Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][O:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([C:41]4[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=4)[CH2:36][CH2:37]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][O:15][CH2:16][CH:8]12
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCOCC12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)C3COCCN43)CC2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
3-(hydroxymethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one (70.0 mg, 0.298 mmol) was suspended in propionitrile (0.74 mL) and (cyanomethyl)trimethylphosphonium iodide (87.0 mg, 0.357 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (115 ul, 0.893 mmol). To the stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile (56.0 mg, 0.298 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature and left to sit 48 h. The precipitate was filtered off, washed with methanol (5 mL) and dried in vacuum to afford the title compound (72.5 mg, 60.1%) as a white solid. 1H NMR(CHLOROFORM-d) δ: 8.41 (d, J=1.8 Hz, 1H), 8.20 (br. s., 1H), 7.80 (d, J=2.0 Hz, 1H), 7.61 (dd, J=9.0, 2.4 Hz, 1H), 6.99 (br. s., 1H), 6.59 (d, J=9.1 Hz, 1H), 4.42 (dd, J=11.5, 3.7 Hz, 1H), 4.26 (dd, J=13.3, 1.6 Hz, 1H), 3.95-4.12 (m, 2H), 3.58-3.80 (m, 6H), 3.45 (s, 2H), 2.92-3.08 (m, 1H), 2.53 (br. s., 4H). [M+H] calc'd for C21H23N7O2, 406; found, 406.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH3:22])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][CH:12]=2.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:23][CH2:22][C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:19])[F:20])[N:10]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc2nc(CBr)c(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-(2-Chlorophenyl)-2-methyl-5-(trifluoromethyl)quinoxaline (0.9969 g, 3.089 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.5299 g, 1.853 mmol) were suspended in carbon tetrachloride (30.89 mL, 3.089 mmol). To the mixture was added benzoyl peroxide (0.09977 g, 0.3089 mmol) and the mixture was heated at reflux. After 20 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 5% gradient of EtOAc in hexane over 10 min, then 5% isocratic of EtOAc for 30 min, then 5 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 4 min as eluent to give 2-(bromomethyl)-3-(2-chlorophenyl)-5-(trifluoromethyl)-quinoxaline as an off-white syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (1 H, dd, J=8.6, 0.8 Hz), 8.37 (1 H, d, J=6.7 Hz), 8.09 (1 H, t, J=7.8 Hz), 7.55-7.77 (4 H, m), 4.73 (2 H, d, J=61.8 Hz); LC-MS (ESI) m/z 403.0 [M+H]+.
Reaction SMILES: [N:1]([CH:4]([O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1C(O)=O)=[N+:2]=[N-:3].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.[F:44][C:45]([F:50])([F:49])[C:46](O)=[O:47].[NH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:60])C(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:19][CH2:18][CH2:17][O:16][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:5][O:6][C:7]1[CH:8]=[CH:12][CH:13]=[C:14]([C:55](=[O:60])[NH:54][CH2:53][CH2:52][NH:51][C:46](=[O:47])[C:45]([F:50])([F:49])[F:44])[CH:15]=1)[CH3:25]
Reactant: CCOC(=O)COCCOC(COc1ccccc1C(=O)O)N=[N+]=[N-]
Reactant: NCCNC(=O)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)COCCOC(COc1cccc(C(=O)NCCNC(=O)C(F)(F)F)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
3-[(2-Azido-2-(2-ethoxycarbonylmethoxy-ethoxy)-ethoxy]-benzoic acid (0.212 g, 0.6 mmol) was stirred with N,N′-disuccinimidyl carbonate (0.184 g, 0.72 mmol) and DMAP (0.088 g, 0.72 mmol) in dry DMF (1 ml) at room temperature. After 10 minutes, trifluoroacetic acid salt of N-(2-amino-ethyl)-2,2,2-trifluoro-acetamide (0.194 g, 0.72 mmol) was added followed by diisopropylethylamine (DIPEA) (0.251 ml, 1.44 mmol). The reaction mixture was then stirred at room temperature for 17 hours. All the solvents were evaporated under reduced pressure and the residues were partitioned between DCM (50 ml) and aqueous NaH2PO4 (1 N, 50 ml). The aqueous layer was further extracted with DCM (2×25 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography (1×20 cm). The title compound, eluted with 1% methanol in DCM, was obtained as an oil (0.255 g, 86.6%). ES-MS, m/z 490.10 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C(Br)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CCCCBr)cc1
Reactant: CCOP(OCC)OCC
Solvent: CCBr
Solvent: O
Product: CCOP(=O)(CCCCc1ccc(Cl)cc1)OCC
Yield: 78 %

