Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2([C:13]([CH3:16])([CH3:15])[CH3:14])C[O:11]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([OH:11])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(C=Cc2ccc(Cl)cc2)CO1
Solvent: CCO
Product: CC(C)(C)C(O)(C=Cc1ccc(Cl)cc1)n1cncn1
Yield: 80.9 %

Procedure:
A solution of 17.75 g (0.075 mol) of 2-(4-chlorophenyl-ethenyl)-2-tert.-butyl-oxirane and 6.9 g (0.1 mol) of 1,2,4-triazole in 30 ml of ethanol was heated in a bomb tube at 150° C. for 20 hours. The reaction mixture was thereafter concentrated, and the crystalline residue was stirred with ether. The solid material was then filtered off under suction and was recrystallized from acetonitrile. 17.7 g (77% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl)-1-penten-3-ol of melting point 139°-141° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([CH2:18][CH2:19][CH3:20])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:21][CH3:22])[CH:14]=3)[C:9]=2[O:23][CH2:24]OC)=[CH:4][CH:3]=1.Cl.O1CCOCC1.FC1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[C:37]([C:43]([F:46])([F:45])[F:44])[CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([CH2:18][CH2:19][CH3:20])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:21][CH3:22])[CH:14]=3)[C:9]=2[O:23][C:24]2[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[C:37]([C:43]([F:44])([F:46])[F:45])[CH:36]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CCCc1cc2cc(OC)ccc2c(OCOC)c1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)c(C(F)(F)F)c2)c1-c1ccc(F)cc1
Yield: 98.1 %

Procedure:
2-(4-Fluoro-phenyl)-6-methoxy-1-methoxymethoxy-3-propyl-naphthalene (225) (0.6 g, 1.69 mmol), 4 N HCl/Dioxane (12 mL), 4-fluoro-2-trifluoromethyl-benzaldehyde (0.277 mL, 2.03 mmol), Cs2CO3 (1.38 g, 4.23 mmol) and DMSO (12 mL) were reacted as described above to give 0.80 g (98%) of the title compound (226) as oil. 1H NMR (400 MHz, d-CDCl3): δ 0.83 (t, J=7.3 Hz, 3H), 1.47-1.55 (m, 2H), 2.54 (t, J=7.8 Hz, 2H), 3.95 (s, 3H), 6.75 (dd, J=2.3, 8.7 Hz, 1H), 6.94-6.99 (m, 3H), 7.06-7.10 (m, 3H), 7.19 (m, 1H), 7.63-7.66 (m, 2H), 7.89 (d, J=8.8 Hz, 1H), 10.18-10.19 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(N(CC)CC)C.[NH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>C(#N)C>[NH2:26][CH:27]1[CH2:31][CH2:30][N:29]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:28]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)nc21
Yield: 89.2 %

Procedure:
A mixture containing 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (2.7 g), triethylamine (1.01 g), 3-aminopyrrolidine (1.72 g), and acetonitrile (100 ml) was heated under reflux for 1.5 hours. After cooling the mixture, the resulting precipitate was collected and suspended in water (20 ml). The suspension was adjusted to pH 7.5-8.0 with acetic acid. The precipitate was collected, washed with water, and dried to yield 2.85 g of 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 259°-262° C. (decomp.).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:51]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][CH:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[CH:59]=[CH:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:51]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1ccc2ccccc2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1ccc2ccccc2n1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 99 %

