Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1ncc(Br)c(Nc2ccccc2)n1

Procedure:
In analogy to compound 1.1, a solution of 0.3 g (1.32 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 5 ml of acetonitrile is reacted with 0.13 ml (1.42 mmol) of aniline in the presence of 0.22 ml (1.6 mmol) of triethylamine. Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%) results in 0.289 g (77% of theory) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](SC)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:31]1C=CC=C(C(OO)=O)C=1.[S:41](=[O:44])(O)[O-:42].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11]([S:41]([CH3:31])(=[O:44])=[O:42])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])O
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cc(Cl)cc(Cl)c2)n1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1.41 g (3.15 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 20 ml of dichloromethane. 1.09 g (6.30 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 12 hours. 1 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[F:31][C:32]1[CH:33]=C(CCN)[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:35]=[CH:36][CH:37]=1
Reactant: NCCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCc1cccc(F)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(3-fluorophenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 381 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (1H, br. s.) 10.38 (1H, s) 8.22 (1H, t, J=5.66 Hz) 8.05 (1H, d, J=6.05 Hz) 7.82 (1H, d, J=5.47 Hz) 7.42 (1H, d, J=5.27 Hz) 7.37 (1H, d, J=3.51 Hz) 7.26 (1H, td, J=8.00, 6.44 Hz) 7.04 (2H, dd, J=8.00, 2.54 Hz) 6.98 (1H, td, J=8.88, 2.93 Hz) 6.77 (1H, d, J=6.05 Hz) 6.54 (1H, d, J=3.51 Hz) 3.42-3.51 (2H, m) 2.82 (2H, t, J=7.13 Hz)
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[CH:10]3[O:12][CH:11]3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].[H-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C@@H:10]([OH:12])[C@H:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Reaction time: 22 h

Procedure:
6-Acetyl-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran (0.33 g, prepared as described in Example 1 of U.K. Pat. No. 1,511,187), and 2-pyrrolidone (0.15 g), were stirred in dimethylsulphoxide (25 ml) under nitrogen at room temperature. Sodium hydride (0.5 g, 80%) was added during 2 mins and the reaction stirred for a further 22 hours. Addition of water, extraction with ethyl acetate, drying of the organic layer with magnesium sulphate, filtration, evaporation and recrystallisation from ethyl acetate gave the title compound (0.04 g) of m.p. 218°-219°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][CH:10]=[CH:11][CH:12]=1>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][C@H:8]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1CNc1cccnc1-c1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COc1ccccc1CN[C@H]1CCCN[C@H]1c1ccccc1
Reaction time: 2.5 h
Yield: 58.8 %

Procedure:
3-(2-Methoxybenzylamino)-2-phenylpyridine (25 mg) was dissolved in 3 mL of acetic acid. To this solution was added 3 mg of platinum oxide and the mixture was placed on a Parr apparatus (35-40 p.s.i. H2) for ca. 2.5 hours. During this period, three additional 2.5 mg portions of catalyst were added to the system. The mixture was filtered through Celite® which had been rinsed well with ethanol and the filtrate was concentrated with a rotary evaporator. The residue was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, the layers were separated and the aqueous phase was extracted with three portions of CH2Cl2. The combined organic fractions were dried (Na2SO4) and concentrated to afford 15 mg of the title compound contaminated with a trace of 3-(2-methoxy-benzylamino)-2-phenylpyridine and a trace of material in which the 2-phenyl substituent had been reduced to a cyclohexyl moiety. The material prepared in this manner has spectral properties identical to those of the free base of the title compound of Example 1C.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)([Cl:15])=O>ClCCl>[ClH:15].[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][Cl:15])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc2ccc(CO)cc2o1
Solvent: ClCCl
Product: Cl
Product: Nc1nc2ccc(CCl)cc2o1
Reaction time: 4.5 h

