Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[NH:28][C:29]([CH:32]4[CH2:36][CH2:35][CH2:34][NH:33]4)=[N:30][CH:31]=3)=[CH:23][C:22]=2[CH2:37][NH:38][CH3:39])=[CH:7][CH:8]=[C:9]([C:11]2[NH:12]C(C3CCCN3)=[N:14][CH:15]=2)[CH:10]=1)=O.C([N:43]([CH:46]([CH3:48])[CH3:47])[CH2:44][CH3:45])(C)C>N1C=CC=CC=1>[CH3:39][N:38]1[CH2:37][C:22]2[CH:23]=[C:24]([C:27]3[NH:28][C:29]([CH:32]4[CH2:36][CH2:35][CH2:34][NH:33]4)=[N:30][CH:31]=3)[CH:25]=[CH:26][C:21]=2[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[NH:12][C:48]([CH:46]4[CH2:47][CH2:45][CH2:44][NH:43]4)=[N:14][CH:15]=3)=[CH:10][C:5]=2[C:3]1=[O:2]
Reactant: CNCc1cc(-c2cnc(C3CCCN3)[nH]2)ccc1-c1ccc(-c2cnc(C3CCCN3)[nH]2)cc1C(=O)OC
Reactant: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CN1Cc2cc(-c3cnc(C4CCCN4)[nH]3)ccc2-c2ccc(-c3cnc(C4CCCN4)[nH]3)cc2C1=O
Temperature: 100 °C

Procedure:
To the solution of 2′-methylaminomethyl-4,4′-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-2-carboxylic acid methyl ester (90 mg) in pyridine (5 ml) was added diisopropylethylamine (1 ml). The mixture was heated at 100° C. for 2 hours. The solvents were evaporated. The mixture was diluted with acetonitrile and water, was freezer-dried to give 6-Methyl-3,9-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-6,7-dihydro-dibenzo[c,e]azepin-5-one as brown powder. m/z: 494.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[N:11]([C@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[C:12]=S>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[N:9]=[C:12]([NH:11][C@H:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][CH2:15]3)[NH:10][C:4]=2[CH:3]=1
Reactant: S=C=N[C@@H]1CCCc2ccccc21
Reactant: Cc1cc(N)c(N)cc1C
Product: Cc1cc2nc(N[C@@H]3CCCc4ccccc43)[nH]c2cc1C

Procedure:
The title compound was prepared from 4,5-dimethylphenylenediamine and (R)-l-isothiocyanato-1,2,3,4-tetrahydronaphthalene by Procedure D. The title compound was isolated by column chromatography as the free base (solid, mp 121-124° C.). MS(ES+) m/z 292 ([M+1]+, 100).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:38][N:39]([CH3:46])[C@H:40]1[CH2:44][NH:43][CH2:42][C@@H:41]1[OH:45]>CC(O)C>[CH3:38][N:39]([CH3:46])[C@@H:40]1[C@@H:41]([OH:45])[CH2:42][N:43]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=3)=[O:16])=[CH:4][N:3]=2)[CH2:44]1
Reactant: CN(C)[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C[C@@H]1O
Temperature: 110 °C
Reaction time: 16 h

Procedure:
2-Chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Stage 236.1, 60 mg, 0.137 mmol) and DIPEA (0.167 mL, 0.959 mmol) were added to a vial containing iPrOH (1 mL). (3S,4S)-4-(dimethylamino)pyrrolidin-3-ol (50 mg, 0.246 mmol) was added. The mixture was stirred at 110° C. for 16 h. The solvent was evaporated off under reduced pressure and the residue was purified by preparative SFC (Column DEAP, from 15% to 20% in 6 min) to afford the title product as a beige foam. HPLC (Condition 10) tR=5.93 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=506.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 6H) 2.52-2.58 (m, 1H) 2.88 (dd, J=11.14, 5.28 Hz, 1H) 3.21 (dd, J=11.34, 5.86 Hz, 1H) 3.28 (dd, J=10.56, 5.86 Hz, 1H) 3.44 (dd, J=11.34, 7.00 Hz, 1H) 4.07 (quin, J=5.28 Hz, 1H) 5.07 (d, J=5.08 Hz, 1H) 7.35 (d, J=9.38 Hz, 2H) 7.85 (d, J=9.38 Hz, 3H) 8.09 (d, J=2.35 Hz, 1H) 8.52 (s, 1H) 8.61 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:20][P:21](=[O:24])([OH:23])[OH:22])([O:17]CC)=[O:16]>CC(O)C.O.Cl>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:20][P:21](=[O:22])([OH:23])[OH:24])([OH:17])=[O:16]
Reactant: CCOP(=O)(CCCCCCCCCCCN)CP(=O)(O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: NCCCCCCCCCCCP(=O)(O)CP(=O)(O)O
Temperature: 10 °C

