Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I.C(=O)([O-])O.[Na+].[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[NH:27][C:26]=2B2OC(C)(C)C(C)(C)O2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>COCCOC.O.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>[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[NH:27][C:26]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:13])[NH:4][CH2:3][CH2:2][OH:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(NCCO)c1ccccc1I
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
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: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C(=O)NCCO)[nH]c2c1
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a suspension of N-(2-hydroxyethyl)-2-iodobenzamide (5.12 g, 17.5 mmol), sodium hydrogen carbonate (5.80 g, 69.8 mmol) and tetrakis(triphenylphosphine)palladium (2.00 g, 1.73 mmol) in 1,2-dimethoxyethane (70 ml) and water (35 ml) was added methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (7.50 g, 19.5 mmol) in five divided portions at 90° C., and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium is sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1-20:1) to give methyl 3-cyclohexyl-2-[2-(2-hydroxyethylcarbamoyl)phenyl]-1H-indole-6-carboxylate (7.40 g, yield 100%).
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][C:50]1[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[C:51]=1[NH2:52]>C(O)(=O)C>[CH3:49][C:50]1[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[C:51]=1[N:52]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Cc1cccc(C)c1N
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: Cc1cccc(C)c1-n1cnc2c(-c3ccccc3)csc2c1=O
Yield: 56 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (43 mg, 0.18 mmol), triethyl orthoformate (0.34 ml), 2,6-dimethylaniline (0.04 ml, 0.33 mmol), and acetic acid (0.042 ml) were used to give 34.8 mg (0.10 mmol, 56% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl[Si](C)(C)C.[C:23]([N:26]1[CH2:33][C:32](=[O:34])[CH2:31][C@H:27]1[C:28](O)=[O:29])(=[O:25])[CH3:24].CN1CCOCC1.ClC(OC)=O.O=C1N=CC=CC1C(O)=O>ClCCl.C(N(CC)CC)C>[C:23]([N:26]1[CH2:33][C:32](=[O:34])[CH2:31][C@H:27]1[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(O)C1C=CC=NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)N1CC(=O)C[C@H]1C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A suspension of 8.0 g (34.6 mM) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 10 g (99 mM of triethylamine, and 560 ml of dichloromethane was stirred at room temperature for 11.3 g (0.104 mol) of chlorotrimethylsilane was added and solution was observed in 30 min. A suspension of 11.9 g (0.069 mol) of N-acetyl-4-oxo-L-proline in 160 ml of dichloromethane was stirred at -10° and 6.9 g (0.069 mol) of N-methylmorpholine was added followed by 6.6 g (0.069 mol) of methyl chloroformate over a ten min period. The reaction was stirred at -10° for 30 min and cooled to -30°. The above oxonicotinic acid solution was added in aliquots keeping the temperature below -5°, and the reaction mixture was stirred in an ice bath overnight, allowing the bath to come to room temperature. The reaction was evaporated to a gum and water was added. The resulting solid was filtered, dried, and digested with hot ethanol. The purified solid was filtered and dried to give 12 g of 6-[4-(N-acetyl-4-oxo-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid;
Reaction SMILES: C=CC1C=CC=CC=1.C(C1C=CC=CC=1C=C)=C.[C:19]1([C:25]2[NH:26][C:27]3[C:32]([C:33]=2[CH2:34][CH2:35]OC2CCCCO2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1C=CC(S([O-])(=O)=[O:51])=CC=1.C1C=C[NH+]=CC=1>ClCCCl.C(O)C>[C:19]1([C:25]2[NH:26][C:27]3[C:32]([C:33]=2[CH:34]([OH:51])[CH3:35])=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: c1ccc(-c2[nH]c3ccccc3c2CCOC2CCCCO2)cc1