Procedure:
A mixture of 12.38 g of 4(p-chlorophenyl)butyl bromide and 20 g of triethyl phosphite was refluxed at 160° for seven hours. During this period the circulating water in the condenser was maintained at 50° to allow the ethyl bromide to distill off. After removal of the excess of triethyl phosphite, distillation under reduced pressure gave 11.9 g (39 mmol) of a white viscuous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]([OH:17])[CH3:16])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To the solution of 1-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethanone (3.12 g, 9.91 mmol) in Ethanol (60 ml), was added NaBH4 (0.450 g, 11.90 mmol). The solution was stirred at room temperature under nitrogen for 1 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice. The solvent was dried over Na2SO4, concentrated to afford the title compound (2.3 g, 73.2% yield) as light yellow oil. LCMS: rt=3.63 min, [M+H+]=299
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][F:17]>CN(C=O)C>[F:17][CH2:16][CH2:15][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5]1
Reactant: FCCBr
Reactant: Oc1cccc(N2CCNCC2)c1
Solvent: CN(C)C=O
Product: Oc1cccc(N2CCN(CCF)CC2)c1
Yield: 48 %

Procedure:
1 g (5.61 mmol) 3-Piperazin-1-yl-phenol and 0.5 mL (1.25 eq) 1-bromo-2-fluoroethane are stirred 20 h at 60° C. in 5 mL DMF, the reaction mixture allowed to reach room temperature and evaporated, and the residue column chromatographed (silica gel, ethyl acetate/petroleum ether 9:1) to yield 600 mg (48%) of the desired product as a brown oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([NH:1][CH:2]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:34])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-phenyl-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.69 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (322 mg, 1.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (487 mg, 2.54 mmol) and 1-hydroxy-1H-benzotriazole (259 mg, 1.69 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (650 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>C1COCC1.CN(C=O)C.[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>[F:1][C:2]1[CH:23]=[C:22]([C:27]#[C:26][CH2:25][OH:28])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)NCCCO)c(Nc2ccc(I)cc2F)cc1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Yield: 89 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with propargyl alcohol in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a cream solid (89%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.27 (s, 1H), 8.40 (t, J=5.4 Hz, 1H), 8.25 (s, 1H), 7.48 (t, J=8.5 Hz, 1H), 7.39 (dd, J=11.6, 1.8 Hz, 1H), 7.27 (dd, J=8.3, 1.4 Hz, 1H), 5.70 (s, 1H), 5.34 (t, J=6.1 Hz, 1H), 4.47 (t, J=5.1 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 3.46 (q, J=5.9 Hz, 2H), 3.38 (s, 3H), 3.27 (q, J=6.5 Hz, 2H), 1.66 (pentet, J=6.7 Hz, 2H). LCMS (APCI+) calcd for C19H21FN3O4 374 (MH+), found 374.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[N:6][C:7]1[N:8]2[CH:13]=[N:14][C:15]=1[C:16](=[N:18][OH:19])[NH2:17].[CH:26]1([C:29](OCC)=O)[CH2:28][CH2:27]1.[H-].[Na+]>CN(C=O)C.C(O)(=O)C.C(Cl)Cl>[CH:26]1([C:29]2[O:19][N:18]=[C:16]([C:15]3[N:14]=[CH:13][N:8]4[C:9]5[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=5)[C:5]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[N:6][C:7]=34)[N:17]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)C1CC1
Reactant: COc1cccc2c1c(N1CCOCC1)nc1c(C(N)=NO)ncn12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cccc2c1c(N1CCOCC1)nc1c(-c3noc(C4CC4)n3)ncn12
Temperature: 120 °C

Procedure:
A mixture of 6-methoxy-5-morpholino-imidazo[1,5-a]quinazoline-3-carboxamide oxime (0.9 g), ethyl cyclopropylcarboxylate (1.7 g), molecular sieves (3 g), and 80% sodium hydride (0.1 g) in 20 ml of dry DMF was heated for 11/2 hours at 120° C. The mixture was cooled to room temperature, diluted with acetic acid (0.5 ml) and methylene chloride (20 ml) and filtered. The filtered mixture was evaporated and the residue was purified by column chromatography (HPLC) (eluent: methylene chloride:acetone (2:1)) to give yellow crystals of the title compound, m.p. 227°-228° C. Yield 0.38 g.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][CH2:30][S:31][CH3:32])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:43])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][CH2:30][S:31]([CH3:32])=[O:43])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CSCCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-1-[3-(methylsulfanyl)propyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 61 in dichloromethane (2 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (˜85%)(0.045 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 3% to 9% methanol in dichloromethane. The product fractions are combined and recrystallized from ethyl acetate-methanol-hexanes to afford 0.07 gm of the title compound as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.[CH:18]1([C:21]2[C:22]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[C:22]([N:30]3[CH2:31][CH2:32][N:33]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[CH3:16])=[O:13])[CH2:34][CH2:35]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:19][CH2:20]1
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 28.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (255 mg) described in Preparation Example 29 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (243 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Example 87, the title compound (137 mg) was obtained.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1.Cl>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)/C=C\C(=O)O
Yield: 85 %

