Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([O:21][CH2:22][C:23]([NH:25][NH2:26])=[O:24])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)[CH:29]=[O:30].C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([O:21][CH2:22][C:23]3[O:24][C:29](=[O:30])[NH:26][N:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc3ncccc3c(OCC(=O)NN)n2)cc1OC
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3ncccc3c(OCc3n[nH]c(=O)o3)n2)cc1OC
Temperature: 70 °C

Procedure:
54 mg [7-(3,4-Dimethoxy-phenyl)-[1,6]-naphthyridine-5-yloxy]-acetic acid hydrazide (I.34) was placed in tetrahydrofuran (10 mL) and N,N-dimethyl formamide (1 mL) at ambient temperature before 37 mg carbonyl diimidazole and 43 μl triethylamine were added. The reaction mixture was heated to 70° C. where it was maintained for 16 h. After this time additional carbonyl diimidazole and triethylamine were added and the reaction was maintained at 70° C. for a further 5 h. After this time additional carbonyl diimidazole and triethylamine were added and the reaction was maintained at 70° C. for a further 19 h. The solvent was then removed under reduced pressure and the crude product that remained was partitioned between dichloromethane and water. The dichloromethane layer was separated and the aqueous phase was extracted with additional dichloromethane (×2). The combined organic fractions were washed with water, saturated sodium chloride solution and then dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification twice by chromatography on silica gel (methanol/ethyl acetate: 0%-5% and then methanol/ethyl acetate: 0%-2%) followed by trituration with dichloromethane provided the title compound.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].C[O-].[Na+].C(OCC)(=O)C>CO.O>[C:15]([C:17]1[C:18](=[O:19])[NH:20][C:5]([CH3:6])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1)#[N:16]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(=CN(C)C)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1

Procedure:
A mixture of 4-dimethylamino-3-phenyl-3-butene-2-one (14.1 grams) and cyanoacetamide (5.9 grams) in 100 ml methanol was added to sodium methoxide (7.9 grams) in 100 ml methanol. The mixture was refluxed for 18 hours and then the crude reaction was stripped and the residue dissolved in a small amount of hot water. Acidification to pH 6-7 gave a gum-like solid which was collected by filtration. Further acidification to a lower pH gave only an oil. Trituration of the gum with ethyl acetate and chilling resulted in an off-white solid which was identified by NMR as the desired product, yield 2.8 grams, m.p. 280°-290° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:17]([O-])(=[O:19])C.[Na+]>CN(C=O)C.O>[CH3:6][O:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([CH:17]=[O:19])=[CH:10][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: COc1cccc2ccsc12
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c2ccsc12
Temperature: 117 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Phosphorous oxychloride (7.1 mL, 76.7 mmol) is added dropwise to a cooled dry DMF (13.2 mL, 170.4 mmol) at such rate that the temperature does not exceed 5° C. After 30 minutes at this temperature, a solution of 7-methoxybenzo[b]thiophene (7.00 g, 42.6 mmol) in dry DMF (2 mL) is added dropwise. The stirring continues at 5° C. for 30 minutes and at room temperature for 45 minutes. Afterward, the mixture is heated to 117° C. and then at 90° C. for 2 hours, cooled to 0° C., and neutralized with a solution of sodium acetate (62 g) in water (300 mL). The resulting mixture is extracted with diethyl ether (5×150 mL) and the organic layers are washed with cooled water (5×100 mL), saturated aqueous sodium chloride (100 mL), dried (MgSO4) and concentrated. The crude material is purified on slica gel (hexanes/EtOAc 9:1) to give 7-methoxybenzo[b]thiophene-4-carbaldehyde as a yellow solid (5.5 g, 68% yield). To a stirred solution of the intermediate (14.9 g, 77.5 mmol) in acetone (300 mL) is slowly added a solution of potassium permanganate (14.9 g, 94.3 mmol) in water (525 mL) at 0° C. and the mixture is stirred for 75 minutes. Then, isopropanol (100 mL) is added and the mixture is divided in two portions. Each portion is treated with HCl (100 mL, 12%), diluted with water (300 mL) and extracted with EtOAc (3×300 mL). Organic layers are washed with water (300 mL), saturated aqueous sodium chloride (300 mL), dried (MgSO4), and concentrated. Residue is collected and diluted with EtOAc (600 mL) and the suspension is warmed to 70° C. and filtered to give the title compound as a white solid (10.3 g, 63% yield). At room temperature, the filtrate forms a suspension. After filtration, an additional 3.2 g is obtained. ES+(m/z) 207 [M−H].
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][CH2:10][O:11][C:12]([CH:14](P(OCC)(OCC)=O)[CH3:15])=[O:13].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O>O1CCCC1.O>[CH3:15][C:14](=[CH:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[C:12]([O:11][CH2:10][CH3:9])=[O:13]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)C(C)=Cc1cccs1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a solution of 5.1 g of sodium hydride in oil (prewashed by decantation with hexane.) in 60 ml of dry tetrahydrofuran was added dropwise 30 g of triethyl 2-phosphonopropionate over a period of 30 minutes under dry argon atmosphere at room temperature. After the mixture was stirred for further 1 hour, a solution of 11.8 g of 2-thiophenealdehyde in 30 ml of tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate. Drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 11.0 g of ethyl 2-methyl-3-(2-thienyl)acrylate as a yellow oil. Next, 150 ml of ethanol and 60 ml of aqueous 2N sodium hydroxide were added to the oil, and the mixture was refluxed for 1 hour. After cooling, ethanol was removed under reduced pressure, and the residue was acidified with dilute hydrochloric acid. Crystalline precipitate was collected by filtration to give 8.2 g of 2-methyl-3-(2-thienyl)acrylic acid as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH3:12].C([Li])CCC.CON(C)[C:21](=[O:24])[CH2:22][CH3:23]>C1COCC1>[CH3:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(C(F)(F)F)cc1C
Temperature: -71 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
Cool a solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (2.00 g, 8.367 mmol) and THF (17 mL) to −71° C., and then add n-butyl lithium (2.5 M in hexanes, 9.204 mmol, 3.681 mL) over 5 minutes. Stir the mixture for 15 minutes at −71° C. Add N-methoxy-N-methylpropanamide (0.980 g, 8.367 mmol) to the mixture drop-wise over 3-4 minutes keeping temperature below −65° C. Continue to stir the solution at −71° C. for 15-20 minutes; then warm the solution to room temperature. Stir at room temperature for 40 minutes. Quench the reaction with a saturated ammonium chloride aqueous solution. Extract the aqueous layer with Et2O. Wash the combined organic extracts with water and brine. Dry the mixture over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (40 g RediSep® column) eluting with a gradient of 0-40% DCM/pentane to give the title compound as a colorless oil (1.490 g, 82% yield). 1H NMR (399.80 MHz, d6-DMSO) δ 7.84 (d, J=7.8 Hz, 1H), 7.64-7.61 (m, 2H), 2.93 (q, J=7.1 Hz, 2H), 2.39 (s, 3H), 1.03 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1)=O.O.NN.[OH-].[Na+]>C(O)COCCO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccccn1)c1ccnc2ccccc12
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc(CCc2ccnc3ccccc23)nc1
Temperature: 160 °C

