Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3]>CO.[Pd]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2F)CC1
Reaction time: 2 h

Procedure:
A mixture of 3,6-dihydro-4-[4-amino-2-fluorophenyl]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 3, 11.44 g) and 10% palladium-on-carbon (4 g) in methanol (400 mL) in four Parr bottles is shaken on the Parr apparatus under a hydrogen atmosphere at 40 psi for two hours, the catalyst is removed by filtration through Celite, and the filtrate is concentrated under reduced pressure to give the 4-[4-amino-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester intermediate. A mixture of this intermediate (11.17 g) and sodium bicarbonate (6.57 g) in dry tetrahydrofuran (390 mL) is treated with benzyl chloroformate (5.86 mL), and the resulting mixture is stirred at ambient temperature for 15 hours and washed with water (200 mL). The aqueous phase is extracted with methylene chloride (150 mL), and the combined organic phase is washed with saline (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (70-230 mesh, 800 g), eluting with a gradient of ethyl acetate/hexane (15/85-25/75). Pooling and concentration of those fractions with an Rf =0.38 by TLC (ethyl acetate/hexane, 25/75) gives the title compound, mp 96-98° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:32])[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[N:29]O)[NH2:28])=[CH:23][C:22]=3[Cl:31])=[O:19])[C:12]2=[O:33])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]([OH:37])=[O:36]>CCO.[Ni]>[C:35]([OH:37])(=[O:36])[CH3:34].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18](=[O:19])[C@@H:17]([C@H:13]2[O:14][CH2:15][CH2:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)[C:12]2=[O:33])[OH:32])=[C:22]([Cl:31])[CH:23]=1)(=[NH:28])[NH2:29]
Reactant: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C(N)=NO)cc3Cl)C2=O)cc1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C(=N)N)cc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound 66-2 (19 mg) in EtOH (3 mL), were added cat. Raney-Ni and AcOH (0.1 mL). The mixture was stirred under hydrogen atmosphere for 3 hours at room temperature. The mixture was filtered with Celite® pad to remove catalyst. The filtrate was concentrated with toluene in vacuo. The residue was dried by vacuum pump to obtain EXAMPLE 66 (15 mg) as a colorless amorphous solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[C:8]([F:20])[CH:7]=2)[CH2:2]1.CO[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34](OCC)=[O:35])=[N:31][N:30]=2)=[CH:25][CH:24]=1>>[F:20][C:8]1[CH:7]=[C:6]([O:5][CH:3]2[CH2:4][N:1]([C:34]([C:32]3[O:33][C:29]([C:26]4[CH:25]=[CH:24][CH:23]=[CH:28][CH:27]=4)=[N:30][N:31]=3)=[O:35])[CH2:2]2)[CH:19]=[CH:18][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CN1CCN(Cc2ccc(OC3CNC3)cc2F)CC1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: CN1CCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2F)CC1
Yield: 32 %

Procedure:
Using a similar protocol as described in Example 10 employing 29D (0.10 g, 0.36 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.11 g, 0.43 mmol) as starting materials afforded 52 mg (30%) of 29 as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[C:5]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:2].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[CH:29]1.N1CCCCC1>CO>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:9]2\[O:10][C:6]3[C:5]([CH2:14][N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]4)=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:7]=3[C:8]\2=[O:11])=[CH:29]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: CCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of tert-butyl 4-[(6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.138 g, 0.367 mmol) in methanol (1.5 mL) was added with indole-3-carboxaldehyde (0.0553 g, 0.367 mmol) and piperidine (0.0250 g, 0.294 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.137 g, 74%).
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)=[C:2]=S.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:15][C:14]1[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([NH:1][C:2]3[O:25][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=3)=[CH:5][CH:6]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccccc1O
Reactant: Cc1cccnc1Oc1ccc(N=C=S)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1cccnc1Oc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 75 °C

