Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:8][C:7]([CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.O1CCCC1>[Si:18]([O:1][CH2:2][CH2:3][C:4]1[S:8][C:7]([CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccc(CCO)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CC(=O)O)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
To a solution of 2-[5-(2-hydroxyethyl)-2-thienyl]acetic acid (1.35 g, 7.26 mmol) and imidazole (1.04 g, 15.25) in N,N-dimethylformamide (18 mL) was added tert-butyldimethylsilyl chloride (2.29 g, 15.25 mmol) over 20 minutes. The resultant solution was stirred at room temperature for one hour. Tetrahydrofuran (18 mL) was then added and reaction solution cooled to 0° C. A solution of potassium carbonate (1.04 g, 7.6 mmol) in water (18 mL) was added and the solution stirred for 20 minutes. The reaction solution was then partitioned between ethyl acetate and brine. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-50% ethyl acetate in iso-hexane to give the title compound as a yellow oil (500 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11][CH2:12][C:13](Cl)=C.[CH3:16]COC(C)=O.O>CC(O)=O.[Fe]>[NH2:8][C:5]1[C:4]2[CH:16]=[C:12]([CH3:13])[S:11][C:3]=2[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOC(C)=O
Reactant: C=C(Cl)CSc1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(N)ccc(Cl)c2s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A solution of 1.09 g (4.67 mmol) of compound 260A in 20 mL AcOH with 10 mL EtOAc and 2 mL H2O was heated to 80° C. and treated with iron powder (1,3 g, 23.4 mmol). The mixture was heated at 80° C. for 40 min and then allowed to cool to rt. The mixture was filtered through Celite eluting with EtOAc. The filtrate was washed with sat. aq. NaHCO3, dried over MgSO4, and concentrated in vacuo. N,N-diethylaniline (10 mL) was added, and the reaction was heated at 215° C. for 6 h. After cooling to rt, 1 N aqueous HCl (20 mL) was added, and the reaction was stirred at room temperature for 2 h. The mixture was extracted with EtOAc (3×30 mL). The organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting with 25% EtOAc in hexanes to give compound 260B (320 mg, 35%) as a beige solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][N:8]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl-:3].[Cl:3][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][NH+:8]=1
Reactant: COc1cnc(CO)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1c[nH+]c(CCl)cc1OC
Product: [Cl-]
Temperature: 20 °C
Reaction time: 4 h

Procedure:
3 ml of thionyl chloride, dissolved in 10 ml of methylene chloride, are added dropwise to a solution, cooled to 0° C., of 5 g of 2-hydroxymethyl-4,5-dimethoxypyridine in 40 ml of methylene chloride in the course of one hour, the reaction mixture is then stirred at 20° C. for 4 hours, during which it becomes red-colored, 5 ml of toluene are added and the mixture is concentrated completely on a rotary evaporator (30° C./5 mbar). The oily residue is dissolved in 50 ml of warm isopropanol and the solution is clarified with a little Tonsil®, filtered and concentrated again. The residue is taken up in 10 ml of toluene and the solution is made to crystallize with petroleum ether. After cooling in an ice-bath, the precipitate is filtered off with suction, washed with petroleum ether and dried. 4.6 g (70% of theory) of the title compound 2-chloromethyl-4,5-dimethoxy-pyridinium chloride are obtained as a colourless soldi; decomp. at 160°- 61° C.
