Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35].CC(O)=O>CCO>[C:34]([NH:33][CH2:32][CH2:31][NH:30][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4])(=[O:36])[CH3:35]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.065 mmol) and N-(2-amino-ethyl)-acetamide in EtOH (3 mL) was refluxed for 48 h. After cooling to r.t., AcOH (0.1 mL) was added, and solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (0-3% MeOH/CH2Cl2) to give 12 mg of the title compound as a light yellow solid. MS: (+) m/z 457.35 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]([Cl:15])([Cl:14])[C:8]1[N:12]=[C:11](Cl)[S:10][N:9]=1>CCOCC>[Cl:6][C:7]([Cl:15])([Cl:14])[C:8]1[N:12]=[C:11]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:10][N:9]=1
Reactant: Clc1nc(C(Cl)(Cl)Cl)ns1
Reactant: C1CCNC1
Solvent: CCOCC
Product: ClC(Cl)(Cl)c1nsc(N2CCCC2)n1
Reaction time: 1 h

Procedure:
To 14.2 grams (0.2 mole) pyrrolidine in 100 milliliters ether was added 23.8 grams (0.1 mole) 3-trichloromethyl-5-chloro-1,2,4-thiadiazole in 100 milliliters ether. The solution was refluxed with stirring for one hour after addition. Filtration to remove salt by-products yielded a clear filtrate which was concentrated on a steam bath to give 16.4 grams (60% molar yield) of white solid. Recrystallization from ligroin yielded a pure product (melting point 105.5°-107° C.). The structure was confirmed via infrared and elemental analysis. Analysis for C7H8N3Cl3S:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:20][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH2:9][CH2:8]2
Reactant: COc1ccc(C(=O)C=Cc2cc(Br)ccc2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C2CCc3cc(Br)ccc3O2)cc1
Reaction time: 0.5 h

Procedure:
5-Bromo-2-hydroxy-4'-methoxychalcone (16.7 g) was suspended in ethanol (200 ml) and sodium borohydride (3.78 g) added in portions. The resulting solution was stirred for 30 min, then allowed to stand overnight. The solvent was evaporated off, and the residue dissolved in chloroform and washed with water. Evaporation of the solvent gave the crude carbinol intermediate which was boiled under reflux with acetic acid for 2 hr. On cooling, 6-bromo-4'-methoxyflavan crystallised out and was filtered off and dried, 10.2 g, m.p. 121°-123°.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:19][C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NCCCCN
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)NCCCCNC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Carbomethoxybenzoyl chloride (19.07 g, 0.096 mol) was dissolved in toluene (380 mL) in a 3-necked, 1000 mL round-bottomed flask equipped with mechanical stirrer, thermometer, and addition funnel A solution of 1,4-butanediamine in water (80 mL) was added dropwise over a period of 40 minutes while the temperature of the reaction mixture was maintained at 25° C. by a water bath. A white solid formed immediately and the reaction mixture stirred for an additional 2 hours. The solid was collected on a frit and washed with toluene, water, 5% HCl, and water. Recrystallization from DMF gave white crystals which were dried in a vacuum oven at 60° C.; yield 17.91 g (90%); m.p. 260°-261° C. 1H NMR (200 MHz, DMSO-d6) δ8.70 (2H, m), 8.05-7.93 (8H, m) 3.88 (6H, s) 3.34 (4H, s), 1.58 (4H, s); IR (nujol) 3300, 1720, 1625, 1530, 1275, 1105, 860, 730 cm-1 ; low res. MS (CI, isobutane) 413 (MH+); 13C NMR (75 MHZ, DMSO-d6) δ166.9, 165.7, 165.4, 165.2, 138.7, 131.6, 129.0, 127.5, 127.2, 52.3, 26.5.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:33]=[CH:32][C:9]([CH2:10][NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]3[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)=[C:8]([O:34][C:35]([F:38])([F:37])[F:36])[CH:7]=1.C([O-])(O)=O.[Na+].[ClH:44]>CC(O)=O.CCOC(C)=O.Cl[Cu]>[ClH:44].[ClH:44].[Cl:44][C:6]1[CH:33]=[CH:32][C:9]([CH2:10][NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]3[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)=[C:8]([O:34][C:35]([F:38])([F:37])[F:36])[CH:7]=1
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](NCc3ccc(N)cc3OC(F)(F)F)CC2)nc2ccccc12
Agent: Cl[Cu]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NCc3ccc(Cl)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A mixture of conc. HCl (420 μL) and NaNO2 (44 mg, 0.64 mmol) were stirred at 70° C. for 10 min. To the reaction mixture was added a solution of cis-N2-[4-(4-amino-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine (free) obtained in step A of example 77 in AcOH (15 mL), and stirred at ambient temperature for 10 min. To the reaction mixture was added a solution of CuCl (146 mg, 1.47 mmol) in conc. HCl (1 mL), and stirred at 80° C. for 6 hr. The reaction mixture was alkalized with saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give a yellow oil. To a solution of above oil in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. A solution of the residue in Et2O (20 mL) was stirred at ambient tempareture for 1 hr. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give cis-N2-[4-(4-chloro-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine dihydrochloride (70 mg, 29%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([C:14]1[C:15]2[N:16]([C:20]([CH3:23])=[N:21][N:22]=2)[N:17]=[CH:18][CH:19]=1)[CH3:13]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([C:14]2[C:15]3[N:16]([C:20]([CH3:23])=[N:21][N:22]=3)[N:17]=[CH:18][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1nnc2c(C(C)Br)ccnn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2c(C(C)Oc3ccc(Cl)cc3)ccnn12
Reaction time: 1 h

