Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1.[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][N:24]([CH3:35])[C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=2[N:29]=1>>[ClH:1].[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][N:24]([CH3:35])[C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH:34][C:17]([C:14]3[CH:13]=[CH:12][C:11]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]=4[Cl:1])=[CH:16][CH:15]=3)=[O:19])[CH:31]=[CH:30][C:28]=2[N:29]=1.[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][N:24]([CH3:35])[C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH:34][C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]=4[Cl:1])=[CH:12][CH:13]=3)=[O:18])[CH:31]=[CH:30][C:28]=2[N:29]=1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: CCOc1ccc(-c2ccc(C(=O)O)cc2)c(Cl)c1
Product: CCOc1ccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)CCN(C)C)sc4c3)cc2)c(Cl)c1
Product: Cl

Procedure:
The title compound is prepared by following Method A, using 2′-chloro-4′-ethoxy-biphenyl-4-carboxylic acid (0.48 g, 1.73 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.33 g, 1.33 mmol) to afford 2′-chloro-4′-ethoxy-biphenyl-4-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (0.48 g, 71%). The material is dissolved in EtOH and treated with 1.0 M HCl in EtOH (0.94 mL). Organic solvent is removed in vacuo, the residue is dissolved in i-PrOH, heptane is added and the resulting precipitate is collected to give 0.43 g (84%) of the hydrochloride salt. LC/MS: Retention time=5.51 min; (m/z): calcd for C27H29ClN4O2S (M+H)+: 510.1; found: 510.0.
Reaction SMILES: [Cl-].C([P+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.Cl[CH2:23][Si:24]([Cl:27])([Cl:26])[Cl:25].[Cl:28][SiH:29]([Cl:31])[Cl:30]>>[Cl:25][Si:24]([Cl:27])([Cl:26])[CH2:23][Si:29]([Cl:31])([Cl:30])[Cl:28]
Reactant: Cl[SiH](Cl)Cl
Reactant: ClC[Si](Cl)(Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Yield: 59.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.22 g (0.67 mmol) of benzyltributylphosphonium chloride, 1.23 g (6.69 mmol) of (chloromethyl)trichlorosilane, and 2.71 g (20.0 mmol) of trichlorosilane were reacted at 160° C. for 15 hrs. The resulting mixture was distilled to give 1.13 g of 1,1,1,3,3,3-hexachloro-1,3-disilapropane (yield; 68%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[NH:7][C:8]1[C:9]2[N:10]=[CH:11][N:12]([C:22]=2[N:23]=[CH:24][N:25]=1)[C@@H:13]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[C@H:14]1[OH:15].[H][H]>[Pt].C(O)C>[OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[C:9]2[N:10]=[CH:11][N:12]([C:22]=2[N:23]=[CH:24][N:25]=1)[C@@H:13]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[C@H:14]1[OH:15]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4C=CC[C@@H]4O)ncnc32)[C@H](O)[C@@H]1O
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCC[C@@H]4O)ncnc32)[C@H](O)[C@@H]1O
Yield: 74.6 %

Procedure:
A mixture of N-(cis-2-hydroxycyclopent-4-enyl)adenosine (1.6 g), 5% platinum on charcoal (0.3 g) and ethanol (80 ml) was stirred in the presence of hydrogen for 20 h. The resulting mixture was filtered and the filtrate was evaporated. The residue was dissolved in methanol (50 ml) and the solution was evaporated to yield the title compound (1.2 g) as a foam.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)(=O)[CH3:13].[OH-].[K+].CC[OH:24]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:12]1[CH:13]=[C:4]([C:2]([OH:24])=[O:3])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: CCO
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(=O)c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(-c2ccco2)nc2ccccc12

