Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:20])[N:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:23].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:11]2[C:12]3[C:17](=[N:16][C:15]([CH3:20])=[CH:14][CH:13]=3)[C:18](=[O:19])[C:9]([C:7](=[O:8])[C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([CH3:23])[CH:5]=3)=[CH:10]2)[CH:28]=[CH:29][CH:30]=1
Reactant: BrCc1cccc(Br)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccc(C)nc3c2=O)cc1C
Yield: 33.9 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 100 mg (0.324 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 97.7 mg (0.389 mmol) of 2-bromo-6-bromomethyl-pyridine, 15.6 mg (0.389 mmol, 60% dispersion in oil), and 1 mL of N,N-dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 52.6 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(4-methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C24H20BrN3O3 [M+H]: 478.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.1 min
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:38])[CH:25]=3)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH3:36][C:33]([CH3:34])([CH3:35])[C:32](=[O:37])[CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:11]3[CH:12]=[C:7]([CH2:6][C:5]([OH:39])=[O:4])[CH:8]=[N:9][CH:10]=3)=[CH:14][CH:15]=2)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:25][C:26]=1[CH3:38]
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)O)c2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.182 mL, 0.182 mmol) was added to a solution of [5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethylpropyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 143-(5); 30.4 mg, 0.061 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature for three days. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (19.8 mg, 67%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1.[C:18](O)(=[O:22])[C@@H:19]([CH3:21])[OH:20].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:20][C@H:19]([CH3:21])[C:18]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1)=[O:22]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](N)CC1
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trans-tert-butyl(R)-1-(4-aminocyclohexyl)ethylcarbamate (125 mg, 0.52 mmol) was dissolved in DMF (3 mL). D-Lactic Acid (49.52 mg, 0.52 mmol), diisopropylethylamine (166.6 mg, 224.5 μL, 1.29 mmol) and TBTU (165.6 mg, 0.5158 mmol) were successively added. The reaction mixture was allowed to stir at ambient temperature for 3 hours. The crude mixture was partitioned between ethyl acetate and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by column chromatography (ISCO Companion, 12 g column, 0-10% MeOH/DCM) to afford the title compound (66.1 mg, 41% yield).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.N([O-])=[O:12].[Na+]>S(=O)(=O)(O)O.O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([OH:12])=[N:3][C:4]=1[CH3:10]
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)nc(C)c1Br
Reaction time: 1 h
Yield: 90.9 %

Procedure:
2-amino-5-bromo-4,6-dimethylpyridine (15 g) was dissolved in a mixed solution of sulfuric acid (14.2 mL) and water (212 mL). A solution of sodium nitrite (6.18 g) in water (31 mL) was added to the solution at 0° C. The reaction mixture was stirred at mom temperature for one hour, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure. MTBE was added to the residue to precipitate the solid, followed by filtration. The filtration residue was washed with MTBE to give the title compound (13.7 g).
Reaction SMILES: [C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])[CH3:21]>CO>[CH3:21][CH:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:3][CH2:2][C:1]([N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=3)[CH2:6]2)=[O:4])[CH2:25][CH2:24]1)[CH3:22]
Reactant: CC(C)N1CCNCC1
Reactant: C=CC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN1CCN(C(C)C)CC1)CC2
Temperature: 65 °C
Yield: 45.1 %

Procedure:
A solution of 2-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (425 mg, 1.62 mmol) in methanol (5 mL) was treated with 1-isopropylpiperzine (1.0 mL, 7.0 mmol, Oakwood Products) and heated at 65° C. in a sealed tube for 16 h. The mixture was cooled, concentrated, and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, dried over magnesium sulfate, filtered, and purified by chromatography on SiO2 (dichloromethane to 25% methanol/dichloromethane) to give 2-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (285 mg, 0.731 mmol, 45%). ESIMS (M+H)+=391.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=1>CN(C=O)C.CO.C(Cl)Cl>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:28][CH:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[OH:27])[C:4]=2[CH2:3]1
Reactant: COc1ccc(C2CO2)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CCN(C)C3)cc1
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (1.0 g, 5.0 mmol) was dissolved in 15 mL DMF and sodium hydride (600 mg, 15 mmol) was added portionwise at 0° C. and stirred for 10 min. 2-(4-Methoxy-phenyl)-oxirane (900 mg, 6.0 mmol) was added dropwise at the same temperature and stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water and filtered through a Celite bed. A cake of compound was formed which was dissolved in MeOH and DCM. This was again filtered through a Celite bed and the filtrate concentrated. The solid thus obtained was crystallized in ether & hexane to get 600 mg of 2-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-(4-methoxy-phenyl)-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 7.27 (m, 3H), 7.24 (d, 1H), 7.00 (d, 1H), 6.98 (d, 2H), 4.98 (t, 1H), 4.09 (d, 2H), 3.81 (s, 3H), 3.67 (d, 1H), 3.32 (d, 1H), 2.79 (m, 3H), 2.7 (m, 1H), 2.49 (s, 3H), 2.45 (s, 3H). Separation by chiral HPLC provided enantiomers 20a and 20b. Optical rotations: Compound 20a, (−)10.20 (c 0.58, Chloroform, 99.61% HPLC purity); Compound 20b, (+)10.00 (c 0.59, Chloroform, 96.54% HPLC purity).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:26])[C@@H:6]([OH:25])[C@@H:7]([N:10](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:8][CH3:9])[CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[NH2:10][C@@H:7]([CH2:8][CH3:9])[C@H:6]([OH:25])[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:26]
Reactant: CC[C@@H]([C@H](O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](N)[C@H](O)C(=O)NC1CC1

