Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>CC(C)=O.ClCCl>[Cl:20][C:21]1[N:26]=[C:25]([N:9]([CH:10]([CH3:12])[CH3:11])[CH2:8][C:2]([F:13])([F:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(F)CNC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
Ethyl 2,2-difluoro-3-(isopropylamino)propanoate (1.50 g, 7.68 mmol) was dissolved in acetone and K2CO3 (2.12 g, 15.3 mmol) was added. The solution was purged with nitrogen gas and cooled to 0° C. A solution of 2,4-dichloro-5-nitropyrimidine (1.64 g, 8.45 mmol) in acetone (10 mL) was added dropwise at 0° C. over 1 h. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. It was diluted with dichloromethane (50 mL) and filtered thru a celite plug. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1) to afford the title compound as a yellow oil (1.96 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.82 Hz, 6 H) 1.34 (t, J=7.20 Hz, 3 H) 3.63-3.75 (m, 1 H) 4.24 (t, J=13.14 Hz, 2 H) 4.34 (q, J=7.07 Hz, 2 H) 8.74 (s, 1 H).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11](C1C=CC=CC=1Cl)[N:12]1[CH2:17][CH2:16][C:15]2[O:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)C.C(O)C.[OH-].[Na+]>O>[O:18]1[C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3])[CH2:13][C:14]=2[CH:20]=[CH:19]1
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2occc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCCCN1CCc2occc2C1)C(=O)O
Yield: 73.5 %

Procedure:
8-(2-Chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (0.5 g, 1.16 mmol) was added to a mixture of ethanol (20 mL) and sodium hydroxide (0.32 g, 8.0 mmol) in water (6.6 mL). The mixture was heated to reflux for 6.5 hours. Evaporated solvent under reduced pressure and water (20 mL) was added to the residue. The aqueous solution was washed with a mixture of ethyl acetate/heptane 1/10 (10 mL), and the extract was discarded. The aqueous fraction was acidified with concentrated hydrochloric acid to pH=6 and the product was extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 842-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid (0.25 g, 46.9%) as a yellow oil. The material was dissolved in diethyl ether (5 mL) and added to hydrochloric acid solution (2N HCl in diethyl ether, 0.34 mL). Water (12 mL) was added and after mixing the aqueous portion was separated and freeze dried to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid, hydrochloride salt (Compound Io hydrochloride, 0.16 g, light yellow powder, 59.3% yield). 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.77 (br s, 1H), 7.63-7.48 (m, 5H), 6.37 (br s, 1H), 5.05 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.02 (m, 2H), 2.36-2.24 (m, 2H), 1.42-1.40 (m, 2H), 1.32 (m, 2H), 1.20-1.18 (m, 4H), 1.11 (s, 6H), 1.08-0.92 (m, 1H). 13C NMR (Field: 75 MHz, Solvent: CD3OD/TMS) δ (ppm): 181.70, 147.11, 144.55, 137.40, 132.15, 131.89, 130.08, 128.21, 129.87, 112.37, 109.71, 66.34, 52.10, 50.05, 43.07, 41.60, 35.10, 31.67, 30.56, 26.64, 25.85, 22.31. HRMS (FIR, DIP-CI): Calculated for C23H30ClNO3 (M+H)+: 404.1987. Found 404.2009. CHN analysis: Calculated; 62.73; C, 7.09; H, 3.18; N, 16.10; Cl. found; 59.13; C, 7.04; H, 3.03; N, 13.58; Cl.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:3]=1)[CH3:21]
Reactant: CCc1ccccc1B(O)O
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Product: CCc1ccccc1-c1cccc(NC(=O)OC2CN3CCC2CC3)c1
Yield: 78 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromophenylcarbamate, 2-ethylphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title v compound as a white solid (110 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.42-7.28 (m, 5H), 7.25-7.16 (m, 2H), 7.03-7.00 (m, 1H), 6.88 (br s, 1H), 4.83 (m, 1H), 3.27 (m, 1H), 2.98-2.70 (m, 5H), 2.61 (q, J=7.6 Hz, 2H), 2.08 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.65 (m, 1H), 1.63-1.55 (m, 1H), 1.46-1.37 (m, 1H), 1.10 (t, J=7.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 152.1, 141.7, 140.4, 139.9, 136.4, 128.6, 127.5, 127.4, 126.4, 124.3, 123.2, 118.4, 115.9, 71.0, 54.3, 46.2, 45.3, 25.0, 24.2, 23.4, 18.3, 14.5 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.61 min; (M+1) 351.