Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][OH:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].Cl.C(O[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=N)C.C(N(CC)CC)C.O>ClCCCl>[CH3:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C@H:3]2[O:4][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:1][C@@H:2]2[CH2:15][OH:16])=[CH:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1

Procedure:
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) (about 10 g, 0.04077) is reacted at about 0° C. in a reaction vessel with benzenecarboximidic acid ethyl ester hydrochloride (Compound IV hydrochloride wherein R2 is phenyl and R4 is ethyl) (about 8.3 g, 0.0448 moles) in 1,2-dichloroethane (about 650 mL) containing triethylamine (about 4.1 g, 0.04077 moles). Next, water (about 500 mL) is added. The resulting solids are filtered, then dried to yield (4R,5R)-4,5-Dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is phenyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[CH:18]=[CH:17][S:16][C:12]3=[CH:13][N+:14]=2[O-])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:37]>CS(C)=O>[CH2:36]([N:38]1[CH2:43][CH2:42][N:41]([C:13]2[N:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]3[CH:18]=[CH:17][S:16][C:12]=23)[CH2:40][CH2:39]1)[CH3:37]
Reactant: CCN1CCNCC1
Reactant: COc1ccc(-c2cc3ccsc3c[n+]2[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3ccsc23)CC1
Temperature: 0 °C

Procedure:
5-(4-Methoxyphenyl)thieno[2,3-c]pyridine-6-oxide (3.0 g) was reacted with phosphorus oxychloride (15 ml) at 100° C. for 3 hr. The reaction mixture was poured into ice-water, neutralized with sodium carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and dried. The extract was filtered through silica gel, and the column was washed with ethyl acetate. The filtrates were combined and concentrated. The resulting 7-chloro-5-(4-methoxyphenyl)thieno[2,3-c]pyridine (2.1 g) was reacted reacted in N-ethylpiperazine (5 ml) and dimethyl sulfoxide (20 ml) with potassium carbonate (5.0 g) at 100° C. for 1 day. The reaction solution was evaporated, and the resulting residue was partitioned between ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and dried. Then, the solvent was removed, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.93 g of the title compound of as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]([CH3:17])[C:10]1=[O:18].Cl[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:22][N:21]=2)=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]([CH3:17])[C:10]1=[O:18]
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc(O)ccc2Br)c1=O
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(2-bromo-5-hydroxyphenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (5.29 g, 0.0168 mol), 2,3-dichloro-5-trifluoromethylpyridine (5.44 g, 0.025 mol) and potassium carbonate (3.45 g, 0.025 mol) in N,N-dimethylformamide is stirred at 80° C. for 18 hours, cooled to room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. The solid is recrystallized from an ether/hexanes solution to give the title product as a yellow solid, mp 97°-110° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[O:4][CH2:5][C:6]=1Br.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.[Cl-].[Na+].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>[Br:1][C:2]1[C:3](=[O:8])[O:4][CH2:5][C:6]=1[C:14]1[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=1
Reactant: O=C1OCC(Br)=C1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCC(c2ccc(C(F)(F)F)cc2)=C1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.4 %