Procedure:
5 g (34.0 mmol) of isatin, 4 ml (40.8 mmol) of 2-acetylfuran and 6.3 g (112.2 mmol) of potassium hydroxide were dissolved in 40.9 ml of abs. EtOH and the slurry heated at 80° C. for 12 hours. After cooling of the reaction mixture, 50 ml of water were added and the solution extracted with 50 ml of Et2O. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl and the precipitate collected by filtration and washed with water. The crude product obtained was dried in-vacuo at 40° C. to yield 8.5 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]([NH:19][C@H:20]([C:24]([NH:26][CH:27]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH:28]([OH:45])[CH:29]([NH:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].CN1CC[O:57][CH2:56]C1>[N+](C)([O-])=O.CN(C)C=O>[C:9]([NH:19][C@H:20]([C:24]([NH:26][CH:27]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH:28]([OH:45])[CH:29]([NH:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH:40][C:56]([NH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:57])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: CC(C)[C@H](N)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: NCc1cccnc1
Reactant: CN1CCOCC1
Solvent: C[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)NCc1cccnc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A solution of 3-(aminomethyl)pyridine (12 μl, 0.11 mmol) in 0.5 ml of nitromethane was cooled to -20° C. and treated with 0.23 ml (0.12 mmol) of a 0.5M solution of carbonyl bis (N-methyl) imidazole triflate (Rappoport, et. al., J. Am. Chem. Soc. 1989, 111, 6856) in nitromethane. After 30 min, the solution was treated with a solution of 50 mg (0.08 mmol) of the resultant compound of Example 240 in 1.0 ml of dimethylformamide and 26 μL. (0.24 mmol) of 4-methylmorpholine. The resulting solution was stirred at 0° C. for 1 h, concentrated in vacuo, partitioned between chloroform and aqueous NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 3% methanol in chloroform to provide 40 mg (65%) of the desired compound (Rf 0.4, 10% methanol in chloroform) as a white solid, m.p. 205°-206° C. Mass spectrum: (M+H)+ =737.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)=[CH:5][C:4]=1[N+:16]([O-])=O>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)=[CH:5][C:4]=1[NH2:16]
Reactant: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.6 %

Procedure:
To a stirred solution of 5.01 g (20.0 mmol) (1S,4S)-5-(4-methoxy-3-nitro-phenyl)-2-oxa-5-aza-bicyclo[2.2.1]heptane in 375 ml methanol and 62.5 ml dichloromethane was added 500 mg 10% palladium on charcoal and the mixture was then stirred for 3.5 hours at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate concentrated in vacuo to afford 4.30 g (98%) 2-methoxy-5-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-phenylamine as a brown crystalline solid. ES-MS m/e (%): 221 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C([Cl:56])(=O)C.Cl>C1COCC1.O1CCOCC1.CO>[ClH:56].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][O:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][C:4](=[O:12])[CH:3]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CN(C)CCCO
Reactant: CC(=O)Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)CCCOc1cc(=O)oc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
4-Hydroxycoumarin (3.0 mmol, 0.487 g) is dissolved in 10 mL of THF. Triphenylphosphine (3.15 mmol, 0.825 g) and 3-dimethylamino-propan-1-ol (3.15 mmol, 0.372 mL) is added and the solution is cooled to 0° C. DIAD (3.30 mmol, 0.647 g) is added dropwise at 0° C. The reaction is stirred 30 min. at 0° C then is allowed to warm to ambient temperature and is stirred overnight. The solvent is evaporated under reduced pressure, and a solution of anhydrous HCl/MeOH (prepared by adding ˜5 mL acetyl chloride dropwise to 100 mL MeOH) is added to the residue. Alternatively 4M HCl in dioxane may be used. The solvent is removed under reduced pressure and the residue is treated with Et2O. The resulting solid is filtered, is washed with Et2O, and is dried to afford the title compound as the hydrochloric acid salt (0.485g, 57%). 1H NMR (DMSO-d6, 300 MHz) δ 10.35 (1H, br s), 7.90 (1H, dd, J=1.25, 7.75 Hz), 7.68 (1H, m), 7.41 (2H, m), 5.92 (1H, s), 4.32 (2H, t, J=5.75 Hz), 3.27 (2H, m), 2.80 (6H, s), 2.25 (2H, m); MS (ESI, Pos.) calcd for C14H17NO3 m/z [M+H]=248.1, found 248.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccc(F)cc1
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(F)cc3)c12

Procedure:
The title compound, off-white solid (59 mg, 79%), MS (ISP) m/z=299.3 [(M+H)+], mp 304° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: C([O:5][P:6]([C:13]([F:52])([F:51])[C:14]1[CH:50]=[CH:49][C:17]([CH2:18][C:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([P:37]([O:44]C(C)(C)C)([O:39]C(C)(C)C)=[O:38])([F:36])[F:35])=[CH:30][CH:29]=2)([C:23]([O:25][CH3:26])=[O:24])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)([O:8]C(C)(C)C)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.O>[F:52][C:13]([F:51])([P:6]([OH:8])([OH:7])=[O:5])[C:14]1[CH:50]=[CH:49][C:17]([CH2:18][C:19]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[P:37]([OH:44])([OH:39])=[O:38])=[CH:32][CH:33]=2)([C:23]([O:25][CH3:26])=[O:24])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)O
Yield: 35 %

Procedure:
A solution of 2,2-di{4-[(di-tert-butoxyphosphoryl) (difluoro)methyl]benzyl}-3-methoxy-3-oxopropanoic acid(80 mg) in 5 mL of 10:1 TFA/water was stirred for 1 h and then concentrated. The residue was dissolved in 4 mL of water and washed with 2×5 mL of ether and the aqueous solution was lyopholized to give 20 mg of the title compound as a white solid.
Reaction SMILES: C([C:4]1[C:5]([C:10](=O)[CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)C.[CH2:13]([O:33][C:34]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[C:53]1([CH3:59])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH2:13]([O:33][C:34]1[C:35]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[CH:36][C:37]([N:38]=[C:10]([C:5]2[CH:4]=[CH:9][CH:8]=[C:7]([C:37](=[N:38][C:55]3[CH:56]=[C:57]([C:42]4[CH:41]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:58]([O:33][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:53]([C:59]4[CH:39]=[CH:40][CH:34]=[CH:35][CH:47]=4)[CH:54]=3)[CH3:36])[N:6]=2)[CH3:11])=[CH:39][C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N)cc1-c1ccccc1
Reactant: Cc1ccccc1
Reactant: CC(=O)c1cccnc1C(C)=O
Product: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N=C(C)c2cccc(C(C)=Nc3cc(-c4ccccc4)c(OCCCCCCCCCCCCCCCCCCCC)c(-c4ccccc4)c3)n2)cc1-c1ccccc1

Procedure:
Diacetylpyridine (1.43 g, 8.77 mmol and 4-eicosanoxy-3,5-diphenylaniline (9.5 g, 17.53 mmol) were dissolved in 400 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 1 week, further 4 Å molecular sieves were added and the mixture was filtered. Most of the solvent was removed in vacuo. On standing a red precipitate was formed. The product, J, was isolated (5.52 g, 51%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13]Br)=[O:6])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[CH:26][C:27]=1[F:28].C(OCC)(=O)C>CC(C)=O>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13][S:29][C:24]1[CH:25]=[CH:26][C:27]([F:28])=[C:22]([F:21])[CH:23]=1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1CCCCC1CBr
Reactant: Fc1ccc(S)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: N#CCNC(=O)C1CCCCC1CSc1ccc(F)c(F)c1
Reaction time: 16 h

Procedure:
To a solution of N-cyanomethyl 2-bromomethylcyclohexanecarboxamide (3.0 g, 11.58 mmol) in acetone (100 mL) at room temperature were added, in two portions, cesium carbonate (5.77 g, 17.5 mmol) and the crude 3,4-difluorothiophenol (2.69 g, 18.4 mmol). After 16 h, ethyl acetate (100 mL) was added. The solution was washed with 1M HCl (40 mL), brine (20 mL), evaporated, and purified on a short plug of silica gel (30% ethyl acetate/hexane to elute non-polar impurities, then 20-30% ethyl acetate/dichloromethane to give N-cyanomethyl 2-(3,4-difluorophenylsulfanylmethyl)-cyclohexanecarboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[OH:24])[N:7]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cccc(C2=C(c3cc(C)ccc3O)CCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(C2=C(c3cc(C)ccc3OCc3ccc(F)cc3)CCC2)n1
Yield: 85.7 %

Procedure:
A mixture of 6-[2-(5-methyl-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylic acid ethyl ester (129 mg, 0.4 mmol), 4-fluorobenzyl bromide (83 mg, 0.44 mmol) and potassium carbonate (138 mg, 1 mmol) in acetone (4 ml) was stirred and refluxed for 20 hours. After cooling the mixture was diluted with water/diethyl ether and the organic phase dried (magnesium sulphate) evaporated and purified by chromatography on silica (8% ethyl acetate in iso-hexane) to give the title compound as a colourless gum (148 mg, 86%). 1H NMR (CDCl3)δ:1.41 (3H, t, J=7 Hz), 2.04–2.09 (2H, m), 2.18 (3H, s), 2.88–2.91 (2H, m), 3.11–3.15 (2H,m), 4.41 (2H, q, J=7 Hz), 4.91 (2H, s), 6.80 (1H, d, J=8 Hz), 6.87 (1H, d, J=2 Hz), 6.95–7.04 (4H, m), 7.17–7.21 (2H, m), 7.40 (1H, t, J=8 Hz), 7.79 (1H, d, J=8 Hz).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([O-])([O-])=O.[K+].[K+].[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C=O)C.O>[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(I)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
To a stirred solution of phthalimide (0.6 g, 4.0 mmol) in DMF (5 ml) was added K2CO3 (2.25 g, 16.00 mmol), followed by 4-iodobenzyl bromide (1.33 g, 4.4 mmol) at 0° C. and the reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was washed with diethyl ether to get the desired compound as a white solid (700 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.84 (m, 4H), 7.70-7.66 (m, 2H), 7.12 (d, J=8.3 Hz, 2H), 4.72 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35]S(C)=O.CI>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:18]([CH3:35])([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
Dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)malonate (250 mg, 0.58 mmol) was dissolved in THF (5 mL) and 60% oil dispersion NaH was added (24 mg, 0.6 mmol). After 1 h, added DMSO (2 mL) followed by MeI (5.8 mmol). After 72 h, the reaction was quenched with MeOH then poured into brine and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC using a 1:9 to 1:3 EtOAc/hexane gradient. Obtained 215 mg (83% yield) of dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-2-methylmalonate. MS found: (M+H)+=447.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:12]1=[O:23])[CH2:8]2>[Pt].C(OCC)(=O)C.CCCCCCC>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH2:15][CH:14]([CH:16]([CH3:18])[CH3:17])[N:13]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:12]1=[O:23])[CH2:10]2.[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH2:15][CH:14]([CH:16]([CH3:18])[CH3:17])[N:13]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:12]1=[O:23])[CH2:10]2
Reactant: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)n1CC1CC1
Agent: [Pt]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)C1CN(C2C3CC4CC(C3)CC2C4)C(=O)N1CC1CC1
Product: CC(C)CN1C(=O)N(C2C3CC4CC(C3)CC2C4)CC1C(C)C

Procedure:
These materials were obtained in analogy to the procedure outlined in example 50 from 1-adamantan-2-yl-3-cyclopropylmethyl-4-isopropyl-1,3-dihydro-imidazol-2-one (53 mg, obtained in example 23) by hydrogenation over platinum on charcoal. Separation of the crude reaction mixture by flash chromatography (silica gel, ethyl acetate/heptane 9:1) provided 1-adamantan-2-yl-3-isobutyl-4-isopropyl-imidazolidin-2-one as the less polar component (16 mg, Rf=0.7, ethyl acetate/heptane 1:1, MS (ESI): 319.3 (MH+)) and 1-adamantan-2-yl-3-cyclopropylmethyl-4-isopropyl-imidazolidin-2-one as the more polar component (24 mg, Rf=0.65, ethyl acetate/heptane 1:1, MS (ESI): 317.3 (MH+).
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[N+:27]([O-])=O)[CH:13]([C:30]([OH:32])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O.C(=O)(O)[O-].[K+].O>[Ni].C(O)C>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][CH:21]=1)[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH:13]1[C:30](=[O:32])[NH:27]2
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCNCC12
Reaction time: 0.75 h