Reaction SMILES: [CH2:1]([N:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[S:6]([C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])(=[O:8])=[O:7])[CH2:2][CH:3]=[CH2:4].B.C1C[O:32]CC1.O.B(O[O-])=O.[Na+]>C1COCC1>[OH:32][CH2:4][CH2:3][CH2:2][CH2:1][N:5]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[S:6]([C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=1[F:15])(=[O:7])=[O:8]
Reactant: C1CCOC1
Reactant: C=CCCN(c1ccc(OC)cc1)S(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: B
Agent: O=BO[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(N(CCCCO)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 1-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene (410 mg, 1.01 mmol) in THF (6.5 mL) at −78° C. was added BH3.THF (1.00 mL of a 1 M solution in THF, 1.00 mmol). After stirring at −78° C. for 1 h and at 0° C. for 1 h, the reaction mixture was treated with H2O (20 mL) and sodium perborate (513 mg, 5.14 mmol). After stirring at rt for 2 h, the mixture was poured onto H2O (20 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with sat. NaCl (20 mL) and dried (MgSO4). Concentration followed by chromatography (2:1/hexanes:EtOAc) afforded 270 mg (64%) of product as a white solid, mp 88-90° C. 1H NMR (CDCl3): d 7.08(m, 2H), 6.85(m, 2H), 3.80(s, 3H), 3.77(m, 2H), 3.64(t, J=6.0; 2H), 1.63-1.55(m, 5H), 1.50(bs, 1H). Anal. Calcd. for C17H16F5NO4S: C, 48.00; H, 3.79; N, 3.29; S, 7.54. Found: C, 48.08; H, 3.76; N, 3.34; S, 7.46.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[Na+].[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O>[C:23]1([S:29]([C:2]2[CH:19]=[CH:18][C:17]3[C:16](=[O:20])[C:15]4[C:6](=[CH:7][C:8]5[C:13]([CH:14]=4)=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:5](=[O:21])[C:4]=3[CH:3]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccc(S(=O)(=O)c3ccccc3)cc2C(=O)c2cc3ccccc3cc21

Procedure:
1 g (3.62 mmol) of 2-fluoro-naphthacene-5,12-dione, 0.89 g (5.43 mmol) of benzenesulfinic acid sodium salt (sodium benzenesulfinate) and 10 ml of DMSO are stirred at 100° C, for 3 hours. After cooling, the mixture is poured onto water. The crystals are filtered off and dissolved in THF/toluene. The solution is dried over sodium sulfate and evaporated. The residue is recrystallized from THF/toluene/pentane. Yield: 1.35 g (94%), melting point >260° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=2[N:11]=1.[I:12]N1C(=O)CCC1=O>C(#N)C>[I:12][C:9]1[C:4]2[S:3][C:2]([CH3:1])=[N:11][C:5]=2[C:6](=[O:10])[NH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1nc2c(=O)[nH]ccc2s1
Solvent: CC#N
Product: Cc1nc2c(=O)[nH]cc(I)c2s1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-5H-thiazolo[4,5-c]pyridin-4-one (770 mg, 4.6 mmol) was suspended in 25 ml acetonitrile and N-iodosuccinimide (1.04 g, 4.6 mmol) was added. The reaction mixture was refluxed for 3 hrs. The brown suspension was cooled to 5° C. and stirred for 15 min. The solid was filtered, washed with cold acetonitrile and dried for 1 hour at 50° C. and <30 mbar. The crude product (830 mg, 61%) [MS: m/e=292.9 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: C(O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[H-].[Na+].C[C:12]1([CH3:31])[O:17][C:16](=[O:18])[C:15]2[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[N:24]=3)=[CH:20][CH:21]=[CH:22][C:14]=2[O:13]1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[N:37]=[C:36](S(C)(=O)=O)[N:35]=1.P(=O)(O)(O)O>CN(C)C=O>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[N:37]=[C:36]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[N:24]=3)[C:15]=2[C:16]([O:17][CH2:12][C:31]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:18])[N:35]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COc1cccc(-c2cccc3c2C(=O)OC(C)(C)O3)n1
