Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:14].O.O.[Sn](Cl)[Cl:18]>O.Cl>[ClH:18].[NH:5]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:14])[NH2:1]
Reactant: Cc1cc(C#N)ccc1N
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(C#N)ccc1NN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36 %

Procedure:
A solution of sodium nitrite (0.52 g, 7.57 mmol) in water (3 mL) was added dropwise to a cold (0° C.) mixture of 4-amino-3-methylbenzonitrile (1 g, 7.57 mmol) and concentrated HCl (12 mL) keeping the internal temperature below 0° C. After 5 min stirring, tin dichloride dihydrate (3.75 g, 16.6 mmol) in concentrated HCl (4 mL) was added at 0° C. The reaction mixture was allowed to warm to rt and stirred for 2 h. The resulting precipitate was collected by vacuum filtration and dried to provide 500 mg of the title compound. tR: 0.24 min (LC-MS 2); ESI-MS: 148 [M+H]+ (LC-MS 2).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=1[OH:15])=[O:8].[CH3:17][C:18](O)([CH3:20])[CH3:19]>FC(F)(F)C(O)=O>[C:18]([C:11]1[C:12]([OH:16])=[CH:13][C:14]([OH:15])=[C:9]([C:7](=[O:8])[CH3:6])[CH:10]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cc(C(C)(C)C)c(O)cc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Sulphuric acid (4 ml, 75 mmol) was added to a suspension of 2,4-dihyroxyacetophenone (22.8 g, 150 mmol) in a mixture of 2-methyl-2-propanol (35 g, 470 mmol) and trifluoroacetic acid (80 ml), under a nitrogen atmosphere. The resulting suspension was heated, oil bath temperature 75° C., for ˜3 hrs. to give a pale red solution. The resulting solution was allowed to cool and poured into ice/water (350 ml), to give a pale pink precipitate. The solids were removed by filtration and washed with water (600 ml) and hexane (200 ml) to give a pale pink powder. Dried in vacuo (40° C.), to give 1-(5-tert-butyl-2,4-dihydroxy-phenyl)-ethanone as a pale orange powder (28.8 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([N+:20]([O-:22])=[O:21])=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=Cc1c(Cl)[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 1 h

Procedure:
15 g of (1) was added to a mixture of 150 ml acetic acid and 150 ml of acetic anhydride at 0°. 3.5 ml of 100% HNO3 was slowly added, and after 1 hour another 3.5 ml of 100% HNO3 was added. Stirring was continued for 1 hour at 0° C. The mixture was then added to ice, left in the cold overnight, and filtered to give 10 g of (65), which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([Cl:14])[N:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.C(=O)([O-])[O-].[Ce+3].C(=O)([O-])[O-].C(=O)([O-])[O-].[Ce+3]>C1COCC1.O1CCOCC1.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>[Cl:14][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([C:19]3[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=3)[CH:3]=2)[N:8]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: COc1cc2nc(Cl)ncc2cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)nc3cc2OC)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 37.7 %

Procedure:
A mixture of 6-bromo-2-chloro-7-methoxyquinazoline (2.4 g, 8.82 mmol), 3,5-dimethoxyphenylboronic acid (1.6 g, 8.82 mmol), cerium carbonate (8.6 g, 26.46 mmol) and Pd(PPh3)2Cl2 (1.4 g, 2.1 mmol) in THF (10 mL), dioxane (10 mL) and water (2 mL) was degassed with nitrogen three times and stirred at 85° C. for 3 h. LCMS monitored the reaction was completed. The mixture was cooled to RT and extracted with dichloromethane (3×50 mL). The organic layers were separated, combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:4) to give the title compound (1.1 g, 38%) as a white solid. MS (ES+) C17H15ClN2O3 requires: 330, 332. Found: 331, 333 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1)=O.[CH3:27][NH:28][CH3:29].C1C(C(O)=O)=CC=C(NCC(NCC#N)=O)C=1>>[CH3:27][N:28]([CH2:1][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1)[CH3:29]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)nc(C(F)(F)F)n2)CC1
Agent: N#CCNC(=O)CNc1ccc(C(=O)O)cc1
Product: CN(C)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared according to the method of Example 41, Step 2 using tert-butyl 4-{[6-formyl-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate and dimethylamine as starting materials. LCMS (M+H-100)+: 405.2.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[N:9][C:8]=2[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[C:13]2[NH:12][CH2:11][CH2:10][NH:9][C:8]=2[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c2nccnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1ccc(N)c2c1NCCN2
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Compound 468A (0.037 g, 0.18 mmol) was dissolved in a mixture of ethyl acetate (1.0 mL)/ethanol (1.0 mL) and 10% Pd/C (0.050 g) was added. Hydrogen was then introduced via a balloon. After 2 h, the reaction was purged with nitrogen and filtered through Celite, rinsing with ethyl acetate. Concentration in vacuo gave 0.029 g (90%) of compound 469A as a red oil, which was taken on without further purification. HPLC: 97% at 3.217 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: C(OCC)(=O)CCC.CCC(O)CC.[C:15]([O:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:19])[CH2:16]CC>C(O)C>[C:15]([O:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:19])[CH3:16]
Reactant: CCCC(=O)OC(CC)CC
Solvent: CCC(O)CC
Solvent: CCO
Solvent: CCCC(=O)OCC
Product: CCC(CC)OC(C)=O