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:31]1([CH3:43])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39](Cl)(=[O:41])=[O:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([I:12])=[CH:10][CH:11]=1)[S:39]([C:32]1[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=1[CH3:43])(=[O:41])=[O:40]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(I)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2Cl)c2ccc(I)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-(4-iodophenyl)-amine (3.00 g, 6.76 mmol) in 4 mL methylene chloride was added triethylamine (2.84 mL, 20.3 mmol) and 2-mesitylenesulfonyl chloride (2.96 g, 13.5 mmol). The reaction mixture was stirred at room temperature overnight. Additional triethylamine (1 mL, 7.15 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. DMAP was added and the reaction mixture was allowed to stir at room temperature for three days. Additional methylene chloride (2 mL), triethylamine (1 mL, 7.15 mmol) and 2-mesitylenesulfonyl chloride (1.00 g, 4.57 mmol) were added. The reaction mixture was stirred at 30° C. overnight. Additional triethylamine (2.84 mL, 20.3 mmol) and DMAP were added and the reaction was stirred at 30° C. overnight. Additional 2-mesitylenesulfonyl chloride (0.54 g, 2.47 mmol) was added and the reaction mixture was stirred at 30° C. overnight. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography of the residue afforded 2.30 g (54%) of the title compound of Step B.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[O:12]>C(O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[CH2:10][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1NC(=O)CCl
Reactant: NCc1ccccc1
Solvent: CCO
Product: COc1ccccc1NC(=O)CNCc1ccccc1

Procedure:
To ethanol (100 mL) add benzylamine (35 g, 0.33 mol) and 2-chloro-N-(2-methoxyphenyl)acetamide (22 g, 0.11 mol). Stir and heat the reaction at 50° C. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction remove the precipitate that has formed by suction filtration and discard. Evaporate the filtrate and partition the residue between ethyl acetate and 2N NaOH(aq). Separate the organic layer and dry it over Na2SO4. Remove the drying agent by filtration and remove the solvent in vacuo. Chromatograph the residue on silica gel (400 g) using hexane/EtOAc (3/1) as eluent to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:21]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH:31]3[CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:19])=[O:5].[CH2:34](OC(OCC)OCC)C>>[CH:16]1([NH:15][C:13](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:23][CH:22]=[C:21]([O:24][CH:25]5[CH2:26][CH2:27][N:28]([CH:31]6[CH2:33][CH2:32]6)[CH2:29][CH2:30]5)[CH:20]=4)[N:1]=[CH:34]3)[CH:12]=2)[CH2:17][CH2:18]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C3CC3)CC2)ccc1N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C4CC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described in Example 1, 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(1-cyclopropylpiperidine-4-yl)oxy] benzamide was reacted with triethylorthoformate. There was thus obtained the title compound (0.063 g); NMR Spectrum: (DMSOd6) −0.01 (m, 2H), 0.12 (m, 2H), 0.27 (m, 2H), 0.40 (m, 2H), 1.34 (m, 3H), 1.65 (m, 2H), 1.84 (s, 3H), 2.18 (m, 2H), 2.53 (m, 3H), 4.28 (m, 1H), 7.23 (m, 2H), 7.29 (s, 1H), 7.43 (d, 1H), 7.53 (s, 1H), 7.60 (d, 1H), 7.89 (s, 1H), 8.14 (s, 1H); Mass Spectrum: M+H+ 459.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[C:8]=2[N+:13]([O-:15])=[O:14])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2nc(Cl)ccc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2nc(Cl)ccc2c1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
4.12 g of 2-chloro-6-methylquinoline (J. Med. Chem. 1992, pp. 2761-2768) is added at 0° C. to a solution that consists of 15 ml of 100% nitric acid and 2 ml of 96% sulfuric acid. After 4 hours at 0° C., it is added to water, and the product is filtered off. 4.66 g of 2-chloro-6-methyl-5-nitroquinoline is obtained as a beige solid. The latter is reacted for 80 hours at 100° C. in 46 ml of glacial acetic acid and 26 ml of water. The thus obtained 6-methyl-5-nitroquinolin-2(1H)-one is filtered off from the reaction solution. The 3.45 g of product that is obtained is reacted on activated carbon to form aniline with hydrogen under normal pressure in methanol on palladium. 2.89 g of the title compound is obtained as a beige solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])=[CH:10][CH:9]=1>>[F:5][CH:6]([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15]([Cl:3])=[O:16])=[CH:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Product: CC(C)[C@H](C(=O)Cl)c1ccc(OC(F)F)cc1
