Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[S:24]1[CH2:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH2:26][CH2:25]1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:27]3[CH2:28][CH2:29][S:24][CH2:25][CH:26]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCSCC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting materials 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine and 2-(3,6-Dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. 1H-NMR (CDCl3, 400 MHz): 6=1.79 (d, J=6.8 Hz, 3H), 2.47-2.68 (m, 2H), 2.82 (t, J=5.8 Hz, 2H), 3.20-3.46 (m, 2H), 4.68 (br. s., 2H), 6.31-6.38 (m, 1H), 6.44 (q, J=6.7 Hz, 1H), 6.97 (t, J=8.5 Hz, 1H), 7.30 (s, 1H), 8.14 (s, 1H). MS (ES+): m/z (MH+, 35Cl, 37Cl), 440.94 (MH+, 37Cl, 37Cl). HPLC: tR=3.69 min (polar—5 min, ZQ3).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31]C(OC)=O)=[CH:26][C:25]=1[OH:36]>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:36][C:25]3[CH:26]=[C:27]([OH:31])[C:28]([CH3:30])=[CH:29][C:24]=3[F:23])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: COC(=O)Oc1cc(O)c(F)cc1C
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Oc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccccc1
Yield: 73.8 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (132 mg, 0.4 mmol), (prepared as described for the starting material in Example 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylphenol (96 mg, 0.48 mmol) in pyridine (2 ml) was heated at reflux for 3 hours. The mixture was allowed to cool, the solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ether (70/30). The resulting solid was crystallised from methylene chloride and methanol to give 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline (120 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][C:4]=1[CH3:13].CO.CCOC(C)=O.CCCCCCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][C:4]=1[CH3:13]
Reactant: COc1ccc(CC(=O)O)cc1C
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCO)cc1C
Reaction time: 18 h
Yield: 106.8 %

Procedure:
2-(4-methoxy-3-methylphenyl)acetic acid (1 g, 5.55 mmol) was dissolved in Tetrahydrofuran (27.7 ml). A solution of borane tetrahydrofuran complex (12.21 ml, 12.21 mmol) was added slowly under nitrogen. The reaction was stirred for about 18 h. Methanol was slowly added to quench the reaction The solution was rotovapped. More methanol was added. The solution was rotovapped. This was repeated twice. The solution was passed through a short pad of silica gel eluting with 1:1 EtOAc/heptane and then rotovapped to give 2-(4-methoxy-3-methylphenyl)ethanol (0.986 g, 5.93 mmol, 107% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.05 (m, 1H), 7.04 (m, 1H), 6.80 (m, 1H), 3.85 (s, 3H), 3.84 (t, 2H), 2.81 (t, 2H), 2.25 (s, 1H), 1.64 (s, 1H)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C@H:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].S(=O)(=O)(O)O.II.O.O.[I:26](O)(=O)(=O)=O>C(O)(=O)C.O>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][C@H:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:26])=[CH:10][CH:9]=1)=[O:4]
Reactant: C[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](Cc1ccc(I)cc1)NC(=O)C(F)(F)F
Temperature: 70 °C
Yield: 185.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[(1R)-1-methyl-2-phenylethyl]acetamide (3.75 g) in acetic acid (32 ml)—water (6.5 ml)—sulfuric acid (0.97 ml) were added iodine (1.65 g) and periodic acid dihydrate (740 mg) at room temperature, and the mixture was heated to 60-80° C. for 5 hours. After being allowed to cool to room temperature, the mixture was partitioned between hexane/ethyl acetate and water. The organic layer was separated, washed successively with water, sodium sulfite solution, water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was recrystallized from diisopropyl ether (44 ml) to give 2,2,2-trifluoro-N-[(1R)-2-(4-iodophenyl)-1-methylethyl]acetamide (2.15 g) as a colorless needle.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])#[N:15]>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([CH:19]([OH:20])[C:18]2[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=2)[C:14]#[N:15])[CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)c2cccc(Br)n2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 2,6-dibromopyridine (6 g, 25.33 mmol) in anhydrous THF (150 mL) under N2 @−78° C. was added n-BuLi (10.13 mL, 2.5M) dropwise. The mixture was stirred @ −78° C. for 15 min and 3-cyanobenzaldehyde (3.32 g, 25.33 mmol) in anhydrous THF (10 mL, rinsed with 5 mL) was added. The mixture was stirred for 20 min @ −78° C. then warmed to 0° C. and stirred for 1 hr. The mixture was quenched with saturated aqueous NH4Cl, and the resulting mixture was extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (15-30% EtOAc in Hexanes) to give 3-[(6-bromopyridin-2-yl)(hydroxy)methyl]benzonitrile. LRMS m/z (M+H) Calcd.: 289.0, found 289.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[N:12]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1.CN(C)C.[C:22]1([CH3:28])[CH:27]=[CH:26]C=CC=1>>[CH:27]1([CH2:26][N:12]([C:13]2[NH:17][CH2:16][CH2:15][N:14]=2)[C:3]2[C:4]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:22][CH2:28]1
Reactant: Fc1cccc(C(F)(F)F)c1N=C1NCCN1
Reactant: Cc1ccccc1
Agent: CN(C)C
Product: Fc1cccc(C(F)(F)F)c1N(CC1CC1)C1=NCCN1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
A mixture consisting of 8 gm (0.032 mol) of 2-[(2-fluoro-6-trifluoromethyl-phenyl)-imino]-imidazolidine, 4.6 gm (105% of the stoichiometrically required amount), 5 cc of trimethylamine acid 25 ml of absolute toluene was heated at 120° C for 18 hours in a closed tube. After cooling, the liquid phase was decanted, the solid residue was dissolved in about 150 cc of 1N hydrochloric acid, the solution was extracted several times with ether, and the ethereal extracts were discarded. The acidic aqueous phase and fractionally extracted with ether at stepwisely increasing pH-values (alkalization with dilute sodium hydroxide). The thin-layer chromatographically uniform fractions were combined, dried over Drierite (calcium sulfate) and evaporated to dryness in vacuo. The residue was caused to crystallize by stirring it with petroleum ether, the mixture was suction-filtered, and the filter cake was dried, yielding 5.7 gm (58.4% of theory) of 2-[N-(cyclopropyl-methyl)-N-(2-fluoro-6-trifluoromethyl-phenyl)-amino]-2-imidazoline, m.p. 126°-127° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[OH:11])([O-])=O.CO>C1COCC1.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(Br)c1O
Reaction time: 4 h