Agent: C=Cc1ccccc1C=C
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClCCCl
Solvent: C=Cc1ccccc1
Product: CC(O)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 70 °C

Procedure:
1-[4-Benzyloxycarbamoyl]phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-2-phenyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (7.87 g) was suspended in a mixture of DCE (125 ml) and ethanol (12.5 ml) containing PPTS (5.83 g) and warmed to 70° C. for 18 h. The resin was then filtered off and washed with DMF (4×25 ml), DCM (4×25 ml), MeOH (4×25 ml) and ether (25 ml). A portion of the recovered resin (100 mg) was then suspended in dry DMF (3.0 ml) containing 5% pyrrolidine and heated to 110° C. for 4 h. The resin was filtered off and the solvent removed from the filtrate under reduced pressure to afford 2-phenyl-1H-indol-3-ylethanol. 1H (360 MHz, CDCl3) δ3.21 (2H, t, J=7.0 Hz), 3.97 (2H, t, J=7.0 Hz), 7.13-7.22 (2H, m), 7.38 (2H, m), 7.45 (2H, m), 7.62 (3H, m) and 8.12 (1H, br s).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])=[O:4])[CH3:2].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH2:7][CH2:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCS(=O)(=O)CCCO
Solvent: ClCCl
Product: CCS(=O)(=O)CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
A mixture of 3-(ethylsulfonyl)-1-propanol (see step (i) above; 13.4 g, 88 mmol) and p-toluenesulfonyl chloride (16.8 g, 88 mmol) in DCM (150 mL) was treated with TEA (13.4 g, 132 mmol), added dropwise. The resulting mixture was stirred at rt for 3 h before being washed with aqueous ammonium chloride solution. The organic layer was then separated, dried and concentrated in vacuo. The product was crystallised from ether containing a small amount of DCM to yield 17.9 g (66%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6](Br)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.[F-].[K+].CC#N>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1nc(Br)c(Cl)c(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(Cl)c(N)c1OC
Temperature: 115 °C
Yield: 47.9 %

Procedure:
To a 5 mL microwave vial were added methyl 4-amino-6-bromo-5-chloro-3-methoxypicolinate (200 mg, 0.677 mmol), 4-chlorophenylboronic acid (116 mg, 0.744 mmol), KF (102 mg, 1.760 mmol), and PdCl2(PPh3)2 (48 mg, 0.068 mmol). Subsequently, CH3CN (1.1 mL) and H2O (1.1 mL) were added, and the reaction vial was sealed and heated in a Biotage microwave at 115° C. for 20 min. The reaction mixture was cooled to room temperature and diluted with EtOAc (3 mL). The organic phase was separated, and the aqueous phase was washed with EtOAc (2×2 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was using a Teledyne ISCO purification system with a gradient eluent system of EtOAc and hexanes to yield the title compound as a white solid (106 mg, 47%): mp 139-141° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.54 (m, 2H), 7.54-7.47 (m, 2H), 6.68 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H); ESIMS m/z 326.00 ([M−H]−).
Reaction SMILES: [Na].Cl[C:3]1[C:8]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:13][O:14][CH2:15][CH2:16][OH:17]>>[CH3:13][O:14][CH2:15][CH2:16][O:17][C:3]1[C:8]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COCCO
Reactant: NS(=O)(=O)c1cccnc1Cl
Agent: [Na]
Product: COCCOc1ncccc1S(N)(=O)=O
Reaction time: 0.08 h

Procedure:
4.36 g of a 55% dispersion of sodium in oil is added in portions over 15 minutes and under nitrogen to 25 ml of methyl cellosolve. A solution of 9.6 g of 2-chloro-3-pyridylsulfonamide in 25 ml of methyl cellosolve is then added dropwise, with stirring, to the above dispersion over 5 minutes. The reaction mixture is then stirred for 1 hour at reflux temperature and concentrated in vacuo. The residue is acidified to pH 2 with about 25 ml of aqueous HCl at a temperature below 15° C., then stirred and filtered, affording 11.3 g of the desired 2-(2-methoxyethoxy)-3-pyridylsulfonamide, which is recrystallised from acetonitrile and has a melting point of 102°-103° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2Cl.Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:17][NH:18][C:19]([NH2:21])=[O:20]
Reactant: NNC(N)=O
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(NNC(N)=O)c2cc1OC
Yield: 30 %

Procedure:
2.2 g of 6,7-dimethoxy-4-chloro-quinazoline were dissolved in 50 ml of absolute dimethylformamide, 2.2 g of semicarbazide hydrochloride and 5 g of anhydrous potash were added thereto while stirring. The mixture was stirred for 5 hours at 50° C., and the precipitate formed thereby was suction-filtered off, stirred with water, and then recrystallized from dimethylformamide. The crude product was obtained with a 30% yield; m.p. 247°-249° C.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[CH:9]=[N:8][C:7]=1[Cl:14].ClCCl.Cl>C1COCC1>[Cl:14][C:7]1[N:8]=[CH:9][C:10]([CH2:12][CH3:13])=[CH:11][C:6]=1[C:5]([OH:15])=[O:4]
Reactant: CCc1cnc(Cl)c(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cnc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 1 N aqueous LiOH solution (3.3 ml, 3.3 mmol) was added to a solution of 2-chloro-5-ethyl-nicotinic acid methyl ester (325 mg, 1.6 mmol; T. Y. Zhang, E. F. V. Scriven, WO 9318005 A2) in THF (3.3 ml). The reaction mixture was stirred for 3 h at ambient temperature, poured onto ice water/isopropyl acetate 1/1 and acidified with 1 N aqueous HCl solution. The layers were separated and the aqueous layer was extracted two times with isopropyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure to give 2-chloro-5-ethyl-nicotinic acid as white solid (292 mg, 1.57 mmol; 97%) which was used in the next step without further purification. MS: m/e=184.1 [M−H−].
Reaction SMILES: CO.[OH-].[Na+].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([NH:24][C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:32]=2)=[O:26])[CH:12]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:24][C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:32]=2)=[O:26])[CH:12]=1
Reactant: Cn1cccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cccc1-c1ccc(C(=O)O)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
Methanol (1.5 mL), dioxane (1.5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.24 mL) were added the obtained tert-butyl 4-(1-methyl-1H-pyrrol-2-yl)-2-(5-phenylpyridine-3-carboxamido)benzoate (71 mg), followed by stirring at 50 to 55° C. for 2 hours. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid was added thereto. The solid substance was collected by filtration to obtain 50 mg of 4-(1-methyl-1H-pyrrol-2-yl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a white solid.
Reaction SMILES: O[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].C([CH2:14][C:15]([OH:17])=[O:16])#N>>[OH:11][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH2:14][C:15]([OH:17])=[O:16])=[CH:2]1
Reactant: O=C1c2ccccc2CC1O
Reactant: N#CCC(=O)O
Product: O=C(O)CC1=CC(O)c2ccccc21

Procedure:
In an alternative preparation scheme, the intermediate hydroxyindanone can be reacted with cyanoacetic acid to give the corresponding hydroxyindene-3-acetic acid, which is then esterified before introduction of the R5 -methylene grouping in order to facilitate the purification of desired intermediates. Since introduction of the R5 -methylene grouping is accompanied by ester hydrolysis, the intermediate free acid is re-esterified to facilitate purification followed by reaction with an appropriate haloalkyl-A group to yield the desired final product ##STR20## can be prepared by reacting a halo-indene-3-acetic acid with a A(CH2)n -containing benzaldehyde prepared from the corresponding individual components ##STR21##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[OH-:24].C[N+](C)(C)C.Br[CH2:31][CH2:32][CH:33]1[O:38][CH2:37][CH2:36][CH2:35][O:34]1>C(#N)C.C(OCC)(=O)C>[O:34]1[CH2:35][CH2:36][CH2:37][O:38][CH:33]1[CH2:32][CH2:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:31][CH2:32][CH:33]3[O:38][CH2:37][CH2:36][CH2:35][O:34]3)=[CH:12][CH:11]=2)([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:31][CH2:32][CH:33]3[O:34][CH2:35][CH2:36][CH2:37][O:24]3)=[CH:21][CH:22]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: [OH-]
Reactant: BrCCC1OCCCO1
Agent: C[N+](C)(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(c1ccc(OCCC2OCCCO2)cc1)(c1ccc(OCCC2OCCCO2)cc1)c1ccc(OCCC2OCCCO2)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
26.8 g of tris(4-hydroxyphenyl)ethane was dissolved in 180 ml of acetonitrile in a flask and added with 126 ml of tetramethylammonium hydroxide (25% aqueous solution) and then, with 39.4 ml of 2-(2-bromoethyl)-[1,3]-dioxane. The resulting solution was heated to 80° C. and stirred for 10 hours. The reactant mixture was diluted with 250 ml of ethyl acetate and washed with 300 ml of 5% aqueous sodium hydroxide solution and then, with 300 ml of saline. The organic layer was dried over magnesium sulfate, filtered and deprived of the solvent. The residue was crystallized in methanol, to give 46 g of 1,1,1-tris-[4-(2-[1,3]-dioxan-2-yl ethoxy)phenyl]ethane as a white powder (mp=101° C.), represented by the following formula. ##STR9##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)#[N:7].[OH-].[K+]>C(O)C.O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:2][CH2:3][CH2:4][OH:5])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)#[N:7]
Reactant: OCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(OCCCO)cc2)cc1
Temperature: 25 °C

Procedure:
3-Bromo-1-propanol (5.6 g, 0.04 mol) and 4-cyano-4'-hydroxybiphenyl (6.0 g, 0.02 mol) were dissolved in ethanol (300 ml) and agitated at room temperature. To this solution was gradually dropwise added a solution of KOH (10 g) dissolved in water (20 ml), over 30 minutes, followed by stirring for 40 hours, distilling off about 200 ml of ethanol under reduced pressure, adding water (500 ml) to deposit solids, adding toluene (300 ml) to the mixture system, filtering off insoluble matter, washing the toluene solution twice with 2N-NaOH, then three times with water, drying over anhydrous sodium sulfate, distilling off toluene, and recrystallizing the resulting crystals from methanol to obtain 4-cyano-4'-(3-hydroxypropoxy)biphenyl. Yield: 2 g (28%). C-N: 109.0°-110.7° C. N-I: 113.6° C.
Reaction SMILES: [Na+].[Cl-].[Cl-].[K+].[C:5]([O-:8])([OH:7])=O.[Na+].[O:10]=[CH:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])O>>[CH2:11]([OH:10])[C@H:12]1[O:7][C@H:5]([O:8][C@:12]2([CH2:11][OH:10])[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@@H:14]2[OH:15])[C@H:18]([OH:19])[C@@H:16]([OH:17])[C@@H:14]1[OH:15]
Reactant: O=C([O-])O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
The Ringer solution contained: 124 mM NaCl, 3 mM KCl, 1.3 mM NaH2PO4, 2 mM MgCl2H2O, 2 mM MgCl2-6H2O, 26 mM NaHCO3, and 10 mM Dextrose. The pH was adjusted to 7-7.5 using bubbled 95% O2-5% CO2 This Ringer solution was used for storing nerves and for filling the two stimulating pools (500 ul) and the recording “intracellular” pool.
