Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+:2].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]([OH:11])=[O:10].S1C=CC=C1[CH2:17][C:18]([O-])=[O:19].[K+].[CH3:22][O:23][C:24](=[O:40])[CH2:25][NH:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=O)[CH2:36]Cl)[CH:29]=1>CO>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]([O-:11])=[O:10].[K+:2].[CH3:22][O:23][C:24](=[O:40])[CH2:25][NH:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[S:3])[CH2:36][C:18](=[O:19])[CH3:17])[CH:29]=1
Reactant: COC(=O)CNC(=O)c1cccc(NC(=O)CCl)c1
Reactant: O=C(O)Cc1cccs1
Agent: O=C([O-])Cc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CNC(=O)c1cccc(NC(=S)CC(C)=O)c1
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of potassium thiolacetate is prepared by adding 495 ml. of 2N-methanolic potassium hydroxide (0.99 mole) during a period of 15 min. to a solution of 74.3 ml. of thiolacetic acid (79.1 g., 1.04 mole) and 500 ml. of methanol while maintaining a temperature of 1°-5° C. The methanolic potassium thiolacetate solution thus prepared is added over 0.5 hr. to a mixture of N-[3-(chloroacetylamino)benzoyl]glycine methyl ester (267.5 g., 0.94 mole) in 2 l. of methanol while maintaining a temperature of 0°-5° C. After stirring for a period of 1 hr. without cooling, the reaction mixture is warmed at 40°-45° C. for 2 hrs., cooled, and filtered. The material collected is sequentially washed with 50% methanol, water, and 50% methanol, and then air dried to afford 262.4 g. (86% yield) of N-[3-(acetylthioacetylamino)benzoyl]glycine methyl ester, m.p. 86°-88° C. Crystallization from methanol provides analytically pure N-[3-(acetylthioacetylamino)benzoyl]glycine methyl ester, m.p. 90.0°-92.0° C.
Reaction SMILES: [C:1](=O)([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[C:15]([F:17])[C:14]([C:18]2[CH:23]=[N:22][C:21]([NH2:24])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].BrCC>CO>[CH2:1]([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([C:18]2[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=2)=[C:15]([F:17])[CH:16]=1)[CH3:2]
Reactant: CC(=O)SCc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCBr
Product: CCSCc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.7 %

Procedure:
To a solution of S-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methyl ethanethioate (100 mg, 0.280 mmol) in CH3OH (30 mL) were added Ph3P (150 mg, 0.560 mmol), K2CO3 (78 mg, 0.56 mmol), and bromoethane [drop-wise addition (60 mg, 0.56 mmol)] at rt. The reaction mixture was stirred at rt for 16 h, before removing the solvent in vacuo. The crude product was purified first by preparative-TLC followed by HPLC to give the title compound (70 mg HCOOH salt, 73%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31]O)[CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O.Cl>O1CCCC1.CS(C)=O>[F:34][C:24]([F:23])([F:33])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:26]=1
Reactant: OCc1cc(C(F)(F)F)ccn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C1N(Cc2cc(C(F)(F)F)ccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.2 %

Procedure:
To a solution of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.753 g, 2.55 mmol), [4-(trifluoromethyl)pyridin-2-yl]methanol (Ashimori et al., Chem. Pharm. Bull. (1990) 38:2446-2458) (0.655 g, 3.70 mmol) and tri-n-butylphosphine (0.93 mL, 3.7 mmol) in anhydrous tetrahydrofuran (20 mL) and anhydrous dimethylsulfoxide (0.2 mL) at ambient temperature was added over a period of 10 min a solution of diethyl azodicarboxylate (0.64 mL, 4.1 mmol) in anhydrous tetrahydrofuran (10 mL). The reaction mixture was stirred at ambient temperature for 3 h and was poured into 1 M hydrochloric acid (50 mL). The mixture was extracted with diethyl ether (3×50 mL) and the combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 80% to 100% gradient of dichloromethane in hexanes, followed by a 0% to 20% gradient of ethyl acetate in dichloromethane and recrystallization from methanol afforded 1′-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.164 g, 10%) as a colorless solid: mp 154-155° C. (methanol); 1H NMR (300 MHz, CDCl3) δ8.76 (d, J=5.1 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J=5.1 Hz, 1H), 7.24-7.16 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.27 (d, J=16.1 Hz, 1H), 5.04 (d, J=16.1 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.23-4.11 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.8, 157.3, 155.3, 150.8, 144.8, 141.9, 139.8, 138.5, 132.3, 129.0, 124.1, 123.9, 121.1, 118.7, 117.6, 111.8, 109.3, 99.5, 80.1, 64.7, 64.0, 58.2, 45.8; MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)C(C)C)(C)C.[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>C(#N)C>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1c[nH]cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1