Procedure:
A mixture of 15.8 g of 2-(2-pyridyl)-1-(4-quinolyl)-ethanone and 25 ml of 85% hydrazine hydrate in 250 ml of diethylene-glycol is heated at 160° C. for 30 minutes. After cooling to 60° C., 22 g of sodium hydroxide pellets are added and the mixture is heated at 160° C. for 2 hours. The reaction mixture is diluted with water, then extracted 3 times, each by 300 ml of methylene chloride. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. 12.5 g are thus obtained of 4-[-2-(2-pyridyl)-ethyl]-quinoline in the form of a lacquer. N.M.R. spectrum of the product obtained:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]3)(=[O:13])=[O:12])[CH2:6][CH2:5]2.[O:24]=[C:25]1[C:30]2=[CH:31][NH:32][C:33]([CH:34]=O)=[C:29]2[CH2:28][CH2:27][O:26]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]3=[CH:34][C:33]1[NH:32][CH:31]=[C:30]3[C:25](=[O:24])[O:26][CH2:27][CH2:28][C:29]=13)(=[O:12])=[O:13])[CH2:6][CH2:5]2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4cc(Br)ccc43)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4cc(Br)ccc43)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-(5-Bromo-2,3-dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]1([C:21]2[CH:25]=[CH:24][S:23][C:22]=2[CH3:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27](O)(=[O:31])[C:28](C)=[CH2:29]>ClCCl>[CH3:26][C:22]1[S:23][C:24]2[CH2:29][CH2:28][C:27](=[O:31])[C:25]=2[C:21]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=C(C)C(=O)O
Reactant: Cc1sccc1-c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1sc2c(c1-c1ccccc1)C(=O)CC2
Temperature: 100 °C

