Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1>>[CH3:18][O:17][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:19])[C:2]([C:49]1[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=1)=[C:10]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(Br)C2=O
Reactant: OB(O)c1ccncc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc2c(c1)C(c1ccccc1)=C(c1ccncc1)C2=O
Reaction time: 0.17 h
Yield: 74 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-5-methoxy-3-phenyl-1H-inden-1-one obtained in Step 4 of Example 129 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 4-pyridinylboronic acid instead of 3-pyridinylboronic acid, and being stirred for 10 min to obtain the title compound (74%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.Cl[C:20]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: Nc1nccc(-c2cccnc2Cl)n1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Temperature: 100 °C

Procedure:
To a resealable tube was added 4-aminophenol (1.3 g, 12 mmol), cesium carbonate (7.8 g, 24 mmol), and DMSO (16 ml, 0.75 M). The mixture was heated to 100° C. for 5 minutes, and then 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (2.5 g, 12 mmol) was added, and the reaction mixture was heated to 130° C. overnight. Upon completion, as judged by LCMS, the reaction mixture was allowed to cool to RT and diluted with water. The resulting precipitate was filtered, and the solid washed with water and diethyl ether. The solid was then taken up in 9:1 CH2Cl2:MeOH and passed through a pad of silica gel with 9:1 CH2Cl2:MeOH as eluent. The solvent was concentrated in vacuo to provide the desired product, 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine. MS m/z=280 [M+1]+. Calc'd for C15H13N5O: 279.30.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+].Cl>CO.C1COCC1.CCOCC>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:18])=[O:2])=[CH:8][CH:9]=1
Reactant: COC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc(-c2ccco2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic acid methyl ester (2.0 g, 8.2 mmol) (reference example 30a) in MeOH/THF (20 mL, 1/1) is added NaOH (2 mL, 6M). The resulting solution is stirred for 1 hour then heated to 65° C. and stirred at this temperature for 2 hours. The reaction mixture is then cooled and acidified (to pH 1) with hydrochloric acid (2 M). The resulting mixture is diluted with ether, washed with water and brine, dried over MgSO4 and concentrated to give 1.78 g of the title compound as a solid. 1H NMR (CDCl3) d 1.61 (s, 6H), 6.45 (dd, J 3, 2 Hz, 1H), 6.62 (d, J=3 Hz, 1H), 7.42 (m, 2H), 7.45 (d, J=2 Hz, 1H), 7.64 (m, 2H). MS (EI) m/z 230 (M+)
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][N:23]=1>ClCCl.N1C=CC=CC=1>[Cl:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][N:23]=2)=[O:13])[CH:27]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cc(Cl)ncn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ncn1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(Cl)ncn1
Yield: 12.3 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-amino-6-chloropyrimidine (1.51 g, 11.7 mmol) in 12 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol, filtered, and recrystallized from acetonitrile-DMF to yield 0.38 g of the title compound, mp 254-256° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][C@H:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[O:26][C:7](=[O:11])[CH2:6][C@H:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc2c(c1)[C@H](c1ccccc1)CC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(c1)[C@H](c1ccccc1)CC(=O)O2
Reaction time: 48 h
Yield: 90.9 %