Procedure:
4-Methylimidazole (45.1 g, 0.55 M) and N,N-diisopropylethylamine (161 g, 1.25 M) were dissolved in acetonitrile (800 ml), and 3,4-difluoronitrobenzene (79.5 g, 0.5 M) added. The mixture was stirred and heated to reflux under nitrogen for 24 hours. Solvent was evaporated, the residue dissolved in ethyl acetate (800 ml), washed with water (400 ml), brine (200 ml), and dried (magnesium sulfate). The residue was dissolved in toluene (250 ml), treated with charcoal, filtered, and diluted with hot cyclohexane (75 ml) to crystallise 3-fluoro-4-(4-methylimidazol-1-yl)nitrobenzene (64.7 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH3:38])[CH:36]=2)[CH:31]=[CH:30][N:29]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH2:38][C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][N:29]=[C:28]2[Cl:27])=[CH:33][CH:34]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccnc(Cl)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1nccc2ccc(CBr)cc12
Temperature: 25 °C
Yield: 97 %

Procedure:
N-Bromosuccinimide (1.10 g, 6.19 mmol) and benzoyl peroxide (0.39 g, 1.13 mmol) are added to a solution of 1-chloro-7-methylisoquinoline (1 g, 5.63 mmol) in carbon tetrachloride (70 mL). The resulting mixture is heated to reflux for 6 hours then cooled to room temperature and diluted with methylene chloride. The organic layer is washed with 1N NaOH and brine, then dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 25% EtOAc/hexanes to give the product (1.4 g, 5.46 mmol) as a white solid.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1C=CC=CC=1.[O:15]([CH2:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:15]([CH2:22][C:23]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)COc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)[C@@H]1CCCN1C(=O)COc1ccccc1
Temperature: 25 °C

Procedure:
2.53 grams (g) of L-proline and 20 milliliters (ml) of anhydrous pyridine are mixed in a flask cooled by an ice bath, and 3.42 g of phenoxyacetyl chloride is added dropwise over about a 20-minute period. The mixture is warmed by water bath to room temperature, and the solvent evaporated under reduced pressure (in vacuo), leaving a viscuous syrup. The syrup is dissolved in 15 ml water and the water is evaporated in vacuo. The residue is dissolved in 20 ml water, and the resulting solution is filtered, and subsequently treated with 10 ml of 2 N hydrochloride. The resulting precipitate, crude phenoxyacetyl-L-proline, is purified on a chromatographic column containing 80 g of silica gel. The column is eluted with a solvent mixture composed of equal volumes of isopropanol and toluene to provide phenoxyacetyl-L-proline.
Reaction SMILES: C([Cl:9])(=O)C1C=CC=CC=1.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]([CH2:40][CH3:41])=[CH:34][CH2:35][CH2:36][CH:37](O)[CH3:38]>>[Cl:9][CH:37]([CH2:36][CH2:35][CH:34]=[C:33]([CH3:32])[CH2:40][CH3:41])[CH3:38]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(C)=CCCC(C)O
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: CCC(C)=CCCC(C)Cl

