Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[O:28][C@@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:7]1[O:8]C(=O)C1C=CC=CC=1)(=[O:4])C.[C:39](Cl)(=O)[CH3:40]>ClCCl.C(OCC)(=O)C>[C:2]([O:5][C@@H:6]1[O:28][C@@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:7]1[OH:8])(=[O:4])[C:40]1[CH:39]=[CH:27][CH:17]=[CH:7][CH:6]=1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 63.7 %

Procedure:
HCl (gas) was bubbled for 1.5 hours into a solution of 50 g (99.16 mole) of the compound (12) dissolved in 460 ml of anhydrous dichloromethane and 7.5 ml of acetyl chloride at 0° C. The resulting solution was kept in a refrigerator for 12 hours and then evaporated in vacuo. The residue was coevaporated with toluene (3×150 ml) at 45° C. and redissolved in 105 ml of acetonitrile. To this solution, 13 ml of water was added dropwise at 0° C. A white solid began to precipitate from the mixture after 30 minutes, after which the mixture was kept in a refrigerator for 2 hours to induce additional precipitation. After filtration of the resulting solid, the filter cake was. carefully washed with cold diethylether to remove the reaction by-product 1-hydroxy-isomer, which is indistinguishable by TLC from the compound (13). The white solid thereby obtained was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate to remove the remaining HCl, dried over MgSO4 and filtered. The solvent was removed from the filtrate to obtain 29.2 g (Yield: 63.7%) of the compound (13) in the form of a white solid.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.CN(C)C=O.[CH2:29]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([OH:44])[CH2:41][C@@H:40]1[C:45]([OH:47])=[O:46])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[CH2:29]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([O:44][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:41][C@@H:40]1[C:45]([OH:47])=[O:46])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.32 g of tert-butyldiphenylsilyl chloride and 2.32 g of imidazole were added in order to a dimethylformamide (60 ml) solution of 3.61 g of (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated ammonium chloride and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2) to obtain the entitled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=3[CH3:20])=[CH:11][CH:12]=2)=[C:4]([CH3:21])[CH:3]=1.Br.C1C2C(=CC=CC=2)C=CC=1CS[C:35](=[NH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl>>[C:35]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[NH:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:3][C:4]=3[CH3:21])=[CH:12][CH:11]=2)=[C:14]([CH3:20])[CH:15]=1)(=[NH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cc(N)ccc1-c1ccc(-c2ccc(N)cc2C)o1
Reactant: N=C(SCc1ccc2ccccc2c1)c1ccccc1
Agent: Br
Agent: Cl
Product: Cc1cc(NC(=N)c2ccccc2)ccc1-c1ccc(-c2ccc(NC(=N)c3ccccc3)cc2C)o1
Yield: 60 %

Procedure:
2,5-Bis[4-(benzimidoyl)amino-2-methylphenyl]furan (4e, DB626) was prepared according to the procedure for 4f using diamine 3b and S-(2-naphthylmethyl)-thiobezimidate hydrobromide as starting materials. Free base: yellow crystalline solid. Yield: 60%. 1H NMR (DMSO-d6): 2.48 (s, 6H), 6.50 (br s, 4NH), 6.75 (s, 2H), 6.84 (s, 4H), 7.44 (m, 6H), 7.71 (d, 2H), 7.95 (d, 4H). Hydrochloride: orange/yellow hygroscopic solid. 1H NMR (DMSO-d6): 2.61 (s, 6H), 7.03 (s, 2H), 7.38-7.44 (m, 4H), 7.63-7.68 (m, 4H), 7.75-7.80 (m, 2H), 7.94 (d, 6H). MS (EI): m/z 484 (M+, 100), 3.81 (87.2), 278 (37.9), 235 (5.4), 218 (3.1), 190 (5.5), 144 (11.1), 103 (32.8), 76 (9.3). Anal. Calcd. for C32H28N4O.2HCl.0.66H2O (569.39): C, H, N.
Reaction SMILES: [C:1]1(=[O:15])[N:5](C(CCCC)C(Cl)=O)[C:4](=[O:14])[CH:3]=[CH:2]1>C(OCC)(=O)C.CCCCCC>[C:4]1(=[O:14])[NH:5][C:1](=[O:15])[CH:2]=[CH:3]1.[CH3:1][CH:2]1[CH2:3][CH2:4][O:14]1
Reactant: CCCCC(C(=O)Cl)N1C(=O)C=CC1=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1CCO1
Product: O=C1C=CC(=O)N1

