in 120 mL ethyl acetate, and 80 mL n-hexane were added. This solution was stirred vigorously and seeded with a crystal of N-carbobenzoxy-L-prolyl-L-valinol. After 5 minutes, crystalline product (100 mg) was separated by filtration. High performance liquid chromatography (HPLC) indicated that the product contained 76% N-carbobenzoxy-L-prolyl-D-valinol (L-D isomer) and 24% N-carbobenzoxy-L-prolyl-L-valinol (L-L isomer). HPLC analysis was conducted using a 4.6 mm ID×25 cm column packed with 5-6 μm diameter particles of porous silica, and a linear gradient (3→100% B in 30 minutes), using 1-chlorobutane as solvent A and 1:1 methanol/acetonitrile as solvent B. A first peak (11.2 minutes) was the desired L-D isomer, and a second peak (11.6 minutes) was the L-L isomer, characterized in Example 2 above. HPLC separation was repeated with a series of 5 mg injections to give a total of 64 mg (0.19 mmol) pure N-carbobenzoxy-L-prolyl-D-valinol. This product could also be isolated directly from the crude reaction product by a series of fractional crystallizations from ethyl acetate/n-hexane, then ethanol/n-hexane. Pure N-carbobenzoxy-L-prolyl-D-valinol melted at 118.0°-118.2°, α25D-27.6°, (C=1.01 g/100 mL in acetone).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:23]([NH2:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>CO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:23]([NH:31][CH2:12][C@H:10]([OH:11])[C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(N)Cc2ccccc2)cc1OC
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CO
Product: COc1ccc(C(Cc2ccccc2)NC[C@H](O)c2ccc3nnnn3c2)cc1OC

Procedure:
A solution of 0.178 g (1 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (see Fisher and Wyvratt, EP 0 318 092 A2 for the synthesis of this compound) and 0.518 g (2 mmol) of α-(3,4-dimethoxyphenyl) benzeneethanamine in dry methanol (10 mL) was heated at reflux in a gas tight vessel for 14 hours. The reaction mixture was concentrated and the residue was chromatographed on silica gel (5% methaol in methylene chloride) to give the product as a white solid: 1H NMR (500 MHz, CDCl3)δ 8.76 (d, 1H, J=15 Hz), 7.91 (dd, 1H, J=9, 3 Hz), 7.41 (t, 1H, J=11 Hz), 7.10-7.32 (m, 5H), 6.77-6.83 (m, 3H), 4.51-4.73 (m, 1H), 3.89 (s, 3H. OCH3), 3.88 and 3.86 (s, 3H, OCH3), 3.74-3.89 (m, 1H), 2.96-3.0 (m, 1H), 2.84-2.92 (m, 2H), 2.94-2.61 (m, 1H).
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl (RS)-1-(4-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9 mmol) in CH2Cl2 (10 ml) at 0° C. under an argon atmosphere was added triethylsilane (0.28 g, 2.4 mmol), followed by boron trifluoride etherate (1 ml, 8.1 mmol). The resulting solution was stirred at 0° C. for 10 min, and was then partitioned between EtOAc and 3M HCl. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacua, and the residue was filtered through a pad of silica gel, eluting with CH2CH2. The title compound (mixture of Δ1 and Δ2 double bond isomers) was obtained as a glassy, yellow solid (0.72 g, 94%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][N:9]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([O:25][CH2:26][C:27]4[N:28]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[S:30][CH:31]=4)=[CH:23][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][N:9]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([O:25][CH2:26][C:27]4[N:28]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[S:30][CH:31]=4)=[CH:23][CH:24]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
After a mixture of ethyl [3-phenyl-1-(6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]acetate (536 mg), 1N sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain [3-phenyl-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]acetic acid (459 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 118–119° C.
Reaction SMILES: C(OC(C)C)(C)C.P(OP(O)(O)=O)(O)(O)=O.[CH:17]1([C:20](=O)[CH2:21][C:22]#[N:23])[CH2:19][CH2:18]1.[NH2:25][C:26]1[CH:40]=[CH:39][CH:38]=[CH:37][C:27]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=O>>[CH:17]1([C:20]2[C:21]([C:22]#[N:23])=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:27]3[C:26](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:25]=2)[CH2:19][CH2:18]1
Reactant: N#CCC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: O=P(O)(O)OP(=O)(O)O
Solvent: CC(C)OC(C)C
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Into a glass flask having an internal volume of 10 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 5 mL of diisopropyl ether was put in an atmosphere of nitrogen, and 0.82 g (4.6 mmol) of pyrophosphoric acid, 0.29 g (2.5 mmol) of 3-cyclopropyl-3-oxopropanenitrile and 0.50 g (2.3 mmol) of 2-amino-4′-fluorobenzophenone were added thereto with stirring at room temperature. Then, the temperature was raised to 70° C., and reaction was carried out for 3 hours. After completion of the reaction, the reaction liquid was cooled to room temperature, and analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 0.60 g (yield: 91%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:19])=[C:15]([CH2:17]Cl)[N:16]=2)[CH:7]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[O:26]=[CH:27][C:28]1[CH:36]=[CH:35][C:33]([OH:34])=[C:30]([O:31][CH3:32])[CH:29]=1.CN(C)C=O>O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:19])=[C:15]([CH2:17][O:34][C:33]3[CH:35]=[CH:36][C:28]([CH:27]=[O:26])=[CH:29][C:30]=3[O:31][CH3:32])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3]
Reactant: Cc1oc(-c2cccc(OS(C)(=O)=O)c2)nc1CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
A mixture of 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)phenyl methanesulfonate (8.35 g), potassium carbonate (3.65 g), vanillin (4.02 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate as colorless crystals (7.95 g, 72%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° C.