Procedure:
In a 2 l 5 neck round bottled flask equipped with nitrogen inlet, 250 ml pressure equalized addition funnel, reflux condenser, thermometer, and mechanical stir was added 1 Kg polyphosphoric acid (Aldrich, 84%). The temperature was raised to 100° C., then 180 g-phosphorus pentoxide was added and the temperature was raised to 130° C. Stirring was continued until all the phosphorus pentoxide had dissolved then the flask and contents were cooled to 80° C. A solution containing 79.2 g (455 mmol) 3-phenyl-2-methylthiophene and 40.1 g (465 mmol) methacrylic acid (Aldrich) dissolved in 100 ml dichloromethane was added slowly. Stirring continued with refluxing dichloromethane for 7 h, during which time an additional 130.8 g (1.52M) methacrylic acid in 250 ml dichloromethane was added (in portions, every 1.5 h). The contents of the flask were poured on to ice, the organic layer was collected with 20% dichloromethane in hexane, washed with water, neutralized with a saturated solution of sodium bicarbonate, then again washed with water. The organic fraction was dried over magnesium sulfate, filtered, then the solvents were removed in vacuo. Yield: 71.4 g (65%) (89.32 g dark orange oil, 80% by GC: used in subsequent steps without further purification). The title compound was analysed by 1H-NMR spectroscopy.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([CH2:33][O:34][CH3:35])[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:36])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:37]C(=O)CCCC)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C1COCC1.[OH-].[Na+].Cl>CO>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([CH2:33][O:34][CH3:35])[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:36])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:37])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Oc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4COC)cc3)c(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A solution of 2-n-Butyl-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-6-valeryloxy-4(3H)-quinazolinone (4.03 g) in a mixture of methanol (20 ml), THF (10 ml) and 1N aqueous sodium hydroxide (20 ml) was stirred at room temperature for 1 hour. After addition of 1N hydrochloric acid (25 ml), the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The resulting crystalline product was recrystallized from ethyl acetate-hexane to give colorless crystals (3.13 g, 91%), mp. 157°-159° C.
Reaction SMILES: Cl.[CH:2]12[CH:7]([CH2:8][OH:9])[CH:6]1[CH2:5][NH:4][CH2:3]2.CCN(CC)CC.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C(Cl)Cl>[C:21]([O:20][C:18]([N:4]1[CH2:5][CH:6]2[CH:2]([CH:7]2[CH2:8][OH:9])[CH2:3]1)=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: OCC1C2CNCC12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2C(CO)C2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of (3-Aza-bicyclo[3.1.0]hex-6-yl)-methanol-HCl (11.8 gm, 78.7 mmol) in 350 mL of anhydrous CH2Cl2 at room temperature was added Et3N (32.9 mL, 236 mmol), followed by (BOC)2O (18.9 gm, 86.6 mmol) in portions. The reaction was stirred at room temperature for 18 hours. The mixture was washed with saturated NaHCO3, water, brine and dried over anhydrous MgSO4. The mixture was filtered and concentrated under reduced pressure to yield the crude material, which was purified via flash chromatography with 10% MeOH/EtOAc. The product containing fractions were collected and concentrated to yield the desired product (15.6 gm). 400 MHz 1H NMR (CDCl3) δ 3.42-3.56 (m, 4H), 3.24-3.37 (m, 2H), 1.72 (brs, 1H), 1.37-1.41 (m, 10H), 0.87-0.93 (m, 1H); MS (M+1) 213.2.
Reaction SMILES: C([Li])CCC.[C:6]1([OH:17])[C:15]([F:16])=[C:13]([F:14])[C:11]([F:12])=[C:9]([F:10])[C:7]=1[F:8].Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CCCCCC>[C:6]1([O:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([F:8])=[C:9]([F:10])[C:11]([F:12])=[C:13]([F:14])[C:15]=1[F:16]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[Si](C)(C)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 59.8 %