Procedure:
This compound was prepared via BOP coupling of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step A of Example 1; 288 mg; 1.0 mmol) and 2-aminoquinoline (180 mg; 1.2 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 1, Step B) to provide 3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-quinolin-2-yl-propionamide as a white solid in 99% yield: EI-HRMS m/e calcd for C26H27N3O2 (M+) 413.2103, found 413.2103.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[C:24]([CH3:30])=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:25]3[C:24]([CH3:30])=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1nn(C)cc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1,3-dimethyl-1H-pyrazole-4-carboxylic acid as starting materials, MS (LC/MS): 425.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([NH:23][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=3)=[O:22])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:43](=[O:44])[CH2:42][O:41][CH3:40])[N:7]=3)=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)n3)c3ccccc23)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1nccc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
A suspension of 1-(4-((2-aminopyrimidin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate H) (52 mg, 0.100 mmol) in DCM (1.0 mL) and DMF (100 μl) was treated with methoxyacetyl chloride (27 μl, 0.299 mmol) followed by DIPEA (52 μl, 0.299 mmol). After stirring overnight at RT, the volatiles were evaporated and the residue suspended in a mixture of MeOH (2.0 mL) and AcOH (2.0 mL). The suspension was subjected to SCX capture and release. Very little material eluted off hence the SCX from the cartridge was removed and extracted with MeOH (50 mL). After evaporation, an off white solid was obtained and this was triturated from MeOH (1.0 mL) and diethyl ether (5.0 mL) to give N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyrimidin-2-yl)-2-methoxy acetamide (Example 23) as a white solid (12 mg, 19% yield): m/z 594 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.40 (3H, s), 3.34 (3H, s), 4.24 (2H, s), 5.34 (2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.35 (2H, d), 7.44 (3H, m), 7.60 (3H, m), 7.95 (1H, m), 8.36 (1H, m), 8.59 (1H, br s), 8.68 (1H, d), 8.80 (1H, br s), 10.44 (1H, br s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][CH2:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:18][CH2:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COP(=O)(CN)OC
Agent: Cl
Product: COP(=O)(CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)OC

Procedure:
In a manner analogous to Example 13(a) starting from 64.0 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine and 35.1 g of dimethyl aminomethylphosphonate hydrochloride, there were obtained 73.3 g of dimethyl [(N-benzyloxycarbonyl-L-alanyl)amino] -methylphosphonate as an oil. This oil was refluxed in a mixture of 200 ml of trimethylchlorosilane and 100 ml of acetonitrile under exclusion of moisture for 100 hours. The mixture was then cooled, filtered and evaporated in vacuo on a rotary evaporator. The residue was re-evaporated several times with toluene. The final residue was dissolved in 250 ml of dioxane and treated with 25 ml of water. Crystallization began after several minutes and this was completed by storing overnight. The separated solid was filtered off, washed with ethyl acetate and dried in vacuo. There were obtained 29.0 g of solid of melting point 147°-148° C (decomposition). A further 28.0 g of solid of the same melting point were obtained by concentration of the mother liquors and treatment with ethyl acetate. The combined solids were recrystallized by dissolving in 1.5 parts by volume of tepid methanol, filtering and then adding 15 parts by volume of ethyl acetate to the filtrate. There were obtained 39.5 g of pure [(N-benzyloxycarbonyl-L-alanyl)amino] -methylphosphonic acid of melting point 153°-155° C (decomposition); [α]D20 = - 28.9° (c = 1% in water).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[C:18]1([C:24]#[C:25][C:26](OCC)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:26](=[O:27])[CH:25]=[C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: ClCC(=Nc1ccccc1Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccccc2)n(-c2ccccc2Cl)c(-c2ccccc2)c1Cl

Procedure:
To 300 ml of toluene were added 7.4 g (0.030 mole) of 2-chloro-N-(2-chlorophenyl)-1-phenylethaneimine, 5.2 g (0.030 mole) of ethyl phenylpropiolate and 6.7 g (0.050 mole) of aluminum chloride. The reaction mixture was then heated under reflux for 20 hours under nitrogen atmosphere. After cooling, the reaction mixture was poured into 500 ml of 2N sulfuric acid, followed by extraction with chloroform. After washing the organic layer with 50 ml of a 10% aqueous solution of sodium hydroxide and then with water, it was dried with anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate) to yield 3-chloro-1-(2-chlorophenyl)-2,6-diphenyl-4(1H)-pyridinone having a melting point of 230°-233° C.
Reaction SMILES: C([N:9]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][N:10]1C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[ClH:30].O>C(O)CCC>[ClH:30].[ClH:30].[C:16]1([N:13]2[CH2:14][CH2:15][NH:9][NH:10][CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)N1CCN(c2ccccc2)CCN1C(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: c1ccc(N2CCNNCC2)cc1
Reaction time: 72 h