Procedure:
1.8 ml allyl alcohol (26 mmol, 1.3 eq.) were added to a 2 g solution of maleic anhydride (20 mmol) in chloroform. The reaction mixture was stirred at reflux for 5 h. The resulting solution was treated with 1N HCl and was extracted with chloroform. The organic extracts were washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate and filtered. The solvent was evaporated at reduced pressure, and the residue obtained was identified as intermediate VI in the form of an oil (95% purity, 85% yield).
Reaction SMILES: [C:1](Cl)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1>C1C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1)=[O:9]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1O
Solvent: c1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
1.2 Grams (7.7 m-mol) of salicyloyl chloride and 1.0 g (4.9 m-mol) of 6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone in 10 ml of benzene were stirred for 6 hours at 50° C. After cooling, the resultant crystals were washed with benzene and recrystallized from methanol-water whereby 750 mg of the title compound was obtained. M.P. 218°-220° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.CN(C)CC(O)=O.I[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]([CH3:40])=[N:38][N:39]=2)=[CH:31][CH:30]=1>O1CCOCC1.[Cu](I)I>[CH3:40][C:37]1[O:36][C:35]([C:32]2[CH:31]=[CH:30][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:34][CH:33]=2)=[N:39][N:38]=1
Reactant: COC(=O)c1cc(O)cc(OC2CCN(C)C2=O)c1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(OC2CCN(C)C2=O)c1
Yield: 30.7 %

Procedure:
To a stirred mixture of Methyl 3-hydroxy-5-(1-methyl-2-oxopyrrolidin-3-yloxy)benzoate (15 g) (Intermediate 3), N,N-dimethylglycine hydrochloride (2.3 g), copper (II) iodide (1 g) in dry 1,4-dioxane was added 2-(4-iodophenyl)-5-methyl-1,3,4-oxadiazole (15.4 g) (Intermediate 4) under nitrogen. The reaction mixture was refluxed for 24 h. The reaction mixture was cooled, quenched with water and extracted with DCM. Combined organic washings were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to get the crude product. The crude product was purified by column chromatography using silica gel as stationary phase and ethyl acetate: petroleum ether (9:1) as mobile phase to give the product (7 g) as thick liquid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][NH:25][C:26]([N:28]([CH3:30])[NH2:29])=[O:27]>>[CH3:24][NH:25][C:26]([N:28]([CH3:30])/[N:29]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])=[O:27]
Reactant: CNC(=O)N(C)N
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: CNC(=O)N(C)/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and N,1-dimethyl-hydrazinecarboxamide. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 8.89 (m, 1H), 8.36 (dd, 1H), 8.03 (s, 1H), 8.00 (d, 1H), 7.53 (dd, 1H), 7.19 (m, 1H), 6.21 (s, 2H), 3.31 (s, 3H), 2.72 (d, 3H), 2.49 (d, 3H). LCMS (method B): [MH]+=390, tR=1.99 min.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:20]=1[CH3:31])(=[O:18])=[O:17])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8].[OH-].[Na+].Cl>C1COCC1>[Cl:14][C:11]1[S:10][C:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:20]=2[CH3:31])(=[O:18])=[O:17])[C:3]([OH:32])=[O:2])=[O:8])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NS(=O)(=O)c1cccc(-c2cccnc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Intermediate 77 (589 mg, 1.19 mmol) was dissolved in 20 ml THF and sodium hydroxide (1N aq solution) (2.38 ml, 2.38 mmol) was added. After stirring at RT for 2 h, HCl 1 N (2 ml) was added, solvents were evaporated and DCM was added. The organic layer was dried with Na2SO4, filtered and evaporated to dryness. The solid was triturated with diisopropyl ether and filtrated. 550 mg (yield: 96%) of crude product were obtained and used without further purification in the next step.
Reaction SMILES: C([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[CH:22]4)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])(C)(C)C.C(N)CN>CN(C=O)C.O>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[C:14]2[N:15]=[C:16]3[C:8]([C:6]([NH2:5])=[O:7])=[CH:9][NH:10][C:11]3=[N:12][CH:13]=2)[CH:22]=[CH:23]1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc4cc[nH]c34)nc12
Solvent: CN(C)C=O
Solvent: NCCN
Solvent: O
Product: NC(=O)c1c[nH]c2ncc(-c3cccc4cc[nH]c34)nc12
Temperature: 60 °C
Reaction time: 72 h
Yield: 43.5 %

Procedure:
To a stirred solution of N-tert-butyl-2-(1H-indol-7-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (54 mg, 116 μmol) in DMF (3 mL) was added ethylenediamine (350 mg, 393 μL, 5.82 mmol) and the mixture heated at 60° C. After 72 h, the reaction mixture was cooled, diluted with water, and extracted into ethyl acetate. The organic phases were combined and washed with water and brine then dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with ether, then water, diluted with dichloromethane, and finally the solvents removed in vacuo to give N-tert-butyl-2-(2-(1H-indol-7-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (14 mg). MS (M+H)+=334.1; 1H NMR (DMSO-d6) δ: 12.83 (br. s., 1H), 11.46 (br. s., 1H), 9.01 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.52 (br. s., 1H), 7.30 (t, J=7.5 Hz, 1H), 6.69 (br. s., 1H), 1.55 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (301 mg) in DMF (5 mL) was added sodium hydride (67 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added 2-bromo-acetophenone (273 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an off-white solid.