Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][C:5]([O:13][CH3:14])=[C:4]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH:3]=1.C(O)(=O)C.[CH:28](N)=[NH:29]>COCCO>[CH3:14][O:13][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[O:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)[N:1]=[CH:28][NH:29][C:8]2=[O:10]
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Reactant: N=CN
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(C)CC1
Temperature: 115 °C
Yield: 83.7 %

Procedure:
A solution of ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1 g, 50 mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (5.2 g, 50 mmol) was heated at 115° C. for 2 hours. Formamidine acetate (10.4 g, 100 mmol) was added in portions every 30 minutes over a period of 4 hours and the reaction was heated for 30 minutes after the last addition. The reaction was cooled, the volatiles were removed in vacuo, and the residue was dissolved in ethanol (100 ml) and dichloromethane (50 ml). The reaction was filtered and the filtrate was concentrated to a final volume of 100 ml. Collection of the precipitated solid by suction filtration (at 5° C.) followed by drying in vacuo yielded 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (12.7 g, 70% yield) as a white solid:
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26].[Li+].CC([N-]C(C)C)C.C(Br)C=C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]([CH2:7][CH:5]=[CH2:6])[C:28]([O:30][CH3:31])=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CCCCCC
Product: C=CCC(C(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a solution of N,N-diisopropylamine (1.79 mL, 12.8 mmol) in tetrahydrofuran (10.0 mL, 123 mmol) was added 2.50 M of n-butyllithium in hexane (4.68 mL, 11.7 mmol) dropwise at 0° C. The solution was stirred under an atmosphere of Nitrogen for 10 min, and then cooled to −78° C. A solution of methyl 3,4-dichlorophenylacetate (2.27 g, 10.4 mmol) in tetrahydrofuran (10.0 mL) was added to the LDA solution dropwise via cannula. After 10 min of stirring, the reaction was warmed to 0° C. for 1 hr. The solution was cooled back to −78° C., and allyl bromide (2.24 mL, 25.9 mmol) was added in one portion. In 10 min, the reaction was warmed back to 0° C. After 1 hr of stirring, the reaction was quenched with NH4Cl sat soln and extracted with EtOAc (×3). The combined organic layer was dried and concentrated to provide an orange oil. Further purification on a silica gel column (gradient elution, 0-10% EtOAc/hexanes) provided methyl 2-(3,4-dichlorophenyl)pent-4-enoate as a colorless oil (2.47 g, 92.0% yield). 1H NMR (400 MHz, CDCl3) δ 7.43-7.37 (m, 2H), 7.18-7.12 (dd, J=8.3, 2.1 Hz, 1H), 5.73-5.60 (ddt, J=17.1, 10.2, 6.8 Hz, 1H), 5.12-4.98 (m, 2H), 3.70-3.64 (s, 3H), 3.63-3.55 (t, J=7.8 Hz, 1H), 2.85-2.71 (m, 1H), 2.55-2.43 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][N:22]([CH2:24][CH3:25])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[OH:27])[CH3:2].[CH2:28]([C@@H:30]1[O:32][CH2:31]1)Cl>C(O)(C)C.[OH-].[Na+]>[CH2:24]([N:22]([CH2:21][C:16]1[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:26])[C:4]([O:27][CH2:28][C@@H:30]4[CH2:31][O:32]4)=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:13]=2)[CH:15]=1)[CH3:23])[CH3:25]
Reactant: ClC[C@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a bi-phasic mixture of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (1.74 g, 4.76 mmol) in isopropanol (100 mL) and 3M aq. NaOH (23 mL), (R)-epichlorohydrin (4.40 g, 47.6 mmol) is added. The mixture is stirred at rt for 16 h before it is concentrated to about half its volume. The remaining solution is extracted with EA, the org. extract is washed with 1M aq. NaOH followed by water. The washings are extracted back with EA. The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. HPLC (Waters XBridge Prep C18, 50×150 mm ID, 10 μm, eluting with a gradient of MeCN in water containing 0.5% of sat. aq. ammonia) to give ethyl-{3-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-5-methyl-benzyl}-methyl-amine as a colourless resin (950 mg). LC-MS*: tR=1.26 min; [M+1]+=422.23; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.24 (t, J=7.5 Hz, 3H), 2.14 (s, 3H), 2.36 (s, 3H), 2.41-2.48 (m, 5H), 2.69-2.78 (m, 3H), 2.86 (t, J=5.0 Hz, 1H), 3.37-3.42 (m, 1H), 3.54 (s, 2H), 3.69 (dd, J=11.0, 6.8 Hz, 1H), 4.21 (dd, J=11.3, 2.5 Hz, 1H), 7.47 (s, 1H), 7.80 (s, 2H), 7.90 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](Cl)[N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[CH:4][N:3]=1.Cl.[CH3:31][NH:32][CH3:33].C(N(C(C)C)CC)(C)C.O>N1C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4]([N:32]([CH3:33])[CH3:31])[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CNC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N(C)C)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 67 %