Procedure:
These reactions were also studied with unsymmetrical esters. The reaction of ethyl butyrate with 3-pentanol in the presence of 1 mol % of 1 under refluxing toluene led to 75% conversion of ethyl butyrate with the formation of 73% of 3-pentyl butyrate as the exclusive product (entry 16). Traces of 3-pentyl acetate, resulting from reaction with the formed ethanol, were also observed. The remaining ethanol probably evaporated from the reaction mixture under the reflux conditions. Similarly, the reaction of methyl hexanoate with cyclohexanol results in 42% conversion after 17 h with the formation of 42% of cyclohexyl hexanoate (entry 17).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(Cl)=[O:20].[CH2:23]1[C:30]2([CH2:31][NH2:32])[N:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25][CH2:24]1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:23]1[C:30]2([CH2:31][NH:32][C:19](=[O:20])[NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[O:4][CH:1]([CH3:3])[CH3:2])[N:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25][CH2:24]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)Oc1ccccc1N
Reactant: NCC12CCCN1CCC2
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1NC(=O)NCC12CCCN1CCC2
Reaction time: 1.5 h
Yield: 85 %

Procedure:
2-isopropoxy-aniline (123 mg, 0.813 mmole) was dissolved in CHCl3 (1 ml), added triethyl amine 0.113 ml, 0.813 mmole). Cooled soln. to 0° C., added a solution of 20%. phosgene in toluene 0.458 ml. 0.927 mmole) and stirred for 1.5 hours. To this solution was added tetrahydro-1H-pyrrolizin-7a(5H)-methylamine (114 mgs, .813 mmole) in CHCl3 and stirred for 18 hours. Solvent removed via rotary evaporator to give crude product as a solid. Solid was chromatographed on silica gel eluting with 5% CH3OH(NH3↑)/CHCl3 to give 220 mg (85%) of title compound as free base.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].[C:14](Cl)([Cl:16])=[O:15]>C1(C)C=CC=CC=1>[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]([Cl:16])=[O:15])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CCCCCNCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCN(CCCCC)C(=O)Cl
Reaction time: 0.5 h

Procedure:
A mixture of 7.86 g. (50.0 mmole) of dipentylamine, 18.05 ml (50.0 mmole) of 2.77M NaOH solution and 60 ml of toluene was vigorously stirred at -7° to -5° C., and 60 ml (115.8 mmole) of 1.93M phosgene in toluene was added dropwise over 1 hour. After stirring an additional 30 min., the cold mixture was separated and the toluene layer was dried over solid NaCl. After filtering, nitrogen was bubbled through the solution for 1 hour and the solution was concentrated in vacuo to 10.5 g. (95%) of light yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[Cl:18])[N:9]=[CH:8][C:7]=1[C:19]#[N:20].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[Cl:18])[N:9]=[CH:8][C:7]=1[C:19]#[N:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(-n2ncc(C#N)c2N)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1c(C#N)cnn1-c1ccc(C)cc1Cl