Procedure:
The mixture of 2-amino-6-hydroxymethylbenzoxazole (0.5 g) and thionyl chloride (0.66 ml) in dichloromethane (5 ml) was stirred for 4.5 hours under ice-cooling. The isolated precipitate was collected by filtration, washed with diethyl ether and dried to give 2-amino-6-chloromethylbenzoxazole hydrochloride (0.57 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-hydroxy-ethyl)-phenol (50 g, 0.36 mol) in ethanol (400 ml) is added potassium carbonate (75 g, 0.54 mol, 1.5 eq) and benzyl bromide (47.2 ml, 0.39 mol, 1.1 eq), the reaction mixture is stirred at room temperature overnight. The reaction mixture is then filtered off through celite and concentrated under vacuum. 2-(4-Benzyloxy-phenyl)-ethanol is isolated after crystallization with diethyl ether.
Reaction SMILES: O[Li].O.C([C@@H]1COC(=O)N1[C:17](=[O:35])[C@@H:18]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])C1C=CC=CC=1.C[O:37]C1C=C(OC)C=CC=1C=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:23]([O:22][C:21]([NH:20][CH2:19][C@H:18]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:17]([OH:35])=[O:37])=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Agent: O=S([O-])[O-]
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 93.8 %

Procedure:
35% 11202 (0.240 mL, 2.91 mmol) was added to a solution of LiOH—H2O (0.0978 g, 2.33 mmol) in 2:1 THF:H2O (33 mL). The reaction mixture was stirred at room temperature for 35 minutes, and then cooled to 0° C. A solution containing a mixture of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (0.535 g, 1.17 mmol) and 2,4-dimethoxybenzaldehyde (0.194 g, 1.17 mmol) in THF (7 mL) was added dropwise by addition funnel. The ice bath was allowed to slowly warm, and the reaction mixture was stirred overnight. The reaction mixture was then cooled to 0° C., and 1M Na2SO3 (7 mL) was added. The mixture was stirred for 5 minutes, and then warmed to room temperature and stirred an additional 20 minutes. The reaction mixture was then transferred to a separatory funnel and washed with ether (3×). The aqueous layer was acidified with KHSO4(s), and the mixture was extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated to give (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 94.2% yield) as a white residue. LC/MS (APCI+) m/z 200 [M-BOC+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1COCC1>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of aniline (9.31 g, 100 mmol) and triethylamine (15.2 g, 150 mmol) in THF (150 mL) is cooled to −40° C. before chloroacetic acid chloride (11.3 g, 100 mmol) is slowly added in portions such that the temperature does not rise above 0° C. After completion of the addition, the brown suspension is stirred at rt for 1 h. The dark purple mixture is poured onto water (300 mL) and extracted twice with EA (300 mL). The organic extracts are washed with sat. aq. NaHCO3, 0.5 N aq. HCl, followed by water, and evaporated. The brown residue is suspended in diethyl ether, filtered off, washed with additional diethyl ether and dried under high vacuum to give 2-chloro-N-phenyl-acetamide. LC-MS: tR=0.75 min, [M+1]+=170, 1H NMR (CDCl3): δ 8.22 (s br, 1H), 7.56-7.51 (m, 2H), 7.40-7.24 (m, 2H), 7.20-7.14 (m, 1H), 4.20 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:16]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:17][N:18]([CH2:28][CH3:29])[C:19]=2[NH:20]C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11](OC)=[O:12])=[C:4]([CH3:36])[CH:3]=1.BrC1C=CC(C=O)=CC=1.C(N1C(N)=CC(C2C=CC=CN=2)=N1)C.C(O)(C(F)(F)F)=O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[NH:20][C:19]3[N:18]([CH2:28][CH3:29])[N:17]=[C:16]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:15]2=3)=[C:4]([CH3:36])[CH:3]=1
Reactant: CCn1nc(-c2ccccn2)c(C(CCC(=O)OC)c2ccc(Br)cc2C)c1NC(=O)OC(C)(C)C
Agent: CCn1nc(-c2ccccn2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCn1nc(-c2ccccn2)c2c1NC(=O)CCC2c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
A solution of methyl 4-(4-bromo-2-methylphenyl)-4-(5-((tert-butoxycarbonyl)amino)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)butanoate (0.072 g, 0.129 mmol, Prepared using W from 4-bromobenzaldehyde, X from 1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine, Y then Z) in DCM (3 mL) was treated with TFA (3 mL) and the reaction was stirred for about 20 min at rt. Solvents were removed in vacuo and the residue was taken up in toluene (5 mL) containing p-TSA (0.049 g, 0.26 mmol) and the reaction was heated at about 100° C. for about 3 h. The reaction was cooled to rt, diluted with EtOAc (5 mL) to solubilize the product and washed with sat. aq. NaHCO3 (5 mL), then water (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Crude