Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[CH3:3][NH:4][CH2:5][CH2:6][OH:7].[C:8](O)(=O)C.[OH:12][CH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[CH:28]=[C:27]([C:29]3[C:38]4[C:33](=[C:34]([C:39]5[CH:40]=[N:41][C:42]6[C:47]([CH:48]=5)=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][N:30]=3)[CH:26]=[CH:25][C:21]=2[C:22]([NH2:24])=[O:23])[CH2:15][CH2:14]1>C(O)C.C(Cl)Cl>[OH:12][CH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[CH:28]=[C:27]([C:29]3[C:38]4[C:33](=[C:34]([C:39]5[CH:40]=[N:41][C:42]6[C:47]([CH:48]=5)=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][N:30]=3)[CH:26]=[CH:25][C:21]=2[C:22]([NH:24][CH2:3][N:4]([CH2:5][CH2:6][OH:7])[CH3:8])=[O:23])[CH2:15][CH2:14]1
Reactant: NC(=O)c1ccc(-c2nccc3c(-c4cnc5ccccc5c4)cccc23)cc1NC1CCC(O)CC1
Reactant: CC(=O)O
Reactant: CNCCO
Agent: C=O
Solvent: ClCCl
Solvent: CCO
Product: CN(CCO)CNC(=O)c1ccc(-c2nccc3c(-c4cnc5ccccc5c4)cccc23)cc1NC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of paraformaldehyde (0.122 g), 2-(methylamino)ethanol (0.330 g), and acetic acid (0.13 ml) in ethanol (4 ml) was stirred at 80° C. for 2 hours. After cooling, a solution of compound (6) (0.200 g) in methylene chloride (4 ml) was added to the reaction solution, and the mixture was stirred overnight at room temperature. The reaction solution was partitioned between chloroform and water. The organic layer was neutralized with an aqueous sodium bicarbonate solution, then washed with brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was then purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (37) (0.130 g, 56%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:26])[CH:8]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C1(OC)C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[NH:6][C:7](=[O:26])[CH:8]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3C)N=C(c3ccc(F)cc3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1CC1N=C(c2ccc(F)cc2)c2cc(Cl)ccc2NC1=O
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
7-Chloro-5-(4-fluorophenyl)-1-(4-methoxybenzyl)-3-(2-methylbenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (44 mg, 0.086 mmol) was dissolved in dichloroethane (1 mL) under nitrogen and 200 μL of anisole was added followed by AlCl3 (69 mg, 0.515 mmol). This mixture was heated to 85° C. for 2.5 h then allowed to cool and diluted with ethyl acetate and ice. This biphasic mixture was stirred vigorously for 20 min, then partitioned, and the organic layer was washed with water twice, then brine once. The aqueous layers were back-extracted once with ethyl acetate, and the combined organic extracts dried over MgSO4. Chromatography on silica gel (5%-30%-40%-50% ethyl acetate in hexanes) provided the title compound (27 mg, 80%) as a yellow solid. APCI MS m/z 415.1 [M+Na+], 393.1 [M+H+]; 1H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 7.61-7.16 (m, 11H), 3.91 (t, J=7 Hz, 1H), 3.72-3.69 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:16](=[O:17])[C:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:13]=[C:12]1[CH3:37].IC.[C:40](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:33]([C:14]1[N:13]=[C:12]([CH3:37])[N:11]([CH2:10][C:2]2[N:3]([CH3:40])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:16](=[O:17])[C:15]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(C)n(Cc2nc3ccccc3[nH]2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2nc3ccccc3n2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
A mixture of 4′-{[1-(1H-benzimidazol-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.24 g), iodomethane (0.036 mL), potassium carbonate (0.14 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([N+:30]([O-:32])=[O:31])=[C:20](Cl)[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].Cl>CCO.O>[C:1]([O:5][C:6]([NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]([NH:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:21]([N+:30]([O-:32])=[O:31])=[CH:22][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(Cl)c([N+](=O)[O-])cc3-c3ccccc3)cc2)CCC1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1nc(-c2ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc2)c(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl(1-(4-(6-chloro-5-nitro-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (1.03 g, 2.14 mmol) in EtOH (8 ml) was added triethylamine (1.49 ml, 10.72 mmol) and ethyl 3-aminopropanoate.HCl (1.65 g, 10.72 mmol) under nitrogen. The resulting mixture was stirred for 1.5 hours at 80° C. under microwave irradiation. Water was added and the mixture was extracted with AcOEt (3×15 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 30% EtOAc in cyclohexane) to give the title compound (1.2 g, quantitative). 1H NMR (500 MHz, CDCl3): 8.50 (1H, s), 8.38 (1H, s), 7.32 (2H, d), 7.23-7.18 (5H, m), 7.09-7.07 (2H, m), 5.00 (1H, br s), 4.12 (2H, q), 3.98 (2H, q), 2.71-2.68 (2H, t), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br), 1.20 (3H, t).