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.36 g of benzyl alcohol dissolved in 50 ml of dimethylformamide are treated with 380 mg of sodium hydride (80% strength in liquid paraffin) and the mixture is subsequently stirred at room temperature for 1 h. 3.0 g of 2,2-dimethyl-5-(6-methoxypyridin-2-yl)-4H-(1,3)benzo-dioxin-4-one are added, the mixture is stirred at room temperature for 3 h and 2.65 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine are finally added. The mixture is stirred at room temperature for 2 h, at 80° C. for 1.5 h and at 115° C. for 3 h, poured into ice-water containing phosphoric acid and extracted with ethyl acetate, and the extract is washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel 60 using cyclohexane/toluene/ethyl acetate.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C@@H:5]([C:14]([OH:16])=O)[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[CH2:17]([N:19](CC)CC)[CH3:18].ClC(OCC(C)C)=O.C(N)C>O1CCCC1.C(OCC)(=O)C>[CH2:17]([NH:19][C:14](=[O:16])[C@H:5]([CH2:4][S:3][CH2:1][CH3:2])[NH:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH3:18]
Reactant: CCSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@H](CSCC)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To 14.92 g (100 mmole) of S-methyl-L-cysteine were added 55 ml of water and 21 ml (110 mmole) of triethylamine and the mixture was dissolved in 55 ml of dimethylformamide at room temperature. Thereafter, 26.4 g (110 mmole) of t-butyl-S-4,6-dimethylpyrimidin-2-ylthiol carbanate was added and the mixture was stirred for about 10 hours at room temperature. After addition of 150 ml of water, the mixture was extracted with 2×200 ml of ethyl acetate. The aqueous layer was ice-cooled, adjusted to pH 2 with addition of 6 N hydrochloric acid and extracted with 1×150 ml and 2×80 ml of ethyl acetate. The organic layers were washed with 3×100 ml of 5% hydrochloric acid and 2×100 ml of aqueous saturated sodium chloride and then dried over magnesium sulfate. The solution was concentrated in vacuo to give 24.5 g (98% yield) of S-ethyl-N-butyloxycarbonyl-L-cysteine as an oil. ##STR10## To a solution of 6.23 g (25 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine dissolved in 60 ml of tetrahydrofuran was added 3.48 ml (25 mmole) of triethylamine. To the resulting mixture cooled to -15° C. was added dropwise 3.28 ml (25 mmole) of isobutyl chloroformate and the mixture was stirred at that temperature for 20 minutes. After cooling to -40° C., 3.2 g of aqueous 70% ethylamine solution (50 mmole) was added in a portion and the mixture was stirred for 2.5 hours under ice cooling. After addition of 70 ml of ethyl acetate, the organic layer was washed successively with 30 ml of aqueous 5% sodium bicarbonate, 2×30 ml of aqueous 10% citric acid, 2×30 ml of aqueous 5% sodium bicarbonate and 2×30 ml of saturated saline and dried over anhydrous magnesium sulfate. The solution was then concentrated in vacuo, resulting in precipitation of crystals, which were recrystallized from ethyl acetate-n-hexane to give 4.93 g of S-ethyl-N-t-butyloxycarbonyl-L-cysteine ethylamide, 71% yield, m.p. 109°-110° C. ##STR11## To 40 ml of ice-cooled 16% solution of hydrogen chloride in ethyl acetate was added dropwise a solution of 2.00 g (7.25 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine ethylamide in 50 ml of ethyl acetate over 20 minutes. After stirring for 2.5 hours at room temperature, the mixture was concentrated in vacuo and the residual oil was treated with ethyl ether to give 1.31 g (85% yield) of S-ethyl-L-cysteine ethylamide hydrochloride as powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([F:13])[CH:12]=1)C=O)([CH3:4])([CH3:3])[CH3:2].