Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:10]=1.[OH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:11]2[CH:10]=[C:9]([C:35]3[CH:36]=[CH:37][C:32]([CH2:31][OH:30])=[CH:33][CH:34]=3)[CH:21]=[CH:20][C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:24][CH:25]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(CO)cc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 29.8 %

Procedure:
To toluene 4.0 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.20 g were added ethanol 1.2 mL, water 0.60 mL, 4-(hydroxymethyl)phenylboronic acid 91 mg, sodium hydrogen carbonate 0.12 g and tetrakis(triphenylphosphine)palladium(0) 35 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, water was added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give tert-butyl 2-(4-fluoroanilino)-4-(4-(hydroxymethyl)phenyl)benzoate 64 mg of a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:6]=2[CH:22]=1.[H-].[Na+].[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl.O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[N:9]([CH2:31][O:30][CH2:29][CH2:28][Si:27]([CH3:34])([CH3:33])[CH3:26])[C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[N:7][C:6]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(F)c(Br)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(Br)c(F)cc2n1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of (S)-tert-butyl 2-(6-bromo-5-fluoro-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (2.5 g, 6.4 mmol) in THF (32 mL) was added sodium hydride (0.27 g, 6.8 mmol) and stirring was continued for 30 minutes. 2-(Trimethylsilyl)-ethoxymethyl chloride (1.2 mL, 6.8 mmol) was added and stirring was continued for 30 minutes. Water was added to quench the reaction. The mixture was diluted with EtOAc, washed with 1N HCl, H2O, and brine, dried (Na2SO4), filtered and concentrated to an oil. The oil was purified by flash chromatography (0-30% EtOAc/hexane) to give the title compound (2.9 g, 5.7 mmol, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:16](F)=[N:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[CH3:7])=[O:5].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([OH:47])[CH:45]=3)[N:40]=[CH:39][N:38]=2)=[N:32]1>O>[Cl:1][C:2]1[C:16]([O:47][C:44]2[CH:45]=[C:46]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][N:38]=[C:37]3[NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=2)=[N:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[CH3:7])=[O:5]
Reactant: CN(C)CCN(C)C(=O)c1ccnc(F)c1Cl
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)CCN(C)C(=O)c1ccnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
3-Chloro-N-[2-(dimethylamino)ethyl]-2-fluoro-N-methylisonicotinamide (116 mg, 0.45 mmol) and potassium tert-butoxide (70 mg, 0.62 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (650 mg, 0.25 mmol), and stirred under a nitrogen atmosphere at 80° C. for 2 hours. The reaction solution was cooled to room temperature, water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate to chloroform:methanol=1:3 to 100:2) to obtain the entitled compound (101 mg, yield: 84%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][CH:2]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10]O)[CH2:3][CH3:4].S(Cl)([Cl:14])=O>>[ClH:14].[CH3:1][CH:2]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][Cl:14])[CH2:3][CH3:4]
Reactant: CCC(C)n1ccnc1CO
Reactant: O=S(Cl)Cl
Product: CCC(C)n1ccnc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 1-(2-butyl)-2-hydroxymethylimidazole (2.70 g) was added thionyl chloride (27 ml) at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate, to give 1-(2-butyl)-2-chloromethylimidazole hydrochloride (3.09 g) as brown crystals.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:23]=[CH:24]/[C:25]2[N:39]=[C:28]3[CH:29]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[CH2:30][CH2:31][CH2:32][N:27]3[N:26]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.[Na].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C.C(O)(=O)C>[CH2:1]([N:36]1[CH2:37][CH2:38][CH:33]([CH:29]2[CH2:30][CH2:31][CH2:32][N:27]3[N:26]=[C:25](/[CH:24]=[CH:23]/[C:13]4[CH:14]=[CH:15][C:16]([N:17]5[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]5)=[C:11]([O:10][CH3:9])[CH:12]=4)[N:39]=[C:28]23)[CH2:34][CH2:35]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCNCC2)ccc1-n1cnc(C)c1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(Cc3ccccc3)CC2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzaldehyde (15 μl) and glacial acetic acid (16 μl) were added to a solution of racemic 2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained in Examples 118 and 119 (30 mg) in THF (2 ml), and the reaction solution was stirred at room temperature for 30 minutes. Sodium triacetoxyhydroborate (46 mg) was added to the reaction solution, and the reaction solution was stirred at room temperature for four hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate) to obtain 27 mg of racemic 8-(1-benzylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: 50% ethanol-hexane) to obtain the title optically active compound with a retention time of 14 minutes and positive optical rotation (9.4 mg; >99% ee) and the title optically active compound with a retention time of 20 minutes and negative optical rotation (8.9 mg; 99% ee).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(C1(C2C=CC=CC=2SC2C=CC(F)=CC=2)CCNCC1)#N.[C:46](OC(=O)C)(=[O:48])[CH3:47]>N1C=CC=CC=1>[C:46]([N:18]1[CH2:17][CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]1)(=[O:48])[CH3:47]
Reactant: O=C(O)C1(c2ccccc2Sc2ccc(F)cc2)CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: N#CC1(c2ccccc2Sc2ccc(F)cc2)CCNCC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccc(F)cc2)CC1

Procedure:
A mixture of 0.7 g of 4-[2-(4-fluorophenylthio)phenyl]-piperidine-4-carboxylic acid, free amino acid of Example 30, and 0.83 ml of acetic anhydride in 4.2 ml of pyridine is stirred at reflux for 4 hours. Thereafter, the excess pyridine is removed by rotary evaporation and the residue is taken up in 10 ml of water and treated with 10 ml of 1 N hydrochloric acid. The acidic mixture is extracted thrice with 20 ml portions of an ether-benzene (1:1) mixture and the combined extracts are successively washed twice with 40 ml portions of water, once with 15 ml of saturated sodium chloride solution and dried. The resulting product is recrystallized from acetone-ether to provide 1-acetyl-4-[2-(4-fluorophenylthio)phenyl]piperidine-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(COC)OC.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([N:22](CC)CC)C>>[NH:22]1[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=2[N:1]=[CH:20]1
Reactant: CCN(CC)CC
Reactant: Nc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: c1cnc2nc[nH]c2c1

Procedure:
Imidazopyridine salt E-3 is prepared from aminopyridine E-1 (also D-1) (refer to Chart D) (commercial source) or the amino pyridine A-2 (refer to Chart A) and dihaloacetone E-2 (Aldrich) either by a two-step procedure whereby E-1 and E-2 are stirred in a solvent such as dimethoxyethane with or without the addition of a base such as triethylamine or potassium carbonate to give imidazopyridine salt E-3. If dimethoxyethane alone is used as solvent, it is then replaced with alcoholic solvent and E-3 is heated until no additional E-4 is formed.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:23][C:24]([F:31])([F:30])[C:25](OCC)=[O:26]>CO>[F:23][C:24]([F:31])([F:30])[C:25]([NH:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1)=[O:26]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NC1CCc2cc3c(cc2C1)OCC3)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture containing 5 g of the compound of Example 2, 3.35 ml of triethylamine and 4 ml of ethyl trifluoroacetate in 7 ml of methanol is stirred for 4 hours at room temperature. The mixture is then evaporated to dryness and the dry residue obtained is recrystallized in isopropyl ether.
Reaction SMILES: C([O:8][C:9](=[O:35])[C:10]1[CH:15]=[C:14]([C:16]([CH3:18])=[CH2:17])[C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][C:11]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C1C=CC=CC=1.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[CH2:28]([O:27][C:11]1[CH:12]=[C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:16]([CH3:18])=[CH2:17])=[CH:15][C:10]=1[C:9]([OH:35])=[O:8])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=C(C)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid benzyl ester (40.8 g, 87.9 mmol) in THF-MeOH-water (3:1:1, 300 mL total) was added lithium hydroxide (8.42 g, 352 mmol). The mixture was heated at 50° C. for 16 h, allowed to cool to ambient and then diluted with water (300 mL). The mixture was taken to pH˜1 using conc. HCl (˜30 mL) and then extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and reduced in vacuo. The solid residue was taken up in P.E-MeOH (9:1, 300 mL total), the slurry stirred for 1 h at ambient and the solid collected by filtration. The solid was dried in vacuo to give the title compound (26.8 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 12.30 (s, 1H), 7.61 (s, 1H), 7.53 (d, J=7.0 Hz, 2H), 7.47-7.31 (m, 8H), 6.94 (s, 1H), 5.23 (d, J=14.0 Hz, 4H), 5.08 (d, J=9.0 Hz, 2H), 2.04 (s, 3H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[CH3:34][NH:35][CH2:36][CH:37]([OH:45])[C:38]1[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=1.O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:35]([CH2:36][CH:37]([OH:45])[C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[CH3:34])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: CNCC(O)c1ccc(O)cc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccc(O)cc1
Temperature: 90 °C
Yield: 58.9 %

Procedure:
N,N-Diisopropylethylamine (0.14 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) were added to a solution of synephrine (0.137 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature, poured into water (25 mL), and extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography (CH2Cl2/methanol; 98/2, 97/3) followed by recrystallization from ethyl acetate/methanol to yield 0.120 g of the title compound as a white solid. Physical characteristics. M.p. 117-122° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 9.21, 8.54, 7.41-7.33, 7.09, 6.85, 6.65, 4.88, 4.614.57, 4.55, 3.89, 3.71, 2.58-2.45, 2.30; 13C NMR (100 MHz, CDCl3) δ 173.7, 164.8, 156.1, 153.2, 150.9, 141.2, 137.1, 132.9, 132.8, 128.9, 128.7, 127.4, 116.6, 115.3, 114.8, 106.6, 69.5, 64.0, 54.0, 42.6, 42.2, 37.8; MS (ESI+) m/z 496 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[C:5]2[CH2:18][CH:19]([CH2:21][OH:22])[O:20][C:4]=2[CH:3]=1.O.S(=O)(=O)(O)[OH:25]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[C:5]2[CH2:18][CH:19]([C:21]([OH:25])=[O:22])[O:20][C:4]=2[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: OCC1Cc2c(cc(Cl)c3c(-c4ccccc4F)noc23)O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1Cc2c(cc(Cl)c3c(-c4ccccc4F)noc23)O1
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A portion (4.3 g) of the 4-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol obtained in Example 22 was dissolved in 120 ml of acetone. To the solution, a mixture of chromium (VI) oxide (6.5 g), water (15 ml) and concentrated sulfuric acid (9.3 g) was added dropwise under stirring. The stirring was continued at room temperature for 2 hours, then the mixture was left to stand overnight. The insolubles were filtered off by suction, and the solvent was distilled off. Water was added to the residue, followed by extraction with ether. The ether layer was washed with water and dried, and the solvent was distilled off. The residue was recrystallized from acetone/water to yield 2.7 g of 4-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 191°-193° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>O1CCCC1>[Cl:34][CH2:35][CH2:36][C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)=[O:38]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
2 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)-ethyl]piperazine and 0.82 g of Hunig base are introduced into 40 ml of tetrahydrofuran, and a solution of 0.8 g of 3-chloropropionic acid chloride is added dropwise thereto. The solution is left to stand overnight. The resulting suspension is concentrated by evaporation and taken up in methylene chloride and water. There is obtained from the organic phase 1-[4-(3-chloropropionylamino)benzoyl]-4-[2-(4-chlorophenyl)-ethyl]piperazine having a melting point of 190°-191°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:10]3([CH2:15][CH2:14][N:13]([C:16]4[S:20][C:19]([C:21]5[N:22]=[N:23][N:24]([CH2:26][C:27]([O:29]CC)=[O:28])[N:25]=5)=[N:18][N:17]=4)[CH2:12][CH2:11]3)[CH:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C3C(=CC=CC=3)OC3(CCNCC3)C=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:10]3([CH2:15][CH2:14][N:13]([C:16]4[S:20][C:19]([C:21]5[N:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=[O:28])[N:25]=5)=[N:18][N:17]=4)[CH2:12][CH2:11]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1nnc(-c2nnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)n1
Agent: Fc1ccc(C2=CC3(CCNCC3)Oc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(O)Cn1nnc(-c2nnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)n1
Temperature: 81 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2-(5-(5-(4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine]-1′-yl)-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl)acetate A mixture of 4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine] (171 mg, 0.58 mmol) (Example 6, Step 2), Intermediate 2 (203 mg, 0.64 mmol) and K2CO3 (144 mg, 1.04 mmol) was suspended in dry DME (3 mL). The reaction mixture was stirred under N2 at an external temperature of 81° C. for 1.5 h. Then the reaction mixture was cooled down to room temperature, diluted with DCM (5 mL), washed with 5% KHSO4 (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting oily residue was purified by Combiflash™ chromatography (SiO2 (12 g), eluting with 10-60% EtOAc/hexanes) to afford the title compound as an oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:1]([CH:2]=[CH2:3])=[O:4]
Reactant: c1ccoc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccco1