Procedure:
n-Butyllithium (9.75 mL, 22.39 mmol, 2.5 M in hexane) was added dropwise, at 0° C., to a 200 mL hexane solution of C6F5OH (4.08 g, 22.17 mmol). After the addition of n-butyllithium was complete, the reaction mixture was allowed to warm to room temperature. Chlorotrimethylsilane (2.65 g, 24.39 mmol) was added to the reaction at −40° C. After slowly warming to room temperature, the reaction was refluxed for 19 hours. Isolation of the crude product was achieved by ether extraction. The organic was washed with ammonium chloride, water, brine, and dried over sodium sulfate. Solvent was removed in vacuo to yield 4.0 g of crude product. The resulting liquid was purified by vacuum distillation to give 3.4 g (60%) of a colorless liquid. 1H NMR (C6D6): δ 0.081 (br. s).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[N:34]=[CH:33][CH:32]=[N:31]3)=[CH:26][CH:25]=2)=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([O:15]CC)=[O:14])[CH:9]=1.CO>CC1CCCO1.O>[F:3][C:4]1[C:5]([C:24]2[CH:25]=[CH:26][C:27]([N:30]3[N:34]=[CH:33][CH:32]=[N:31]3)=[CH:28][CH:29]=2)=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14])[CH:9]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)S(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC1CCCO1
Solvent: O
Product: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
Potassium hydroxide (1.30 g, 23.2 mmol) was added to a solution of ethyl (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate (1.54 g, 3.33 mmol) in 2-methyltetrahydrofuran:water (2:1 42.5 mL) and the solution was stirred at rt overnight. Methanol (5 mL) was added and the reaction was heated to 60° C. The reaction mixture was stirred at this temperature for 2 h. The reaction was concentrated and triturated in 3 M aq HCl. The solid was collected via filtration and washed with water (20 mL) and hexanes (20 mL). The solid was dried under vacuum to afford the title compound as a white solid (1.39 g, 96.1%). MS (LCMS) m/z 435.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.13-2.30 (m, 0H) 2.41-2.61 (m, 1H) 3.17 (s, 3H) 3.89-4.13 (m, 2H) 6.59 (d, J=7.81 Hz, 1H) 6.56-6.63 (m, 1H) 7.79 (dd, J=8.78, 1.76 Hz, 3H) 8.09 (d, J=6.83 Hz, 1H) 8.12-8.17 (m, 2H) 8.19 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][C:31]([O:33]CC)=[O:32])=[CH:24][C:23]=3[O:36][CH3:37])[CH:15]=[CH:16][C:17]=2[F:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O>CN(C=O)C.[OH-].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:22]3[C:23]([O:36][CH3:37])=[CH:24][C:25]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][C:27]=3[O:28][CH3:29])[CH:15]=[CH:16][C:17]=2[F:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(OC)c(-c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=CO
Product: COc1cc(CC(=O)O)cc(OC)c1-c1ccc(F)c2c1CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8-(4-ethoxycarbonylmethyl-2,6-dimethoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (9.5 mg, 0.02 mmol, 1 eq.) in DMF (0.1 mL), 2M aq. NaOH soln. (68 μL) was added. The solution was stirred at r.t. for 18 hours. Formic acid was added (0.1 mL). The resulting acidic solution was purified by prep. HPLC (column: Waters XBridge, 19×30 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C@@H:7]([OH:14])[C@@H:6]2[N:15]=[N+]=[N-])#[N:2].C(N(CC)CC)C.C(S)CCS>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C@@H:7]([OH:14])[C@@H:6]2[NH2:15])#[N:2]
Reactant: CC1(C)c2ccc(C#N)cc2[C@@H](N=[N+]=[N-])[C@@H]1O
Agent: SCCCS
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(C)c2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Yield: 95.9 %

Procedure:
A solution of trans-5-cyano-1,1-dimethyl-3-azido-indan-2-ol (0.93 g), triethylamine (1.2 ml) and 1,3-propanedithiol (0.9 ml) in dry methanol (20 ml) was stirred at room temperature for 48 h. After filtration, the solution was evaporated in vacuo to give the title compound (0.79 g) as a gum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.[CH2:18]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CN1CCCC1=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:29][CH:28]([OH:30])[CH2:27][O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: CCCCCCCCOCC1CO1
Reactant: Oc1ccc(-n2nc3ccccc3n2)c(O)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CN1CCCC1=O
Product: CCCCCCCCOCC(O)COc1ccc(-n2nc3ccccc3n2)c(O)c1

Procedure:
A mixture of 2-(2,4-dihydroxyphenyl)-2H-benzotriazole (7.0 grams, 0.031 mole), 3-n-octyloxy-1,2-epoxypropane (10.7 grams, 0.046 moles), N-methylpyrrolidone (40 ml) and ethyltriphenylphosphonium bromide (0.2 gram) was heated for four hours at 135°-150° C. The solvent and excess epoxide were then removed by distillation. The resulting residue was dissolved in methylene chloride, washed with hydrochloric acid, water and sodium chloride solution before passing through a silica gel column. The product was obtained as a yellow oil which crystallized on standing. Recrystallization from heptane gave the above named product with a melting point of 51°-55° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[C:17]([CH3:27])=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][CH:26]=[C:16]([F:15])[C:17]=3[CH3:27])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: Cc1c(F)cccc1C=CC(=O)O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(F)c3C)nc2n(CC)c1=O
Yield: 50.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.50 g (13.9 mmol) of 3-fluoro-2-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.18 g (yield 51%) of Compound 171 as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH:5]=[C:6]2[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)C2CCC(=O)C1C2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)C2CC=C(N3CCCC3)C1C2
Yield: 95.1 %

Procedure:
A solution of 30 g of nopinone ([α]D20 =+39.90; c=8 in ethanol), 29 g of pyrrolidine and 0.4 g of p-toluenesulfonic acid in 150 ml anhydrous benzene was heated at reflux for 40 h under nitrogen atmosphere in a vessel fitted with a water separator. After evaporation of the solvent and distillation of the residue, there were obtained 39.5 g (95% yield) of 1-(6,6-dimethyl-norpin-2-en-2-yl)-pyrrolidine having b.p. 117°-118° C./10 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCCN1CCCC1

Procedure:
5-Chloro-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide to give the title compound.