Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[N:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[N:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2
Reactant: COc1cnc2[nH]ccc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cnc2[nH]ccc2c1
Temperature: -30 °C

Procedure:
Adding boron tribromide in methylene chloride to a solution of 5-methoxy-7-azaindole in methylene chloride cooled at about −30° C. Leaving the mixture to warm up to ambient temperature and stirring it for a period of time, for example overnight. Pouring the mixture onto ice and water and adjusting the pH of the aqueous phase to about 6. Separating the organic phase and further extracting the aqueous phase with ethyl acetate. Combining the organic phases washing them with brine, drying them, for example over magnesium sulphate, and then evaporating them. The residue may then be purified, for example by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol to give 5-hydroxy-7-azaindole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][CH:16]=3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31](I)[CH3:32].O>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[CH:19][C:18]([C:24]([O:26][CH2:31][CH3:32])=[O:25])=[CH:17][CH:16]=3)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2oc(-c3ccc(OCc4ccccc4)cc3)cc(=O)c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc2oc(-c3ccc(OCc4ccccc4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
4'-Benzyloxy-6-carboxyflavone (1 eq.) was dissolved in HMPA (hexamethylphosphoramide), followed by the addition of sodium hydride (1.1 eq.). Thirty minutes later, ethyl iodide (2 eq.) was added, and the resulting mixture was stirred further for 2 hours at room temperature. The mixture was charged into water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby the title compound represented by the following formula was obtained (yield: 25%). ##STR18##
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([OH:25])=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:30]O>>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([O:25][CH3:30])=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCn1c(C)nc2cc(C(=O)O)cc(OCc3ccccc3)c21
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COCCn1c(C)nc2cc(C(=O)OC)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of 7-(benzyloxy)-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole-5-carboxylic acid (10.0 g, 29.4 mmol, Step 5) in methanol was added dropwise thionyl chloride (8.57 mL, 118 mmol) at room temperature, and the mixture was refluxed with stirring for 2 hours. After cooling to room temperature, the solvent was evaporated in vacuo. The residue was poured onto saturated sodium hydrogencarbonate aqueous solution, and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was suspended in diisopropyl ether (100 mL), and the precipitate was collected by filtration to afford the title compound as a gray solid (9.22 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:19])[CH3:18])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Br)c(C)c1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A stirred solution of 4-bromo-3-methylaniline (3.0 g, 0.016 mole) and triethylamine (4.5 fml, 0.032 mole) in dichloromethane (30 ml) at 0° C. was treated with acetyl chloride (1.2 ml, 0.017 mole) and allowed to warm to room temperature over 1 h. The mixture was washed with water, then 5M HCl acid and dried (Na2SO4), then concentrated in vacuo to afford the title compound as a pale yellow solid (3.07 g, 83%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)=[O:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.CCO>[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:2]3[N:11]=[C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:9]4[C:4](=[CH:5][C:6]([C:18]5[O:19][C:20]([CH3:23])=[CH:21][CH:22]=5)=[CH:7][CH:8]=4)[N:3]=3)=[CH:41][CH:42]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(NC(=O)Nc5ccc(C(=O)N(C)C)cc5)cc4)nc3c2)o1
Temperature: 95 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline (1.4 g, 0.0036 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (2.25 g, 0.0055 mol), sodium carbonate (0.775 g, 0.0073 mol), toluene (12 mL), EtOH (12 mL) and water (12 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd (PPh3)2Cl2 (128 mg, 0.000023 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 0-4% MeOH in chloroform) followed by preparative HPLC (0.1% TFA in water and ACN) to yield the title compound [0.65 g, 27%]. 1H NMR (400 MHz, DMSO-d6): δ 9.49 (brs, 1H), 9.27 (brs, 1H), 8.30 (d, J=8.8 Hz, 2H), 8.11 (t, J=9.2 Hz, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.22 (d, J=3.2 Hz, 1H), 6.37 (s, 1H), 4.22 (brs, 4H), 3.83 (brs, 4H), 2.95 (s, 6H), 2.40 (s, 3H); LC-MS (ESI): Calculated mass: 576.2; Observed mass: 576.7 [M+H]+ (RT: 0.64 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH2:7]2.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1.O.C(N(CC)CC)C>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:28])=[CH:25][CH:24]=1)[CH2:5]2
Reactant: C1COCCN1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)O)cc1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)N3CCOCC3)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoic acid (3.50 g), morpholine (1.42 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.12 g), 1-hydroxybenzotriazole monohydrate (2.45 g), and triethylamine (2.30 ml) in THF (70 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride and dried. Removal of the solvent in vacuo gave the entitled compound (4.00 g).