Procedure:
2-amino-chloro-9-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)purine (1) [M. J. Robins and B. Uznanski, Can. J. Chem., 59, 2601-2607 (1981)1(18.6 mmol, 7.96 g) was dehydrated three times azeotropically with anhydrous pyridine, and dissolved in anhydrous pyridine (180 ml), then dimethylamine hydrochloride (55.8 mmol, 4.55 g) and diisopropylethylamine (74.4 mmol, 12.9 ml) were added thereto with stirring at room temperature. The mixture was stirred at room temperature for 15 hours. After confirming completion of the reaction by TLC, water was added to the reaction mixture and concentrated in vacuo. Chloroform was added to the residue, and the organic layer was washed 3 times with water, 2 times with 5% aqueous sodium hydrogen carbonate, once with water and 2 times with 10% aqueous citrate solution, then the organic layer was dried with magnesium sulfate, and dried in vacuo after filtration. The residue was treated with azeotropic distillation with toluene until no odor of pyridine was noted, the product was purified by silica-gel chromatography (dichloromethane-ethanol) to obtain the product (2) 5.42 g (12.4 mmol) (67%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][CH:30]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([NH:17][C:18](=[O:27])[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:4]=2)=[CH:30][CH:31]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2N)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(C(C)=O)cc3)ccc2N)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
In a pressure vessel, N-[2-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-4-methoxybenzamide (116) (170 mg, 0.462 mmol), 1-(4-bromophenyl)ethanone (184 mg, 0.923 mmol), (or any aryl bromide from the tables below), DME (4.6 mL per mmol of 116) and H2O (2.15 mL per mmol of 116) were added. Air was then removed by vacuum and then the vessel was purged with nitrogen. Pd(PPh3)4 (27 mg, 0.023 mmol, 0.05 eq.) and Na2CO3 (147 mg, 1.38 mmol, 3.0 eq.) were then added and oxygen was removed after each addition. The pressure vessel was sealed and the mixture was stirred at 75° C. overnight. The mixture was cooled at room temp., water was added and the mixture was extracted with EtOAc. The combined organic layers were rinsed with brine, dried over MgSO4 and concentrated to give 42 mg (25%) of the title compound 117. 1H NMR (DMSO-d6) (ppm): 9.61 (s, 1H), 7.96 (dd, J=12.8, 8.8 Hz, 4H), 7.70 (d, J=8.8 Hz, 2H), 7.60 (d, J=2.1 Hz, 1H), 7.42 (dd, J=8.4, 2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.2 Hz, 1H), 5.26 (s, 2H), 3.84 (s, 3H), 2.58 (s, 3H). MS (m/z): 360.41 (calc) 361.1 (MH+) (found).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].O[O:6][S:7]([O-:9])=O.[K+].[CH3:11][C:12]([CH3:14])=O>O>[CH2:1]([S:7]([CH2:14][CH:12]=[CH2:11])(=[O:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: O=S([O-])OO
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: C=CCS(=O)(=O)CC=C
Yield: 72 %

Procedure:
A solution of allyl alcohol isomer A from Step 2: (7.11 g, 16.65 mmol) and oxone (30.75 g, 50.0 mmol) in acetone (100 mL) and water (25 mL) was stirred at RT overnight then filtered, diluted with water and AcOEt, extracted with AcOEt, dried and concentrated. The residue is purified was purified by flash-chromatography over silica gel (eluted with Hexanes/AcOEt 99:1 to 60:40) to provide 5.50 g (72%) of allylsulfone.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][SH:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[S:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1c(C=O)c(C)nn1C
Temperature: 80 °C
Yield: 27.8 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (5.0 g), ethyl thioglycolate (3.97 g), potassium carbonate (5.53 g), and N,N-dimethylformamide (150 mL) was stirred at 80° C. for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 90:10-50:50 hexane/ethyl acetate) to provide the title compound (2.12 g, 28%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2].[CH2:21](OC(C1C=CN(CC2C=CC=CC=2)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH2:13][C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:21]=2)[C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(Br)n(-c2ccccc2)c1CBr
Reactant: CCOC(=O)c1ccn(Cc2ccccc2)c1C
Product: CCOC(=O)c1c(Br)c(Br)n(Cc2ccccc2)c1CBr

Procedure:
Prepared in analogy to that of 4,5-dibromo-2-bromomethyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (Example 1(a)) from 1-benzyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester; the title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=7.30 (m, 3H), 7.00 (m, 2H), 5.40 (s, 2H), 4.77 (s, 2H), 4.35 (q, 2H, J=6.8 Hz), 1.40 (t, 3H, J=6.8 Hz).
Reaction SMILES: CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[Cl-].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C@H:31]2[CH2:35][CH2:34][CH2:33][NH2+:32]2)=[O:30])=[CH:24][CH:23]=1.[O:36]=[C:37]1[CH2:42][O:41][CH2:40][CH2:39][N:38]1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][C:50](O)=[O:51])=[CH:45][CH:44]=1>CN(C=O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]([C@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2[C:50](=[O:51])[CH2:49][C:46]2[CH:45]=[CH:44][C:43]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][C:37]3=[O:36])=[CH:48][CH:47]=2)=[O:30])=[CH:26][CH:27]=1
Reactant: O=C(Nc1ccc(Cl)cc1)[C@H]1CCC[NH2+]1
Reactant: O=C(O)Cc1ccc(N2CCOCC2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(Cl)cc1)[C@H]1CCCN1C(=O)Cc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.26 ml (2.4 mmol) of 4-methylmorpholine and 230 mg (1.2 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 261 mg (1.00 mmol) of (R)-2-(4-chlorophenylcarbamoyl)pyrrolidinium chloride and 235 mg (1.00 mmol) of 4-(3-oxomorpholin-4-yl)phenylacetic acid in 2 ml of DMF, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is introduced into water, and the precipitate formed is filtered off, giving N-(4-chlorophenyl)-(R)-1-{2-[4-(3-oxomorpholin-4-yl)phenyl]acetyl}pyrrolidine-2-carboxamide as a slightly brownish solid; ESI 442.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH3:8][NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([Cl:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11]
Reactant: CN=C=O
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
Triethylamine (0.40 g, 4.0 mmol) and methyl isocyanate (0.25 g, 4.4 mmol) were added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (1.24 g, 4.0 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.87 g, yield: 59.0%). mp: 113-114° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.60 (d, J=0.7 Hz, 3H), 2.88 (d, J=4.9 Hz, 3H), 5.77 (d, J=0.7 Hz, 1H), 6.50-6.75 (m, 1H), 7.66 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:12]Br)[C:7]([CH2:10]Br)=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH2:12][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)c(CN2CCCCC2)c1
Temperature: 25 °C
Yield: 59 %

Procedure:
In a 500 ml. round-bottomed reaction flask equipped with magnetic stirrer, reflux condenser and nitrogen-inlet tube, there were placed 10 g. (0.032 mole) of crude 4-nitro-α,α'-dibromo-o-xylene [M. Kerfanto, Bulletin de la Societe Chimique de France, Vol. 12, p. 3537 (1965)] and 44.8 g. (0.526 mole) of piperidine (52 ml.) all dissolved in 100 ml. of benzene. The resulting mixture was then heated at the reflux point for a period of 18 hours and finally cooled to room temperature (~25° C.). The spent reaction mixture was then diluted with 500 ml. of benzene and thereafter washed with four-100 ml. portions of water, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was obtained a 59% yield of crude 1,1'-[4-nitro-1,2-phenylenebis(methylene)]bispiperidine as a residue in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(N3CCCC3)c3cc(N4CCCCC4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C21H23FN6O2, 410.2
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH3:10])[CH2:4][CH:3]1[C:11]([O:13][CH3:14])=[O:12].C1([CH:22]=[CH:21][CH:20]=[C:18]([OH:19])[CH:17]=1)O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH3:35]>C1(C)C=CC=CC=1.O>[CH2:34]([O:19][C:18]1[CH:17]=[C:14]2[C:22]([C:2]3[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH3:10])[CH2:4][C:3]=3[C:11](=[O:12])[O:13]2)=[CH:21][CH:20]=1)[CH3:35]
Reactant: CCCC1CCC(=O)C(C(=O)OC)C1
Reactant: Oc1cccc(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCC1CCc2c(c(=O)oc3cc(OCC)ccc23)C1

Procedure:
16.6 g (78.5 mmol) of methyl 2-oxo-5-propylcyclohexanecarboxylate, 7.65 g (69.5 mmol) of resorcinol and 5.6 ml (6.1 mmol) of phosphoryl chloride are dissolved in 55 ml of toluene, and the mixture is heated under reflux for 3 h. After hydrolysis using water, the deposited precipitate is filtered off with suction, washed with toluene and dried. The product is dissolved in 200 ml of acetone, 20 g (145 mmol) of potassium carbonate and 9.00 g (57.7 mmol) of ethyl iodide are added, and the mixture is heated under reflux for 5 h. The majority of the solvent is removed under reduced pressure, and the residue is taken up in MTB ether/water. The aqueous phase is separated off and extracted with MTB ether. The combined organic phases are washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure, and the crude product is recrystallised from ethanol, giving 3-ethoxy-8-propyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one as colourless crystals. The melting point is 108° C. The other physical properties are: Δ∈=−7.5 (extrapolated from 5% solution in ZLI-2857), Δn=0.1302 (5% in ZLI-4792).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][C:32](O)=[O:33])[C:6]=2[CH:35]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][C:32]([N:55]3[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]3)=[O:33])[C:6]=2[CH:35]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)O)c3cc(Cl)ccc32)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-chloro-5-carboxymethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in dichloromethane (10 ml) is added with stirring N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.2 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. Subsequently, to the mixture are added with stirring N-methylpiperazine (0.09 ml) and triethylamine (0.17 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethoxy]-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([O-])([OH:11])=[O:10]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1O
Solvent: CC(=O)O
Product: Cc1cccc([N+](=O)[O-])c1O
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 2-methylphenol (10.8 g, 0.1 mmol) in acetic acid, fuming nitric acid (6.3 g) was slowly added with stirring to start reaction. The reaction mixture was stirred at a temperature of 20° C. or below for 1 h and thereafter poured into ice water. The reaction product was extracted with ethyl acetate and the extracted layer was washed with water, saturated sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in the order written. Thereafter, the washed layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography with a benzene-ethyl acetate mixture used as eluant, thereby giving the desired compound, 2-methyl-6-nitrophenol, in an amount of 1.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[I:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[C:10]=1[I:12])[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(O)cc(C(=O)O)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: Nc1cc(C(=O)O)cc(O)c1I
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
To a solution of 3-amino-5-hydroxy-benzoic acid (0.33 g, 2.16 mmol, 1.0 equiv; [CAS RN 76045-71-1]) in methanol (18 mL) at 0° C. was added within 10 min N-iodo succinimide (0.58 g, 2.59 mmol, 1.2 equiv), dissolved in methanol (3 mL). After stirring for 15 min, the reaction mixture was poured on ice and partly decolorized by addition of a 5% solution of sodium thiosulfate. The solution was extracted with ethyl acetate (3×50 mL), the combined organic phases dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate/methanol (9:1) providing 0.21 g (35%) of the title compound. 1H NMR (300 MHz, DMSO): δ 5.25 (br s, 2H), 6.61 (d, J=1.9 Hz, 1H), 6.78 (d, J=1.9 Hz, 1H), 10.16 (br s, 1H), 12.58 (br s, 1H). MS (ISP): 280.0 [M+H]+.