Procedure:
A mixture containing 3,4-dibromofuran-2(5H)-one (0.518 g, 2.142 mmol), 4-trifluoromethylphenylboronic acid (0.509 g, 2.680 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.069 g, 9.831×10−2 mmol), tetrabutylammonium iodide (0.038 g, 1.029×10−1 mmol) and cesium fluoride (0.872 g, 5.740 mmol) in toluene (10 mL) and water (10 mL) was stirred at room temperature for 72 h under nitrogen. Brine (50 mL) was added and the product extracted with ethyl acetate (3×50 mL). The organic fractions were combined, washed with brine (3×50 mL), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give an orange solid. The resulting solid was chromatographed (silica gel: eluent 25:75 dichloromethane/light petroleum) to give 3-bromo-4-(4′-(trifluoromethyl)phenyl)furan-2-(5H)-one 16 (0.312 g, 47%) as a pale yellow powder. Further purification by recrystallisation from dichloromethane/light petroleum furnished colourless needles, (ref. PDS-2-115); 1H NMR (CDCl3, 300 MHz) δ 7.94 (d, 2H, J=8.3 Hz, H3′, H5′), 7.78 (d, 2H, J=8.3 Hz, H2′, H6′), 5.21 (s, 2H, H5).
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].C(O)(=O)C>C(#N)C>[CH2:7]([N:9]([CH2:10][CH3:11])[CH:3]=[CH:4][C:5]#[N:6])[CH3:8]
Reactant: CCNCC
Reactant: N#CC=CO
Agent: [Na]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(C=CC#N)CC
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
32.5 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 70%) is added to a solution of 25.6 g (0.35 mol) of diethylamine, 21.0 g (0.35 mol) of acetic acid and 150 ml of acetonitrile, and the mixture is stirred for 16 h at 25° C. After working up as in Example 50, 19.7 g of 3-diethylaminoacrylonitrile was obtained (63.6%).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36].C(O)(=O)C.C1CCCCC=1>C1(C)C=CC=CC=1.[Pd]>[C:11]([CH:10]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:18]1=[O:36])[CH2:9][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([OH:13])=[O:12]
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1=CCCCC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, then added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. After completion of the reaction the catalyst is filtered off through Celite, 50 ml of acetic acid are added and the solvent mixture is evaporated to kettle temperature of 110–120° C. The residue is taken up in 200 ml of toluene, 50 ml of acetic acid then cyclohexene (50 ml) and 10% Pd—C (26 g, 22 mmoles) are added. The reaction mixture is heated to 80° C. for 18 h, after that the catalyst is filtered off through Celite and solvents are evaporated off. The residue is taken up with isopropanol (500 ml) and the resulting precipitate is filtered, washed with 20 ml of isopropanol and dried to give 3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (15) (60.7 g, yield: 54%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH2:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)[CH3:16].C(=O)(O)[O-].[Na+]>ClCCl>[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:21]([C:20]1[CH:24]=[CH:25][C:17]([CH2:15][CH3:16])=[CH:18][CH:19]=1)=[O:22])=[CH:9][NH:10]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2c[nH]c3cccc(Br)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a suspension of AlCl3 (3.0 g, 22.5 mmol) in dichloromethane (50 mL) was added a solution of 4-bromoindole (2.21 g, 11.3 mmol) in dichloromethane (25 mL) at room temperature over the period of 20 mins, followed by the addition of a solution of 4-ethyl-benzoyl chloride (2.5 mL, 17 mmol) in dichloromethane (25 mL) over the period of 20 mins. The resulting solution was stirred at room temperature overnight, and saturated sodium bicarbonate solution was added in a water-ice bath to quench the reaction. The aqueous layer was extracted with dichloromethane. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was triturated in diethyl ether to obtain the title compound (1.8 g, 48%) as white solids.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])=[CH:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][C:41]=1B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:19][C:17]1[CH:16]=[C:15]([F:20])[CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:7]1[C:2]([C:41]3[CH:40]=[CH:39][N:38]=[CH:37][C:36]=3[O:35][CH3:34])=[N:3][CH:4]=[C:5]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:6]=1)=[C:10]([CH3:27])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:12]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1Cl
Reactant: COc1cnccc1B(O)O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cnccc1-c1ncc(N2CCOCC2)cc1Nc1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Temperature: 90 °C
Reaction time: 19 h