Reaction SMILES: [C:1]1(OB(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][B:13]([OH:15])[OH:14].[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[B:13]([O:15][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])([O:14][CH2:16][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[O:12][CH2:11][CH2:3][CH2:2][CH2:1][CH2:6][CH3:5]
Reactant: COB(O)O
Reactant: OB(O)Oc1ccccc1
Reactant: Oc1ccccc1
Product: CCCCCCOB(OCCCCCC)OCCCCCC

Procedure:
Reaction is conducted in the same manner as described above except that phenylboric acid or methylboric acid is used instead of boric acid in the above example and a corresponding alcohol or phenol is used instead of hexyl alcohol, and then, the solvent is concentrated under reduced pressure, followed by distillation or crystallization and recrystallization with an appropriate solvent, whereby a corresponding boron compound can be obtained.
Reaction SMILES: F[C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20](S(C4C=CC(C)=CC=4)(=O)=O)[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1.[OH-].[K+].C(O)(=O)C>CO.CC(C)=O>[F:13][C:12]1[C:2]([NH:48][CH:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)=[C:3]([CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:11]=1)[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: CN1CCC(N)CC1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(F)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(NC4CCN(C)CC4)c(C(=O)N(C)C)c3)cc12
Reaction time: 48 h
Yield: 4.5 %

Procedure:
Into a 5 mL screw-cap vial were added 2,3-Difluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (100 mg, 0.178 mmol) and 1-methyl-piperidin-4-ylamine (102 mg, 0.712 mmol). The vial was sealed and placed in heated block at 120° C. for 48 h. The reaction solution was dissolved in 1:1 methanol/acetone (2 mL total) and treated with 100 μL of 50% w/w aqueous potassium hydroxide for 1 h. Glacial Acetic acid was added to obtain pH 7, then the reaction mixture was concentrated. The residue was purified by reverse-phase HPLC to afford the title compound as a white powder (4 mg, 0.008 mmol, 4% yield). 1H-NMR (500 MHz, d6-DMSO) δ=11.87 (d, J=2 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.61 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.54 (dd, J=13.5 Hz, J2=2.0 Hz, 1H), 7.24-7.3 (m, 2H), 7.12 (dd, J1=8.5 Hz, J2=1.0 Hz, 1H), 7.04 (td, J1=7.5 Hz, J2=1.0 Hz, 1H), 4.57 (dd, J1=5 Hz, J2=2.5 Hz, 1H), 3.81 (s, 3H), 3.14 (m, 1H), 3.00 (s, 3H), 2.9 (s, 3H), 3.14 (m, 1H), 2.12 (s, 3H), 1.87 (m, 2H), 1.74 (m, 2H), 1.41 (m, 2H); MS: m/z 502 [MH+].
