Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[N:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[N:15]1[CH:14]=[CH:13][C:18]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH2:1])=[CH:4][CH:5]=2)=[CH:17][N:16]=1
Reactant: Brc1ccnnc1
Reactant: NCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: NCc1ccc(-c2ccnnc2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a sealed tube was added 4-(aminomethyl)phenylboronic acid 1-1 (1.87 g, 10 mmol), 4-bromopyridazine 1-2 (1.58 g, 10 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), saturated Na2CO3 (15 mL), ethanol (15 mL) and toluene (45 mL). The reaction was heated to 110° C. and stirred for 2 hours. The reaction was cooled down to room temperature. The solvent was removed by rotary evaporation. The residue was dissolved in 10% methanol in DCM. The salt was removed by filtration. The filtrate was dried. The crude product was purified by silica-gel flash chromatography, eluted with 10% methanol in DCM to give (4-(pyridazin-4-yl)phenyl)methanamine 1-3 as off-white solid. MS m/z 186.2 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:40])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])=[CH:31][CH:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][C:10]1([CH3:40])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CN(C)C(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cc1
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)cc1
Yield: 55 %

Procedure:
A solution of the compound (318 mg, 0.55 mmol) obtained in Example 6-1) and 4 M hydrochloric acid (1,4-dioxane solution, 0.69 mL) in methanol (2 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 30:70, gradient) to obtain the title compound (140 mg, 55%) as a colorless solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[S:19][CH:18]=[N:17][CH:16]=3)[N:14]=1)[N:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:20]([N:11]1[C:12]2[C:7](=[C:6]([OH:34])[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]=2[C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cncs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 40.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-thiazol-5-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (61 mg, 0.13 mmol), β-alanine (695 mg, 7.8 mmol) and NaOMe solution (11.7 mL, 5.9 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 28 mg of the title compound. MS: (+) m/z 527.33 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(NC(=O)c3ccccc3)sc2Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a 100 ml three-necked flask were added 0.50 g (1.69 mmol) 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1, 1.42 g (10.12 mmol) triethylamine and 40 ml ethyl acetate, and then added dropwise 0.48 g (3.38 mmol) benzoyl chloride dissolved in 10 ml ethyl acetate. The resulting mixture was magnetically stirred overnight at room temperature, filtrated, washed with ethyl acetate, the filtrate was washed with 1N aqueous sodium hydroxide solution, then washed with water until neutrality, dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure to give a crude product, which was subjected to a silica gel column chromatography eluted with petroleum ether/ethyl acetate (5:1) to obtain a 0.39 g product as a white solid in a yield of 57.4%, mp: 146-147 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.88 (3H, s, OCH3), 4.20 (2H, s, CH2), 7.01 (2H, d, J=8.72 Hz, ArH), 7.31 (2H, d, J=8.72 Hz, ArH), 7.42˜7.65 (7H, m, 6ArH+CONH), 8.09 (2H, d, J=7.28 Hz, ArH), 8.17 (2H, d, J=7.28 Hz, ArH); EI-MS m/e (%): 400.0 (M+, 94), 104.9 (100); HREI-MS Calcd. for C24H20N2O2S: 400.1245. found: 400.1235.
Reaction SMILES: I[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:37])[C:35]#[CH:36])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.ClCCl.CO.N>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:37])[C:35]#[C:36][C:2]3[CH:19]=[CH:18][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Ic1ccc(CN2CCC(N3CCCC3)CC2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(CN2CCC(N3CCCC3)CC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)-4-pyrrolidin-1-ylpiperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 15 mg (7% of theory); melting point: 191° C.-192° C.; C31H32ClN3O (M=498.07); calc.: molecular ion peak (M+H)+: 498/500; found: molecular ion peak (M+H)+: 498/500; Rf value: 0.45 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#N.CC(C[AlH]CC(C)C)C.ClCCl.[O:33]1CCCC1>>[CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)=[O:33]
Reactant: Cc1c(C#N)cccc1NC(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1c(C=O)cccc1NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
To a solution of benzyl 3-cyano-2-methylphenylcarbamate (6.41 g, 24.07 mmol) in tetrahydrofuran (250 mL) at −78° C. was added DIBAL-H in dichloromethane (96 mL, 96 mmol) over 1 hr. The mixture was stirred at −78° C. for 45 min and then at room temperature for 5 hr. It was poured into ice cold water (300 mL) and the resulting mixture was stirred at room temperature for 30 min. The mixture was filtered through CELITE®, and the filtrate was concentrated to remove most of the THF. The remaining aqueous solution was extracted with ethyl acetate (4×150 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (5.65 g, 20.98 mmol, 87% yield) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12]([O:16][CH3:17])[C:13]([OH:15])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:13](=[O:15])[CH:12]([C:3]2[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:16][CH3:17])=[CH:22][CH:21]=1)#[N:18]
Reactant: COc1cc(F)c(C(OC)C(=O)O)cc1OC
Reactant: N#Cc1ccc(CN)cc1
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1OC