Procedure:
(2S,3S)—N-Cyclopropyl-3-(dibenzylamino)-2-hydroxypentanamide (4.42 g, 12.5 mmol, Eq: 1.00) was hydrogenated with Pd(OH)2 (20% on carbon, 890 mg, 1.27 mmol, Eq: 0.101) in methanol (50 ml) under a hydrogen pressure of 3.5 bar for 4 h. The catalyst was removed by filtration, and residual solvent was removed under vacuum. The title compound was obtained as a light yellow solid (2.09 g, 96.8%, MS (m/e)=173.2 [M+H+]).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:25])[C:12]=1[NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[CH:21][NH:22]2)=[CH:18][CH:17]=1)=[O:15].CN(C)[CH:28]=[O:29]>>[Cl:25][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:6])[C:12]=1[NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:28]=[O:29])=[CH:21][NH:22]2)=[CH:18][CH:17]=1)=[O:15]
Reactant: CN(C)C=O
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc2cc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of dimethylformamide (10 ml), under nitrogen and at 0° C., was treated with phosphorus oxychloride (0.6 ml). After stirring for 30 minutes at 0° C. the mixture was treated with a solution of N-(3,5-dichloro-pyridin-4-yl)-1H-indole-6-carboxamide [1.55 g, Example 1(bg)] in dimethylformamide (5 ml). The mixture was then heated at 40° C. for 45 minutes then cooled to room temperature and then partitioned between ethyl acetate (25 ml) and saturated sodium bicarbonate (50 ml). The organic layer was washed with water (75 ml) then dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:2, v/v) to yield the title compound (0.53 g) as a white solid. [Elemental analysis:— C, 53.83; H, 2.99; N, 12.31%. Calculated for C15H9Cl2N3O2:— C, 53.92; H, 2.71; N, 12.57%].
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([O:16][C:17]1[CH:22]=[CH:21][C:20]([S+:23]([C:35]2[CH:40]=[CH:39][C:38]([O:41]C(C)(C)C)=[CH:37][CH:36]=2)[C:24]2[CH:29]=[CH:28][C:27]([O:30]C(C)(C)C)=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([S+:23]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)Oc1ccc([S+](c2ccc(OC(C)(C)C)cc2)c2ccc(OC(C)(C)C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: Oc1ccc([S+](c2ccc(O)cc2)c2ccc(O)cc2)cc1
Yield: 97 %

Procedure:
A solution of 6.5 g (0.01 mol) of tris(p-tert-butoxyphenyl)sulfonium p-toluenesulfonate and 0.95 g (0.005 mol) of p-toluenesulfonic acid in 40 g of methanol was heated at 60° C. for 7 hours with stirring. The reaction mixture was evaporated in vacuo. The residual oil was washed two times with 200 g of diethyl ether. The amount of this crude product was 4.7 g (97% yield). Without further purification, the crude product was used in subsequent reaction.
Reaction SMILES: [P:1](=[O:53])([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])([O:45][CH3:46])[O:2][CH:3]([CH2:22][O:23]C(C1C=CC(OC)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO.C(Cl)(Cl)Cl>[P:1](=[O:53])([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])([O:45][CH3:46])[O:2][CH:3]([CH2:22][OH:23])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1)OP(=O)(OC)OCCCCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOCC(CO)OP(=O)(OC)OCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 152 %