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(N(CC)CC)C.[CH:32](OC)([O:35][CH3:36])[O:33][CH3:34]>CO>[C:1]([C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[C:7]([CH:32]([O:35][CH3:36])[O:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)cc(C=O)c1
Reactant: COC(OC)OC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(OC)c1cc(F)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
3-tert-Butyl-5-fluoro-benzaldehyde (252 g, 1.4 moles) was dissolved in methanol (4 vol, 1000 ml) and trimethyl orthoformate (1 vol, 252 ml). Toluenesulfonic acid (3.4% w/w, 6 g) was added in one portion and the resulting solution stirred at rt for 1 hour. Triethylamine (0.12 vol, 30 mL) was added and the reaction concentrated to an oil, and then re-suspended in ethyl acetate (3 L) and NaHCO3 (aq. sat., 1 L) and water (1 L) with vigorous mixing. The organic phase was washed with additional water (1 L), polish filtered and then concentrated to provide an orange oil (311.2 g, 98.5%), used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:5][C:4]=1[CH3:12])([O-:15])=[O:14]
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Reactant: O=[N+]([O-])O
Product: Cc1cc(C(C)(C)C)cc(C)c1[N+](=O)[O-]

Procedure:
contacting the 1,3-dimethyl-5-tertiary-butylbenzene with nitric acid in the presence of a mercuric acetate catalyst at a temperature of from about 0° C. to about 100° C. to form 2-nitro-1,3-dimethyl-5-tertiary-butylbenzene;
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH:10]1([C:13]#[CH:14])[CH2:12][CH2:11]1.C(N(CC)CC)C>C1COCC1.[Cu]I>[CH:10]1([C:13]#[C:14][NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: C#CC1CC1
Reactant: Nc1ccc(F)cc1I
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc(NC#CC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 4-fluoro-2-iodoaniline (2 g, 8.4 mmol) in THF (15 mL) and cyclopropylacetylene (1.4 mL, 16.9 mmol) is treated with PdCl2(PPh3)4 (177 mg, 0.25 mmol), CuI (48 mg, 0.25 mmol) and triethylamine (3.5 mL, 25.2 mmol) and stirred at rt for 2 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 0%-35% EtOAc in heptane to afford 2-cyclopropylethynyl-4-fluoro-phenylamine (1.1 g, 74%). MS: 176 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.93 (m, 1H), 6.81 (m, 1H), 6.59 (m, 1H), 4.00 (s, NH2, 2H), 1.49 (m, 1H), 0.82 (m, 4H).
Reaction SMILES: [N:1]([C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:7][CH2:6][CH2:5][C:4]([N:1]=[N+:2]=[N-:3])([CH3:9])[CH3:8])(=[O:22])=[O:21]
Reactant: CC(C)(CCO)N=[N+]=[N-]
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutan-1-ol (3.33 g, 25.8 mmol) and DIEA (9.0 mL, 2 equiv, 51.6 mmol) in anhydrous DCM (200 mL) was added methanesulfonyl chloride (2.99 mL, 1.5 equiv, 38.7 mmol) over 5 min. The reaction was stirred and left at 0° C. for 1.5 h. The reaction mixture was extracted with 1 N HCl (2×200 mL), saturated NaHCO3 (2×200 mL) and brine (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give a colorless liquid. The crude oil was purified on an ISCO purification system with gradient elution from 5-40% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a colorless liquid (4.45 g, 83.4). 1H NMR (CDCl3, 400 MHz): δ 1.36 (s, 6H), 1.93-1.98 (t, J=6.8, 2H), 3.32-4.36 (t, J=6.8, 2H).