Procedure:
A mixture of 1,2-dibenzoylhexahydro-5-phenyl-1H-1,2,5-triazepine (101.3 g), n-butanol (450 ml), 12N hydrochloric acid (915 ml) and water (915 ml) was mechanically stirred and heated under reflux on a steam bath overnight. Additional 12N hydrochloric acid (400 ml) and water (400 ml) were added and stirring and heating under reflux on a steam bath were continued for three days. n-Butanol (150 ml) was added and stirring and heating under reflux on a steam bath were continued for a further three days. After this time (7 days) the solid had dissolved. The mixture was extracted twice with ether and the aqueous solution was evaporated to smaller volume. Coevaporation with ethanol and concentrated hydrochloric acid caused crystallization of the titled product; wt. 57.5 g (66%), mp=211°-218°.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1ccccc1
Yield: 55 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and N-methylpiperazine to give the title compound in 55% yield; NMR Spectrum: 2.10 (s, 3H), 2.22 (s, 3H), 2.22-2.55 (m, 8H), 2.77 (t, 2H), 4.41 (t, 2H), 5.13 (s, 2H), 7.01 (d, 1H), 7.31-7.48 (m, 7H), 8.17 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 474 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)([CH3:14])[C:9](OCC)=[O:10].O.[OH-].[Na+]>O1CCCC1>[CH3:14][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)([CH3:7])[CH2:9][OH:10]
Reactant: CCOC(=O)C(C)(C)c1cccc(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C(C)(C)CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (3.52 g, 92.9 mmol) in tetrahydrofuran (150 ml) was dropwise added a solution of ethyl 2-methyl-2-(3-methylphenyl)propionate (19.16 g, 92.88 mmol) in tetrahydrofuran (100 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. After ice-cooling the reaction solution, water (3.5 ml), 15% aqueous sodium hydroxide solution (3.5 ml) and water (9 ml) were successively added dropwise to decompose excess lithium aluminum hydride. The mixture was stirred as it was at room temperature for 2 hrs. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the recovered filtrate was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:30][CH2:31][CH2:32][N:33]1C(=O)C3=CC=CC=C3C1=O)[CH:25]=[CH:24]2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:30][CH2:31][CH2:32][NH2:33])[CH:25]=[CH:24]2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc2c(ccn2CCCN2C(=O)c3ccccc3C2=O)c1)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCn1ccc2cc(NC(=O)c3nc4ccc(Cl)cc4n3Cc3ccccc3)ccc21
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To 5 g of 1-benzyl-6-chloro-2-[1-(3-phthalimidopropyl)indol-5-ylaminocarbonyl]benzimidazole was added 100 ml of ethanol and stirred, then 0.5 ml of hydrazine hydrate was added thereto, the mixture was refluxed overnight. After cooled the reaction mixture to room temperature, then white crystals were removed by filtration. Water was added to the filtrate, and made alkaline with 10% aqueous solution of potassium hydroxide. This mixture was extracted with dichloromethane, the extract was washed with water, an aqueous solution saturated with sodium chloride then was dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was crystallized from ethyl acetate-n-hexane, there was obtained 3.2 g of 1-benzyl-6-chloro-2-[1-(3-aminopropyl)indol-5-ylaminocarbonyl]-benzimidazole as in the form of yellow granular crystals. Melting point: 106-108° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[CH:17](=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=[C:2]1[C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) in DMF (0.5 mL) was added salicylaldehyde (61 mg, 53 μL, 0.5 mmol) followed by potassium carbonate (138 mg, 1.0 mmol) and the resulting mixture stirred vigorously at room temperature for 2 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over Na2SO4 and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate:=100:0 to 1:1) afforded the title compound (131 mg, 86%) as a white solid. MS m/e: 304.0 [M+H]+.
Reaction SMILES: [C:1]([C:4]([C:15](=[O:17])[CH3:16])=[CH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:14])(=O)[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=1>C(O)(C)C>[C:15]([C:4]1[CH:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=2[CH3:14])[C:20]2[C:21](=[O:25])[NH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:1]=1[CH3:2])(=[O:17])[CH3:16]
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(=O)C(=Cc1ccc(C#N)cc1C)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1C