Procedure:
5-Methyl-3-(S)-phenyl-indan-1-one (400 mg, 1.8 mmol) and mCPBA (98%, 485 mg, 2.8 mmol) were suspended in dry CH2Cl2 (6 ml) at 0° C. followed by TsOH:H2O (20 mg). The reaction was kept at 4° C. for 48 h. The mixture was diluted with 10 ml of CH2Cl2 and washed with 2×10 ml of saturated Na2SO3, saturated NaHCO3 and brine. Flash chromatography eluting with ethyl acetate:pentane 10:90 gave 390 mg (90%) of the title compound. Rf 0.83 (ethyl acetate:pentane 20:80) (ChiralCel OD-H) 0.5 mL/min of hexane/isopropanol 95/5 (S)-isomer 15.18 min, (R)-isomer 17.42 min, 89% ee. IR (neat cm−1): 2900, 2360, 1769, 1495, 1208, 1145. 1H NMR δ: 2.28 (s, 3H), 3.05 (m, 1H), 4.32 (t, J=6.8Hz, 1H), 6.98 (s, 1H), 7.04 (d, J=8.4Hz, 1H), 7.11 (dd, J=2.0, 8.4Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.19 (s, 1H), 7.33 (m, 3H) 13C NMR δ: 20.7, 37.1, 40.7, 116.8, 125.3, 127.5, 127.6, 128.6, 129.1, 129.3, 134.3, 140.5, 149.6, 167.8. MS (EI 70 eV) m/z (rel. intensity): 238 (55) [M+], 220 (57), 195 (100), 181(10), 165 (12), 152 (9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7](=O)[CH2:8][N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH2:10][CH2:11][C:5]=2[CH:4]=1.C(O)(=O)C.Cl.CCO>[C].[Pd].O1CCOCC1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[CH2:7][CH2:8][N:9]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(C)cc1)CC2=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(C)cc1)CC2
Reaction time: 8 h

Procedure:
7-Methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[d]azepin-1-one (6.91 g, 20 mmol) (prepared essentially as described by Kanao et al. (1982) Chem. Pharm. Bull. 30:180-88) is added to a mixture of acetic acid (20 ml), 37% hydrochloric acid (8 ml), EtOH (8 ml) and dioxane (80 ml). 1.0 g of 10% palladium-carbon is added to the mixture, and the resulting mixture is hydrogenated under 30-55 psi at rt overnight. The palladium-carbon is removed by filtration, and the filtering cake is washed with MeOH (30 ml×3). The combined organic phase is evaporated to dryness under reduced pressure to give the title compound as a white solid. MS (+VE) m/z 332.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.C1CCC=CC=1>C1(C)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2
Reactant: COc1ccc(OC)c2c1CCC2=O
Solvent: C1=CCCC=C1
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2c1CCC2

Procedure:
A mixture of intermediate A (1 g, 6 mmole), 1,3-cyclohexadiene (0.6 ml, 6 mmole), and toluene (15 ml) was refluxed about 15 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure to yield 1.5 g of crude Diels-Alder adduct (intermediate B), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].C(O)C.[H-].[Na+].Cl.[C:24](=O)([O:28]CC)[O:25][CH2:26][CH3:27]>O>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:24]([O:25][CH2:26][CH3:27])=[O:28])=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyloxyacetophenone (36 g, 159 mmol) in diethyl carbonate (200 ml) was added ethanol (0.6 ml) and sodium hydride (60% in oil, 12.7 g, 318 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hrs. To the reaction solution was added 6N hydrochloric acid to stop the reaction, and water (500 ml) was added. Then, the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the objective substance (49.3 g, 100%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[C:19]1([NH:25][C:26]2[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]3[N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N:32]=3)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccccc3n2-c2ccccc2)[nH]1
Yield: 51.7 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 423 mg of N-phenylbenzene-1,2-diamine and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2.5 ml of pyridine and 2.5 ml of dimethylformamide and then in 5 ml of acetic acid. After purification by silica column chromatography, eluent: CH2Cl2/MeOH: 95/05, 230 mg of 6-(morpholin-4-yl)-2-[(1-phenyl-1H-benzimidazol-2-yl)methyl]pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][CH:4]=1.Cl.Cl.[NH:16]1[CH2:19][CH:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:17]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:13]=[C:11]([N:16]1[CH2:19][CH:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:17]1)/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[N:8][CH:7]=1
Reactant: c1cc(COC2CNC2)ccn1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc(/C=C/C(=O)N2CC(OCc3ccncc3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a solution of (2E)-3-(6-aminopyridin-3-yl)acrylic acid hydrochloride (42 mg, 0.21 mmol; which may be prepared as described in Step 2) in DMF (5 mL) were added 4-[(azetidin-3-yloxy)methyl]pyridine dihydrochloride (50 mg, 0.25 mmol; which may be prepared as described in Step 4), DIPEA (171 μL, 1.04 mmol), DMAP (2.5 mg, 0.02 mmol) and EDAC (48 mg, 0.25 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was partitioned between a NaHCO3 5% solution and DCM. The aqueous phase was extracted twice with DCM, dried over sodium sulfate, filtered and concentrated under vacuum to give an orange solid. The crude was purified on preparative TLC (eluent: 90/10 DCM/MeOH+1% NH4OH) to give the title compound (21 mg, 33%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[N:33]1[CH2:38][CH2:37][CH:36](OS(C)(=O)=O)[CH2:35][CH2:34]1>CN(C)C=O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:36]3[CH2:37][CH2:38][N:33]([C:28]4[N:27]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:34][CH2:35]3)[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)OC1CCN(c2ncccn2)CC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OC3CCN(c4ncccn4)CC3)cc12