Procedure:
((11—N-phthalimidoundecyl)-ethoxyphosphinyl)methylphosphonic acid dimethyl ester (37.15 g, 78 mmol) was dissolved in a mixture of 2-propanol (165 mL) and water (26 mL). The mixture was cooled to about 10° C. in an ice bath and NaBH4 (11.11 g, 293 mmol, 3.8 eq.) was added slowly. The mixture was filtered and then cooled to below 5° C. in an ice bath. Acetic acid (70 mL) was then added slowly to the mixture. When the addition was complete the mixture was heated to 90° C. for 6 days. The mixture was then cooled to room temperature and the solvent removed. Residual water and acetic acid were removed from the residue azeotropically using ethyl acetate (200 mL), and then again using acetone two times (500 mL) and then again using toluene two times (500 mL). The resulting residue was free from acetic acid. This residue was partitioned between water (300 mL) and ethyl acetate (300 mL). The layers were separated and the organic layer was discarded. The aqueous layer was lyophilized to give a mixture of inorganic salts and ((11-aminoundecyl)-ethoxyphosphinyl)methylphosphonic acid. This solid was suspended in HCl (36%, 75 mL) and heated to 90° C. overnight. A clear solution was obtained. The mixture was cooled to room temperature and a solid precipitate formed. This solid was removed by centrifugation and found (by NMR) to contain no product. This solid was discarded. The supernatant was concentrated and again a solid appeared as a suspension in solution. HCl was removed from this suspension azeotropically using water (100 mL). After removal of HCl, an oily suspension was obtained. When additional water was added (100 mL), the product appeared as a white solid. This solid was collected by centrifugation. The solid was washed two times with acetone (70 mL) and dried in vacuum oven at 35° C. (recovery=9.98 g). A second crop was obtained by concentrating the supernatant and heating it with HCl (36%, 40 mL) for 2 hours. The solvent was removed to dryness and the mixture was suspended in water (20 mL), centrifuged to collect solid product, and the solid was washed with water (10 mL) and two times with acetone (20 mL) (recovery=2 g). 1H NMR (D2O) δ=2.3 (t, 2H), 1.6 (t, 2H), 1.4 (m, 2H), 1.2-1.0 (m, 18H). 31P NMR (D2O) δ=13.8, 42.6.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH3:23].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:24][C:25]1[N:26]=[C:27]([C:32]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH3:23])=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CC
Yield: 79.5 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (110c) (0.35 g, 1.45 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.11 g, 0.6 mmol), WSC hydrochloride (0.38 g, 2 mmol), HOBt (0.13 g, 1 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 3/2, 2/1) to obtain 0.23 g of the title compound as a colorless solid (80%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH2:21])[N:3]=1.C(Cl)Cl.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:18]([C:10]1[CH:11]=[C:12]([O:16][CH3:17])[C:13]([CH3:15])=[CH:14][C:9]=1[O:8][C:7]1[C:2]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:3][C:4]([NH2:21])=[N:5][CH:6]=1)([CH3:20])[CH3:19]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2Cl)cc1C
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2Nc2ccccc2)cc1C
Temperature: 100 °C

Procedure:
A suspension of 4-chloro-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-pyrimidin-2-ylamine (0.043 g, 0.14 mmol) in aniline (4 ml) was placed in a sealed tube and heated at 100° C. over night. Methylene chloride was added and insoluble solid was removed by filtration through celite. The combined methylene chloride filtrate was washed with water and dried over anhydrous sodium sulfate. After removal of the drying agent, the organic phase was concentrated under reduced pressure. The residue was purified with silica gel chromatography (2% methanol in methylene chloride) to yield a yellow oily residue, which was further purified with preparative TLC and HPLC (5 to 100% acetonitrile in water with 0.1% trifluoroacetic acid to yield 5-(2-Isopropyl-4-methoxy-5-methyl-phenoxy)-N4-phenyl-pyrimidine-2,4-diamine, M+H: 365.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=12)[NH2:5].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.Cl.[OH-].[Na+]>O>[Cl:20][C:21]1[N:22]=[C:23]([NH2:28])[N:24]=[C:25]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:26]=1
Reactant: Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12