Procedure:
Following the addition, the resulting dark brown solution was mixed at room temperature over-night. Thin-layer chromatography (1/1 vol., ethyl acetate/hexane) indicated that the reaction was complete based on the depletion of maleimidocaproic chloride. White solids were filtered from the reaction solution which was then washed four times with distilled water (300 ml each). Methylene chloride was stripped from the reaction solution via roto-evaporation and replaced with an ethyl acetate/hexane solution (2/1, respectively, by volume). The dark brown solution was then passed through a column of silica gel to purify. Next, the solvent was stripped in vacuo resulting in a clear orange product with a viscosity of 750 cPs. The compound had a weight loss of 8% at 200° C. as measured by TGA.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Mg].CI.[CH3:13][S:14]SC.Cl>C(OCC)C.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([S:14][CH3:13])[CH:7]=1
Reactant: CSSC
Reactant: Cc1ccc(F)cc1Br
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Solvent: O
Product: CSc1cc(F)ccc1C

Procedure:
To a solution of 2-bromo-4-fluorotoluene (45 g) in dry diethyl ether (500 ml) is added magnesium (for Grignard reagent, 7 g), and the mixture is refluxed with stirring. To the reaction mixture is added methyl iodide (1 ml), by which the reaction initiates vigorously, and then the mixture is stirred for 30 minutes after taking off the heating bath. Thereafter, the reaction becomes mild, and then the reaction mixture is refluxed for 30 minutes. After allowing to cool, dimethyl disulfide (24 ml) is added to the reaction mixture, and the mixture is refluxed for 3 hours. After allowing to cool, water and 10% hydrochloric acid are added to the reaction mixture, and the mixture is extracted with diethyl ether. The extract is washed with water (500 ml×3), dried over anhydrous sodium sulfate and then the solvent is distilled off. The resulting residue is distilled under reduced pressure to give 4-fluoro-2-methylthiotoluene (30 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:27]([C:29]([OH:31])=O)[N:28]=1.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([CH2:45][NH:46][C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[NH:40]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:27]([C:29]([N:40]2[C@H:41]([CH2:45][NH:46][C:47](=[O:52])[C:48]([F:50])([F:51])[F:49])[CH2:42][C@H:43]3[C@@H:39]2[CH2:44]3)=[O:31])[N:28]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
TBTU (3.22 mmol, 1.05 eq) is added to a solution of 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid (3.07 mmol, 1.0 eq), N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide (3.07 mmol, 1.0 eq) and DIPEA (9.20 mmol, 3.0 eq) in DCM (15 mL) and DMF (3.0 mL). After 2 h the mixture is washed twice with water, once with sat. aqueous NaHCO3 solution, once with hydrochloric acid (0.2 M) and three times with water. The organic layer is dried over Na2SO4, the solvents are removed in vacuo and the residue is purified by preparative TLC (DCM/MeOH 9/1) to give the desired product as an orange foam. LC-MS (acidic): tR=0.87 min; [M+H]+=429.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].C(OCC)(=O)C>CN1CCCC1=O>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:5][CH:6]=1
Reactant: NCCc1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=C(C)C(=O)NCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12.4 Gram of 4-(2-aminoethyl)phenol and 9.15 g of triethylamine were dissolved in 100 mL of N-methylpyrrolidone, and the solution was cooled to 0° C. in a nitrogen stream. Thereto, 9.45 g of methacryloyl chloride was added dropwise over 0.2 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 4 hours. After adding 500 mL of ethyl acetate, the organic layer was washed, in sequence, twice with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated to obtain 12.2 g of N-(4-hydroxyphenethyl)methacrylamide as a brown oil. Thereafter, 7.49 g of the oil and 11.5 g of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride were dissolved in 100 mL of THF, and the resulting solution was cooled to 0° C. Thereto, 4.43 g of triethylamine was added dropwise over 0.3 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 3 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated, and the brown oil as residue was dissolved in 100 ml of methanol. Thereto, 10 g of sodium hydrogencarbonate as solid was added, and the mixture was stirred at 50° C. for 6 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with saturated brine and twice with water and dried over sodium sulfate to obtain 15.7 g of 3-((4-(2-methacrylamido)ethyl)phenoxy)sulfonyl)-1,1,2,2,3,3-hexafluoropropane-1-sulfonylfluoride as a brown oil. Thereafter, 7.29 g of this brown oil was dissolved in 100 mL of methanol, and 4.81 g of triphenylsulfonium bromide was added thereto, followed by stirring at room temperature for 3 hours. After adding 200 mL of chloroform, the organic layer was washed with water, and the solvent was concentrated, as a result, 10.1 g of a brown transparent oily compound was obtained. 1H-NMR (300 MHz, CDCl3) δ 1.91 (s, 3H), 2.87 (t, 2H), 3.50 (quartet, 2H), 5.27 (s, 1H), 5.66 (s, 1H), 6.39 (bs, 1H), 7.14 (d, 2H), 7.23 (d, 2H), 7.67-7.76 (m, 15H), 19F-NMR (300 MHz, CDCl3) δ −107.4 (m, 2F), −114.0 (m, 2F), −118.1 (m, 2F).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH2:11]([O:13][CH2:14][CH2:15]Br)[CH3:12]>C(O)C>[CH2:11]([O:13][CH2:14][CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:1][CH3:2])[CH3:12]
Reactant: CCNCc1ccccc1
Reactant: CCOCCBr
Solvent: CCO
Product: CCOCCN(CC)Cc1ccccc1
Yield: 61 %