Procedure:
The mixture of 2-(4-isothiocyanatophenoxy)-3-methylpyridine (136 mg, 0.56 mmol), 2-aminophenol (74 mg, 0.67 mmol), and N,N′-dicyclohexylcarbodiimide (174 mg, 0.84 mmol) in THF (5 mL) was heated at 75° C. for 16 h. The solvent was evaporated and the crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-(4-(3-methylpyridin-2-yloxy)phenyl)benzo[d]oxazol-2-amine as white solid. MS (ESI, pos. ion) m/z: 318.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14])[CH3:3].[CH3:15][O:16][C:17](=[O:21])/[CH:18]=[CH:19]\Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][O:16][C:17](=[O:21])/[CH:18]=[CH:19]/[N:8]1[C:7](=[O:14])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)[N:10]=[CH:9]1
Reactant: CC(C)c1ccc2nc[nH]c(=O)c2c1
Reactant: COC(=O)/C=C\Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C/n1cnc2ccc(C(C)C)cc2c1=O
Yield: 82 %

Procedure:
A mixture of 30.1 g. (0.16 mol) of 6-(1-methylethyl)quinazolin-4(3H)-one, 21.2 g. (0.18 mol) of (Z)-3-chloro-2-propenoic acid methyl ester and 33.2 g. (0.24 mol) of anhydrous potassium carbonate in 375 ml. of anhydrous acetone was stirred at reflux for 22 hr. The solvent was removed in vacuo, water was added to the solid residue and the solid was removed by filtration. Recrystallization from methanol gave 35.5 g, m.p. 142°-145°, (82% yield) of (E)-3-[6-(1-methylethyl)-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][C:34](O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:34](=[O:35])[CH2:33][CH2:32][NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCNC(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-tert-butoxycarbonylamino-propionic acid to yield (3aR,4S,7aR)-4-(3-tert-butoxycarbonylamino-propionyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-methyl 4-(3-aminopropanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+Na]=407; RT=4.395 min; LC-MS Method II
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:7][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(C)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(N)c(C)n1

Procedure:
Ethyl 2-(6-methyl-5-nitropyridin-2-yl)acetate (1.10 g, 4.91 mmol) was dissolved in ethyl acetate and added Pd/C (0.5 g) then stirred under a balloon of hydrogen for 2 hrs. Filtered over catalyst and concentrated to yield ethyl 2-(5-amino-6-methylpyridin-2-yl)acetate: LC-MS: M+1=195;
Reaction SMILES: [H-].[Na+].[C:3]([O-])(=O)[CH2:4]C.[OH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(I)C>CN(C)C=O>[CH2:3]([O:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:4]
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Yield: 98 %

Procedure:
To a slurry of sodium hydride (60% suspension in oil, 7.5 g) and dimethyl formamide (70 ml) was added a solution of the racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl(propionate of the formula (10) (40 g) obtained according to the procedure described in step (iii) above in dimethylformamide (105 ml) at 5–10° C. over a period of 15–30 minutes. The temperature was allowed to attain room temperature and maintained at the same temperature for 1–3 h. Ethyl iodide (36 g) was added slowly by maintaining the temperature at 25–30° C. over a period of 2–3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford the title compound of the formula (12a) (47–48 g, 98–99%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([OH:18])=[C:13]([N:19]=O)[CH:12]=[CH:11]2>CCCCCC>[Cl:7][C:8]1[CH:17]=[CH:16][C:15]([C:14]([Cl:2])=[O:18])=[C:10]([CH:9]=1)/[CH:11]=[CH:12]\[C:13]#[N:19]
Reactant: O=Nc1ccc2cc(Cl)ccc2c1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCCCCC
Product: N#C/C=C\c1cc(Cl)ccc1C(=O)Cl