Procedure:
6-(1-Pyrimidin-2-yl-piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime was prepared using the procedure described in example 85A, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and methanesulfonic acid 1-pyrimidin-2-yl-piperidin-4-yl ester (example 169B) in dimethylformamide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=[CH:5][C:4]=2[C:3]1=[O:22].C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[CH:8]=2)[C:3]1=[O:22]
Reactant: CC1CC(C)(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2C1=O
Yield: 104.6 %

Procedure:
Following General Procedure D and using trifluoro-methanesulfonic acid 6,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Intermediate 196, 1.45 g, 4.3 mmol), triethyl amine (5 mL), copper(I)iodide (0.21 g, 0.26 mmol), trimethylsilyl acetylene (3 mL, 21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.75 g, 1.07 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5% ethyl acetate in hexane as the eluent, the title compound (1.28 g, 100%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].C1(S(C2C=CC=CC=2)(=O)=[O:16])C=CC=CC=1.[C:24]1([CH3:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:16][C:27]1[CH:28]=[CH:29][C:24]([C:30]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)=[CH:25][CH:26]=1
Reactant: O=S(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Reactant: Nc1ccccc1N
Product: Oc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 150 °C
Yield: 64 %

Procedure:
A mixture of 1,2-diaminobenzene (25.17 g, 0.233 mol), phenyl-4-hydroxphenylbenzoate (50.17 g, 0.234 mol), diphenylsulfone (121.15 g), and toluene (100 ml) were heated under a nitrogen atmosphere for 16 hours at 150° C. The toluene was removed and the temperature increased to 260° C. and maintained for two and one-half hours. A vacuum was subsequently applied and the temperature increased to 290° C. and maintained for one and one-half hours. The warm reaction mixture was precipitated in toluene, washed in hot toluene, and subsequently dried at 110° C. to afford 45.00 g (92% crude yield) of a red-tan powder, m.p. (DTA) 279° C. (broad). The solid was recrystallized from 40% aqueous ethanol using charcoal to afford a light tan crystalline product (31.46 g, 64% yield). The compound exhibited a sharp melt by DTA with an endothermic minimum at 280° C. Anal. calcd for C13H10N2O: C, 74.27%; H, 4.79%; N, 13.32%; Found: C, 74.21%; H, 4.75%; N, 13.21%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OCC)(=O)C.O>C(OC(=O)C)(=O)C>[C:16]([CH:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][C:10]1=[O:15])(=[O:18])[CH3:17]
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Temperature: 120 °C

