Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[N:34]1[CH2:43][CH2:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[O:42]=[C:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33](=[O:32])[N:34]1[CH2:43][CH2:44][S:45]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:47])=[O:46]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCN4C(=O)c5ccccc5C4=O)CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (84.8 mg, 0.265 mmol) in CH2Cl2 at 0° C., triethylamine (0.15 mL, 1.06 mmol) and 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonyl chloride (87.03 mg, 0.32 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between CH2Cl2 and water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic phase washed with brine, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give the crude product (90 mg, 61%).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 28.5 g of 2-phenoxyaniline and 25.8 ml of triethylamine in 250 ml of methylene chloride was added dropwise 11.5 ml of acetyl chloride under ice-cooling. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate. The extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:4) to give 33.7 g of N-acetyl-2-phenoxyaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](Cl)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([O-:17])=[O:16].N1C=CC=CC=1>CC(C)=O>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:10](=[O:11])[CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(Cl)C=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(C=Cc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 95.5 %

Procedure:
193.2 g (1 mole) of 4-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and was poured into hexane and then the precipitated solid was separated by filtration and dried. 210 g of 4-nitrocinnamoyl chloride was yielded. 64.5 g (0.3 mole) of 4-nitrocinnamoyl chloride and 300 g of acetone were placed in a reaction vessel. The reaction mixtures were heated at 50° C. with stirring under a nitrogen current. 41.73 g (0.3 mole) of 4-nitrophenol, 60 g of pyridine, and 300 g of acetone were added dropwise to the above reaction vessel using a dropping funnel. After the completion of the addition, the reaction mixtures were refluxed with stirring under a nitrogen current for 2 hours. After the reaction, a precipitate was separated by filtration, and the filtrated solid was washed by water and dried. 90 g of light yellow colored needle-like crystals ((4-nitrophenyl)-4-cinnamate)was yielded.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: CCc1cc2c(NCc3ccccc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: Cc1cccc2c1nc([C@@H](C)N)n2-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2c1nc([C@@H](C)Nc1ncnc3[nH]cnc13)n2-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (R)-1-(4-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 2 (100 mg, 0.398 mmol), 6-chloro-9H-purine (68 mg, 0.438 mmol) and DIPEA (83 μL, 0.478 mmol) in n-butanol (1 mL) was stirred in a sealed vial at 100° C. for 20 h. After cooling to RT, the mixture was partitioned between DCM and water. The organic layer was then separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then sonicated in cyclohexane affording 109 as a brown solid (62 mg, 42%) LCMS: RT 3.17 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.18-8.06 (2H, m), 7.95-7.86 (1H, m), 7.66-7.45 (5H, m), 7.11-7.00 (2H, m), 6.86 (1H, d, J=7.81 Hz), 5.49 (1H, br), 2.56 (3H, s), 1.57 (3H, d, J=6.84 Hz)
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[Si](C)(C)C.C([Li])CCC.[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][CH2:20][C:19](=O)[CH2:18]1>O1CCCC1.C(OCC)C>[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][CH2:20][C:19](=[C:2]2[S:3][CH2:4][CH2:5][CH2:6][S:1]2)[CH2:18]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CCCC(=C2SCCCS2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1,3-dithian-2-yl)trimethylsilane (5.0 g) in tetrahydrofuran at −78° C. was added n-butyllithium (1.6M, 16.24 mL). After stirring for 30 minutes, 3,3-dimethylcyclohexanone (3.3 g) was added as a solution in tetrahydrofuran and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with diethyl ether (100 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 0.13% to 2.5% ether/hexanes gave the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12]C(OCC2C=CC=CC=2)=O)[C:9]([NH2:11])=[O:10])=[CH:3][CH:2]=1.[BrH:23]>C(O)(=O)C.CCOCC>[BrH:23].[NH2:12][C@H:8]([C:9]([NH2:11])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 0.08 h

Procedure:
6.55 g (22 mmoles) of Z--Phe--NH2, prepared as described in Example 1, Step 1, are dissolved in 13 ml of acetic acid, and 30 ml of 5 n hydrogen bromide in acetic acid are added to the solution. After 5 minutes of stirring a thick precipitate separates. The suspension is allowed to stand for one hour, thereafter it is diluted with dry ether and filtered. The crude product is dissolved in 240 ml of ethanol, the solution is decolorized, and the product is precipitated with 740 ml of ether. 4.90 g (91 %) of H--Phe--NH2.HBr are obtained; the white, crystalline substance is chromatographically uniform. (Two spots appear on the thin layer chromatogram: one of them belongs to the product and the other to hydrogen bromide). M.P.: 249-250° C., Rf8 : 0.50; Rf8,HBr: 0.35.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1.[CH2:14](N(CC)CC)[CH3:15].C(#N)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH:14]([C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1)=[CH2:15]
Reactant: CC(C)C(=O)Nc1ncc(Br)cn1
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: CC#N
Product: C=Cc1cnc(NC(=O)C(C)C)nc1
Temperature: 80 °C

Procedure:
A glass-lined pressure vessel was charged with 4.85 g of 5-bromo-2-(isobutyramido)pyrimidine, 5.0 ml of triethylamine, 15 ml of acetonitrile, 245 mg of tris(O-tolyl)phosphine, and 55 mg of palladium acetate. The vessel was placed under an ethylene atmosphere at 200 psi and heated at 80° C. for 18 hours in a rocking autoclave. The vessel was cooled and then vented. The residue was treated with 50 ml of ether and the resulting mixture filtered. The solid was further washed with ether (2×25 ml). The organic filtrate was concentrated and then chromatographed on silica gel. Elution with methylene chloride:methanol (95:5) afforded 2.99 g of product, mp 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:8][CH2:7][C:5]=2[N:6]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:8][CH2:7][C:5]=2[N:6]=1)(=[O:27])=[O:26]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CCC(=O)NC1CCc2nc(N)sc2C1
Product: CCC(=O)NC1CCc2nc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)sc2C1

Procedure:
The title compound was prepared from N-(2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide (47 mg, 0.21 mmol) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (20.3 mg) with purity >90%. MS (pos) m/z 448.1, 450.1.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C=NC1CCCCC1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)NC1CCCCC1
Yield: 66.7 %

Procedure:
Using the general method of Example 47, cyclohexyl isocyanate (61 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.14 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-cyclohexylurea as a white solid. Analysis: Calculated for C24H35N7O : %C, 65.88; %H, 8.06; %N, 22.41. 1H NMR (300 MHz, CDCl3) δ8.60 (dd, J=4.4, 1.4 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.44 (dd, J=8.5, 4.4 Hz, 1H), 5.55 (br s, 2H), 4.92 (t, J=5.8 Hz, 1H), 4.82 (apparent t, J=7.8 Hz, 2H), 4.13 (d, J=8.6 Hz, 1H), 3.48 (m, 1H), 3.35 (apparent q, J=6.4 Hz, 2H), 2.93 (apparent t, J=7.8 Hz, 2H), 1.80-2.05 (m, 4H), 1.45-1.75 (m, 6H), 1.2-1.4 (m 2H), 1.0-1.2 (m, 2H), 1.03 (t, 7.4 Hz, 3H); HRMS (EI) calcd for C24H35N7O (M+) 437.2903, found 437.2903.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:6][C:7]([C:9]1[S:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:8])[CH3:2].[CH3:23]CN(C(C)C)C(C)C.COS(OC)(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:6][C:7]([C:9]1[S:10][C:11]([NH:14][CH3:23])=[CH:12][CH:13]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)s1)C(=O)OCC
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC)s1)C(=O)OCC
Temperature: 60 °C
Reaction time: 42 h
Yield: 15.5 %

Procedure:
A solution containing N-(5-aminothiophene-2-carbonyl)-L-glutamic acid diethyl ester (III-3 where R2 is H) (1.78 g, 5.42 mmol), (i-Pr)2NEt (1.0 mL, 0.74 g, 5.7 mmol), and Me2SO4 (0.59 mL, 0.79 g, 6.2 mmol) in 20 mL N,N-dimethylformamide (DMF) was warmed at 60° C. for 2 hours, then left at 20°-25° C. for 42 hours. The solution was evaporated in vacuo (1 mm, bath 25°-30° C.), and the residue was dissolved in EtOAc-cyclohexane (1:1 by volume) for application to a silica gel column. Elution by the same solvent system afforded fractions homogeneous by TLC of the product. Fractions were combined and evaporated to afford 16% yield (287 mg) of N-[5-(methylamino)thiophene-2-carbonyl]-L-glutamic acid diethyl ester (III-3) R2 =CH3 as an amber oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.Br[CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18]1)=[O:12])=[CH:5]2
Reactant: O=C(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1cc2cc(Cl)ccc2[nH]1)N1CCN(CCO)CC1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
The product from Step B (1.0 g) was dissolved in CH3CN (10 mL) and treated with 2-bromoethanol (0.5 g) and then K2CO3 (0.8 g). The resulting mixture was heated at 60° C. overnight. The mixture was cooled to ambient temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give the title compound (0.5 g). 1H NMR (400 MHz, CDCl3): δ 10.09 (br s, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.23 (dd, J=2.0, 8.8 Hz, 1H), 6.69 (d, J=0.8 Hz, 1H), 3.95 (br m, 3H), 3.72-3.69 (m, 2H), 2.67-2.64 (m, 4H), 2.52 (br s, 3H). MS (electrospray): exact mass calculated for C15H18ClN3O2, 307.78; m/z found, 308.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]#[N:22].[OH:23]S(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]([NH2:22])=[O:23]
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C#N)c21
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Temperature: 105 °C
Yield: 66 %