Procedure:
To a rapidly stirring suspension of phosphorus pentachloride, 68.0 g, 0.326 mole in dry hexane (1.6 liters) is added 78.03 g (0.322 mole) of 6-chloro-2-nitroso-1-naphthol (I). The mixture is stirred at room temperature for 3 hours, the refluxed for 2 hours. The warm solution is then decanted and the residue in the reaction vessel refluxed for another hour with 1.0 liter of dry hexane. The hexane extracts are combined and evaporated to dryness. Yield: 75.0 g semi-solid brown residue. This crude product is recrystallized by taking it up in 2.0 liters of hot hexane, evaporating the solution down to a minimum volume (ca 300 ml) and cooling in an ice-water bath. Yield 31.0 g (42.59%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH:10][CH2:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1>>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Product: CC(C)(C)OC(=O)N1CC(COc2nc(Cl)ncc2Br)C1
Yield: 67 %

Procedure:
Using the procedure of Example 1 Step 1, 5-bromo-2,4-dichloropyrimidine was reacted with tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate to provide the title compound at 67% yield. 1H NMR (CDCl3, 400 MHz) 8.46 (s, 1H), 4.61 (d, 2H), 4.10 (m, 2H), 3.82 (m, 2H), 3.03 (m, 1H), 1.45 (9H); MS (ESI) m/z: Calc: 377.0 (M+). Found. 322.9 (M+-(CH3)3C+1).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([O:7][N:8]=[C:9]2[CH2:26][CH2:25][C:12]3([O:16][N:15]=[C:14]([C:17]#[C:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4][O:3]1.[OH-:27].[Na+]>O1CCOCC1>[OH:27][CH2:4][CH2:5][CH:6]([O:7][N:8]=[C:9]1[CH2:26][CH2:25][C:12]2([O:16][N:15]=[C:14]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)[CH2:11][CH2:10]1)[C:2]([OH:3])=[O:1]
Reactant: [OH-]
Reactant: O=C1OCCC1ON=C1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C(CCO)ON=C1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Temperature: 40 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
To a solution of the Compound of Example 47 (14 mg, 0.4 mmol) in 1.75 mL of dioxane was added 1M sodium hydroxide (40 μL, 0.4 mmol) and the reaction mixture was stirred at 40° C. for 2 h. After evaporation to dryness, the crude was purified by automated RP flash chromatography (SP1®TM-Biotage; gradient 20 mM aqueous ammonium carbonate-MeCN from 1:0 to 6:4) to give 10 mg of the title compound as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][N:20]([CH2:22][CH2:23][N:24]1[C:28](=[O:29])[CH:27]([CH:30](C)[CH2:31][C:32](C)([O:37][SiH3])C(C)(C)C)[S:26][CH:25]1[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH3:21]>O1CCCC1>[CH3:19][N:20]([CH2:22][CH2:23][N:24]1[C:28](=[O:29])[CH:27]([CH2:30][CH2:31][CH2:32][OH:37])[S:26][CH:25]1[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH3:21]
Reactant: CC(CC(C)(O[SiH3])C(C)(C)C)C1SC(c2cccnc2)N(CCN(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)CCN1C(=O)C(CCCO)SC1c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A lM solution (15 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added dropwise to a solution of 3-dimethylaminoethyl-5-(3-t-butyldimethyl-silyloxypropyl)-2-(3-pyridyl)thiazolidin-4-one (2.6 g, 6.02 mmol) in dry tetrahydrofuran (12 ml) under cooling with ice. Then the mixture was stirred at room temperature for 2 hours to complete the reaction. Saturated aqueous NaHCO (10 ml) was added dropwise to the product mixture, and the resulting aqueous layer was extracted 6 times with ethyl acetate. The extract wad dried over MgSO4, and the solvent was removed under reduced pressure. The residual crude product was purified by medium-pressure liquid chromatography (Si-60® Art. 9385, eluent : hexane : ethanol : aqueous ammonia = 3000 : 400 : 50), giving 3-dimethylaminoethyl-5-(3-hydroxypropyl)-2-(3-pyridyl)thiazolidin-4-one (1.7 g, 88% yield).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].O[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][C:28]=1[O:41][CH3:42].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][C:28]=3[O:41][CH3:42])[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: COc1cc(-c2ccccc2C#N)ccc1CO
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3OC)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4′-(hydroxymethyl)-3′-methoxybiphenyl-2-carbonitrile (1.7 g), 1,1′-(azodicarbonyl)dipiperidine (2.2 g), tributylphosphine (2.2 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (1.9 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>N1C=CC=CC=1>[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N+:24]([O-:26])=[O:25])(=[O:34])=[O:35])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4ccccc4[N+](=O)[O-])c2)c1=O)CCCC3
Temperature: 80 °C
Yield: 100.2 %