product was further purified on silica gel (4 g) using a gradient of 60-90% EtOAc in heptane. Product fractions were combined and concentrated to solids and dried in the vacuum oven overnight to yield 4-(4-bromo-2-methylphenyl)-1-ethyl-3-(pyridin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]azepin-7(1H)-one as an off-white solid (0.037 g, 0.087 mmol, 67%); LC-MS (Table 1, Method g) Rt=2.31 min, m/z 425/427 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.37-8.30 (m, 1H), 7.84 (br. s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.58-7.48 (m, 1H), 7.14 (s, 1H), 7.06-6.94 (m, 2H), 6.61 (d, J=8.3 Hz, 1H), 5.30-5.20 (m, 1H), 4.20 (q, J=7.3 Hz, 2H), 2.74-2.66 (m, 2H), 2.47 (s, 3H), 2.41-2.30 (m, 1H), 1.94-1.83 (m, 1H), 1.50 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2].[Li+].[OH-].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate (750 mg, 0.0015 mol) was treated with 1 M of LiOH/H2O (1.6 mL) in MeOH (10 mL). The reaction was allowed to stirred at room temperature for 2 hours. The mixture was acidified by 10% citric acid aqueous solution was until PH=5, extracted with EtOAc twice, dried with MgSO4, and concentrated in vacuo. The crude was purified by Prep HPLC to provide 251. LC/MS (ESI+): m/z 462 (M+H). 1H NMR (500 MHz, DMSO) δ 8.44 (s, 1H), 8.36 (d, J=8.4, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.4, 1.7, 1H), 7.35 (d, J=1.7, 1H), 5.82 (dt, J=13.1, 6.6, 1H), 4.52 (s, 3H), 2.25 (s, 2H), 1.78 (s, 4H), 1.45 (t, J=13.9, 4H)
Reaction SMILES: Br.C(O[NH:7][CH:8]([CH3:20])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:19])(C)(C)C.C(N(CC)CC)C.[CH3:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C(Cl)Cl>[NH2:7][CH:8]([CH3:20])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([CH3:28])=[CH:30][CH:31]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(Cn1c(N)nc2ccccc21)NOC(C)(C)C
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2nc3ccccc3n2CC(C)N)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-tert-butoxyaminopropyl)-2-aminobenzimidazole hydrobromide (1.00 g, 2.70 mmol) and triethylamine (1.9 mL, 3.79 mmol) in CH2Cl2 (50 mL) was added 4-methylbenzoyl chloride (0.46 g, 29.73 mmol) at 0° C. This mixture was stirred at 0° C. for 1 h and at room temperature overnight. The volatiles were evaporated and the residue was purified by flash chromatography using ethyl acetate-hexane (1:1). The fractions collected were concentrated in vacuo and the residue was dissolved in trifluoroacetic acid (5 ml) and stirred overnight. The trifluoroacetic acid was evaporated and the residue was dissolved in ethyl acetate and washed with a saturated solution of bicarbonate. Ethyl acetate was evaporated and the residue was purified by flash chromatography using CH2Cl2-MeOH (9.5: 0.5). The oil recovered after evaporation of solvent was transformed to the hydrochloride salt. MS 308 (M+1). 1HNMR (DMSO): δ 1.3(d, 3H), 2.37 (s, CH3), 3.80 (m, 1H), 4.45 (m, 2H), 7.26 (m, 4H), 7.55 and 7.62 (2d, 2H), 8.15 (d, 2H), 11.61 (bs, NH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=1>>[ClH:1].[CH:17]([NH:16][C:14]1[N:13]([CH3:20])[C:12]2[CH:21]=[CH:22][C:9]([N:8]([CH3:23])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1)([CH3:19])[CH3:18]
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Product: CC(C)Nc1nc2cc(N(C)c3ccnc(Nc4ccc(OS(C)(=O)=O)cc4)n3)ccc2n1C
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (83 mg, 0.25 mmol) and methanesulfonic acid 4-amino-phenyl ester (47 mg, 0.25 mmol) as a white solid (45 mg, 35%). 1H NMR (300 MHz, d6-DMSO) δ 9.30 (s, 1H), 7.78-7.86 (m, 3H), 7.17-7.21 (m, 3H), 7.09 (d, J=1.5 Hz, 1H), 6.82 (dd, J=8.1 and 1.8 Hz, 1H), 6.51 (d, J=7.5 Hz, 1H), 5.67 (d, J=6.0 Hz, 1H), 4.05 (m, 1H), 3.52 (s, 3H), 3.43 (s, 3H), 3.31 (s, 3H), 1.24 (d, J=6.6 Hz, 6H) ppm. MS (ESI) m/z=482 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[F:34])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:35][CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:17]([O:35][CH3:36])[CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A suspension of 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline (318 mg, 0.64 mmol) in methylene chloride (5 ml) containing TFA (2.5 ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was partitioned between methylene chloride and water. The aqueous layer was adjusted to pH10-11. The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation to give 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (220 mg, 87%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:28]
Reactant: CCN
Reactant: CCOC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Product: CCNC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Yield: 61 %