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].NN.[OH-].[K+].C(O)COCCOCCO>O>[CH2:1]([C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC(=O)c1ccncc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCCCCCCCCCCc1ccncc1
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A mixture of 8.50 g (34 mmol) of 4-n-undecanoylpyridine, 5.55 g (0.11 mol) of hydrazine.monohydrate, 4.41 g (74 mmol) of potassium hydroxide, and 30 ml of triethylene glycol was heated at 110° to 125° C. for one hour, and further, at 180° to 185° C. for 4 hours. After cooling, 50 ml of water was added, and the mixture was extracted with diethyl ether, washed with water and then dried over anhydrous potassium carbonate. After concentration under a reduced pressure, the residue was purified by distillation under a reduced pressure to give 6.40 g of the desired product (yield 79.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH3:21])[N:11]=[C:10]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:9]=23)[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.O.[Ni](Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH3:21])[N:11]=[C:10]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:9]=23)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc2c(cnn2CC)c1-c1cncc(Br)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCc1c(C)nc2c(cnn2CC)c1-c1cncc(Br)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
To a solution of ethyl (2E)-3-[4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]acrylate (47 mg) in MeOH (2 ml) was added nickel chloride hexahydrate (7.26 mg) and sodium borohydride (10.7 mg) at −10° C. and the mixture was stirred at −10° C. for 15 minutes. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of EtOAc and n-hexane (1:1.5) to give ethyl 3-[4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (12 mg) as a light yellow oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10].[CH2:11]([NH:18][C@@H:19]([CH3:22])[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:11]([N:18]([C@@H:19]([CH3:22])[CH2:20][OH:21])[CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[OH:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-][n+]1ccccc1C1CO1
Reactant: C[C@@H](CO)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H](CO)N(Cc1ccccc1)CC(O)c1cccc[n+]1[O-]
Reaction time: 24 h
Yield: 47.8 %

Procedure:
To a solution of 2-(oxiran-2-yl)pyridine 1-oxide (6.6 g, 48.48 mmol) in ethanol (150 mL) were added (S)-2-(benzylamino)propan-1-ol (16 g, 96.96 mmol) and potassium carbonate (13.3 g, 96.96 mmol), After 24 h, the mixture was concentrated under reduced pressure and the resulting residue was purified via alumina chromatography (1% methanol in dichloromethane) to afford 2-(2-(benzyl((S)-1-hydroxypropan-2-yl)amino)-1-hydroxyethyl)pyridine 1-oxide as a yellow liquid (7 g, 22%).
Reaction SMILES: [C:1](=[O:25])([O:23][CH3:24])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([C:12]#[C:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C.O.CO.[Zn]>[C:1](=[O:25])([O:23][CH3:24])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:12]#[C:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCC(C)C)cc1C1CCCC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)Oc1cc(N)c(C#CCC(C)C)cc1C1CCCC1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
2-Cyclopentyl-4-(4-methylpent-1-ynyl)-5-nitrophenyl methyl carbonate (75 mg, 0.22 mmol) was dissolved in a mixture of glacial acetic acid (940 μL) and water (235 μL). Zn dust (71 mg, 1.09 mmol) was added at room temperature and the reaction stirred for 10 min. The reaction was diluted with methanol (5 mL), filtered and concentrated. The product was brought up in dichloromethane, washed with 50% saturated NaHCO3, dried over Na2SO4, filtered, and dried down to provide 5-amino-2-cyclopentyl-4-(4-methylpent-1-ynyl)phenyl methyl carbonate as a clear orange oil (68 mg, 99% yield). LC/MS m/z 316.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.[NH2:10][CH2:11][CH:12]([OH:15])[CH2:13][NH2:14]>CC1C=CC(C)=CC=1>[F:9][C:2]([F:1])([F:8])[C:3]1[NH:10][CH2:11][CH:12]([OH:15])[CH2:13][N:14]=1
Reactant: NCC(O)CN
Reactant: CCOC(=O)C(F)(F)F
Solvent: Cc1ccc(C)cc1
Product: OC1CN=C(C(F)(F)F)NC1
Temperature: 160 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a solution of ethyl trifluoroacetate (5.80 g, 40.8 mmol) in p-Xylene (30 mL) was added 1,3-diamino-2-propanol (3.60 g, 40 mmol). The mixture was stirred at 160° C. for 4 h. Concentration in vacuo then afforded the title compound (6.55 g, 39.0 mmol, 97% yield).