Procedure:
Acetyl chloride (34 ml) was added to a stirred suspension of 5-amino-1-(2-chloro-4-methylphenyl)-4-cyanopyrazole (8.0 g) in chloroform (34 ml) at 0° C. A solution of pyridine (5.4 ml) in chloroform (34 ml) was then added to the suspension thus obtained over 10 minutes, with stirring at 0° C. to 2° C. maintained by external cooling. The reaction mixture was then stirred at laboratory temperature for 2.5 hours and the solution thus obtained was evaporated to dryness. The residue was dissolved in ethanol (100 ml) and basified with aqueous ammonia (d: 0.880). The basified solution was heated at reflux for 10 minutes and then evaporated to dryness. The residue was dissolved in dichloromethane (500 ml) and water (500 ml) and the organic layer was separated, washed successively once with water, twice with 2N hydrochloric acid and twice with water, dried over anhydrous magnesium sulphate and evaporated. The colourless solid thus obtained was crystallised from toluene (30 ml) to give 5-acetamido-1-(2-chloro-4-methylphenyl)-4-cyanopyrazole (6.54 g), m.p. 146°-147° C., in the form of colourless crystals.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]([OH:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:8][C:9]#[CH:10])([CH3:4])[CH3:3].N1C=CN=C1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].CCCCCC>CN(C)C=O>[CH3:23][Si:22]([O:15][C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:1])[CH3:4])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:8][C:9]#[CH:10])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(C#C[Si](C)(C)C)CCCC
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(C#C[Si](C)(C)C)(CCCC)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a stirred mixture of 8.5 g of 4-trimethylsilylethynyl-1-octyn-4-ol and 6.2 g of imidazole in 24 ml of dry dimethylformamide is added, under nitrogen, 5.7 ml of chlorotrimethylsilane, in a slow stream, via a syringe. The mixture is stirred in an ice bath for one hour and then at room temperature overnight. The mixture is poured into hexane, washed with saturated sodium bicarbonate solution, water and then brine and dried over sodium sulfate. The solvents are evaporated to dryness giving 11.1 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Cl[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[C:3]([O:16][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: Cc1ccnc(Cl)c1
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(Oc3cc(C)ccn3)c2CC[C@@H]1C
Temperature: 120 °C
Yield: 42.3 %

Procedure:
A 20-mL microwave tube was charged with 1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (200 mg, 0.70 mmol), 2-chloro-4-methylpyridine (180 mg, 1.41 mmol), N,N-dimethylformamide (15 mL), copper (I) iodide (133 mg, 0.70 mmol), and cesium carbonate (700 mg, 2.10 mmol). The reaction mixture was heated with microwave radiation for 8 h at 120° C. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate (50 mL), washed with water (3×15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (eluting with 2:1, ethyl acetate/petroleum ether) to afford 1-[(2S)-6-bromo-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (111 mg, 42%) as a light yellow solid. MS (ESI, pos. ion) m/z 375, 377 [M+H]+.
Reaction SMILES: [CH2:1]([CH:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]=[O:17])[CH:11]=2)[NH:6]1)[CH2:2][CH2:3][CH3:4].[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1NC(=O)c2cc(C=O)ccc2N1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)c3ccccc3)ccc2[nH]1
Reaction time: 1 h

Procedure:
To a stirred solution of 2.00 g of 2-butyl-1,2-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 100 ml of tetrahydrofuran, cooled at 0° C., is added 13.0 ml of 2.0 M phenyllithium and stirring continued for 1 hour. The cooling is removed and the reaction allowed to reach room temperature followed by an additional 30 minutes at room temperature. The reaction is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried, evaporated to a residue, which is purified by chromatography on silica gel by elution with 0.25:100 methanol-chloroform to give 0.932 g of the desired product. CI MASS SPEC 309(MH+).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH3:11][Si:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>O1CCCC1>[O:4]=[C:2]([CH:15]([CH2:14][CH2:13][Si:12]([CH3:21])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:11])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CCC[Si](C)(C)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(CC[Si](C)(C)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Yield: 92.2 %

Procedure:
In a flask under a nitrogen atmosphere were placed 1.7 g (0.075 mole) metallic sodium and 75 mL of absolute ethanol. When all of the sodium had reacted, the remaining ethanol was evaporated, leaving solid sodium ethoxide. To this solid were added successively 100 mL of dry tetrahydrofuran, 11.0 g (0.075 mole) of diethyl oxalate, and 12.95 g (0.0517 mole) of ethyl 5-methyl-5-phenyl-5-silahexanoate. This mixture was heated at reflux for one hour after which it was cooled to ambient temperature before being poured into 240 mL of 0.5N hydrochloric acid. This mixture was extracted with 200 mL of diethyl ether. The extract was evaporated under reduced pressure, leaving 16.7 g of diethyl 2-oxo-3-(3-methyl-3-phenyl-3-silabutyl)succinate as an oil. This reaction was repeated to provide additional product for subsequent steps in this synthesis.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[OH:11].CC(C)=O.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[O:11][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc2cccc(O)c2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1cc2cccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To the compound from step A, acetone (15 mL) was added followed by benzyl bromide (670 μL, 5.6 mmol) and Cs2CO3 (1.8 g, 5.6 mmol) and the reaction mixture stirred at RT for 18 h. A second aliquot of BnBr (140 μL) and Cs2CO3 (380 mg) was added and stirring continued for 24 h. The reaction mixture was poured into EtOAc and water, the layers were separated, and the aqueous layer was further extracted with EtOAc (3×50 mL). The combined organic extracts were washed with 1N NaOH and water and dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (hexanes then 5% EtOAc/hex) afforded 2-methyl-7-benzyloxy indole as an unstable solid (898 mg, 81% yield). 1H NMR impure; 238.17, M+H.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9]C)(=[O:5])[CH:2]([CH3:4])[OH:3].[C:11](O)(=O)C(C)O.C(O)CCC>Cl.O.C(O)CCC>[C:1]([O:6][CH2:7][CH:8]([CH3:9])[CH3:11])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: CCCCOC(=O)C(C)O
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CC(C)COC(=O)C(C)O