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]([C:14]#N)=[CH:12][C:8](C(O)=O)=[C:7]([O:16][CH2:17][CH3:18])[CH:6]=1)=[N+:2]=[N-:3].C([N:21]([CH2:24][CH3:25])CC)C.ClC(OCC)=[O:28].N>O1CCCC1.C(OCC)(=O)C.O>[N:1]([CH2:4][C:5]1[C:13]([C:12]#[CH:8])=[CH:14][C:25]([C:24]([NH2:21])=[O:28])=[C:7]([O:16][CH2:17][CH3:18])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)O
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(C(N)=O)c(OCC)cc1CN=[N+]=[N-]
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
After dissolving 4-(azidomethyl)-5-cyano-2-ethoxybenzoic acid (0.7 g, 2.85 mmol) in tetrahydrofuran (15 ml), triethylamine (0.48 ml, 3.42 mmol) and ethyl chloroformate (0.3 ml, 3.14 mmol) were added while cooling on ice. The mixture was stirred for 10 minutes while cooling on ice, and then 27% aqueous ammonia (10 ml) was added and the mixture was stirred at room temperature for 10 minutes. Water (30 ml) was added to the reaction mixture, extraction was performed with ethyl acetate (20 ml×3), and then after washing the combined organic layers with brine (30 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product (0.68 g) was used directly for the following reaction.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)=[CH:7][C:6]=1[N:22]1[CH:26]=[N:25][N:24]=[N:23]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)=[CH:7][C:6]=1[N:22]1[CH:26]=[N:25][N:24]=[N:23]1
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)(C)O)c(-n3cnnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccc(OCC(C)(C)O)c(-n3cnnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A reaction mixture solution prepared by dissolving 9.9 mg of ethyl 2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 1.0 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.2 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 3 hours. After the addition of 0.2 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using 4 mL of ethyl acetate. The organic phase was concentrated and purified by a conventional method to obtain 4.8 mg of 2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.Br[CH2:23][C:24]([O:26]CC)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1
Reactant: CC1(C)Cc2cc(F)cc(CCc3ccc(O)cc3)c2O1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)Cc2cc(F)cc(CCc3ccc(OCC(=O)O)cc3)c2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-(2-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)phenol (650) (164.1 mg, 0.573 mmol), ethyl bromoacetate (95.7 mg, 0.573 mmol), cesium carbonate (265 mg, 0.688 mmol) and acetonitrile (5 mL) was heated at 50° C. for 18 hours. The reaction was concentrated in vacuo and then purified by flash column chromatography with hexanes and EtOAc (30%). The ester was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (3 mL). Lithium hydroxide was added and the reaction was stirred at room temperature for 24 hours. The mixture was acidified with 1M HCl and diluted with EtOAc (3 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 2-(4-(2-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)phenoxy)acetic acid (99). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J=7.8 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.65 (s, 2H), 2.96 (s, 2H), 2.88-2.73 (m, 4H), 1.43 (s, 6H). LC-MS ESI m/z: found 343.4 [M−H]−.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][O:10][C:9]1=[O:12])(C)(C)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.FC(F)(F)C(O)=O>>[O:12]=[C:9]1[C@@H:8]([NH3+:7])[CH2:11][O:10]1.[C:14]1([CH3:24])[CH:15]=[CH:16][C:17]([S:20]([O-:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1COC1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: [NH3+][C@H]1COC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a stirred mixture of 2 (1.34 mmol) and anhydrous p-toluenesulphonic acid (72 h under vacuum in the presence of P2O5) (1.43 mmol), kept at 0° C. under N2, trifluoroacetic acid (3 mL) was added dropwise in the course of 10 min. The solution was reacted under stirring at 0° C. for 15 min, allowed to reach room temperature, and concentrated at a temperature below 30° C. The oily residue was kept under vacuum for 1 h, and the resulting white solid triturated and washed with dry diethyl ether, then kept under vacuum for 24 h. Yield 81%. Mp and 1H NMR are in accordance with literature (Arnold, et al., 1988).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH: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][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccccc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>[Zn].C(OC(=O)C)(=O)C>[CH3:2][C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[C:7]=1[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1[nH]c(C)c(CC(C)C)c1C

Procedure:
Acetic anhydride (20 ml) was slowly added to 5 ml of concentrated hydrochloric acid with stirring and cooling and 668 mg of 2,4-dimethyl-5-carbethoxy-pyrrole were dissolved in the resulting solution. Amalgamated zinc (10 gm, 20 mesh) and 0.75 ml of iso-butyraldehyde were then added at 20°, and the mixture was stirred for 15 minutes at 20°-25° C. The zinc was separated, washed with acetic acid, and the liquids were poured into water to precipitate the crude product. It was dried and extracted into pentane (thimble), the pentane was evaporated, and the residue was recrystallized from aqueous ethanol (13 ml of 55%) as colourless needles (681 mg), m.p. 115°-117° C (lit6 116°-117° C.) after changing to fine needles at about 112° C. and to plates at about 115° C. A further 51 mg were obtained from the mother liquors (total 732 mg, 82%). The nmr spectrum and the X-ray powder photograph were identical with those of authentic material, and the mixed m.p. was 115°-117° C.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH:6](=[N:13][N+:14]1[CH:18]=[CH:17][N:16]([N:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1SC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CS>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH:6](=[N:13][N+:14]1[CH:18]=[CH:17][N:16]([N:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1COCCN1