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][C@@H:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C2C(CCCC2)CCC1>[CH3:13][C@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:4][NH:5]1
Reactant: C[C@H](NCCBr)c1ccccc1
Agent: Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCC2CCCCC2C1
Product: C[C@@H]1NCCc2ccccc21
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 73.5 %

Procedure:
5.0 g(16.18 mmole) of (S)-(-)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example (2) above was suspended in 50 ml of decalin and then heated to 140° C. 6.47 g(48.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, and cooled to room temperature. The supernatant was removed and the lower layer was added to 70 g of ice-water with stiring. 20 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100 ml of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 1.75 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:4]=1[NH:5][CH:6]=[C:7]([C:13]([O:15]CC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:1][CH2:2][C:3]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:4]=1[N:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:13]2[OH:15])(=[O:25])[CH3:24]
Reactant: CCOC(=O)C(=CNc1ccc(C)cc1CO)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1cnc2c(COC(C)=O)cc(C)cc2c1O
Temperature: 130 °C

Procedure:
A mixture of diethyl 2-((2-(hydroxymethyl)-4-methylanilino)methylene)malonate (Preparation 24, 5.0 g) and acetic anhydride (5.0 mL) is heated at 130° C. for 1 h. The acetic anhydride is evaporated, and the residual solid is heated at reflux in diphenyl ether (20 ml) for 1 h. The solution is cooled and diluted with acetonitrile (5 mL) and ether (15 mL). The resulting precipitate is filtered to afford 1.8 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2ccc(-c3ccccc3)cn2)CC1
Yield: 15 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (235 mg, 0.872 mmol), 1-(5-phenylpyridin-2-yl)piperazine (200 mg, 0.872 mmol), diisopropylethylamine (0.3047 ml, 1.74 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, then the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduce pressure, and the residue was recrystallized from ethyl acetate to give the titled compound 47 mg (47.0%) as solid product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20](Cl)(=[O:22])=[O:21])=[C:4]([O:24][CH3:25])[CH:3]=1.N1C=CC=CC=1.[CH3:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20]([N:33]([CH3:32])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:22])=[O:21])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)Cl
Reactant: CNc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzenesulfonyl chloride (100 mg, 0.24 mmol) in dichloromethane (3 mL), was added pyridine (0.04 mL, 0.48 mmol), followed by addition of N-methylaniline (0.05 mL, 0.48 mmol). The mixture was stirred at r.t. for 16 hrs, then poured into 1 N HCl solution (10 mL). The product was extracted with ethyl acetate and the organic layer was washed with 1N HCl and water, then was dried over MgSO4. Concentration gave 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-N-phenyl-benzenesulfonamide 15-1, (108 mg). MS: 482.0 (M+H)+; tR=8.76 min (method 2).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:20]=[CH2:21])C1C=CC=CC=1>C(O)C.O1CCOCC1.[OH-].[Pd+2].[OH-]>[CH2:20]([C:14]1[C:13]2[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=2)[N:17]=[C:16]([CH3:19])[CH:15]=1)[CH3:21]
Reactant: C=Cc1cc(C)nc2c(OCc3ccccc3)cccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1cc(C)nc2c(O)cccc12
Temperature: 25 °C
Reaction time: 9 h
Yield: 48.5 %

Procedure:
A mixture of 8-benzyloxy-2-methyl-4-vinylquinoline (200 mg) and palladium(II) hydroxide (40 mg) in a mixture of ethanol (1.5 ml) and dioxane (1.5 ml) was stirred for 9 hours at ambient temperature under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (Ethyl acetate:n-hexane=1:2, V/V) to give 4-ethyl-8-hydroxy-2-methylquinoline (66 mg) as brown oil.
Reaction SMILES: [CH3:1][CH2:2][NH:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH3:18])[C:11](=[O:19])[N:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[C:9]=2[N:8]=[C:7]1[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.O.NN.[H][H]>[Pd]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:10]2[C:9]3[N:8]=[C:7]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[N:6]([CH2:5][CH2:4][NH:3][CH2:2][CH3:1])[C:14]=3[C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH3:18])[C:11]2=[O:19])=[CH:27][CH:26]=1
Reactant: CCCn1c(=O)c2c(nc(Cc3cccnc3)n2CCNCC)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2c(nc(Cc3cccnc3)n2CCNCC)n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2,3-pyridylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By the method of Example 3, this substance is reacted with sodium carbonate, 1,2-dichloroethane and ethylamine to yield 4,7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By the method of Example 4, 7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.