Procedure:
A solution of 10 g of phosphoric acid, 2-(hexadecyloxy)-1-[[(4-methoxyphenyl)-diphenylmethoxy]methyl]ethyl methyl pentyl ester in 100 ml of methyl alcohol and 50 ml of chloroform is brought to a boil, the heat removed and 5 g of Amberlite®-15 resin carefully added. The reaction is stirred at ambient temperature for 2 hours, filtered to remove the resin and the cake washed well with 2:1 methyl alcohol:chloroform. The solvent is removed to give 9.7 g of a thick syrup. The product is chromatographed using dry column silica gel with 1:1 ethyl acetate:hexanes. Product fractions are combined and the solvents evaporated to give 1.38 g of a less polar isomer oily product and 1.46 g of a more polar isomer oily product.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][C:18]1[O:19][C:20]2[CH:26]=[C:25]([O:27][C:28]3[C:37]4[C:32](=[CH:33][C:34]([OH:38])=[CH:35][CH:36]=4)[N:31]=[CH:30][CH:29]=3)[CH:24]=[CH:23][C:21]=2[CH:22]=1>CC#N.[Cl-].[Na+].O>[CH3:17][C:18]1[O:19][C:20]2[CH:26]=[C:25]([O:27][C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:38][CH2:3][CH2:4][N:5]5[CH2:10][CH2:9][O:8][CH2:7][CH2:6]5)=[CH:35][CH:36]=4)[N:31]=[CH:30][CH:29]=3)[CH:24]=[CH:23][C:21]=2[CH:22]=1
Reactant: Cc1cc2ccc(Oc3ccnc4cc(O)ccc34)cc2o1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(Oc3ccnc4cc(OCCN5CCOCC5)ccc34)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A suspension of 4-(2-Chloro-ethyl)-morpholine hydrochloride (153 mg, 0.82 mmol) and Cesium Carbonate (537 mg, 1.65 mmol) in CH3CN (2 ml) was stirred at room temperature for 1 hr. The 4-(2-Methyl-benzofuran-6-yloxy)-quinolin-7-ol 126-D (120 mg, 0.41 mmol) in CH3CN (2 ml) was added and the reaction was heated to reflux for 2 hr. The bright yellow reaction was cooled, poured into brine, and extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 10% MeOH in EtOAc/CH2Cl2 (1:1). This gave slightly impure material which was re-purified by HPLC to give 110 mg (42%) of 4-(2-Methyl-benzofuran-6-yloxy)-7-(2-morpholin-4-yl-ethoxy)-quinoline 126 as the bis TFA salt.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=[O:42].[K+].[K+].OO.[OH-].[Na+]>CN(C=O)C.O.C(O)(=O)C.CO>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]([NH2:34])=[O:42])=[CH:31][CH:30]=2)[N:22]=[CH:21]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(COc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: OO
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(COc2ccccc2-c2c[nH]cn2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 120.6 %

Procedure:
To a stirred solution of 4-((2-(1-trityl-1H-imidazol-4-yl)phenoxy)methyl)benzonitrile (0.328 mmol) in DMF (3 mL) at rt was added K2CO3 (0.164 mmol) followed by H2O2 (1.64 mmol, 30% aq. solution). After stirring for 30 min the reaction mixture was diluted with H2O (10 mL) and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford the crude product. The crude was dissolved in a mixture of glacial acetic acid (1.0 mL) and MeOH (4.0 mL) and was heated to 80° C. for 2h. The solution was allowed to cool to room temperature and the pH was adjusted to ˜10 with 10% NaOH (aq). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed in vacuo to afford the crude residue, which was purified by flash column chromatography on silica gel to afford the desired product (58 mg, 60% yield). 1H NMR: 5.23 (s, 2H), 5.71 (br s, 1H), 6.24 (br s, 1H), 7.01 (d, 1H, J=8.28 Hz), 7.07 (t, 1H, J=7.44 Hz), 7.21 (m, 2H), 7.48 (s, 1H), 7.53 (d, 1H, J=8.19 Hz), 7.60 (s, 1H), 7.85 (d, 1H, J=8.19 Hz)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:37]1([CH2:42][CH2:43]O)[CH2:41][CH2:40][CH:39]=[CH:38]1>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:43][CH2:42][CH:37]3[CH2:41][CH2:40][CH:39]=[CH:38]3)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCC1C=CCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC2C=CCC2)cc1

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopent-2-enyl-1-ethanol in place of 2-ethyl-1-hexanol (yield: 95 mg, 48%). mp 126-127° C. 1H NMR (300 MHz, DMSO-d6) δ 1.30 (m, 1H), 1.57 (sextet, J=7 Hz, 1H), 1.69 (sextet, J=7 Hz, 1H), 1.87 (m, 2H), 2.57 (m, 1H), 3.30 (s, 3H), 4.45 (m, 2H), 5.60 (m, 1H), 5.68 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 473 (M+H)+; (APCI−) m/z 507 (M+Cl)−. Anal. calc. for C24H22F2N2O4S: C, 61.00; H, 4.69; N, 5.92. Found: C, 60.76; H, 4.65; N, 5.80.
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]C(O)=O)=[CH:19][CH:18]=1)([OH:16])=[O:15]>>[CH3:1][C:2]1[C:12](=[O:13])[CH:11]2[CH:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)[C:4](=[O:5])[C:3]=1[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccc(C(=O)O)cc1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Product: CC1=C(Cc2ccc(C(=O)O)cc2)C(=O)C2C=CC=CC2C1=O
Yield: 12 %

Procedure:
As starting materials for the coupling reaction menadione and 4-carboxyphenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:3, UV), 102 mg (0.33 mmol, 12% yield) of P_TM50 were isolated as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:10][C@@H:9]1[C@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:12][Cl:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1COCC1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Si:15]([O:14][C@@H:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:10][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][Cl:13])([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]1[C@@H](CCl)O[Si](C)(C)C(C)(C)C
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](CCl)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a magnetically stirred solution of N-t-butyloxycarbonyl-2(R)-(1(S)-t-butyldimetylsilyloxy-2-chloroethyl)aziridine (36.0 mg, 0.107 mmol) in toluene was added copper bromide dimethyl sulfide complex (11.0 mg, 0.054 mmol) at rt under N2. The reaction mixture was cooled to −78° C. then treated with a 2 M solution of PhMgCl in THF (0.54 mL, 1.072 mmol). The resulting mixture was warmed to −20° C. and stirred overnight. The reaction mixture was treated with sat NH4Cl (4 mL) and extracted with EtOAc(5 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated and column-chromatographed (3% EtAc in n-Hex) to provide 2(S)-t-butyldimetylsilyloxy-3(R)-(t-butyloxycarbonyl)amino-1-chloro-4-phenylbutane (33.5 mg) as a colorless oil.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([CH3:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[CH:8][CH:7]=2.[CH2:20]([OH:23])[CH2:21][CH3:22]>>[N:14]1([CH2:13][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([CH3:19])[C:3]([O:23][CH2:20][CH2:21][CH3:22])=[N:12]3)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Cc1nc2ccc(Cn3ccnc3)cc2nc1Cl
Reactant: CCCO
Agent: [Na]
Product: CCCOc1nc2cc(Cn3ccnc3)ccc2nc1C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
A solution of 0.3 parts of sodium in 24 parts of 1-propanol was added to 2.4 parts of 3-chloro-6-(1H-imidazol-1-ylmethyl)-2-methylquinoxaline. The whole was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of pentane and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.5 parts (57.1%) of 6-(1H-imidazol-1-ylmethyl)-2-methyl-3-propoxyquinoxaline; mp. 85.5° C. (comp. 24).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[CH2:21][C:22]2[C:30]3[C:25](=[N:26][C:27]([NH:31]CC4C=CC(OC)=CC=4)=[CH:28][CH:29]=3)[N:24](CC3C=CC(OC)=CC=3)[N:23]=2)[CH:9]=1)[C:5]#[N:6]>C(O)(C(F)(F)F)=O>[NH2:31][C:27]1[N:26]=[C:25]2[NH:24][N:23]=[C:22]([CH2:21][N:15]3[C:16]4[C:12](=[C:11]([O:10][C:8]5[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=5)[C:5]#[N:6])[C:19]([Cl:20])=[CH:18][CH:17]=4)[CH:13]=[N:14]3)[C:30]2=[CH:29][CH:28]=1
Reactant: COc1ccc(CNc2ccc3c(Cn4ncc5c(Oc6cc(Cl)cc(C#N)c6)c(Cl)ccc54)nn(Cc4ccc(OC)cc4)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2cnn3Cc2n[nH]c3nc(N)ccc23)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-chloro-5-{[5-chloro-1-({1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridin-3-yl}methyl)-1H-indazol-4-yl]oxy}benzonitrile (0.848 g, 1.228 mmol) was dissolved in TFA (10 mL) and placed in an oil bath at 75° C. After 2.5 hours, the reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The resulting residue was suspended in a chloroform and ethyl acetate mixture (4:1, 200 mL) and aqueous sodium bicarbonate (50 mL) was added. Ethyl acetate was then added until both phases had become solutions. The organic phase was separated and the aqueous phase was washed with chloroform (2×100 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was subjected to automated silica gel chromatography eluting with a gradient of 0-10% methanol in chloroform to yield the title product. 1H NMR (DMSO-d6): δ 12.60 (s, 1H), 7.86 (s, 1H), 7.81-7.78 (m, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.49-7.47 (m, 1H), 7.38-7.34 (m, 2H), 6.30 (s, 2H), 6.21 (d, J=8.8 Hz, 1H), 5.82 (s, 2H). LRMS (M+1)=449.7