Procedure:
p-Chlorophenol (0.25 g) was added to a suspension of sodium hydride (0.08 g) in anhydrous dimethylformamide (5 ml). The resultant mixture was stirred at room temperature for 30 minutes then 8-(1-bromoethyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine (0.38 g), in dimethylformamide (20 ml), was added dropwise and the mixture stirred for 1 hour. The reaction mixture was concentrated to dryness and the residue dissolved in dichloromethane (50 ml). The solution was washed with 5% aqueous sodium hydroxide and then with water. The organic layer was separated and dried with sodium sulphate, filtered and concentrated to dryness. The white solid obtained was recrystallized from ethyl acetate:hexane to give 8-[1-(4-chlorophenoxy)ethyl]-3-methyl-1,2,4-triazolo[4,3-b]pyridazine. m.p. 158-160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccc(N)cc1Nc1ncccc1-c1ccncn1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1Nc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-N3-(3-pyrimidin-4-yl-pyridin-2-yl)-benzene-1,3-diamine (30 mg, 0.11 mmol) in toluene (2.0 mL) was added phenyl isocyanate (0.012 mL, 0.11 mmol). The mixture was stirred overnight at RT. The resulting solid was filtered, washed with toluene and dried to yield N-(4-methyl-3-((3-(4-pyrimidinyl)-2-pyridinyl)amino)phenyl)-N′-phenylurea. MS m/z=397 [M+1]+. Calc'd for C23H20N6O: 396.46.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:12][C:11]=2[C:23]([NH2:25])=[O:24])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl>[F:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[C:13]1[O:14][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][S:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)(=[O:42])=[O:41])=[CH:9][CH:8]=2)=[C:11]([C:23]([NH2:25])=[O:24])[N:12]=1
Reactant: NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a suspension of 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide hydrochloride (0.030 g, 0.082 mmol) in DCM (2 mL) was added triethylamine (25 uL, 0.18 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.016 g, 0.082 mmol) and the resulting mixture stirred at room temperature overnight. Triethylamine (13 uL, 0.093 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.016 g, 0.082 mmol) was then added and the reaction stirred for a further 3 hours. After 2 hours triethylamine (6 uL, 0.043 mmol) and 4-fluorobenzenesulfonyl chloride (0.008 g, 0.041 mmol) was added. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-((4-fluorophenylsulfonamido)methyl)phenyl)oxazole-4-carboxamide (0.0230 g, 0.047 mmol, 57%) as a white solid. 1H NMR (DMSO) 4.07 (2H, d), 7.39 (6H, m), 7.74 (3H, m), 7.85 (2H, m), 8.13 (2H, d), 8.32 (1H, t). LCMS (2) Rt: 3.07 min; m/z (ES+) 488.
Reaction SMILES: C[Mg]Br.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=1.[Cl-].[NH4+].[C:14](OCC)(=O)C>O1CCCC1>[OH:11][CH:10]([C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1)[CH3:14]
Reactant: O=Cc1cccnc1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cccnc1
Yield: 76 %

Procedure:
To methylmagnesium bromide (a 0.96 mol/L solution in tetrahydrofuran, 16.6 mL, 15.9 mmol), a solution of 3-pyridinecarboxaldehyde (500 μL, 5.30 mmol) in tetrahydrofuran (5.0 mL) was slowly added under a nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 1. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol 9/1) to give 3-(1-hydroxyethyl)pyridine (Compound CA) (498 mg, yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12]Cl.[CH3:14][S:15]([O-:17])=[O:16].[Na+]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CS(=O)[O-]
Reactant: ClCc1cnc2ccccc2c1Cl
Agent: [Na+]
Product: CS(=O)(=O)Cc1cnc2ccccc2c1Cl

Procedure:
The compounds of general formula V are novel. They may be prepared from the corresponding 4-chloro-3-chloromethylquinoline by reaction with sodium methanesulphinate to give the corresponding 4-chloro-3-methylsulphonylmethylquinoline, followed by reaction with sodium alkoxide NaOR1 to give the compound V.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[C:39]([CH3:45])=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH:29]2[CH2:35][CH2:34][CH:33]1[CH2:32][N:31]([C:36]([C:38]1[C:39]([CH3:45])=[N:40][C:41]([NH:44][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:42][CH:43]=1)=[O:37])[CH2:30]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1nc(N)ccc1C(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: Cc1nc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)ccc1C(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Yield: 26.8 %

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (127 mg, 0.433 mmol, 1.0 eq) was combined with 3-(6-Amino-2-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (180 mg, 0.520 mmol, 1.2 eq) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-methyl-pyridine-3-carbonyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70 mg) in 27% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 10H) 1.61 (t, J=8.34 Hz, 1H) 1.68-1.81 (m, 2H) 1.81-1.93 (m, 1H) 1.95-2.18 (m, 7H) 2.48 (br. s., 2H) 2.56 (d, J=8.59 Hz, 3H) 2.62 (br. s., 1H) 3.09 (d, J=7.58 Hz, 1H) 3.18 (s, 7H) 3.26-3.36 (m, 1H) 3.40 (br. s., 1H) 4.17 (br. s., 1H) 4.37 (br. s., 1H) 4.58 (d, J=13.14 Hz, 1H) 4.74-4.89 (m, J=9.09, 8.84, 8.72, 8.72 Hz, 1H) 6.48 (s, 1H) 7.50 (br. s., 1H) 8.11 (br. s., 1H) 8.38 (d, J=8.08 Hz, 1H) 8.76 (s, 1H). HRMS m/z, (M+H)+: 603.3417.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:28]=3)[C:23](=[O:38])[C:22]=2[CH:21]=1)([O:17][CH2:18][CH3:19])=[O:16]>C(OCC)C>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:23]1([OH:38])[C:24]2[CH:25]=[C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=2[C:30]2[C:22]1=[CH:21][C:20]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:32][CH:31]=2
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)OCC)ccc1-2
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)c1ccc2c(c1)C(O)(c1ccccc1-c1ccccc1)c1cc(C(=O)OCC)ccc1-2
Reaction time: 3 h

Procedure:
 A Grignard reagent prepared from 0.97 g (40 mmol) of magnesium turnings and 9.32 g (6.8 ml, 40 mmol) of 2-bromobiphenyl in 50 ml of dry diethyl ether was added dropwise to a boiling solution of 13 g (40 mmol) of 2,7-dicarbethoxy-9-fluorenone in 100 ml of dry diethyl ether over a period of 2 hours. After addition was complete, the mixture was boiled for a further 3 hours. After cooling overnight, the precipitate formed was filtered off with suction and washed with cold ether. The magnesium complex which had been filtered off with suction was hydrolyzed in a solution of 15 g of ammonium chloride in 250 ml of ice water. After 1 hour, the 9-(2-biphenylyl)-2,7-dicarbethoxy-9-fluorenol formed was filtered off with suction, washed with water and sucked dry. For the ring closure reaction, the dried fluorenol was boiled in 100 ml of glacial acetic acid, after addition of 3 drops of concentrated HCl, for 6 hours. The mixture was allowed to crystallize overnight, the product formed was filtered off with suction and was washed with glacial acetic acid and water.
Reaction SMILES: [C:1]12(CN)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(=O)N(C(CC(O)=O)C(O)=O)C(=O)CC1.C1(=O)N(C(CC(O)=O)C(O)=O)C(=O)CC1.C(O)CO.Cl>ClCCl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C(O)CC(C(=O)O)N1C(=O)CCC1=O
Solvent: ClCCl
Solvent: OCCO
Product: C1C2CC3CC1CC(C2)C3
Temperature: 25 °C
Reaction time: 5 h
Yield: 175.5 %

Procedure:
1-Adamantanemethylamine (0.152 g, 0.92 mmol, Aldrich, Milwaukee, Wis.) was added to Ethylene glycol bis[succinimidylsuccinate] (EGS) (0.2 g, 0.43 mmol, Pierce, Rockford, Ill.) in solution in 10 mL of anhydrous dichloromethane. The resulting solution was stirred for 5 h at room temperature. It was then acidified with 0.1 N HCl and extracted with dichloromethane. The organic phase was dried with MgSO4 and then concentrated to dryness under vacuum. This afforded 0.22 g of solid (yield 90%).
Reaction SMILES: [CH:1]1([N:4]([CH3:20])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17](O)=[O:18])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>O1CCCC1.O>[CH:1]1([N:4]([CH3:20])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]([N:34]=[N+:35]=[N-:36])=[O:18])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C1CC1)C1CCC(C)(C)c2cc(C(=O)O)ccc21
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C(=O)N=[N+]=[N-])ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A stirred, cooled (ice bath) solution of 5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2 carboxylic acid (Intermediate 56, 0.22 g, 0.83 mmol) in anhydrous tetrahydrofuran (4 mL) was treated with triethyl amine (0.16 mL, 1.1 mmol) followed by ethyl chloroformate (0.10 mL, 1.08 mmol). After 5 h, sodium azide (0.081 g, 1.24 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title product that was used as such for the next reaction (0.24 g, 98%).
Reaction SMILES: [C:1]1([N:14]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]1=[O:13].[C:21]([O:29][CH:30]1[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([OH:38])[C:32]([CH3:40])([CH3:39])[CH2:31]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([O:29][CH:30]1[CH2:31][C:32]([CH3:40])([CH3:39])[N:33]([O:38][CH:10]2[C:11](=[O:12])[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:14]3[C:18](=[O:19])[CH:17]([O:38][N:33]4[C:34]([CH3:37])([CH3:36])[CH2:35][CH:30]([O:29][C:21](=[O:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:31][C:32]4([CH3:40])[CH3:39])[CH2:16][C:15]3=[O:20])[C:8](=[O:13])[CH2:9]2)[C:34]([CH3:36])([CH3:37])[CH2:35]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: O=C1C=CC(=O)N1c1ccccc1N1C(=O)C=CC1=O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CC(=O)N(c2ccccc2N2C(=O)CC(ON3C(C)(C)CC(OC(=O)c4ccccc4)CC3(C)C)C2=O)C1=O