Procedure:
35 mg (0.14 mmol) of 3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 24.5 mg (0.15 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 2.5 ml of water. 17 μl (0.18 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 10, resulting in the precipitation of crystals. The crystals are filtered off with suction and purified by column chromatography on silica gel (mobile phase: dichloromethane:methanol (7N ammonia) 100:5).
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH2:15]([O:17][C:18](=[O:55])[C:19]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[F:54])([CH3:46])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH:30]2[CH2:34][N:33](CC3C=CC(OC)=CC=3)[C:32](=[O:44])[N:31]2[CH3:45])=[CH:23][CH:22]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:55])[C:19]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[F:54])([CH3:46])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH:30]2[CH2:34][NH:33][C:32](=[O:44])[N:31]2[CH3:45])=[CH:23][CH:22]=1)[CH3:16]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)Oc1ccccc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Trifluoroacetic acid (55 mL) is added dropwise to a solution of triethylsilane (1.95 mL, 12.18 mmol, d=0.728) and 2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (3.44 g, 6.09 mmol). The reaction mixture is stirred under nitrogen at ambient temperature for 2 h, then concentrated. The residue is diluted with ethyl acetate, then washed. The organic layer is dried and concentrated in vacuo to provide the title compound (2.7 g, 78%). 1H NMR (400 MHz, CDCl3): δ 7.20 (d, 2H, J=8.7 Hz), 7.06-7.01 (m, 1H), 6.97-6.87 (m, 3H), 6.79 (d, 2H, J=8.7 Hz), 5.04-4.98 (m, 1H), 4.20 (q, 2H, J=6.8 Hz), 4.02 (t, 2H, J=6.8 Hz), 3.76-3.69 (m, 1H), 3.55 (t, 1H, J=8.7 Hz), 3.26, 3.14 (ABq, 2H, J=14.5 Hz), 3.21 (t, 1H, J=8.7 Hz), 2.78 (s, 3H), 2.27-2.20 (m, 1H), 1.99-1.90 (m, 1H), 1.38 (s, 3H), 1.23 (t, 3H, J=6.8 Hz), 0.96 (t, 2H, J=7.7 Hz). MS [EI+] 445 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12](=N)[NH:11][C:10]2=[O:19])=[CH:4][C:3]=1[CH3:20].O.C(=O)([O-])[OH:23].[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12](=[O:23])[NH:11][C:10]2=[O:19])=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(N2C(=O)NC(=N)C23CCCC3)cc(C)c1Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N2C(=O)NC(=O)C23CCCC3)cc(C)c1Br
Temperature: 65 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(4-bromo-3,5-dimethylphenyl)-4-imino-1,3-diazaspiro[4.4]nonan-2-one (the crude product obtained in the previous reaction) in acetic acid (1.0 mL) and water (0.25 mL) was stirred for 1.5 hours at 65° C. under nitrogen atmosphere. After further addition of acetic acid (1.0 mL) and water (0.25 mL), the mixture was stirred for 17 hours at 65° C. under nitrogen atmosphere. The reaction mixture was cooled, followed by dilution with water and adjustment of its pH to 8 using a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 1-(4-bromo-3,5-dimethylphenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (121 mg).
Reaction SMILES: [N:1]([CH:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[N+]=[N-]>CCO.[Pd]>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][CH:4]([NH2:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(CCC(N=[N+]=[N-])c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(CCC(N)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the product from Step B (1.08 g, 3.7 mmol) in 30 mL of EtOH containing Pd/C (10%, 100 mg) was stirred at ambient temperature under 1 Atm. of H2 for 20 hours. The reaction mixture was filtered to provide the title product as a clear colorless oil which was sufficiently pure for use in the next step.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:19]2=[C:20]3[C:10]([C:11]([C:13]4[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:12])=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.O>C(O)(=O)C>[Br:1][C:5]1[CH:4]=[CH:3][C:19]2[C:18]3[C:13]([C:11](=[O:12])[C:10]4[C:20]=2[C:6]=1[CH:7]=[CH:8][CH:9]=4)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: BrBr
Reactant: O=C1c2ccccc2-c2cccc3cccc1c23
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2ccc(Br)c3cccc1c23
Yield: 68.1 %