Procedure:
(RS)-(2-Fluoro-4,5-dimethoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4,5-dimethoxy-phenyl)-2-methoxy-acetamide. Red foam. MS 359.2 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:16])[C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH3:17][Mg]Cl.O>C(Cl)Cl.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH3:17])=[N:6][CH:7]=1
Reactant: CC(C)(C)S(=O)/N=C/c1ncc(Br)cc1F
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-[(1E)-(5-bromo-3-fluoropyridin-2-yl)methylidene]-2-methyl-propane-2-sulfinamide (18.63 g, 60.65 mmol) in CH2Cl2 (375 mL) was cooled to −50° C. under N2. Methylmagnesium chloride (3M in THF, 30.32 mL, 90.97 mmol) was added dropwise, the reaction was stirred for 1 h. Additional methylmagnesium chloride (5.0 mL, 15.0 mmol) was added after 30 minutes to drive the reaction to completion. Water (200 mL) and brine (200 mL) were added, and the reaction allowed to warm to room temperature. The aqueous layer was extracted 4× with CH2Cl2, and the combined organics were dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 10–40% ethyl acetate in hexanes to provide N-[(1R)-1-(5-bromo-3-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 325.0 for M+H+(81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH3:13]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:13])=[O:6]
Reactant: Cc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: CO
Product: COC(=O)c1cc(Cl)c(C)c(Cl)c1

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 1), except that 3,5-dichloro-4-methylbenzoic acid (Japanese Unexamined Patent Publication (Kokai) No. 6-192196) was used and methanol was used as the solvent, and that the crude product was purified by silica gel column chromatography.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1[S:46](Cl)(=[O:48])=[O:47]>[Pd]>[CH2:26]([O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:46]([C:37]2[CH:38]=[CH:39][C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:36]=2)(=[O:48])=[O:47])[CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:21][CH:20]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc3ccccc3c2)cc1
Yield: 62 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (500 mg) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 2-naphthalenesulfonyl chloride (463 mg) to obtain (RS)-N-(4-(ethoxycarbonyl-methyl)phenyl)-2-(2-naphthalenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (345.7 mg).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:10][C@H:11]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[NH:1]([C:2]([NH:10][C@H:11]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using isocyanatobenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 499.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:13]1CCC[CH2:14]1>>[O:13]=[C:14]1[NH:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[NH:1]1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(N)c1N
Product: COC(=O)c1cccc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
To a suspension of methyl 2,3-diaminobenzoate (32.9 g, 198 mmol) in tetrahydrofuran (300 mL) was added N,N′-carbonyldiimidazole (33.7 g, 208 mmol), and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated in vacuo, and the residual solid was suspended in ethyl acetate (110 mL) and stirred at 80° C. After 30 min, the mixture was stirred at room temperature for 1 hr, and the resulting solid was collected by filtration and washed with ethyl acetate to give the title compound (35.6 g, 185 mmol, 94%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH2:26])=[N:22]1>>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([NH:26][C:23]2[N:24]=[CH:25][N:21]([CH2:20][C:19]3[CH:27]=[C:28]([F:31])[C:29]([F:30])=[C:17]([F:16])[CH:18]=3)[N:22]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: Nc1ncn(Cc2cc(F)c(F)c(F)c2)n1
Product: COc1cc(Nc2ncn(Cc3cc(F)c(F)c(F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 1b) starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352) and 1-(3,4,5-trifluoro-benzyl)-1H-[1,2,4]triazol-3-ylamine from example 17a). The title compound was obtained as a colorless foam (Yield=49%). MS ISP (m/e): 415.2 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)=[N:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([C:29]4[O:30][C:26]([CH3:25])=[N:27][N:28]=4)=[CH:37][CH:36]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Cc1nnc(-c2ccc(N)cc2)o1
Product: CCC(C(=O)Nc1ccc(-c2nnc(C)o2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.29 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 76 mg (0.43 mmol, 1.5 eq.) of 4-(5-methyl-1,3,4-oxadiazol-2-yl)aniline were reacted according to General Method 7. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 1-10% mixtures). Yield: 144 mg (99% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]=O>OS(O)(=O)=O>[CH3:12][NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1]
Reactant: C=O
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Agent: O=S(=O)(O)O
Product: CNc1ccc([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
15.2 g of 2-methyl-4-nitroaniline were dissolved in 150 ml conc. H2SO4 and heated in a boiling water bath. To this solution 24 g. of paraformaldehyde were added with stirring over a period of 10 minutes. The mixture was stirred an additional hour and was then cooled and poured over 300 g of ice. The precipitate was recrystallized from ethanol water to give 10.1 g of N,2-dimethyl-4-nitroaniline (m.p. 133°-136°C).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[CH2:15])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:15][O:25]1)=[O:16])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCc1ccccc1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCc2ccccc2)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
10 g of 5-phenyl-2-methylenevaleric acid ethyl ester and 18.3 g of m-chloroperbenzoic acid (85% pure) are boiled under reflux in 180 ml of methylene chloride for 40 hours. The mixture is allowed to cool; the m-chloroperbenzoic acid (which has separated out) is filtered off; the filtrate is concentrated; the residue is taken up in 40 ml of acetone; 20 ml of a saturated sodium carbonate solution are added, and the mixture is stirred at 0° C. for 1 hour. It is then diluted with 100 ml of water and extracted 3 times with 50 ml of methylene chloride each time; the organic phase is concentrated, and the residue is distilled. 8.3 g of the liquid title compound (b.p. 115° under 0.03 mm Hg) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.Br[C:24]1[N:28]2[N:29]=[CH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:27]2=[N:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:24]2[N:28]3[N:29]=[CH:30][C:31]([C:33]([F:34])([F:35])[F:36])=[N:32][C:27]3=[N:26][CH:25]=2)=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-c1cccnc1
Yield: 44.2 %

Procedure:
3-[2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine (151 mg, 0.51 mmol) was coupled to 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.09 g, 0.34 mmol) as described in Example 37, step e, using 2 M Na2CO3 (0.51 ml) and tetrakis(triphenylphosphine)palladium(0) (0.019 g) in 1,2-dimethoxyethane (2 ml). The crude residue was purified by flash chromatography (silica gel, 2.5% MeOH/CH2Cl2) and triturated with Et2O to yield the title compound (54 mg, 45%): 1H NMR (400 MHz, CDCl3) δ 7.38-7.47 (2H, m), 7.94-7.97 (1H, m), 8.08-8.12 (1H, m), 8.24 (1H, dd, J 7.0, 2.3 Hz), 8.62 (1H, s), 8.69 (1H, dd, J 4.8, 1.6 Hz), 8.82 (1H, s), 8.88 (1H, s); MS (ES+) m/z 359, 360.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=O)[C:5]2=[N:4][CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[CH:32]1([NH:37]C2CCCC2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([NH:37][C:14]2[C:5]3[N:6]([C:2]([CH3:1])=[CH:3][N:4]=3)[C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1cnc2c(=O)[nH]c3ccccc3n12
Reactant: C1CCC(NC2CCCC2)C1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: Cc1cnc2c(NC3CCCC3)nc3ccccc3n12
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 3.5 g of 1-methylimidazo[1,2-a] quinoxalin-4(5H)-one (example 2), 13 ml of hexamethyl disilazane, 0.5 g of ammonium sulphate and 8.7 ml dicyclopentylamine is stirred at 120° C. in a Dean-Stark apparatus for 24 h. After concentrating the resulting mixture under vacuum, the residue is added with water and extracted with ethyl acetate. The organic extracts are then washed with water and saturated NaCl, dried and evaporated, thereby obtaining 1.5 g of a raw product that is subsequently chromatographed on SiO2 (eluent: CH2Cl2 /AcOEt 97:3). By recrystallizing from ethyl acetate, there is obtained 4-cyclopentylamino-1-methyl imidazo [1,2-a]quinoxaline. m.p. (DSC)=167.3° C. (onset); IR (KBr): 3294, 2948, 1544 cm-1 ; 1H-NMR (CDCl3): δ8.0 (1H,dd), 7.4÷7.05 (3H,m), 6.0 (1H,d), 4.6 (1H,m), 2.8 (3H,s), 2.3÷2.05 (4H,m), 2.0÷1.4 (4H,m); UV (EtOH): λmax =225, 243, 272 301, 316, 329 nm. Elementary analysis for C16H16N4 (m.w. 266.35): calcd. C 72.15, H 6.81, N 21.03%; found C 71.86, H 6.81, N 20.79%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1.[I:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[C:11]([I:12])=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1
Reactant: Clc1csc(-c2cc[nH]n2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1csc(-c2n[nH]cc2I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
3-(4-chloro-2-thienyl)-1H-pyrazole (24.0 mmol) was dissolved in 50 mL N,N-dimethylformamide under argon atmosphere. N-Iodosuccinimide (25.1 mmol) was added in small portions. The reaction mixture was stirred at room temperature overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed thoroughly with water and dried in vacuum to afford 6.80 g of 3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (91% yield) that was used without further purification.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](O)=[O:27])(=[O:19])=[O:18])=[O:15])[N:6]=1.Cl>CCOCC.O1CCCC1>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[O:27])[CH3:1])(=[O:19])=[O:18])=[O:15])[N:8]=1
Reactant: [Li]C
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)=O)n1
Reaction time: 4 h

Procedure:
A methyllithium solution in ether (1.4M, 40 ml) was added to a solution of 1.0 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-carboxybenzenesulfonamide in 50 ml of dry tetrahydrofuran at room temperature. The resulting yellow slurry was stirred for 4 hours and the dilute hydrochloric acid was added. The mixture was then extracted with methylene chloride. The organic extracts were washed, dried, and evaporated in vacuo to dryness. The crude product was purified by preparative TLC, eluted with ethyl acetate/hexane (1:1), m.p. 126°-128° C.