Procedure:
As described for example 50, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using ethylamine instead of methylamine, to the title compound (87 mg, 61%) which was obtained as a white solid. MS: m/e=357.3 [M+H]+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:21]([CH2:22][C@@H:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)=[N:20][NH:19][C:18]4=[O:28])=[CH:13][CH:12]=3)=[CH:10][C:5]=2[CH:4]=[CH:3]1.C(N(CC)C(C)C)(C)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:21]([CH2:22][C@@H:23]5[CH2:27][CH2:26][N:25]([C:38](=[O:41])[CH2:39][CH3:40])[CH2:24]5)=[N:20][NH:19][C:18]4=[O:28])=[CH:13][CH:12]=3)=[CH:10][C:5]=2[CH:4]=[CH:3]1
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(-c2ccc3occc3c2)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 60.9 %

Procedure:
Under nitrogen, a mixture of 4-[4-(1-benzofuran-5-yl)phenyl]-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (116 mg, 0.292 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) in dichloromethane (1.3 mL) was stirred at room temperature for 2 min. The mixture was cooled to 0° C. and treated with propionyl chloride (0.026 mL, 0.292 mmol) dropwise by syringe. The mixture became a dark brown solution and the reaction was stirred at 0° C. for 90 min. The reaction was quenched with water (2 mL) and diluted with ethyl acetate (20 mL). The mixture was transferred to a separatory funnel, water (10 mL) was added and the layers were separated. The pH of the aqueous layer was tested by pH paper and found to be pH˜5-6. The aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a tan foamy solid. Purification of the residue by silica gel chromatography (Analogix IF280, SF10-4 g, 0-10% MeOH/EtOAc, 30 min) provided the title product as an ivory solid (74 mg, 61%). MS(ES)+ m/e 417.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][NH:15][CH3:16].[CH2:17]=O>C1(C)C=CC=CC=1.CCOCC>[C:1]([C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C
Reactant: C=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1c(CN(C)C)cc(C(C)(C)C)c(O)c1C

Procedure:
To 142.4 grams of 6-tert.-butyl-2,3-dimethylphenol dissolved in 270 ml of toluene was added 144.4 grams of a 25% aqueous solution of dimethylamine at about room temperature. 65.7 grams of 36.5% aqueous formaldehyde was then added over a ten minute period to the reaction mixture initially at 15°, the temperature rising to 30° at the end of the addition. The reaction mixture was then warmed to 40° for 3 hours and finally heated at reflux (85°) for two hours. The reaction was diluted with about 1 liter of ether and the aqueous layer spearated, the upper ether layer being washed three times with water. After drying over sodium sulfate, the organic phase was stripped to dryness at reduced pressures yielding 176.3 grams of crude product. The crude product was crystallized from heptane, yielding while crystals melting at 101° to 104°.