Procedure:
A solution of 11.2 g of bromine in 20.5 g of acetic acid was added dropwise to a mixture of 11.5 g of benzanthrone, 184 g of acetic acid and 23 g of water with stirring. The total mixture was heated with stirring to 100° C for 5.5 hours. The precipitated crystals were filtered and washed with water and dried. The product was recrystallized from a mixture of 88.3 g of chlorobenzene and 6.3 g of methanol whereby 10.52 g of 3-bromobenzanthrone were obtained.
Reaction SMILES: [CH3:1][C@H:2](C(O)=O)[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.C([N:20](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[ClH:42].C(=O)=O>C1C=CC=CC=1.O>[ClH:42].[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([CH:2]([NH2:20])[CH3:1])[CH:4]=[CH:5]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2cc(C(C)N)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
A further representative compound of the present invention was prepared according to Scheme 1 in the following manner. To a solution of naproxen (10.0 g, 0.04 mole) in 50 mL benzene at room temperature were added triethylamine (6.1 mL, 0.04 mole) and diphenylphosphoryl azide (9.4 mL, 0.04 mole). The solution was heated to reflux and stirred for two hours before slowly adding concentrated HCl solution (12 M; 7.2 mL, 0.08 mole) via pipet. Evolution of CO2 gas was noted. The mixture was stirred at reflux for thirty minutes, then cooled to room temperature and concentrated in vacuo. Ether was added and the solution was concentrated again. A white solid precipitate was filtered and washed with ether to give 15.4 g of crude salt. Approximately 5.0 g of the salt was then placed in water and an insoluble gum was filtered off. The aqueous layer was basified with 2N NaOH solution and extracted with ethyl acetate (3×50 mL). The organic extract was washed with brine and dried (MgSO4), filtered and concentrated in vacuo to give 2.51 g of the 1-(6-methoxynaphthalen-2-yl)ethyl amine hydrochloride salt 2.1 as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]1=[O:24]>>[CH3:17][N:18]1[C:22](=[O:23])[CH2:21][CH:20]([O:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:19]1=[O:24]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: CN1C(=O)C=CC1=O
Product: CN1C(=O)CC(ON(Cc2ccccc2)Cc2ccccc2)C1=O

Procedure:
The procedure for Example 1 is repeated using 5.33 g (25 mmole) of N,N-dibenzylhydroxylamine and 2.78 g (25 mmole) of N-methylmaleimide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Br:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-bromo-4-methylphenol (5.0 g, 27 mmol) and K2CO3 (7.4 g, 53 mmol) in DMF (20 mL) was added benzyl bromide (3.5 mL, 29 mmol) at ambient temperature. It was stirred at 70° C., for 12 h. The mixture was poured into water (50 mL), extracted with EtOAc (150 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1) to give the title compound (3a).
Reaction SMILES: [Br:1][C:2]1[C:28]([Br:29])=[CH:27][C:5]2[N:6]([C:19](=[O:26])[CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:32](Cl)[CH2:33][CH3:34]>CN(C)C=O.C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:28]([Br:29])=[CH:27][C:5]2[N:6]([C:19](=[O:26])[CH2:20][N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:32][CH2:33][CH3:34])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: CCCCl
Reactant: CCN(CC)CC(=O)N1c2cc(Br)c(Br)cc2-n2c(n[nH]c2=O)-c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CCCn1nc2n(c1=O)-c1cc(Br)c(Br)cc1N(C(=O)CN(CC)CC)c1ncccc1-2
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-dibromo -9-[(diethylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo-[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling propyl chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in exanmple 25 to give 6,7-dibromo-2,9-dihydro-2-propyl-9-[(diethylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[C:19]([F:22])([F:21])[F:20]>C1CCCCC1>[C:1]([NH:4][C:10]1[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]([C:19]([F:20])([F:21])[F:22])=[C:6]([Cl:5])[C:11]=1[N+:12]([O-:14])=[O:13])#[C:2][CH3:3]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: C#CCN
Solvent: C1CCCCC1
Product: CC#CNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The compound was prepared by reacting propargylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in cyclohexane to give the product melting at 86°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([CH:36]=O)=[N:28]1>CO.N1CCCCC1>[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: O=Cc1n[nH]c2ncccc12
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0362 g, 0.100 mmol) in methanol (3 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (0.0147 g, 0.100 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0352 g, 72%).
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)=[CH:4][C:3]=1[CH3:15].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)=[CH:4][C:3]=1[CH2:15][Br:16]
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(C)c1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(O[C@@H]2CCOC2)cc(CBr)c1Br
Temperature: 60 °C
Reaction time: 12 h
Yield: 24.1 %

Procedure:
(R)-3-(4-Bromo-3,5-dimethylphenoxy)tetrahydrofuran 35a (2.27 g, 8.37 mmol), N-bromosuccinimide (1.79 g, 10.04 mmol) and azobisisobutyronitrile (64 mg, 0.42 mmol) were dissolved in 50 mL of carbon tetrachloride. The reaction solution was heated to 60° C. and stirred for 12 hours. The resulting solution was concentrated under reduced pressure, mixed with 50 mL of tert-butyl methyl ether, stirred for 10 minutes, filtered and washed with tert-butyl methyl ether (20 mL×2). The combined filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (R)-3-(4-bromo-3-(bromomethyl)-5-methylphenoxy)tetrahydrofuran 35b (707 mg, yield 24.2%) as a light yellow solid.