Procedure:
The synthesis of FEA was carried out in a manner similar to that of BnEO (process 2) using N-ethylbenzylamine (15 mL, 0.101 mol), bromoethyl ethyl ether (17 mL, 0.101×1.5 mol), and ethanol (100 mL) as a solvent. BnEE (12.79 g, 61.69 mmol, yield 61%) was obtained as a pale yellow clear liquid. [Purification was carried out by medium pressure silica gel column chromatography (ethyl acetate:n-hexane=4:1).]
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[CH:32]=[CH:33][CH:34]=[O:35].[NH4+].[Cl-:41]>C1COCC1>[Cl:41][C:33](=[CH:32][C:31]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:30]=1)[CH:34]([OH:35])[CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:18])([F:19])[F:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CNC(=O)c1ccc(F)cc1C(F)(F)F
Reactant: [Cl-]
Reactant: O=CC=Cc1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)C(Cl)=Cc1ccccc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
At −75° C., 5.0 g (0.0170 mol) of ethyl (4-fluoro-2-trifluoromethylbenzoylamino)acetate dissolved in THF were added dropwise to 25.0 ml (0.050 mol) of a 2M solution of lithium diisopropylamide in THF. After 1 h at −75° C., 3.50 g (0.021 mol) of 2-chlorocinnamaldehyde dissolved in THF were added dropwise, and the mixture was stirred at −75° C. for 1 h. Saturated NH4Cl solution was added dropwise and the mixture was warmed to RT and extracted with CH2Cl2. The combined organic phases were washed and dried, and the solvent was removed. The residue was purified chromatographically (SiO2, cyclohexane/ethyl acetate). This gave 7.5 g (96% of theory) of the title compound as a colorless solid (diastereomer mixture) which was reacted further without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH2:15][CH2:16][CH2:17][C:3]1=2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C[O-].[Na+].Cl>CO>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:15]1[C:4]2[O:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7]=3[C:2](=[O:1])[C:3]=2[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc2oc3c(c(=O)c2c1)CCC3
Reactant: COc1ccccc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C=C1CCc2c1oc1ccc(C(=O)O)cc1c2=O
Temperature: 45 °C
Reaction time: 7 h

Procedure:
1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, m.p. 273°-275° C. (1.6 g) was reacted with 2-methoxy-benzaldehyde (1 g) in methanol (60 ml) in the presence of sodium methylate (1.3 g) under stirring at 45° C. for 7 hours. After cooling, the reaction mixture was acidified with 37% HCl and the precipitate was filtered and washed with methanol and then with water until neutral. Crystallization from chloroform-ethanol gave 1.2 g of 3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, m.p. 291°-295° C., NMR (CH3COOD) δppm: 3.36 (bs) (4H, C-1 and C-2 protons), 4.09 (s) (3H, --OCH3), 7.09-7.87 (m) (4H, phenyl protons), 8.07 (d) (1H, C-5 proton), 8.41 (bs) (1H, =CH--), 8.76 (dd) (1H, C-6 proton), 9.28 (d) (1H, C-8 proton).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24](OCC)=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1.Cl.[C:31]([O:35][C:36](=[O:39])[CH2:37][NH2:38])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1.CCOCC>[F:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24]([NH:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(F)cc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)cc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
DIPEA (939 μL, 5390 μmol) was added to a mixture of ethyl 7-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.00 g, 3594 μmol) and glycine tert-butyl ester hydrochloride (723 mg, 4312 μmol) in dioxane (25 mL). The reaction mixture was stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the desired ester as a white solid (590 mg). MS (m/e)=308.1 (M+H-tBu)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=O.[H][H].C([OH:19])C>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:12][C:7]([OH:19])([CH2:6][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=1[OH:8])[CH3:13]
Reactant: CC1(C)CC(=O)c2cc(F)ccc2O1
Reactant: [H][H]
Reactant: CCO
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CC(C)(O)CCc1cc(F)ccc1O

Procedure:
A solution of 6-fluoro-2,2-dimethyl-chroman-4-one (EP 193493; 1 equiv.) in ethanol (0.24 M) was treated with copper chromite (0.6 equiv.). The reaction was heated to 200° C. for 6 hours at 3000 psi of hydrogen gas. The reaction was filtered and concentrated to a solid. The crude material was recrystallized form hot hexanes to give the title compound. MS found 198 [M+H]+
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:27][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(Sc2ccccc2)c1CC
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)c2ccccc2)c1CC