Procedure:
5-(4-Fluorophenyl)cyclohexane-1,3-dione (500 mg, 2.4 mmol) and sodium acetate (200 mg, 2.4 mmol) were dissolved in acetic anhydride (5 ml) and heated in a sealed tube at 120° C. for 16 h. The reaction mixture was then allowed to cool to ambient temperature whereupon ethyl acetate (20 ml) and water (10 ml) were added. The organic phase was collected and washed 3 times with a saturated solution of sodium bicarbonate (3×15 ml). The organic phase was dried with MgSO4 and filtered. The solvent was removed under reduced pressure. The title compound was purified by column chromatography using ethyl acetate/heptane (1/3) as the eluent.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][OH:19]>>[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][O:19][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCC1CCCO1
Product: O=C(O)c1ccc(OCC2CCCO2)nc1
Yield: 24 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 24% yield starting from ethyl 6-chloronicotinate and tetrahydrofuran-2-ylmethanol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, 1 H), 8.14 (dd, 1 H), 6.90 (d, 1 H), 4.23-4.35 (m, 2 H), 4.10-4.21 (m, 1 H), 3.72-3.82 (m, 1 H), 3.61-3.71 (m, 1 H), 1.92-2.03 (m, 1 H), 1.74-1.93 (m, 2 H), 1.58-1.70 (m, 1 H); MS (ESI) m/z 224[M+H+], m/z 222[M−H+];
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][C:12]([CH3:18])([CH2:16][OH:17])[C:13]([OH:15])=[O:14]>CN(C1C=CN=CC=1)C.CCOCC>[C:1]([O:17][CH2:16][C:12]([CH3:18])([CH3:11])[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(C)(CO)C(=O)O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (4.52, 58.2 mmol) was added dropwise to a cold (0° C.) pyridine solution (10 ml) of 2,2-dimethyl-3-hydroxypropionic acid (5.5 g, 46.5 mmol) and 4-DMAP (0.57 g, 4.65 mmol). After stirring overnight at ambient temperature, the reaction was poured into ether (200 ml). This mixture was washed with 10% HCl (2×20 ml), and saturated brine (2×25 ml) and the resulting ethereal solution was dried (MgSO4). Evaporation gave the title compound as a pale yellow solid which was used in the next step without further purification. NMR (CDCl3) δ4.13 (2H, s), 2.08 (3H, s), 1.26 (6H, s).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[C:6]1([CH3:22])[CH2:11][CH:10](C2C=CC=CN=2)[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[O:7]1.[C:23](Cl)(=O)[C:24]1C=CC=[CH:26][CH:25]=1.[N+:32](C)([O-])=O>C(OCC)C>[N:32]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:6]1[CH:11]=[CH:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[O:7]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Reactant: C[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: C1=CC(c2ccccn2)Oc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
264 mg of aluminum chloride were added to an ice-cooled solution of 237 mg of 3,4-dihydro-2,2-dimethyl-4(2-pyridyl)-2H-1-benzopyran in 6 ml of nitromethane. The mixture was stirred for 5 minutes, 349 mg of benzoyl chloride were added and the stirring was continued at 0° C. for 30 minutes and at room temperature for 16 hours. The reaction mixture was diluted with diethyl ether and washed with sodium hydroxide solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (2:3) for the elution to give 94 mg of 6-benzoyl-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl -2H-1-benzopyran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH2:19][CH3:20])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 16 h

Procedure:
To the liquid mixture of 3-fluoro-4-nitrobenzoic acid 9.71 g and ethanol 35 mL, conc. sulfuric acid 1.6 mL was added, followed by 16 hours' heating under reflux. After distilling the solvent off, water and tert-butyl methyl ether were added to the residue. The organic layer was extracted, washed with water and dried over magnesium sulfate. Distilling the solvent off, 7.40 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].Cl[Mg][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].O1CCCC1.Cl.O>O1CCCC1>[CH3:17][C:18]([CH3:21])([CH3:20])[CH2:19][CH:7]([C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3][C:2]=1[CH3:1])[OH:8]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: Cc1oc(-c2ccccc2)cc1C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C(O)CC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 2-methyl-5-phenylfuran-3-carbaldehyde (1.1 g) in tetrahydrofuran (20 mL) was added dropwise 1N chloro(2,2-dimethylpropyl)magnesium-tetrahydrofuran solution (9 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give the title compound (1.1 g, 70%) as an oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[N:26][CH:27]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:53]([N:60]1[CH2:64][CH:63]([C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=2)[CH:62]([CH:73](O)[CH3:74])[CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[CH2:53]([N:60]1[CH2:64][CH:63]([C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=2)[CH:62]([CH:73]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:27][N:26]=2)[CH3:74])[CH2:61]1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.77 g) in THF (25 mL) at 0° C. were added 5-trifluoromethyl-pyridin-2-ol (0.28 g, 1.75 mmol) and then DBAD (0.43 g). After 5 minutes was added (RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.41 g, 1.17 mmol, described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:4) yielded 0.45 g (78%) of the title compound as a colorless oil. ES-MS m/e: 495.8 (M+H+).