Yield: 91.8 %

Procedure:
Add 32.8 g (0.275 mole) of thionyl chloride to 42 g (0.17 mole) of the obtained (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid, heat with stirring under reflux for 1 hour, and then distill off the unreacted thionyl chloride to give 41 g of (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:22]([CH:26]1[CH2:31][CH2:30][C:29](OC)(OC)[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([CH:26]1[CH2:31][CH2:30][C:29]([O:18][CH2:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=2)=[CH:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1(OC)CCC(C(C)(C)C)CC1
Product: CC(C)c1nc(CCOC2=CCC(C(C)(C)C)CC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 70 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the enol ether with 4-tert-butyl-1,1-dimethoxycyclohexane (1 g, 5 mmol) in the same manner as the example 41 to give the compound 50 (337 mg, 70%). Mp 99.5-100.5° C. PMR (CDCl3 -0.1% d5 -Py): δH0.86 (9 H, s, t-Bu), 1.24 (6 H, d, J 4.4 Hz, (CH3)2C), 3.12 (2 H, t, J 4.2 Hz, CH2 -Im), 3.12 (1 H, m, (CH3)2CH), 3.50 (3 H, s, NCH3), 3.97 (2 H, m, OCH2), 4.61 (1 H, m, =CH), 6.77 (2 H, d, J 1 Hz, arom-H), 7.09 (1 H, t-like, arom-H). Elementary analysis (for C25H34N2Ocl2S) Calcd. : C, 62.35% H, 7.12% N, 5.82% S, 6.66% Cl, 14.72% Found: C, 62.56% H, 7.13% N, 5.76% S, 6.57% Cl, 14.43%
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[S:24](Cl)(=[O:26])=[O:25].O>O1CCCC1>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[S:24]([N:8]1[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:26])=[O:25]
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.00 g) in tetrahydrofuran (70 mL) was added sodium hydride (60% in oil, 348 mg) at room temperature, and the mixture was stirred for 30 min. 2,6-Difluorobenzenesulfonyl chloride (1.36 g) was added to the reaction mixture, and the mixture was stirred for 1.5 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound as colorless crystals (yield 1.36 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH3:13][C:14](C)([O-])[CH3:15].[K+].C(Br)(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[CH:14]([CH3:15])[CH3:13]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [K+]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The (4-bromophenyl)acetic acid methyl ester in the Step 1 and potassium t-butoxide (4.8 g, 1 eq) were dissolved in 200 ml DMF at 0° C. Isopropyl bromide (4 ml. 1 eq) was added into the mixture and stirred at room temperature for 3 hours. When the reaction was completed, the mixture was extracted 3 times with ethyl acetate and water, and washed with saline solution. After the organic layer was dried with anhydrous and the solvent was removed at low pressures, the target compound 2-(4-bromophenyl)3-methylbutyric acid methyl ester was obtained by separation and purification of the mixture using a column chromatography (ethyl acetate:n-hexane=1:10) (6.60 g, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21]OS(C)(=O)=O)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCOS(C)(=O)=O)cc2)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCN3CCCCC3)cc2)cc1

Procedure:
The product from Step 3 (205 mg, 0.4 mmol) was combined with cesium carbonate (197 mg, 0.6 mmol), piperidine (44 mL, 0.44 mmol) in dimethylformamide at room temperature. After four hours the reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. After filtration, concentration the title compound (120 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[Na+].[I-]>C(#N)C.O>[C:17]([O:16][C:14](=[O:15])[CH2:13][N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH2:8]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Brc1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 6-bromo-1,2,3,4-tetrahydro-isoquinoline (10.60 g, 50 mmol) and t-butyl bromoacetate (9.95 g, 51 mmol, 1.02 eq.) in acetonitrile (100 ml) are added sodium carbonate (10.6 g, 100 mmol, 2.0 eq.) and NaI (375 mg, 2.5 mmol, 0.05 eq.). The resulting mixture is stirred at rt for 16 hr. Water (100 ml) is added to quench the reaction, and the acetonitrile is evaporated. The residue is extracted with EtOAc (100 ml×3), and the combined organic phase is dried over sodium sulfate and concentrated. The residue is purified by silica gel flash chromatography (EtOAc/hexane, 1:4) to give the title compound. MS (+VE) m/z 326.10 (M++1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)[CH3:2].OO.C(=O)([O-])[OH:21].[Na+]>C(O)(=O)C.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([O:3][CH2:4][CH2:5][S:6]([C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)=[O:21])[CH3:2]
Reactant: CCOCCSc1nc(-c2cccnc2)cs1
Reactant: O=C([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOCCS(=O)c1nc(-c2cccnc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Dissolved in 1.7 ml of acetic acid were 0.33 g (1.24 mmol) of the compound obtained in Example 1, and 0.15 ml (1.32 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic amount of sodium tungstate were successively added to the solution, which was stirred at room temperature for 4 hours. The reaction solution was poured in 34 ml of water, neutralized with sodium hydrogencarbonate and extracted with 34 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 0.27 g of white crystalline powders (77% yield).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16]C)=[O:15])[CH2:3]1>CO.O1CCCC1.[OH-].[Na+]>[C:10]([O:9][C:7]([N:5]1[CH2:6][C:2]([F:1])([F:18])[CH2:3][C@H:4]1[C:14]([OH:16])=[O:15])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
1.08 g (4.08 mmol) of (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (purchased from Aldrich®; cat. no. 702463) were dissolved in a mixture of 10 mL of methanol and 10 mL of tetrahydrofurane and 6.12 mL of a 2M aqueous solution of sodium hydroxide were added. The solution was stirred at room temperature for 1 hour and then the organic solvents were removed. The remaining solution was diluted with water and 6.12 mL of 2M hydrochloric acid were added. The product that precipitated was extracted with dichloromethane (×3), the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. 1.01 g (99% yield) of the title compound were obtained as a white solid.
Reaction SMILES: [OH:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25]O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:17]1([CH:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:25][O:1][CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=c1[nH]c2c([nH]c1=O)C(OCCC(c1ccccc1)c1ccccc1)c1ccccc1-2
Yield: 12.5 %

Procedure:
A suspension of 9-hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. 1H2O (1.0 g, 4.26 mmol) in benzene (40 ml), 3,3-diphenyl-1-propanol (10 ml) and p-toluensulfonic acid (40 mg) was refluxed with water separation for 48 hours. The reaction mixture was evaporated in vacuo to dryness, the residue was suspended in ethanol (10 ml) and the precipitate was filtered off and washed with ethanol and dried to give 0.224 g (12.5%) of the title compound. M.p. 224°-228° C. 1H-NMR(DMSO-d6, δ): 2.14-2.32 (m, 2H), 3.0-3.22 (m, 2H), 4.13 (t, 1H), 5.22 (s, 1H), 7.0-7.5 (m, 14H), 12.12 (s, 1H), 12.26 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[C:4]31[O:16][O:15][C:14]1([CH2:21][CH2:20][CH:19]([CH2:22][C:23]([O-:25])=[O:24])[CH2:18][CH2:17]1)[O:13]3)[CH2:10]2.Cl>O.C(O)C>[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[C:4]31[O:16][O:15][C:14]1([CH2:21][CH2:20][CH:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]1)[O:13]3)[CH2:10]2
Reactant: O=C([O-])CC1CCC2(CC1)OOC1(O2)C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1CCC2(CC1)OOC1(O2)C2CC3CC(C2)CC1C3
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (3.86 g, 96.57 mmol, 3 equiv.) in water (80 mL) was added to a solution of methyl (1 s, 4 s)-dispiro[cyclohexane-1,3′-[1,2,4]trioxolane-5′,2″-tricyclo[3.3.1.13,7]decan]-4-ylacetate (example 3) (10.83 g, 32.19 mmol, 1 equiv.) in 95% ethanol (150 mL). The mixture was stirred at 50° C. for about 4 h, cooled to 0° C., and treated with 1M hydrochloric acid (129 ml, 4 equiv). The precipitate was collected by filtration, washed with 50% aqueous ethanol (150 mL) and dried in vacuum at 40° C. to give the title compound as colorless solid. Yield: 9.952 g, 96%, mp: 146-148° C. (95% ethanol), 1HNMR (500 Hz, CDCl3): δ 1.19-1.41 (m, 2H), 1.60-2.05 (m, 21H), 2.27 (d, J=6.8 Hz, 2H).