Procedure:
Prepared from product of Example 8 (6.1 g, 15.1 mmol) and MCPBA (2.9 g of an 85% mixture with MCBA, 15.1 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (4.46 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[N:18]([CH2:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=[CH:22][CH:23]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)NC4=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
To an ice cooled solution of 3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (2.5 g, 8.1 mmol) in anhydrous N,N-dimethylformamide (25 ml), sodium hydride (60% emulsion in paraffin oil, 500 mg, 12 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction mixture was again cooled to 0° C. and (2-bromoethyl)benzene (1.5 ml, 8.9 mmol) was added. The solution was then heated to 90° C. for 2 hours. The reaction was monitored by TLC and LCMS, and on completion of reaction, it was cooled to room temperature and ice cooled water (75 ml) was added. The reaction mixture was then extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes to afford 3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (2 g, 60%) as a solid. 1HNMR (400 MHz, DMSO-d6) δ: 9.05 (s, 1H), 8.65 (s, 1H), 7.15-7.3 (m, 7H), 6.85 (d, 2H), 5.77 (s, 2H), 3.85 (t, 2H), 3.70 (s, 3H), 2.95 (t, 2H); LCMS: [M+H] 413. Trifluoroacetic acid (20 ml) was added to 3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (1 g, 2.1 mmol) at 0° C., and then stirred at 100° C. for 5 hours. The reaction was monitored by TLC, and on completion of the reaction, trifluoroacetic acid was evaporated under reduced pressure and the residue was basified using aqueous ammonia to form a solid precipitate. The solid was filtered over a sintered funnel. The solid was washed with hexane and dried under reduced pressure to afford 7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (500 mg, 80%). The compound was used next without further purification. 1HNMR (400 MHz, DMSO-d6) δ: 14.50 (s, 1H), 9.00 (s, 1H), 8.50 (s, 1H), 7.05-7.15 (m, 5H), 3.95 (t, 2H), 2.95 (t, 2H); LCMS: [M+H] 293.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][S:13]([C:16]1[N:17]=[CH:18][N:19]2[CH:23]=[CH:22][S:21][C:20]=12)(=[O:15])=[O:14].[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:12][S:13]([C:16]1[N:17]=[CH:18][N:19]2[CH:23]=[C:22]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])[S:21][C:20]=12)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(C)(=O)=O)c2s1
Reaction time: 0.5 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (2.8 ml) was added to a solution of 404 mg of 7-methanesulfonylimidazo[5,1-b]thiazole in 20 ml of dry THF in an argon atmosphere at −40° C. The mixture was stirred at the same temperature for 30 min. Tri-n-butylstannyl chloride (0.6 ml) was added thereto. A saturated aqueous ammonium chloride solution was added to the reaction solution. Ethyl acetate was then added thereto. The mixture was washed with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 251 mg of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH2:16])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)C)C=CC=CC=1.C(Cl)(=[O:33])C>>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:33])[CH3:16])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: C=Cc1ccccc1C(C)c1ccccc1
Agent: CC(c1ccccc1)c1ccccc1
Product: CC(=O)c1ccccc1C(C)c1ccccc1

Procedure:
They can be prepared by a variety of chemical synthetic manners, and for example, phenyl-(vinylpheny)ethane may be prepared by reacting diphenylethane with acetyl chloride in the presence of a Friedel-Crafts catalyst to form phenyl(acetylphenyl)ethane, reducing the latter with sodium boron hydrine or the like, and dehydrating it. Phenyl(isopropenylphenyl)ethane can be prepared by reacting phenyl(formylphenyl)ethane with a Grignard reagent such as methylmagnesium iodide, and carrying out dehydration.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH:15]=2)[CH2:10]1)=O)(C)(C)C.[ClH:27].O1CCOCC1>C(O)(=O)C>[ClH:27].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[CH:15]=2)[CH2:10]1
Reactant: Cc1ccc(/C=C/c2ccc3c(c2)CC(NC(=O)OC(C)(C)C)C3)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1ccc(/C=C/c2ccc3c(c2)CC(N)C3)cc1

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-[(E)-2-(4-methylphenyl)ethenyl]indan (20 mg, 0.060 mmol) synthesized in Preparation Example 2, 4N hydrochloric acid-dioxane (2.0 ml) and acetic acid (6.0 ml), a similar procedure to Example 24 was carried out to obtain 2-amino-5-[(E)-2-(4-methylphenyl)ethenyl]indan hydrochloride (16 mg, 0.06 mmol) having the following physical properties: