Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:18])=[CH:5][C:6](=[O:17])[C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[CH3:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[C:6]([O:17][CH2:19][CH2:20][CH3:21])[CH:5]=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1cc(=O)c(C(=O)Nc2ccccc2)c(C)[nH]1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cc(C)nc(C)c1C(=O)Nc1ccccc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 75.3 %

Procedure:
A mixture of 2.42 (10 m mol) of 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-3-pyridinecarboxamide, 1.84 g (15 m mol) of n-propyl bromide, 1.52 g (11 m mol) of potassium carbonate and 40 ml of N,N-dimethylformamide was stirred for 7 hours at 90° C. (bath temperature). About 100 ml of water was added to the reaction mixture. The mixture was cooled to room temperature to precipitate crystals. The crystals were filtered off, washed and dried under reduced pressure to obtain 2.14 g of 2,6-dimethyl-N-phenyl-4-propoxy-3-pyridinecarboxamide
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33](Cl)[C:34](OCC)=[O:35])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:40][C:41](N)=[S:42].S1(CCCC1)(=O)=[O:45]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:18])([CH3:20])[CH3:19])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]3[S:42][C:41](=[O:45])[NH:40][C:34]3=[O:35])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3cc(OC(C)=O)c(C(C)(C)CC(C)(C)C)cc3O2)cc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)CC2

Procedure:
The procedure described in Example 2 was repeated, but using 7.0 g of ethyl 3-{4-[6-acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]phenyl}-2-chloropropionate (prepared as described in Preparation 23), 1.2 g of thiourea and 9 ml of sulfolane, to give the title compound as slightly yellow glassy solid, softening at 75°-80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([CH3:15])[O:14][CH2:13][CH2:12][CH2:11][O:10]1.[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([O:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:15]
Reactant: COc1ccccc1C1(C)OCCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1C(C)OCCCO

Procedure:
The solution of 61.9 g of 2-(2-methoxyphenyl)-2-methyl-[1,3]dioxane in 450 ml of toluene is cooled to 0° C. with stirring and admixed at 0-10° C. with 487 ml of diisobutylaluminium hydride (1.5M in toluene) over 1 hour. The mixture is stirred over 2.5 hours and subsequently poured onto the stirred solution of 382 g of citric acid monohydrate in 2 l of water. The organic phase is removed and the water phase extracted with tert-butyl methyl ether (1 l). The organic phases are washed with brine (1 l), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.12 (1:2 EtOAc-heptane); Rt=3.56.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2ccccc2=O)cc1
Temperature: 175 °C
Reaction time: 4 h
Yield: 35.5 %

Procedure:
A mixture of 2-hydroxypryidine (2.40 g), ethyl 4-iodobenzoate (6.97 g), potassium carbonate (3.83 g) and copper (253 mg) in N,N-dimethylformamide (12 ml) was stirred for 4 hours at 175° C. under nitrogen atmosphere. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue was added ethyl acetate and 1N hydrochloric acid, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-(2-oxo-1,2-dihydropyridin-1yl)benzoate (2.18 g) as brown powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>CCO.N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)CC(=O)O
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Yield: 47.2 %

Procedure:
A solution of aldehyde 4-methylsulfonylbenzaldehyde 4 (1.0 g, 5.9 mmol) and malonic acid (0.63 g, 6.0 mmol) in 10:1 EtOH/pyridine (12.1 mL) was heated at a gentle reflux for 24 h. After cooling to 0° C., the resulting precipitate was collected and rinsed with cold Et2O. The solid was resuspended in EtOH (13 mL) and heated at reflux for an additional 2 h. After cooling to 0° C., the resulting precipitate was collected and dried in vacuo to afford 0.63 g (51%) of 3-(4-methanesulfonyl-phenyl)-acrylic acid 5 as a white solid; 1H NMR (DMSO) δ 3.18 (s, 3H), 6.65 (d, 1H, J=16.1), 7.60 (d, 1H, J=16.1), 7.89 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)[C:14](=[O:32])[N:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=1)[C:12]2=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1)[C:14](=[O:32])[N:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=1)[C:12]2=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C(=O)OC(C)(C)C)CC3)c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCNCC3)c2=O)cc1OC
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 3.5 g of 1,1-dimethylethyl 4-[6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate obtained in stage 1.5 and 25 ml of TFA in 50 ml of DCM is stirred at AT for 2 h 00. The mixture is neutralized with K2CO3. It is filtered and the filtrate is evaporated under reduced pressure. The residue is taken up in DCM and washed with a saturated NaHCO3 solution and then with an 8% NaOH solution. The solution is dried over Na2SO4 and filtered, and the solvent is evaporated under reduced pressure to give 2.67 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].CCN(C(C)C)C(C)C>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][NH:11][C:12](=[O:17])[CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O=C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1CN(c2ccc([N+](=O)[O-])nc2)CCN1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a sealed tube were added 5-bromo-2-nitropyridine 141-1 (1.01 g, 5 mmol), piperazin-2-one 141-2 (0.6 g, 6 mmol), DIEA (1.8 mL, 18 mmol) and DMSO (6 mL). The reaction was heated to 120° C. and stirred for 16 hours. The reaction was cooled down to room temperature. DIEA was removed by rotary evaporation. The residue was triturated in 15 mL ethyl acetate. The solid was collected by filtration and washed with small amount of ethyl acetate to give 4-(6-nitropyridin-3-yl)piperazin-2-one 141-3 as light yellow solid. MS m/z 223.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[S:32][CH:33]=1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[S:32][CH:33]=[C:29]([CH3:28])[CH:30]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: Cc1csc(B(O)O)c1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and (4-methyl-2-thienyl)boronic acid (71 mg, 0.50 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and solvent evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E107). MS (ES+) m/e 472 [M+H]+.
Reaction SMILES: O.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=O)[CH2:4]1.O1CCC[CH2:12]1.B(F)(F)F.CCOCC>C=O.C(O)=O>[OH:2][C@H:3]1[CH2:7][N:6]([CH3:12])[C@H:5]([CH2:8][OH:10])[CH2:4]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: C1CCOC1
Agent: C=O
Agent: FB(F)F
Solvent: O=CO
Solvent: O
Solvent: CCOCC
Product: CN1C[C@H](O)C[C@H]1CO
Temperature: 0 °C
Yield: 54.5 %

Procedure:
A 2-L three-necked, round-bottomed flask was equipped with a mechanical stirrer, heating mantel, 250-mL graduated additional funnel, and an 8-in., air-cooled vigreux column topped with a water-cooled distillation head and a 1-L receiving flask. The assembly was flushed with nitrogen and charged with trans-4-hydroxy-L-proline (100 g, 0.76 mol) and tetrahydrofuran (THF, 1.2 L), and boron trifluoride etherate (123.9 g, 0.88 mol). The mixture was heated at a rate sufficient to cause the THF to reflux gently and borane-methyl sulfide complex (360 mL, 3.6 mol) was added dropwise over 2 hrs. The solution was then refluxed for 24 hrs. The methyl sulfide, collected at stillhead was discarded, and the reaction mixture was cooled to 0° C. and quenched by the slow addition of methanol (300 mL). The reaction mixture was concentrated by distillation at reduced pressure and the residue was dissolved in 6N sodium hydroxide (1 L) and refluxed for 6 hrs. After cooling to room temperature, the insoluble material was removed by filtration and the filtrate was concentrared at reduced pressure. In order to remove the insoluble materials, the residue was dissolved in 2-propanol (1 L), filtered and concentrated. The operation was repeated three times, affording an oil, which was dissolved in 35% formaldehyde solution (200 mL) and formic acid (600 mL). The reaction mixture was refluxed for 24 hrs and concentrated at reduced pressure. The residue was dissolved in methanol (800 mL) and treated with potassium carbonate (100 g) and refluxed for 6 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and dissolved in methylene chloride (600 mL) and filtered again. The filtrate was concentrated and Kugelrohr distilled (200°-220° C./1 mmHg) to give (2S, 4R)-4-hydroxy-1-methyl-2-pyrrolidinemethanol (54.48 g, 54.5%) as a viscous oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl-].[CH:15](=[N+:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:23][N:22]([CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][C:11](=[O:13])[CH3:12])[NH:1][CH:2]=1)[CH3:24]
Reactant: CC(=O)Oc1cccc2[nH]ccc12
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CC(=O)Oc1cccc2[nH]cc(C(c3ccccc3)N(C)C)c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from acetic acid 1H-indol-4-yl ester and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.FC(F)(F)C(O)=O.[C:15]1([C:21]2[C:25]3[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:24]=3[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:31]>>[ClH:31].[CH3:7][N:5]([CH2:4][CH:27]1[C:26](=[O:30])[C:25]2[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:22][O:23][C:24]=2[CH2:29][CH2:28]1)[CH3:6]
Reactant: O=C1CCCc2onc(-c3ccccc3)c21
Reactant: CN(C)CN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC1CCc2onc(-c3ccccc3)c2C1=O
Temperature: -10 °C
Reaction time: 48 h

Procedure:
Bis-dimethylaminomethane (0.51 g) was added to 2.5 ml of trifluoroacetic acid which had been previously chilled to -10° C. 6,7-Dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (1.0 g) was then added and the reaction was warmed for 1 hour at 100° C. and then allowed to stand an additional 2 days at room temperature. The reaction mixture was poured into 5% HCl and washed with ether, after which the aqueous phase was treated with solid sodium bicarbonate until basic. Extraction with ether followed by drying and concentration gave an oil. The hydrochloride was formed in etheiral HCl and was recrystallized from dichloromethane/ether to give 0.95 g of 6,7-dihydro-5-dimethylaminomethyl-3-phenyl-1,2-benzisoxazol-4(5H)-one hydrochloride, m.p. 1 178°-180° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[C:4]=1[C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[NH2:22][CH2:23][C@@H:24]([OH:27])[CH2:25][OH:26].C(N(CC)CC)C>CCO>[Cl:20][C:16]1[CH:15]=[C:14]([C:13]2[N:22]([CH2:23][C@@H:24]([OH:27])[CH2:25][OH:26])[CH:2]=[C:3]3[C:4]=2[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[N:8]3[CH3:9])[CH:19]=[CH:18][CH:17]=1
Reactant: NC[C@@H](O)CO
Reactant: Cn1c(CBr)c(C(=O)c2cccc(Cl)c2)c(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(C[C@@H](O)CO)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
A mixture of 6-(bromomethyl)-5-(3-chlorobenzoyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (2 g, 5.38 mmol), (R)-3-aminopropane-1,2-diol (0.490 g, 5.38 mmol) and triethylamine (0.750 ml, 5.38 mmol) in EtOH (17.94 ml) was heated under microwave irradiation at 100° C. for 1 hour. The mixture was evaporated under vacuum and the residue partitioned between DCM (20 mL) and 1M HCl (20 mL). The phases were separated and the organic phase was washed with water (2×20 mL). The organic phase was passed through a hydrophobic frit and evaporate under vacuum to afford the title compound.
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O.[NH2:33][NH2:34]>CO>[CH2:16]([N:13]1[CH2:12][CH2:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([NH:33][NH2:34])=[O:31])=[CH:9][CH:8]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1cccc(C2(c3ccc(C(=O)NN)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methyl ester (9.5 g, 22.9 mmol) in methanol (60 mL) was added hydrazine hydrate (8 mL). The reaction mixture was heated to reflux for 36 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in toluene (50 mL) and concentrated under vacuum, and 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid hydrazide was obtained in quantitative yield. The residue was used in the subsequent steps without purification. 1HNMR (400 MHz, CD3OD) δ 7.82 (d, 1H), 7.67 (d, 1H), 7.39-7.05 (comp, 8H), 6.86 (d, 1H), 6.80 (s, 1H), 6.67 (d, 1H), 3.69 (s, 3H), 3.38 (s, 2H), 2.62-2.37 (comp, 8H); MS (M+1) 416.3.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:19]([OH:20])[C:18]2[CH:22]=[CH:23][C:15]([Br:14])=[CH:16][CH:17]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(Br)cc2)c2ccccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-2-indolinone and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hunig's base (20° C., overnight) and final purification by column chromatography on silica gel with CH2Cl2 /MeOH (20:1) as eluant.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[CH:24]=2)[C:8](=[O:22])[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:11]=1)(=[O:3])[CH3:2].[Cl:32]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClCCl.C(OCC)C>[C:1]([O:4][CH2:5][C:6]1[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[CH:24]=2)[C:8](=[O:22])[C:9]([Cl:32])=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)OCc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(C(N)=O)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OCc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cccc(C(N)=O)c1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
{1-[3-(aminocarbonyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-oxo-1,6-dihydropyridin-2-yl}methyl acetate (from step 2) (1.02 g, 2.39 mmol) was suspended in dichloromethane (15 mL) and N-chlorosuccinimide (0.37 g, 2.75 mmol) was added. Dichloroacetic acid (0.10 ml, 1.22 mmol) was added and the reaction mixture was stirred at 40° C. for 1.5 hours. The reaction was cooled to room temperature and a precipitate formed. The reaction mixture was diluted with diethyl ether and the precipitate was collected by filtration and washed with diethyl ether (3×15 mL) to afford a tan solid (0.940 g, 85%). 1H NMR (400 MHz, DMF-d6) δ 8.21 (br s, 1H), 8.11 (app dt, J=1.48, 7.52 Hz, 1H), 7.95 (app t, J=1.61 Hz, 1H), 7.80 (app dt, J=6.72, 8.59 Hz, 1H), 7.69-7.60 (m, 2H), 7.48 (br s, 1H), 7.35 (ddd, J=2.55, 9.53, 10.61 Hz, 1H), 7.24-7.19 (m, 1H), 6.97 (s, 1H), 5.49 (s, 2H), 4.71 (AB q, JAB=15.04 Hz, 2H), 1.98 (s, 3H). ES-HRMS m/z 463.0883 (M+H calcd for C22H17ClF2N2O5 requires 463.0867).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=1>C(N(CC)CC)C.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.[Cu]I>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([O:10][CH3:9])=[O:20])[CH:13]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: C#Cc1cccc(C(=O)OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C#Cc2cccc(Br)n2)c1
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A solution of 15.1 g of 2,6-dibromopyridine in 500 ml of triethylamine is mixed under ice cooling with 10.2 g of 3-ethinylbenzoic acid methyl ester, 1.1 g of bis-(triphenylphosphine)-palladium(II) chloride ad 150 mg of copper(I) iodide and the mixture is stirred for 1 hour. Then, the ice bath is removed and it is stirred for 48 hours at room temperature. The precipitate is filtered off, the filtrate is evaporated to dryness, mixed with water and shaken out with ethyl acetate. The organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-12% ethyl acetate. 4.8 g of 2-bromo-6[2-(3-methoxycarbonylphenyl)-ethinyl]-pyridine of melting point 124°-126° C. is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:9])[C:3]=1[CH2:2][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: Clc1cncc(Cl)c1CBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2c(Cl)cncc2Cl)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91.2 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine (15 g, 62.2 mmol), 4-hydroxybenzaldehyde (7.97 g, 65.4 mmol) and caesium carbonate (22.3 g, 68.5 mmol) in DMF (150 ml) was stirred for 4.5 h at room temperature. The mixture was poured into water and extracted with EtOAc. The organic extract was washed with sodium carbonate solution (×2) and brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a brown solid (16 g). δH (DMSO-d6), 9.91 (1H, s), 8.74 (2H, s), 7.91 (2H, d, J 8.6 Hz), 7.27 (2H, d, J 8.6 Hz), 5.37 (2H, s); m/z (ESI) 282 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:9](=[O:15])[NH:10][CH:11]=[CH:12][C:13]=1[I:14].Br[CH2:17][CH2:18][C:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[F:7][C:8]1[C:9](=[O:15])[N:10]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=[CH:12][C:13]=1[I:14]
Reactant: O=c1[nH]ccc(I)c1F
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1ccc(I)c(F)c1=O)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Cesium carbonate (1.50 g, 4.60 mmol) was added to a solution of 3-fluoro-4-iodopyridin-2(1H)-one (354 mg, 1.48 mmol) and ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (595 mg, 2.07 mmol in THF (25 mL). The resulting suspension was heated to 50° C. and stirred overnight. The reaction was heated to 70° C. and stirred at this temperature overnight. The reaction was filtered through celite (˜1 inch), and the filter pad was washed with ethyl acetate (2×30 ml). The combined filtrates were concentrated and the crude was purified via flash chromatography on an Analogix SF15-24g column and an eluant of ethyl acetate in heptane (50-100%) to afford the title compounds as a clear gum (366 mg, 55.5%). LC-MS m/z 445.9 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.12 Hz, 3H) 1.76 (s, 3H) 2.43-2.56 (m, 2H) 3.11 (s, 3H) 3.97-4.10 (m, 1H) 4.20-4.38 (m, 3H) 6.50 (dd, 1H) 6.75-6.98 (m, 1H).