Procedure:
N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (60.5 mg, 0.13 mmol), 3-methoxypyridin-4-ylboronic acid (97.1 mg, 0.63 mmol), tris(dibenzylideneacetone)dipalladium (0) (7.5 mg, 8.2 μmol), and tricyclohexylphosphine (4.8 mg, 0.017 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (1.0 mL) and aq. 1.3M potassium phosphate tribasic (0.3 mL, 0.39 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-100% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a yellow film as 5,7-difluoro-N-(3′-methoxy-5-morpholino-2,4′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.73 (2H, m), 8.47 (1H, d, J=5.3 Hz), 8.22 (1H, d, J=2.5 Hz), 7.95 (3H, m), 7.76 (1H, d, J=5.1 Hz), 7.69 (1H, dt, J=9.2, 1.2 Hz), 7.41 (1H, ddd, J=7.4, 4.9, 1.4 Hz), 7.06 (1H, ddd, J=13.8, 8.4, 2.4 Hz), 6.69 (1H, d, J=2.5 Hz), 4.15 (3H, s), 3.90 (4H, m), 3.31 (4H, m), 1.94 (3H, s). Mass Spectrum (pos.) m/e: 541.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a mixture of (S)-tert-Butyl 1-(4-chlorophenyl)-4-hydroxybutan-2-ylcarbamate (686 mg, 2.3 mmol) and TEA (399 μl, 2.9 mmol) in DCM (10 mL) at −8° C. was added methanesulfonyl chloride (214 μl, 2.7 mmol). The resulting mixture was stirred for 2 hours. After warming to room temperature, the mixture was diluted with DCM and washed with H2O (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the product as a light yellow solid (815 mg, 94%). LCMS (API-ES) m/z: 400 (M+Na+).
Reaction SMILES: C[O-].[Na+].O1CCCC1.[CH:9]1([N:12]2[C:17](=[O:18])[C:16]3[C:19]([NH:26][C:27]4[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=4)=[C:20]([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:15]=3[N:14]([C:37]3[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=3[F:44])[C:13]2=[O:45])[CH2:11][CH2:10]1.C(O)(=O)C>CO.O>[CH:9]1([N:12]2[C:17](=[O:18])[C:16]3=[C:15]([NH:14][C:37]4[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=4[F:44])[N:22]([CH3:23])[C:21](=[O:24])[C:20]([CH3:25])=[C:19]3[N:26]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=3)[C:13]2=[O:45])[CH2:11][CH2:10]1
Reactant: CC(=O)Nc1cccc(Nc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(I)cc2F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-n2c(=O)n(C3CC3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Under a nitrogen atmosphere, to a solution (1.57 g) of 28% sodium methoxide in methanol was added tetrahydrofuran (40 ml), N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide 58 (5.00 g) obtained in Step 7 was added, and the mixture was stirred at room temperature for 4 hrs. Acetic acid (0.56 ml) was added, and the mixture was stirred at room temperature for 30 min. Water (40 ml) was added and the mixture was further stirred for 1 hr. The crystals were collected by filtration and dried to give N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 59 (4.75 g, yield 95%) as colorless crystals.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[CH2:18][C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[CH:11][CH:10]=1.[C:24](O)([CH3:27])([CH3:26])[CH3:25].[OH-].[Na+]>O>[C:24]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[O:8][CH3:7])[CH:15]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:14][CH2:13]2)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)O
Reactant: COc1ccc2c(c1)C(Cc1c[nH]cn1)CC2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1C(C)(C)C)CCC2Cc1c[nH]cn1
Temperature: 37.5 °C
Reaction time: 10 h

Procedure:
Sulfuric acid (0.5 ml) is added into the mixture of 4-(6-methoxyindan-1-ylmethyl)-1H-imidazole hydrochloride (50 mg) and tert-butanol (2 ml). The mixture is stirred at 35-40° C. for 10 hours. The reaction mixture is then poured into water and is made alkaline with sodium hydroxide. The product is extracted into methylene chloride which is washed with water, dried with sodium sulfate and evaporated to dryness. The residue consisting of crude product is converted to its hydrochloride salt in ethyl acetate. The yield is 23 mg, m.p. 174-184° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Br:11][C:7]1[N:6]=[C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1cccc(Br)n1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1CCOCC1)c1cccc(Br)n1
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-1-(6-bromopyridin-2-yl)ethanone (250 mg, 0.90 mmol) in tetrahydrofuran (1 mL) and dimethylformamide (1 mL) was added morpholine (0.18 mL, 2.0 mmol). After 45 minutes, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=2[Cl:1])=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(Cl)cc3Cl)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.6 %