Reaction SMILES: [C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([N:8]=[CH:9]3)=[N:6][C:4]([NH:5]1)=[N:3][N:2]=2.[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=[C:27]([NH2:34])[CH:26]=1.NCCCC[C:40]1([OH:60])[C:53]2[O:54][C@@H:50]3[C@@:51]45[CH2:55][CH2:56][N:57]([CH3:58])[C@@H:45]([C@@H:46]4[CH:47]=[CH:48][C@@H:49]3[OH:59])[CH2:44][C:43]([C:52]5=2)=[CH:42][CH2:41]1.CCOC(OC(OCC)=O)=O>CN(C=O)C.C(N(CC)CC)C>[C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([N:8]=[CH:9]3)=[N:6][C:4]([NH:5]1)=[N:3][N:2]=2.[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=[C:27]([NH2:34])[CH:26]=1.[CH:42]1[C:43]2[CH2:44][C@H:45]3[N:57]([CH2:56][CH2:55][C@@:51]45[C@H:46]3[CH:47]=[CH:48][C@H:49]([OH:59])[C@@H:50]4[O:54][C:53]([C:52]=25)=[C:40]([OH:60])[CH:41]=1)[CH3:58]
Reactant: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)CCCCN
Agent: C1=Cc2cc3nnc(nc4nc(cc5ccc(cc1n2)[nH]5)C=N4)[nH]3
Agent: CCOC(=O)OC(=O)OCC
Agent: Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5

Procedure:
A solution of each of the compounds obtained in Examples 31 to 39, i.e., tetraazaporphin (synthesized in Examples 1 to 9)-PABA and 3-(4-aminobutyl)morphine in DMF was treated with DEPC in the presence of triethyl amine in the same manner as described in Examples 31 to 39. Thus, tetraazaporphin-PABA-morphine combined products were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[CH:31][C:32]=2[F:34])[C:27](Cl)=[N:26][N:25]=1.CC(O)(C)C>C(OCC)C>[Cl:23][C:24]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[CH:31][C:32]=2[F:34])[C:27]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([O:6][C:7]3[C:12]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=4)=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:4][CH:3]=2)=[N:26][N:25]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Reactant: Fc1ccc(F)c2c(Cl)nnc(Cl)c12
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4c(F)ccc(F)c34)cc2)n1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.100 g, 0.34 mmol) and 1,4-dichloro-5,8-difluorophthalazine (0.096 g, 0.41 mmol) was added tBuOH (1.0 mL). The resulting mixture was heated to 100° C. in a sealed tube for 45 min. The reaction was diluted with diethyl ether and the resulting solids were filtered and triturated with EtOAc. The solids were dried to yield 4-chloro-5,8-difluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine as a dark gray solid. MS m/z=492 [M+H]+. Calc'd for C24H16ClF2N7O: 491.89.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])/[CH:9]=[C:10](\[NH2:12])/[CH3:11].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[C:47]3[CH:46]=[CH:45][N:44]=[CH:43][C:42]=3[N:41]=[C:40]2[CH3:48])=[O:33])=[CH:26][CH:25]=1>C(O)C>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]1[C:9]([C:8](=[O:13])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:10]([CH3:11])[NH:12][C:30]([C:27]2[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=2)=[C:31]1[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:47]2[CH:46]=[CH:45][N:44]=[CH:43][C:42]=2[N:41]=[C:40]1[CH3:48])=[O:33]
Reactant: O=Cc1ccccc1Cl
Reactant: C/C(N)=C/C(=O)Nc1ccccn1
Reactant: Cc1nc2cnccc2n1CCCCOC(=O)CC(=O)c1ccc(F)cc1
Solvent: CCO
Product: CC1=C(C(=O)Nc2ccccn2)C(c2ccccc2Cl)C(C(=O)OCCCCn2c(C)nc3cnccc32)=C(c2ccc(F)cc2)N1

Procedure:
A solution of N-(pyrid-2-yl)-3-aminocrotonamide (0.50 g, 2.8 mM), 2-chlorobenzaldehyde (0.39 g, 2.8 mM) and 4-(2-methylimidazo[4,5-c]pyrid-1-yl)butyl 3-(4-fluorophenyl)-3-oxopropionate (1.04 g, 2.8 mM--see Preparation 1) in absolute ethanol (15 cm3) was heated at reflux, under nitrogen, for 5 hours. The cooled solution was evaporated to dryness and the residue purified by column chromatography on silica (Merck "Kieselgel 60"--Trade Mark) eluting with dichloromethane:methanol 97:3. The pure product-containing fractions were evaporated to dryness and the residual foam was re-dissolved in dichloromethane (2 cm3). Addition of ether (25 cm3) caused the product to crystallize out, yield 0.21 g, (12%), m.p. 129°-132°.