Procedure:
5 g (22.9 mmol) 2-nitro-6-bromo-phenol (Fluka 67211) is hydrogenated in the presence of 0.1 g Ra—Ni (B113W EtOH, Degussa) in 100 ml of THF:MeOH=1:1. for 4 h. The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane:EtOAc=2:1) to afford the title compound as a reddish oil which slowly solidifies.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[CH2:15]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30](NC(=O)OCCCl)(=[O:32])=[O:31])=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][S:30](=[O:31])(=[O:32])[NH:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:28][CH:27]=2)[CH2:7][CH2:6]1
Reactant: CCCCCCCCc1ccc(NS(=O)(=O)NC(=O)OCCCl)cc1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Product: CCCCCCCCc1ccc(NS(=O)(=O)NC2(CC(=O)OCC)CCN(C)CC2)cc1
Yield: 34.2 %

Procedure:
According to the method described in example 15a, ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (70 mg, 0.35 mmol) and 2-chloroethyl N-(4-octylphenyl)sulfamoylcarbamate (195 mg, 0.5 mmol) were reacted to yield the title compound (56 mg, 34%). MS ESI 468.4 [M+H]+, calcd for [C24H41N3O4S+H]+ 468.29.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:18])=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1cnc2ccc(C)cc2c1O
Product: CC(=O)c1cnc2ccc(C)cc2c1Cl

Procedure:
3-Acetyl-4-hydroxy-6-methylquinoline (0.02 mol), prepared according to R. K. MAPARA and C. M. DESAI (CA 50 1011 b) is added to 40 ml of freshly distilled phosphorus oxychloride. The mixture is brought to reflux for 10 minutes. The solution is brought back to room temperature and then poured onto an ice/caustic soda mixture. After extraction with dichloromethane, the ogranic phase is decanted, washed until neutral, dried and concentrated. The 3-acetyl-4-chloro-6-methylquinoline (m.p. 145° C.) is used without further purification for the following stage.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](OC)=[O:12].C(O)(C)C>O1CCCC1>[O:12]=[C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([C:7]([F:6])([F:18])[F:19])[CH:9]=1)[CH2:4][C:3]#[N:5]
Reactant: CC#N
Reactant: COC(=O)c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a suspension of 7.6 g of sodium hydride (60% dispersion in oil) in 200 mL of tetrahydrofuran under a nitrogen atmosphere was added dropwise at room temperature a solution consisting of 7.8 g of acetonitrile and 38.8 g of methyl 3-(trifluoromethyl)benzoate in 50 mL of tetrahydrofuran. Following addition, the suspension was stirred 1 h at ambient temperature, refluxed about 5 h, and then cooled to room temperature. Isopropyl alcohol (20 mL) was added dropwise at room temperature. After stirring about 15 min, the solvent was removed in vacuo, and about 200 mL of water was added to the residue. The aqueous suspension was washed with 3×50 mL diethyl ether and then acidified with concentrated hydrochloric acid to form a solid. The solid was isolated by filtration, washed 2×100 mL with water and then dissolved in methylene chloride. The organic solution was dried (MgSO4), filtered and concentrated to give 30.0 g of the title compound of Step A as a white solid melting at 51-55° C. 1H NMR (CDCl3): δ 8.1-8.2 (m,2H), 7.95 (d,1H), 7.7 (m,1H), 4.15 (s,2H); IR (mineral oil) 1704.1 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][CH2:4][CH:3]=1.[CH3:7][C:8]([CH3:10])=O.N1CCCC1.OP(O)(O)=O>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[C:8]([CH3:10])[CH3:7])[CH:6]=1
Reactant: CC(C)=O
Reactant: CC1=CCC=C1
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: C1CCNC1
Product: CC1=CC(=C(C)C)C=C1
Reaction time: 8 h