Procedure:
A mixture of 5-amino-3-methyl-2-(2,6-dichlorophenylamino)-3H-benzimidazole-4-carbonitrile (Example 6) (1 g, 3 mmol) and conc. H2SO4 (8 mL) was warmed to 100-110° C. for 1 h and monitored by TLC for the disappearance of starting material. The mixture was cooled and poured onto a mixture of crushed ice, sodium carbonate, and ether. The precipitate was filtered, washed with water, dissolved in MeOH-methylene chloride, treated with carbon (decolorizing charcoal), dried (MgSO4), filtered, and concentrated in vacuo. The aqueous filtrate was washed with EtOAc (3×30 mL). The combined organic layers were washed with brine (25 mL), which was then extracted with EtOAc (20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to yield 190 mg of a crude product. This was combined with the solid product and triturated with ether-methylene chloride to afford 5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzoimidazole-4-carboxylic acid amide (700 mg, 66%). The filtrate was chromatographed on silica gel to afford an additional 128 mg (12%) of product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][N:8]=1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH2:26])[CH:21]=[CH:20]2.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH:26][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:12][CH:11]=1)=[O:14])[CH:21]=[CH:20]2
Reactant: O=C(Cl)c1cnc(-c2ccccn2)nc1
Reactant: Nn1ccc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1 mmol) and K2CO3 (2 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt, and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (65 mg, 20%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, CD3OD): δ 6.56 (m, H) 7.04 (m, H), 7.28-7.79 (m, 3H), 8.04 (m, H), 8.49 (m, H), 8.81 (m, H), 9.48 (s, 2H), 12.22 (s, N—H). IC50=18 nM.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:24]([O:26]C)=[O:25])[C:14]4=[O:32])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:24]([OH:26])=[O:25])[C:14]4=[O:32])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCN(CC5CC5)CC4)cc3c2=O)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(CC4CC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (C) in the portion of Example 1 which is concerned with the preparation of starting material methyl 3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate was hydrolysed with 1N NaOH to give 3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid; NMR Spectrum: (DMSOd6) 0.42 (m, 2H), 0.68 (m, 2H), 1.15 (m, 1H), 2.16 (s, 3H), 3.07 (s, broad, 2H), 3.18 (s, 4H), 3.64 (s, broad, 2H), 4.02 (s, broad, 2H), 7.59 (m, 3H), 7.70 (m, 2H), 7.92 (s, 1H), 8.00 (d, 1H), 8.15 (s, 1H), 10.52 (s, broad, 1H), 13.06 (s, broad, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[CH:31]=[CH:30][C:15]2[C:16]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])=[N:17][O:18][C:14]=2[CH:13]=1>C(Cl)Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[C:16]1[C:15]2[CH:30]=[CH:31][C:12]([NH:11][CH:8]=[O:10])=[CH:13][C:14]=2[O:18][N:17]=1
Reactant: O=CO
Reactant: Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CNc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Acetic anhydride (2.63 mL, 27.9 mmol) was added to formic acid (1.04 mL, 27.9 mmol) at 0° C. The mixture was heated to 60° C. for 30 minutes. After that 2-(6-aminobenzo[d]isoxazol-3-yl)isoindoline-1,3-dione 1-4 (390 mg, 1.39 mmol) dissolved in CH2Cl2 (10 mL) was added at 0° C. The mixture was stirred for 1 h at room temperature. The mixture was concentrated and the residue was triturated with CH2Cl2/hexane (1:1) to give 300 mg (70%) of 1-5 as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) (rotamer ratio: s-cis/s-trans=3:1) δ 10.75 (0.75H, br s), 10.58 (0.25H, br d, J=11.3 Hz), 9.04 (0.25H, br d, J=11.3 Hz), 8.43 (0.75H, br s), 8.29 (0.75H, br s), 8.07 (2H, m), 7.99 (2H, m), 7.81 (1H, d, J=8.4 Hz), 7.80 (0.25H, br s), 7.43 (0.75H, d, J=8.4 Hz), 7.28 (0.25H, br d, J=8.4 Hz); ESI-MS m/z 308 [C16H9N3O4+H]+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH2:25]([O:27][CH2:28][C:29](Cl)=[O:30])[CH3:26].[Cl-].[Na+]>C1COCC1>[CH2:25]([O:27][CH2:28][C:29]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:30])[CH3:26]
Reactant: CCOCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCC(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
36.7 g (207 mmol) of (S)-4-benzyloxazolidin-2-one in 800 ml of THF are introduced into a round-bottomed flask under a stream of nitrogen. The reaction medium is cooled to −78° C. and 83 ml (207 mmol) of 2.5M n-butyllithium hexane are added dropwise. 30 minutes later, 25.4 g (207 mmol) of ethoxyacetyl chloride obtained in Example 81(b) are added, at −78° C. The reaction medium is stirred for 24 hours and then poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. After purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (6/4), 30.6 g (56%) of the expected product are obtained in the form of an orange-colored oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(c2ccccc2)CN1S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCc2cc(S(=O)(=O)N3CC(c4ccccc4)NC3=O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-4,5-dihydro-2-imidazolone (0.20 g, 0.58 mmol) prepared in Preparation 5 was dissolved in 12 m of dichloromethane. Pyridine (0.1 m, 0.58 mmol) and benzoyl chloride (0.1 g, 0.58 mmol) were added dropwise one after another at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 2 hours and further stirred at room temperature for 3 hours. The reaction mixture was diluted with 20 m of dichloromethane, washed twice with 10 m of water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=2/1, v/v) to afford the title compound.