Procedure:
The composition of matter of 1-butyl lactate is and its preparation are disclosed in Gabriel et al. U.S. Pat. No. 1,668,806 (1928). They prepared 1-butyl lactate by dehydrating 70% lactic acid with excess 1-butanol at 117° C., followed by addition of HCl catalyst, followed by refluxing and esterification with addition excess 1-butanol and drawing a 1-butanol water azeotrope overhead. Nakanishi and Tsuda (Japanese Patent JP 46/30176 [71/30176]) consider production of 1-butyl lactate by extraction of an acidified crude fermentation broth with 1-butanol, followed by esterification of the extract phase. BASF (EP 159-285) considers production of isobutyl lactate by extraction of an acidified crude fermentation broth with isobutanol, followed by esterification of the extract phase, which was then distilled in vacuum 80° C./25 mbar to give a purified isobutyl lactate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Reactant: OCCCC1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CCCO)CC1)c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
A mixture of 0.200 g (0.663 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide and 0.190 g (1.33 mmol) of 3-piperdin-4-yl-propan-1-ol in N,N-dimethylformamide (5 mL) is heated to 130° C. and stirred for 2 days. The mixture is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.130 g (47%) of 3-chloro-N-[5′-chloro-4-(3-hydroxy-propyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide as a light brown foam.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C@@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8]>CCO>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C@@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: NN
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)NN)cc2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate (2.29 mL, 47.1 mmol) was added in one portion to a stirred solution of ethyl cis-4-(4-{[methoxy(oxo)acetyl]amino}phenoxy)cyclohexanecarboxylate (8.23 g, 23.6 mmol) in EtOH (200 mL) and the reaction mixture was stirred at 70° C. for 1 h. After cooling to ambient temperature the mixture was filtered and washed with ether (200 mL) to leave the title compound (Intermediate 1) as a white solid (7.80 g, 95%) that was used with no further purification.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:27]2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=[C:23]([NH2:30])[C:22]=2[N:21]=[C:20]1[CH3:31]>>[NH2:30][C:23]1[C:22]2[N:21]=[C:20]([CH3:31])[N:19]([CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[C:27]=2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 17-32, trans-2-phenylcyclopropylcarbonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7trimethyl1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method B. The observed accurate mass was 408.2392.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.Cl.N12CCC(CC1)C(=O)C2.[H][H]>[OH-].[Zr+4].[OH-].[OH-].[OH-]>[OH:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O=C1CN2CCC1CC2
Reactant: [H][H]
Agent: [Zr+4]
Agent: Cl
Agent: [OH-]
Product: OC1CN2CCC1CC2

Procedure:
It has also been found that quinuclidin-3-one or a corresponding salt, such as, quinuclidin-3-one hydrochloride, can be reduced by means of a secondary alcohol as the hydrogen donor in the presence of amorphous, partially dehydrated zirconium hydroxide (ZrO2.xH2O) in the manner of a Meerwein-Ponndorf-Verley reduction to give a good yield of 3-hydroxyquinuclidine or the corresponding salt. If the reduction is carried out using a salt of quinuclidin-3-one, the resulting 3-hydroxyquinuclidine salt can, if desired, be converted into the free 3-hydroxyquinuclidine by addition of a strong base during the work-up of the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21])([O-:12])=[O:11].C(N(CC)CC)C.O>C(OC(=O)C)(=O)C>[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[C:20]([OH:22])=[O:21])([O-:12])=[O:11]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: O=Cc1ccc(Br)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C(=Cc1ccc(Br)cc1)c1ccccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
A solution of 4-bromobenzaldehyde (27.75 g, 0.150 mol), 2-nitrophenylacetic acid (27.18 g, 0.150 mol) and triethylamine (21.0 ml, 0.150 mol) in 150 ml of acetic anhydride was heated at 40° C. for 38 hours and then poured into 900 ml of water and stirred until the organic layer solidified. The solid was isolated by filtration and dried in vacuo to yield 48.3 g (92%) of the title compound as a tan solid which was sufficiently pure to use directly in the next reaction.