Reactant: CSc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Agent: CS
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: C(=Nn1cc[n+](N=Cc2ccccc2)c1N1CCOCC1)c1ccccc1

Procedure:
4.1 g of 1,3-bis(benzylideneamino)-2-(methylthio)imidazolium tetrafluoroborate in 25 ml of absolute acetonitrile are treated under an argon atmosphere with 1.45 g of absolute morpholine, whereby the evolution of methylmercaptan sets in immediately and solution occurs. The solution is left to stir overnight at room temperature until the cleavage of methylmercaptan is complete. The resulting colorless precipitate is removed by filtration. The filtrate is treated with 30 ml of diethyl ether and again filtered. The two filter residues are combined and reprecipitated from acetonitrile/ether. There is obtained 1,3-bis(benzylideneamino)-2-morpholinoimidazolium tetrafluoroborate in the form of colorless crystals of m.p. 244°-247° (dec.).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[CH3:23][C:24]1([CH3:37])[CH:33]2[O:34][CH:32]2[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:35]#[N:36])[CH:30]=2)[O:25]1.[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:23][C:24]1([CH3:37])[CH:33]([OH:34])[CH:32]([N:3]2[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]3[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)=[N:4]2)[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:35]#[N:36])[CH:30]=2)[O:25]1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1O
Temperature: 60 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.60 g), 2,2-dimethyl-3,4-epoxy-6-cyano-3,4-dihydro-2H-chromene (0.80 g), and 60% sodium hydride (0.16 g) in dimethylsulfoxide (6 ml) was stirred for 5 hours at 60° C., and then diluted with ethyl acetate. The mixture was washed with water (10 ml) and sodium chlroide aqueous solution (10 ml), dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) with a mixture of n-hexane and ethyl acetate (2:1). The fractions containing the object compound were combined and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 3-[2-(2,2-dimethyl-3-hydroxy-6-cyano-3,4-dihydro-2H-chromen-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.51 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([C:13]([O:16][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(O)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(F)cc1[N+](=O)[O-])C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
1.41 g (4.51 mmol) 2-dibenzylamino-3-hydroxy-3-methyl-butyric acid and 0.54 ml (4.95 mmol) 2,5-difluoronitrobenzene in 46 ml tetrahydrofuran were treated at 0° C. with 19.8 ml (9.9 mmol) potassium bis(trimethylsilyl)amide (0.5 M in toluene). The solution was stirred overnight at room temperature and was then poured on ice/water. Extraction with ethylacetate and chromatography on silicagel with diethylether/heptane (30:70 to 75:25) and yielded 0.40 g (20%) 2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-3-methyl-butyric acid as yellow solid, MS m/e (%): 453.4 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:11][C:8]2([CH2:10][CH2:9]2)[CH2:7][N:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[CH2:15]([O:14][C:12]([N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:11][C:8]2([CH2:9][CH2:10]2)[CH2:7]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-methyl ester (244 mg, 0.840 mmol) was dissolved in THF (2.0 mL)/MeOH (1.5 mL) An aqueous solution of LiOH (35.5 mg, 0.84 mmol) was added and stirring at room temperature was continued. After 3 hours, the reaction was neutralized with aqueous HCl (1M) and the organic solvents were removed in vacuo. The crude mixture was diluted with water and EtOAc and the organic layer was collected. All volatiles were removed in vacuo and the crude acid was used without further purification. LCMS-ESI+: calc'd for C15H17NO4: 275.3 (M+). Found: 276.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[NH4+].C(O)C>O>[C:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[N:21][OH:22])[C:3]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=2[Cl:1])[CH2:7][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCC(C(=NO)c2ccc(Cl)cc2Cl)CC1
Yield: 31.1 %

Procedure:
A mixture of 13.0 g of 4-(2,4-dichlorobenzoyl)-N-acetylpiperidine, 6.8 g of hydroxylamine hydrochloride, 13.5 g of ammonium acetate, 127 ml of ethanol and 43 ml of water was stirred and heated at 130° for 24 hrs. The reaction mixture was evaporated and 1.3 l of water was added to the residue. The water was decanted from the oil and the oil was dissolved in about 150 ml dichloromethane. After washing with about 150 ml of water, drying over anhydrous magnesium sulfate and evaporating the solvent, an oil was obtained, which after crystallization from methanol/ether gave 4.25 g (31.1%) of product, mp, 167°-168°.