Procedure:
A solution of 2-methyl-1,3-cyclopentadiene (125 g, 1.56 mol) in 1.2 L of ethanol was treated at low temperature with 126 mL (1.72 mol) of acetone and 142 mL (1.72 mol) of pyrrolidine. The resulting solution was kept below room temperature overnight. Then the reaction mixture was neutralized with a 10% aq. solution of H3PO4, extracted with hexane (3×150 mL) and washed with water until neutral pH. The organic phase was separated, dried with MgSO4 and concentrated. The residue was distilled at 70° C./60 mmHg. Yield 112.6 g (60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:18])[C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH3:28]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:18])[C:16]=1[O:17][CH2:26][CH2:27][CH3:28])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: O=Cc1cc(I)c(O)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(I)cc(C=O)cc1OCc1ccccc1
Temperature: 77.5 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
To a mixture of 3-benzyloxy-4-hydroxy-5-iodo benzaldehyde (23.1 g, 0.065 mol) and potassium carbonate (11.70 g, 0.084 mol) in DMF (55 ml) was added 1-bromo propane (12.03 g, 0.09 mol). The reaction mixture was stirred at 75-80° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ether (480 ml). The ether layer was dried Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using (1:18) EtOAc: light petroleum as eluent to give the 3-benzyloxy-4-propoxy-5-Iodo benzaldehyde (21.4 g, 83%). TLC: Ethyl acetate:light petroleum (1:9), Rf=0.5; 1H NMR (CDCl3, 200 MHz): δ 1.03 (t, J=7.21 Hz, 3H), 1.75 (m, 2H), 4.05 (t, J=6.66 Hz, 2H), 5.15 (s, 2H), 7.3-7.45 (m, 6H), 7.83 (d, J=1.54 Hz, 1H), 9.79 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:2]([F:1])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)C(F)(F)Oc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Crude t-butyl 4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-carboxylate (15.30 g, 0.04M) was dissolved in DCM (150 ml) and TFA (30 ml) was added. The mixture was stirred at room temperature overnight, evaporated to dryness and azeotroped with toluene. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic phase was collected, dried over MgSO4, filtered and evaporated to dryness to yield 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a solid (10.97 g, 98%)
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5](=[O:41])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:35]1([CH2:34][O:33][C:20]2[C:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([C:5](=[O:41])[C:4]([OH:42])=[O:3])=[CH:11][CH:10]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
4-[6-[2,3-bis-(Phenylmethoxy)phenyl]hexyloxy]-alpha-oxobenzeneacetic acid ethyl ester (0.5 g) in methanol (50 mL) was treated with sodium carbonate (0.121 g) in water (2 mL), and the reaction was stirred at room temperature for 3 hours. After the solvents were removed in vacuo, dichloromethane and water were added and the mixture was acidified with 3N hydrochloric acid. The dried (Na2SO4) organic layer was evaporated to yield 0.4 g of 4-[6-[2,3-bis-(phenylmethoxy)phenyl]hexyloxy]-alpha-oxobenzeneacetic acid as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[N+:8]([C:7]1[C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCOC(=O)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1 g, 6.31 mmol), ethyl 4-pyridinecarboxylate (1.19 g, 7.57 mmol) and potassium carbonate (1.31 g, 9.47 mmol) in n-butanol (25 mL) was stirred at reflux for 2 hours, cooled to r.t., poured into water and extracted with diethyl ether. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 2:8) affording the title product (1.38 g).
Reaction SMILES: [OH-].[Li+].C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:10]=2[CH2:9]1)=O)C>O.O1CCOCC1>[O:18]([CH2:17][C:15]1[O:16][C:10]2[CH2:9][NH:8][CH2:13][CH2:12][C:11]=2[N:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)N1CCc2nc(COc3ccccc3)oc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(OCc2nc3c(o2)CNCC3)cc1
Temperature: 125 °C
Reaction time: 90 h
Yield: 43.6 %