Procedure:
Triphenylphosphite benzoylchloride (10 g.) is mixed with 1.9 g. of 6-methyl-5-octen-2-ol and kept at room temperature overnight. The crude product is washed with 2N sodium hydroxide and water and dried to yield 2-chloro-6-methyl-5-octene.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]=[C:26]1[CH2:29][CH:28]([C:30]([OH:32])=O)[CH2:27]1.N(CC)(CCC)CCC.O[N:43]=[C:44]([C:46]1[CH:47]=[CH:48][C:49]([CH3:64])=[C:50]([NH:52][C:53]([C:55]2[N:59]3[CH:60]=[CH:61][CH:62]=[CH:63][C:58]3=[N:57][CH:56]=2)=[O:54])[CH:51]=1)[NH2:45]>CN(C=O)C>[CH3:64][C:49]1[CH:48]=[CH:47][C:46]([C:44]2[N:43]=[C:30]([CH:28]3[CH2:27][C:26](=[O:25])[CH2:29]3)[O:32][N:45]=2)=[CH:51][C:50]=1[NH:52][C:53]([C:55]1[N:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]2=[N:57][CH:56]=1)=[O:54]
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: O=C1CC(C(=O)O)C1
Agent: CCCN(CC)CCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
HATU (1.41 g, 3.72 mmol) was added in one portion to a stirred solution of 3-oxocyclobutanecarboxylic acid (0.405 g, 3.55 mmol) and Pr2NEt (0.62 mL, 3.7 mmol) in dry DMF (5 mL). After 10 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (1.0 g, 3.23 mmol) was added in one portion and continued to stir for another 30 minutes. The resulting solution was heated (110° C.) for 30 minutes and then cooled to room temperature. The solvent was evaporated and the residue was partitioned with saturated NH4Cl and EtOAc. The organic layer was dried with MgSO4 and filtered. The residue was purified on silica gel using 10% MeOH in dichloromethane to obtain N-(2-methyl-5-(5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (10). 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1 H), 9.53-9.51 (m, 1 H), 8.71 (s, 1 H), 8.08 (d, J=1.6 Hz, 1 H), 7.91-7.88 (m, 1 H), 7.85 (dd, J=2.0, 8.0 Hz, 1 H), 7.72-7.68 (m, 1 H), 7.51 (d, J=8.4 Hz, 1 H), 7.34-7.30 (m, 1 H), 4.12-4.04 (m, 1 H), 3.70-3.53 (m, 4 H), 2.37 (s, 3 H). MS m/z 388.1 (M+1)+.
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.[C:22]1(C)C=CC(S(O)(=O)=O)=C[CH:23]=1>C(Cl)(Cl)Cl>[CH2:22]([N:7]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[C:4](=[O:3])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2cc3c(cc2c1=O)OCO3
Temperature: 180 °C
Yield: 5655.1 %

Procedure:
A mixture of 2.9 g of ethyl 4-ethoxy-6,7-methylenedioxyquinoline 3-carboxylate and 0.03 g of p-toluenesulfonic acid was melted and heated at 180°C (bath temperature) for 2 hours and cooled. The product was dissolved in chloroform, washed with a dilute aqueous sodium carbonate solution and then with water. The chloroform layer was separated and evaporated to dryness. There was obtained 2.85 g of pure ethyl 1-ethyl-6,7-methylenedioxy-4-quinolone-3-carboxylate, m.p. 175°-177°C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[O:40]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41]1>O1CCCC1.O>[F:3][C:4]1[C:9]([C:10]2[N:14]([S:45]([C:42]3[CH:43]=[CH:44][O:40][CH:41]=3)(=[O:47])=[O:46])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=S(=O)(Cl)c1ccoc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccoc2)c1)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 48 mg) in tetrahydrofuran (2 mL) were added dropwise a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (244 mg) in tetrahydrofuran (1 mL), 15-crown-5 (266 mg) and furan-3-sulfonyl chloride (147 mg) under ice-cooling and the mixture was stirred for 1.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 253 mg, 73%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[O:8][CH:7]=1.[OH:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[OH:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=4)[O:8][CH:7]=3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc2occ(CCCCBr)c(=O)c2cc1OC
Reactant: Oc1cccc(N2CCNCC2)c1
Product: COc1cc2occ(CCCCN3CCN(c4cccc(O)c4)CC3)c(=O)c2cc1OC
Yield: 17 %