Procedure:
The title compound is prepared from N,N'-1,2-phenylenedimaleimide and 4-benzoyloxy-1-hydroxy-2,2,6,6-tetramethylpiperidine according to the general procedure of Example 6.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[N:8]=1)C.[OH-].[Na+]>C(O)C.O>[Cl:13][C:11]1[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[N:8]=[C:7]([NH:6][CH2:5][C:4]([OH:23])=[O:3])[N:12]=1
Reactant: CCOC(=O)CNc1nc(Cl)cc(Nc2cccc(C)c2C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(Nc2cc(Cl)nc(NCC(=O)O)n2)c1C

Procedure:
To the suspension of N-[4-chloro-6-(2,3-xylidino)-2-pyrimidinyl]-aminoacetic acid ethyl ester (2.23 g; examples 3a and 5) in ethanol (27 ml) at 60° C., 1N NaOH (13.5 ml) is added, and the mixture is heated for 5'; then diluted with water, evporated under vacuum and extracted with diethyl ether (2×20 ml). After acidification with glacial acetic acid, the precipitate is filtered and washed with water to neutrality. The solid is then dried under vacuum with CaCT2, and 1.9 g of the desired acid are obtained (I, 1). With the same method the following compounds have been prepared:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12]Cl)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:7]2=[O:21].[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:9]1[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7](=[O:21])[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1c2cccc(Cl)c2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2c(Cl)cccc2c(=O)n1-c1ccccc1Cl
Yield: 38.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2h (100 mg, 0.294 mmol), adenine (44 mg, 0.324 mmol), K2CO3 (45 mg, 0.324 mmol), and DMF (1 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 50 mg of a pale yellow solid (39%), mp 273.3-273.5° C. (discolors). 1H NMR (DMSO-d6) δ: 8.11 (dd, J=1.3, 8.0 Hz, 1H); 8.08 (s, 1H); 8.05 (s, 1H); 8.00 (dd, J=1.3, 7.8 Hz, 1H); 7.79-7.83 (m, 2H); 7.63-7.66 (m, 2H); 7.56 (t, J=7.9 Hz, 1H); 7.21 (br s, 2H); 5.17 (d, J=17 Hz, 1H); 4.97 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 156.1, 152.8, 152.2, 150.2, 143.3, 142.0, 135.6, 133.1, 132.3, 131.9, 131.1, 131.0, 130.9, 129.4, 128.4, 126.0, 122.5, 118.4, 45.0. MS (ES): m/z 438.0 (M+). Anal. calcd. for C20H13Cl2N7O.0.1CH4O.0.6H2O(0.15KCl: C, 52.09; H, 3.18; N, 21.15. Found: C, 51.85; H, 2.93; N, 21.01.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13].O1CCC[CH2:16]1.C[Si](C=[N+]=[N-])(C)C>CO>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1c(C(=O)O)ccc(N)c1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc(N)c([N+](=O)[O-])c1C
Yield: 55 %

Procedure:
4-Amino-2-methyl-3-nitrobenzoic acid (1.87 g, 9.54 mmol) was solubilized in methanol (100 mL) and tetrahydrofuran (100 mL) and was treated with (trimethylsilyl)diazomethane solution (5.3 mL, 10.5 mmol, 2.0M in diethyl ether). After the reaction was shown to be complete, the mixture was concentrated and the residue was purified via column chromatography (silica gel, 5:1 hexanes/ethyl acetate) to give 1.10 g (55% yield) of methyl 4-amino-2-methyl-3-nitrobenzoate. 1H NMR (400 MHz, d6-DMSO): 7.73 (d, 1H), 6.75 (d, 1H), 6.51 (broad s, 2H), 3.75 (s, 3H), 2.37 (s, 3H). MS (EI) for C9H10N2O4: 210 (MH+).