Procedure:
1.10 g (4.84 mmol) of 4-(2-acetyl-3-oxobut-1-en-1-yl)-3-methylbenzonitrile are taken up in 30 ml of isopropanol and, after addition of 592 mg (4.84 mmol) of 4-aminopyridin-2(1H)-one, heated at the reflux temperature for 72 h. The mixture is then concentrated, and the residue is again taken up in isopropanol and filtered through silica gel with isopropanol as eluent. The residue after concentration of the filtrate is mixed with a little methanol and crystallized. The precipitated product is filtered off, washed with diethyl ether and dried under high vacuum. 348 mg (22.5% of theory) of the title compound are obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>CCOCC>[Br:9][C:10]1[C:11]([CH:19]([C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])[OH:20])=[N:12][CH:13]=[N:14][CH:15]=1
Reactant: O=Cc1ccccc1Cl
Reactant: Brc1cncnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: OC(c1ccccc1Cl)c1ncncc1Br

Procedure:
Slowly add freshly prepared lithium diisopropylamide (0.5 M in ether) to a refluxing solution of 5-bromopyrimidine (4.03 g, 25.3 mmol) and 2-chloro-benzaldehyde (3.55 g, 25.2 mmol) in ether (100 mL). After addition is complete, stir at reflux for an additional 2 hours, then quench with 2N HCl (50 mL). Wash the organic layer with water (4×50 mL), dry, filter, and concentrate. Purify the crude material by flash chromatography using a linear gradient of 100% hexanes to 50% EtOAc/hexanes to give the title compound: MS (IS) 298.9 (M+1); 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.77 (s, 1H), 7.40 (dd, 1H, J=1.4, 8.4), 7.23 (dt, 1H, J=1.9, 7.9), 7.15 (dt, 1H, J=1.4, 7.7), 6.92 (dd, 1H, J=1.5,7.9), 6.34 (d, 1H, J=6.4), 4.75 (d, 1H, J=6.7).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1OC
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6]1.[F:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([NH:23][CH:24]([CH2:28][CH2:29][CH3:30])[C:25](O)=[O:26])=[O:22])[CH:16]=[C:17]([F:19])[CH:18]=1>>[CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[CH:24]([NH:23][C:21](=[O:22])[CH2:20][C:15]2[CH:16]=[C:17]([F:19])[CH:18]=[C:13]([F:12])[CH:14]=2)[CH2:28][CH2:29][CH3:30])[N:7]=[CH:6]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)Cn1cnc(N)c1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CC(=O)OC)cn1

Procedure:
(4-Amino-imidazol-1-yl)-acetic acid methyl ester was coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.5, 19.1, 33.8, 42.3, 50.3, 53.6, 54.5, 102.2, 102.5, 102.7, 109.9, 112.4, 112.6, 130.0, 131.4, 139.0, 161.9, 164.2, 166.5, 171.4; MS m/z 409.1 (M+1).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=2[OH:26])[CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])=[CH:7][CH:6]=1)([O-])=O.[H][H]>O=[Pt]=O.CO>[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=2[OH:26])[CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])=[CH:27][CH:28]=1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(O)c(NC(=O)c2ccc(N)cc2)c1

Procedure:
A mixture of 3-(4-nitrobenzamido)-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrochloride (7.37 g, 0.018 mole), PtO2 (250 mg), and methanol (225 ml) was placed in a pressure hydrogenation apparatus at a starting pressure of 2 atm. The hydrogenation was started, and the calculated amount of hydrogen was taken up within 17 minutes. The hydrogenation was interrupted and the platinum catalyst was filtered off. The clear colorless filtrate was evaporated on a rotary evaporator at 40° - 50° C. The residue, a cream-colored foam (7.3 g), was recrystallized three times from methanol/ether, and 3.50 g (50%), m.p. 228.8° - 230° C, of analytically pure 3-(4-aminobenzamido)-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrochloride, was obtained.