Reaction SMILES: N[CH:2]([CH2:15][CH2:16][CH3:17])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][N:6]=1.[CH2:18]=O.[C:20]([BH3-])#[N:21].[Na+].Cl.[OH-].[Na+]>CO.C(OCC)(=O)C>[ClH:14].[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][N:6]=[C:5]([O:4][CH2:3][CH:2]([N:21]([CH3:20])[CH3:18])[CH2:15][CH2:16][CH3:17])[C:9]=2[CH:10]=1
Reactant: CCCC(N)COc1noc2ccc(Cl)cc12
Reactant: C=O
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC(COc1noc2ccc(Cl)cc12)N(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g of 3-(2-aminopentyloxy)-5-chloro-1,2-benzoisoxazole in 5 ml of methanol is added 5 ml of 37% formalin, and then, 0.16 g of sodium cyanoborohydride is added with ice-cooling, and they are subjected to reaction at room temperature for 24 hours, after which 2N hydrochloric acid is added to adjust the pH to 1.5 and then stirring is effected for a further 30 minutes. Ethyl acetate is added to the reaction mixture, and the pH is adjusted to 9.5 with a 10% (w/w) aqueous sodium hydroxide solution, after which the organic layer is separated. The organic layer separated is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:chloroform:methanol=20:1] and thereafter this is dissolved in ethyl acetate. Thereto is added 5 ml of a dioxane solution (2.2N) of hydrogen chloride, and the crystals precipitated are collected by filtration, to obtain 0.17 g of colorless, crystalline 5-chloro-3-(2-dimethylaminopentyloxy)-1,2-benzoisoxazole hydrochloride having a melting point of 137.1°-137.7° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)(=[O:15])=[O:14].CS(O[CH2:35][C:36]1([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:38][CH2:37]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:35][C:36]1([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:38]1)[CH:6]=[C:5]2[S:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)(=[O:14])=[O:15]
Reactant: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2c[nH]c(=O)c3ccc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cn(CC3(CO[Si](C)(C)C(C)(C)C)CC3)c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C

Procedure:
tert-Butyl 4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate (Example 46b, 0.40 g), [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl methanesulfonate (0.24 g) and cesium carbonate (0.536 g) were stirred together in DMF (20 mL) at 110° C. for 72 h under nitrogen, cooled to room temperature, diluted with water (100 mL) and extracted into ethyl acetate (3×20 mL). The combined organics were washed with saturated brine (3×20 mL), dried (MgSO4) filtered and evaporated, and the residue was purified (SiO2 chromatography, elution with 10% ethyl acetate in DCM) to give (tert-butyl 4-[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate) as a solid. This was dissolved in DMF (10 mL), treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.089 g), potassium carbonate (0.077 g) and Pd-118 (0.006 g) and the resulting mixture was stirred at 70° C. under nitrogen for 1 h. After being cooled to room temperature, it was diluted with saturated brine and extracted into ethyl acetate (3×30 mL). The combined extracts were washed with brine (3×30 mL), dried (MgSO4) filtered and evaporated. The residue was dissolved in THF (20 mL), treated with 4 M HCl in dioxane (3 mL), stirred at room temperature for 3 h, evaporated and purified by preparative HPLC (Waters Xbridge column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to give the title compound (0.019 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[N:16]1[C:20](CN2C(=O)C3=CC=CC=C3C2=O)=NN=[C:17]1[CH2:33][N:34]1CCN(C)CC1.O.[NH2:43][NH2:44]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]2[CH:20]=[N:43][N:44]=[C:17]2[CH2:33][N:34]=1
Reactant: CN1CCN(Cc2nnc(CN3C(=O)c4ccccc4C3=O)n2-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1ccccc1C1=NCc2nncn2-c2ccccc21

Procedure:
In the manner given in Example 27, 2',5-dichloro-2-[3-[(4-methylpiperazino)methyl]-5-(phthalimidomethyl)- 4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1-[4-methylpiperazino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.