Procedure:
A solution of 7.5 g. of 4-carbobenzoxy-1-(4-trifluoromethyl-2-nitrophenyl)piperazine-2-carboxylic acid, 4.0 g. of potassium bicarbonate, 150 ml. of water and 50 ml. of ethanol is hydrogenated over three teaspoons of Raney nickel catalyst at 50 p.s.i. for 45 minutes. The catalyst is filtered and the filtrate is acidified and extracted with ethylacetate. The aqueous phase is then basified with dilute sodium hydroxide and extracted with ethyl acetate. Concentration of the organic phase gives 1.2 g. of pale yellow solid product, m.p. 193°-195°. This solid is converted to its hydrogen chloride salt in ethanol giving 0.78 g., m.p. 275°-277° dec.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[CH2:28]([O:30][C:31]([C:33]1[CH:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:54])[NH:46][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[CH:41][CH:40]=2)[C:37]([C:55](=[O:57])[NH2:56])=[C:36]([CH2:58][CH:59]([CH3:61])[CH3:60])[NH:35][C:34]=1[CH2:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)=[O:32])[CH3:29].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:28]([O:30][C:31](=[O:32])[C:33]1[C:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:54])[NH:46][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[CH:41][CH:40]=2)=[C:37]([C:55](=[O:57])[NH2:56])[C:36]([CH2:58][CH:59]([CH3:61])[CH3:60])=[N:35][C:34]=1[CH2:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH3:29]
Reactant: CCOC(=O)C1=C(CCc2ccc(F)cc2)NC(CC(C)C)=C(C(N)=O)C1c1ccc(C(=O)NCc2cccnc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc(CC(C)C)c(C(N)=O)c1-c1ccc(C(=O)NCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.6 %

Procedure:
An aqueous solution of CAN (1 M, 1 mL) was added to a solution of compound 12 (50 mg, 0.08 mmol) and trifluoroacetic acid (0.5 mL) in CHCl3 (30 mL). The resulting mixture was vigorously stirred for 10 min at r.t. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated in vacuo to yield the crude product. Purification by preparative LCMS (PE SCIEX, C18, acetonitrile—water with 0.035% trifluoroacetic acid) yielded the title compound (2.6 mg, 95% purity by LCMS). 1H NMR (500 MHz, CDCl3): δ 8.16 (s, 1H), 8.00 (br. d, 1H), 7.87 (m, 3H), 7.35 (m, 2H), 7.18 (d, J=8.5 Hz, 1H), 7.08 (m, 2H), 6.90 (m, 2H), 6.03 (br. s, 1H), 5.60 (br. s, 1H), 4.75 (m, 3H), 3.94 (q, J=7.0 Hz, 2H), 3.07 (m, 5H), 2.77 (d, J=7.6 Hz, 1H), 1.27 (m, 1H), 0.94 (m, 3H), 0.88 (t, J=7.4 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][C@H:10]2[CH2:14][O:13]C(C)(C)[O:11]2)=[CH:5][CH:4]=1>CC(O)=O.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][C@H:10]([OH:11])[CH2:14][OH:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCC[C@H]2COC(C)(C)O2)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(OCC[C@H](O)CO)cc1

Procedure:
A solution of (4S)-4-[2-(4-methoxyphenoxy)ethyl]-2,2-dimethyl-1,3-dioxolane (8.2 g, 30.8 mmol) in AcOH/water was stirred at rt for 5 h and concentrated in vacuo. The residue was co-evaporated with toluene (3×) and then pumped under high vacuum to give the desired product. 1H NMR (400 MHz, Acetone-d6): δ7.28 (2 H, d), 6.91 (2 H, d), 4.43 (2 H, s), 3.80 (3 H, s), 3.77 (1H, m), 3.66–3.42 (5 H, m), 1.86–1.76 (1 H, m), 1.68–1.60 (1 H, m).