Reaction SMILES: [CH2:1](OC(=O)C)C.Cl.C(OCC)(=O)C.[CH:14]([C:16]1[CH:48]=[CH:47][C:19]([O:20][CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])OC(C)(C)C)=[CH:30][C:29]=3[CH3:46])[CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)=[O:15].C(Cl)(=O)C>C(N(CC)CC)C.ClCCl>[CH:14]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:29]([CH3:46])=[CH:30][C:31]([O:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[CH3:1])=[CH:32][C:33]=3[CH3:34])[CH:25]=[CH:26][CH:27]=2)=[CH:47][CH:48]=1)=[O:15]
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)NCCOc1cc(C)c(-c2cccc(COc3ccc(C=O)cc3)c2)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 4 M hydrogen chloride ethyl acetate solution was dropwise added under ice-cooling to an ethyl acetate solution of tert-butyl [2-({3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)ethyl]carbamate, followed by stirring at 0° C. for 2 hours. Dichloromethane, acetyl chloride and triethylamine were added to the resulting compound, followed by stirring at room temperature for 12 hours to obtain N-[2-({3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)ethyl]acetamide.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[CH2:11][O:12][CH2:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23]CC)=[C:19]([Cl:26])[CH:18]=1)([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[OH-].[K+]>CN1CCN(C)C1=O>[O:1]([C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[CH2:11][O:12][CH2:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:26])[CH:18]=1)([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN1CCN(C)C1=O
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)c(Cl)c1
Yield: 50 %

Procedure:
With respect to the production of the compound of the formula (II), there is known only a process disclosed in Japanese Patent Application Kokai (Laid-Open) No. 212335/1987. The document discloses a process for producing 3-chloro-4-hydroxyneophyl m-phenoxybenzyl ether [a compound of the formula (II) wherein X1 =Cl and X2 =H] by subjecting 4-ethoxy-3-chloroneophyl m-phenoxybenzyl ether to an ether cleavage reaction. It is specifically a process comprising subjecting 4-ethoxy-3-chloroneophyl m-phenoxybenzyl ether to ether cleavage in N,N'-dimethylimidazolidinone, using excessive potassium hydroxide as an ether cleavage agent. According to the document, 4-hydroxy-3-chloroneophyl m-phenoxybenzyl ether was obtained under the reaction conditions of 150° C. and 18 hours, but the yield was as low as about 50%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn](Cl)(C)C.[N-:30]=[N+:31]=[N-:32].[Na+]>C1(C)C=CC=CC=1>[OH2:8].[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[C:11]1[N:30]=[N:31][NH:32][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: C[Sn](C)(C)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O
Product: c1ccc(COc2ccc(-c3nn[nH]n3)c(OCc3ccccc3)c2)cc1
Yield: 137.4 %

Procedure:
A suspension of 2,4-dibenzyloxybenzonitrile (1.89 g) in dry toluene (200 mL) is treated with trimethyltin chloride (6 g) and sodium azide (2 g). The mixture is stirred at reflux for 3 days, evaporated and the residue partitioned between dichloromethane (250 mL) and water (165 mL). The organic phase is washed with brine (165 mL), dried over magnesium sulphate and evaporated. The resulting semi-solid is triturated with ether (30 mL) and the solid washed with pentane and crystallised from a mixture of ethyl acetate and pentane to give 5-(2,4-dibenzyloxyphenyl)-2H-tetrazole hydrate (1.55 g) as a white solid, m.p. 178-179° C. [Elemental analysis:- C,69.7; H,5.02; N,15.4%. Calculated for C21H18N4O2.0.2H2O:- C,68.68; H,5.12; N,15.48%].
Reaction SMILES: [Li][C@H]1CC(C(O)=O)N([Li])C1=O.[Li]CCCC.[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.O>CCOCC>[CH:19]1([CH:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: [Li]CCCC
Agent: [Li][C@H]1CC(C(=O)O)N([Li])C1=O
Solvent: O
Solvent: CCOCC
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 1.5 g of dilithio (s)-(-)-2-pyrrolidone-5-carboxylic acid (12 mmol) in 40 mL of ether was added 16 mL of n-BuLi (1.6M solution in hexanes, 25 mmol) at 0° C. This solution was stirred for 30 min at room temperature. 6-Methyl-6-phenylfulvene, 1.0 g,(6 mmol) in 5 mL of ether was added dropwise at -78° C. and the color of the reaction mixture turned green. The resulting solution was stirred for 7 h at -78° C. and the color of the reaction mixture turned yellow. Water, 25 mL, was added dropwise at -78° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of solvent gave 1.0 g (99% yield) of 1-cyclopentadienyl-1-phenylethane as a light yellow oil. [α]D =6.0° (CHCl3, 17.4% ee.