Procedure:
Acryloyl chloride (0.45 g), furan (0.34 g), and AlCl3 (0.66 g) were reacted in CH2Cl2 at −60° C.
Reaction SMILES: [C:1]1([CH:7]([OH:13])[CH2:8][CH2:9][C:10]#[C:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C[Si]([O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[F:30][C:29]([F:32])([F:31])[S:26]([O:28]/[C:11](=[C:10]1/[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]/1)/[CH3:12])(=[O:27])=[O:25]
Reactant: CC#CCCC(O)c1ccccc1
Reactant: CCCCCC=O
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC1OC(c2ccccc2)CC/C1=C(/C)OS(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 76 %

Procedure:
In dichloromethane (3.0 mL) were dissolved 1-phenylhex-4-yn-1-ol (0.28 mmol) and hexanal (0.34 mmol) and the solution was cooled to −78° C. before the addition of trimethylsilyltriflate (TMSOTf) (0.86 mmol) thereto. At the same temperature, the reaction solution was stirred for 1 hour, followed by slow temperature elevation to room temperature over 3 hours. Stirring was further conducted at room temperature for an additional one to two hours in the reaction solution. After the addition of an aqueous NaHCO3 solution, the reaction solution was diluted with diethylether. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The purification of the concentrate through column chromatography afforded the title compound (Yield 76%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[C:21]([F:22])=[C:20](F)[C:19]([F:24])=[C:18]([F:25])[C:17]=2[C:26]([F:29])([F:28])[F:27])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:32]([C:35]1[CH:41]=[CH:40][C:38]([O-:39])=[CH:37][C:36]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([O-:34])=[O:33].[K+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+]>CS(C)=O>[N+:32]([C:35]1[CH:41]=[CH:40][C:38]([O:39][C:20]2[C:19]([F:24])=[C:18]([F:25])[C:17]([C:26]([F:27])([F:28])[F:29])=[C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:31][CH:30]=3)[C:21]=2[F:22])=[CH:37][C:36]=1[O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc([O-])cc1OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(F)c(F)c2C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c(F)c(F)c2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
40 g of the 2-(4-benzyloxycarbonylphenoxy)-1-trifluoromethyl-3,4,5,6-tetrafluorobenzene (0.09 mol) prepared as described in Example 9 and 25.5 g of potassium 4-nitro-3-benzyloxyphenoxide (0.09 mol) are dissolved in 400 ml of dimethyl sulfoxide. 30 g of potassium carbonate (0.22 mol) are added in portions to the solution. The mixture is then stirred at room temperature for 24 hours and then heated at 60° C. for 24 hours, and 15 g of potassium hydrogencarbonate (0.15 mol) are then added. The reaction solution is then allowed to cool to room temperature and is filtered through a fluted filter. The crude product is extracted by shaking with 300 ml of ethyl acetate and 700 ml of water, and the organic phase is washed three times with water and evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then recrystallized from a mixture of ethyl acetate and n-hexane (volume ratio 1:1) and then dried for 48 hours,under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][C:13]#[N:14])=[N:9][C:8]=2[CH:15]=1)([O-])=O>[Pd].C1COCC1.C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][C:13]#[N:14])=[N:9][C:8]=2[CH:15]=1
Reactant: N#CCc1nc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CCc1nc2cc(N)ccc2o1
Reaction time: 5 h
Yield: 29.6 %

Procedure:
The mixture of 5-nitro-2-benzoxazoleacetonitrile (8 g 39.4 mmole) and Palladium on carbon (1.2 g) in THF (100 ml) and acetic acid (2 ml) in a Parr bottle was hydrogenated at 50 psi for 5 h. It was filtered over a patch of celite (1.5 cm) covered with activated carbon (0.5 cm) and washed with isopropyl ether. The filtrate was evaporated and the residue was purified by flash chromatography and gave 5-amino-2-benzoxazoleacetonitrile (2.02 g, 30%).