Procedure:
2,4-Dichloroaniline (0.383 g, 2.366 mmol), triethylamine (0.239 g, 2.366 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.400 g, 2.366 mmol) were added to a methylene chloride solution (100 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.295 g, 0.789 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.150 g, 0.289 mmol, 37%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].N1C=CN=C1.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([OH:13])[C:21]1[CH2:20][C:19](=[O:25])[CH2:24][CH2:23][CH:22]=1
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Reactant: O=C1C=CCCC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(O)C2=CCCC(=O)C2)c(Cl)n1
Yield: 87 %

Procedure:
The clear solution of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and imidazole (10 mmol, 0.68 g) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 87% yield (2.56 g).
Reaction SMILES: C([Sn](CCCC)(OCCCC)[O:6][Sn:7]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])CCC>C(O)CCC>[CH2:17]([Sn:7]([CH2:13][CH2:14][CH2:15][CH3:16])([O:6][CH2:9][CH2:10][CH2:11][CH3:12])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCCCC
Solvent: CCCCO
Product: CCCCO[Sn](CCCC)(CCCC)OCCCC
Temperature: 140 °C
Reaction time: 0.4 h
Yield: 44.4 %

Procedure:
A feed pump was used to start feeding the starting material 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane prepared in the same manner as in Example 12 from supply line 41 at 280 g/Hr and the reactant 1-butanol (manufactured by Wako Pure Chemical Industries Ltd., Japan, industrial product) from supply line 42 at 1,400 g/Hr. The holding time in the reactor was 24 minutes. Reaction solution which accumulated in the reactor lower portion was circulated at 6,000 g/Hr by the circulation line 44 and the reboiler 45 while heating at a temperature of about 140° C. The liquid temperature inside the reactor was 140° C., and the pressure of the back pressure valve 52 was adjusted to 0.096 MPa-G. Continuous supply was continued in this state for 10 hours, after which the system reached a steady state. Low boiling point components were flowed from the reactor upper portion 47 and through the low boiling point component recovery line 49 for liquefaction at the condenser 50, and were thereby recovered from the liquid-phase recovery line 54 at 1,010 g/Hr. Furthermore, from the reactor lower portion 48, a dibutyltin alkoxide-containing component was recovered at 670 g/Hr from the extraction line 55. Analysis of the recovered liquid showed that, using dibutyltin oxide as a reference, the liquid contained a dibutyltin alkoxide consisting of a yield of about 44.4% dibutyl-di(butyloxy)tin and 55.0% of 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane. Tributyltin butoxide had a yield of 0.05%. Meanwhile, the liquid recovered from the liquid-phase recovery line 54 was transparent and contained 2,300 ppm of moisture. The dehydration rate in the column reactor was 0.20 mol/Hr, which was greater than the value 0.0015 mol/Hr calculated from expression (16).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[CH3:9][O:10][C:11]1[CH:20]=[C:19]([CH:21]=O)[C:14]2[CH:15]=[CH:16][CH2:17][O:18][C:13]=2[C:12]=1[O:23][CH3:24].N1CCCCC1.O>C1C=CC=CC=1.C(O)(=O)C>[C:6]([C:5](=[CH:21][C:19]1[C:14]2[CH:15]=[CH:16][CH2:17][O:18][C:13]=2[C:12]([O:23][CH3:24])=[C:11]([O:10][CH3:9])[CH:20]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:8])#[N:7]
Reactant: COc1cc(C=O)c2c(c1OC)OCC=C2
Reactant: CCOC(=O)CC#N
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=Cc1cc(OC)c(OC)c2c1C=CCO2
Yield: 66.9 %

Procedure:
A mixture of ethylcyanoacetate (11.3 g, 0.1 mole), 7,8-dimethoxy-5-formyl-2H-1-benzopyran (22.0 g, 0.1 mole), piperidine (1.02 g, 0.01 mole) and acetic acid (0.36 g, 0.006 mole) in benzene (100 mL) was heated at reflux for 5 hr with azeotropic removal of water and allowed to cool. The solution was extracted successively with water (200 mL), 0.5N hydrochloric acid (200 mL), saturated sodium bicarbonate solution (200 mL), H2O (200 mL) and dried over magnesium sulfate. The volatiles were removed under reduced pressure to give 21.1 g (66.9%) of an orange solid, mp 104.5°-107.5° C.