Procedure:
A mixture of 4-(3-aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (228 mg, 0.74 mmol), 2-nitrobenzenesulfonyl chloride (247 mg, 1.11 mmol), and dry pyridine (5 mL) was refluxed at 80° C. for 4 hours. After cooling on standing, the solvent was removed by evaporation under reduced pressure. The obtained residue was extracted with chloroform, washed with water and a dilute hydrochloric acid aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the titled compound as a brown crystal (365 mg, yield 100%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (178 mg, 0.51 mmol, 1.00 equiv) in methanol (15 mL). A solution of sodium hydroxide (102.6 mg, 2.56 mmol, 5.00 equiv) in water (1.5 mL) was added. The resulting solution was stirred overnight at 50° C. in an oil bath and concentrated to dryness. The residue and diluted by 10 ml of water and pH value of the aqueous solution was adjusted to pH=3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration as product. This resulted in 130 mg (75%) of (R)-3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]1O[C:4](=[O:5])[CH2:3]1.[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1>C(O)(=O)C>[CH3:15][C:14]1[O:16][C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:13]=1[C:10]1[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Cc1ccncc1
Reactant: C=C1CC(=O)O1
Solvent: CC(=O)O
Product: Cc1cc(=O)c(-c2ccncc2)c(C)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.6 %

Procedure:
Diketene (30 g) was added dropwise to a stirred solution of 1-(4-pyridyl)-2-propanone (20.25 g) in acetic acid (100 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 90 minutes. The mixture was heated to 50° and stirred for a further 90 minutes. The solvent was removed by evaporation and the residue purified by flash chromatography, eluting with dichloromethane/methanol (19:1 v/v) to give 2,6-dimethyl-3-(4-pyridyl)-4H-pyran-4-one (C) (21.6 g), as a yellow solid; NMR (CDCl3): 2.28(s,3H), 2.35(s,3H), 6.2(s,1H), 7.2(dd,2H), 8.65(dd,2H); mass spectrum (chemical ionisation, ammonia): 202 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]4=[O:25])=[CH:14][CH:15]=3)[CH2:10]2)[CH:6]=[C:5]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[N:4]=1.Cl[C:34]1[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=1>>[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([N:19]4[CH2:24][CH2:23][N:22]([C:34]5[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=5)[CH2:21][C:20]4=[O:25])=[CH:14][CH:15]=3)[CH2:10]2)[CH:6]=[C:5]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)[N:4]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(N5CCNCC5=O)cc4C3)nc(N)n2)CC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: Cl
Product: CCOC(=O)c1ccc(N2CCN(c3ccc4c(c3)CN(c3cc(N5CCN(C)CC5)nc(N)n3)CC4)C(=O)C2)nc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 2 starting from 1-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperazin-2-one hydrochloride and ethyl 6-chloronicotinate (Aldrich, Cat. No. 531197). LCMS (M+H)+: m/z=572.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C(OP([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)(=O)OCC)C.[H-].[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH2:4][CH2:3]1
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Reactant: CN1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(=Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
1-Methyl-piperidin-4-one (500 mg, 4.42 mmol) was dissolved in THF (10 ml) and added dropwise to a stirred mixture of (4-cyano-benzyl)-phosphonic acid diethyl ester (1.12 g, 4.42 mmol) and NaH (60% oil dispersion, 212 mg, 5.30 mmol) in THF (10 ml) under N2. The solution was stirred at room temperature for 2 h, then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (DCM/MeOH/NH4OH 95:5:0.2). The collected fractions gave 392 mg of 4-(1-methyl-piperidin-4-ylidenemethyl)-benzonitrile as a yellow oil.