Procedure:
Using the same starting material, 3-(4-bromobutyl)-6,7-dimethoxychromen-4-one obtained in Step 3 of Example 1, but with 3-hydroxyphenylpiperazine, and using a microwave reaction vessel (15 min, 160° C., 150 w), 3-{4-[4-(3-hydroxyphenyl)-piperazin-1-yl]-butyl}-6,7-dimethoxychromen-4-one is obtained in a similar manner to Example 1 in a yield of 17%. M.p. ° C.=177-180; analytical HPLC Sym C8, 4.6×250 mm, 5μ, eluant: CH3CN—H2O, KH2PO4 25-75-6.8 g/l, pH4, r.t.=9.99 min; MS ESI, m/z=439 (MH+); 1H NMR (CDCl3): 7.72 (s, 1H), 7.55 (s, 1H), 7.09 (t, 1H, J=8 Hz), 6.83 (s, 1H), 6.49 (d, 1H, J=8.28 Hz), 6.39 (s, 1H), 6.31 (d, 1H, J=7.84 Hz), 3.97 (s, 6H, OCH3), 3.18 (m, 4H), 2.58 (m, 4H), 2.49 (m, 2H), 2.43 (m, 2H), 1.62 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:6][O:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]#[CH:30]>CC(C)=O>[C:28]([O:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:21])[C:5]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:6][O:7]2)=[C:2]([OH:1])[CH:11]=1)#[C:29][CH3:30]
Reactant: COc1ccc(-c2coc3cc(O)cc(O)c3c2=O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1cc(O)c2c(=O)c(-c3ccc(OC)cc3)coc2c1

Procedure:
A mixture of 5,7-dihydroxy-4′-methoxyisoflavone (2.84 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.25 g of a product with the following characteristics: m.p. 174-176° C.; 1H NMR (CDCl3) δ: 2.6 (m, 1H), 3.86 (s, 3H), 4.8 (s, 2H), 647-7.91 (m, 7H), 12.90 (s, 1H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].O.CC1C=CC(S(O)(=O)=O)=CC=1.ClCCl>O>[Br:7][C:8]1[CH:9]=[C:10]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([O:24][CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[CH2:22][CH2:23]2)(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: C1=COCCC1
Reactant: O=S(=O)(c1ccc(F)c(Br)c1)N1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCC(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
3,4-Dihydro-2H-pyran (0.28 mL, 3.1 mmol) was added dropwise to a 0° C. solution of Example 354a (0.51 g, 1.5 mmol), 4-methylbenzenesulfonic acid hydrate (0.59 g, 3.1 mmol), and dichloromethane (28 mL). The reaction mixture was stirred at ambient temperature for 5 hours. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane/gradient with methanol) to afford the title compound (420 mg, 65.9% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1)=[O:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc2[nH]ccc2c(=O)[nH]1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nc2[nH]ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (186 g, 1.23 mol) in pyridine (2 L) was treated with trimethylacetyl chloride (475 g, 3.94 mol, 485 mL, 3.2 eq) at 90° C. for 2 h, to give a mixture of N(2)-monoacylated and N(2), N(7)-bisacylated material. The solvent was evaporated and the residue was taken up in aqueous ammonia (37% NH3, 310 mL) and MeOH (2 L), and stirred at rt for 30 min, to selectively cleave the N(7)-pivaloyl group. The solid was collected by filtration, washed with water (500 mL×5), and dried on high vacuum to give the title compound as a solid (193 g). Concentration of the mother liquor provided additional solid material, which was collected, washed with water (50 mL×5), and dried (77 g). The combined yield was 93% (HPLC purity 98.6% ). tR: 4.57 min. 1H-NMR (DMSO-d6) δ 12.00, (br. s, 1H), 7.40 (br. s, 1H), 6.96 (q, 1H), 6.40 (q, 1H), 1.24 (s, 9H).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH:15]([OH:16])[C:14]([CH3:18])([CH3:17])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>O1CCCC1>[C:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH:15]([OH:16])[C:14]([CH3:17])([CH3:18])[CH2:13][C:12](=[O:19])[C:11]([CH3:20])=[CH:10]1)(=[O:30])[CH3:29]
Reactant: CC1=CC(NCc2ccccc2)C(O)C(C)(C)CC1=O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccccc1)C1C=C(C)C(=O)CC(C)(C)C1O
Temperature: 50 °C
Yield: 95 %