Procedure:
Alternatively, the compound A7 can be prepared by conventional heating. Briefly, lithium hydroxide (CAS: 1310-65-2; 7.6 g, 320 mmol) was added to a stirred solution of 6,7-dihydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (19.2 g, 63.7 mmol) in a mixture of H2O (70 mL) and 1,4-dioxane (200 mL) under N2. The mixture was stirred at 125° C. for 90 hours and filtered through a pad of diatomaceous earth. The pad was washed with water and AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by short open column chromatography (silica; 7N solution of ammonia in methanol in dichloromethane, 0/100 to 3/97). The desired fractions were collected and evaporated in vacuo to yield 4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (6.4 g, 44% yield) as a brownish oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:9])([CH3:8])[CH3:7].C([Li])CCC.[CH3:15][C:16]1([CH3:27])[C:20]([CH3:22])([CH3:21])[O:19][B:18](OC(C)C)[O:17]1.Cl>C1COCC1>[CH3:15][C:16]1([CH3:27])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:5]2[S:1][C:2]([C:6]([OH:9])([CH3:8])[CH3:7])=[N:3][CH:4]=2)[O:17]1
Reactant: CC(C)(O)c1nccs1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1,3-thiazol-2-yl)propan-2-ol (40 g, 0.28 mol) in THF (400 mL) was add n-butyllithium (2.5 M in hexanes, 260 mL, 0.64 mol) dropwise at −78° C. After 30 minutes, 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (65 g, 0.35 mol) was added at −78° C. The reaction solution was then stirred at −78° C. After 1 hour, the reaction mixture was quenched with acetic acid, filtered, and concentrated under reduced pressure. The residue was diluted with hydrochloric acid (3.0 M solution in diethyl ether, 110 mL, 0.33 mol) and the mixture was filtered to afford 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazol-2-yl]propan-2-ol. MS ESI calc'd. for C12H21BNO3S [M+H]+ 270. found 270. 1H NMR (300 MHz, DMSO-d6): δ 8.01 (s, 1H), 1.49 (s, 6H), 1.28 (s, 12H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:18])[CH2:11][N:12]([OH:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][C:4]=1[Br:19].[BH4-].[Na+]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:18])[CH2:11][N:12]([OH:17])[C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:5][C:4]=1[Br:19]
Reactant: CC(C)(C)N(O)CC(=O)c1cc(F)c(N)c(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)N(O)CC(O)c1cc(F)c(N)c(Br)c1

Procedure:
m.p. 122°-125° C., was prepared from 4'-amino-3'-bromo-5'-fluoro-2-(hydroxy-tert.butylamino)-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:31]=[CH:30][C:11]([C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:32][SiH:33]([CH3:39])[O:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>C1(C)C=CC=CC=1.C1([Pt](Cl)(Cl)C2C=CC=C2)C=CC=C1>[CH3:32][Si:33]([CH3:39])([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][C:8]1[CH:31]=[CH:30][C:11]([C:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:20]=2)=[O:13])=[CH:10][CH:9]=1)[O:34][Si:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: C=CCCCCOc1ccc(C(=O)Oc2ccc(OCCCCCCCC)cc2)cc1
Reactant: C[SiH](C)O[Si](C)(C)C
Agent: Cl[Pt](Cl)(C1C=CC=C1)C1C=CC=C1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(OCCCCCC[Si](C)(C)O[Si](C)(C)C)cc2)cc1

Procedure:
0.94 g (0.024 mmol of Pt) of 0.5% strength dicyclopentadienylplatinum dichloride solution (dichloromethane) was added to a solution of 20.0 g (47.2 mmol) of 4-octyloxyphenyl 4-(5-hexenyloxy)benzoate and 7.10 g (48.0 mmol) of pentamethyldisiloxane in 20.0 g of toluene, and the mixture was refluxed for 5 hours. After complete hydrosilylation of the olefin, the reaction mixture was flushed with nitrogen, and the toluene was removed by vacuum distillation on a rotary evaporator. The crude product was purified by chromatography on silica gel. The 4-octyloxyphenyl 4-(6-pentamethyldisiloxanylhexyloxy)benzoate obtained was additionally recrystallized from ethanol and exhibited the following phase behavior: c 38 s 50 i.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:39]([NH2:42])([CH3:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:39]([NH:42][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:40])[CH3:41])[CH:36]=[CH:37][CH:38]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: COc1cccc(C(C)(C)N)c1
Product: COc1cccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c1
Yield: 64 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(3-methoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10b) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 64%.