Procedure:
The 4-benzylamino-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 1 (17.3 g, 63.4 millimoles) was dissolved in tetrahydrofuran (100 ml), triethylamine (19.2 g, 190 millimoles) was added, and acetic anhydride (12.9 g, 127 millimoles) was added dropwise while stirring on ice. After heating the reaction solution at 50° C. for 3 hours, it was poured into ice water (300 ml). After 30 minutes the aqueous solution was subjected to extraction with benzene, washed with water, and then dried over anhydrous magnesium sulfate. The benzene was distilled off, and the resulting residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 19.0 g (95%) of 4-(N-acetylbenzylamino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:23][N:22]([CH3:31])[N:21]=3)=[CH:16][CH:15]=2)[CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:46](=O)([O-])[O-:47].[Cs+].[Cs+]>CO.[Cu](I)I>[CH3:46][O:47][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:23][N:22]([CH3:31])[N:21]=3)=[CH:16][CH:15]=2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cc(Cl)c4ccccc4n3)cc2)n1
Agent: I[Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1cc(COc2ccc(-c3nn(C)cc3-c3ccncc3)cc2)nc2ccccc12
Temperature: 165 °C
Yield: 59.8 %

Procedure:
To a solution of 4-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (125 mg) in methanol (4 mL) was added phenanthroline (78 mg), cesium carbonate (143 mg) and copper iodide (5 mg). The reaction mixture was heated in a microwave reactor at 165° C. with 50 W of power for 20 min. The reaction mixture was filtered through celite and concentrated. Purification via MPLC biotage chromatography, eluting with 5% methanol/1% ammonium hydroxide/methylene chloride provided the title compound (74 mg). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.4 Hz, 2H), 8.18 (d, J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.68 (m, 1H), 7.55 (s, 1H), 7.49 (t, J=7.1 Hz, 1H), 7.37 (d, J=9.1, Hz, 2H), 7.15 (d, J=6.2 Hz, 2H), 7.01 (m, 3H), 5.32 (s, 2H), 4.02 (s, 3H), 3.95 (s, 3H); MS: (M+H m/z=423.3).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].C1(C)C=CC=CC=1.[CH:18]1([C:23]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([OH:29])[C:24](OCC)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1>CCCCCC>[CH:18]1([C:23]([C:30]#[C:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([OH:29])[C:24]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCC1
Agent: [Na]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)C(O)(C#Cc1ccccc1)C1CCCC1

Procedure:
3-Quinuclidinol (3.8 g., 0.030 mole) and about 0.05 g. of sodium were refluxed in 50 ml. of toluene, in a flask equipped with a reflux head, until all the sodium reacted. Then, ethyl α-cyclopentyl-α-phenylethynylglycolate (5.4 g., 0.02 mole) in 35 ml. of solvent was added dropwise over an hour period. No temperature drop was noted in the reflux head. The reaction mixture was refluxed for about 18 hours and then about 40 ml. of solvent was distilled from the reaction flask over a four hour period. The reaction mixture was cooled, and dry 20°-40° petroleum ether was added. A tarry solid formed and was filtered. The solid was treated with hot hexane to yield 3.2 g. (45%) of crude product melting about 115° C. The pure compound, m.p. 137°-39°, was obtained by recrystallization from hexane.