Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.[CH2:15]([O:22][C:23]1[C:28]([CH2:29][CH3:30])=[CH:27][C:26](B(O)O)=[C:25]([O:34][CH3:35])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.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>[CH2:15]([O:22][C:23]1[C:28]([CH2:29][CH3:30])=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]3[CH3:14])[N:3]=2)=[C:25]([O:34][CH3:35])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(C)n1-c1cccc(Br)n1
Reactant: CCc1cc(B(O)O)c(OC)cc1OCc1ccccc1
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: CCO
Product: CCc1cc(-c2cccc(-n3c(C)ccc3C)n2)c(OC)cc1OCc1ccccc1
Yield: 73.1 %

Procedure:
Under a nitrogen atmosphere, 5.00 g (19.91 mmol) of 2-bromo-6-(2,5-dimethylpyrrol-1-yl)pyridine, 5.98 g (20.91 mmol) of 4-benzyloxy-5-ethyl-2-methoxy-phenylboronic acid (5), 8.44 g (79.64 mmol) of sodium carbonate and 1.15 g (0.996 mmol) of tetrakis(triphenylphosphine)palladium(0) were combined in 90 mL of ethanol and 10 mL of water. The solution was allowed to reflux for 64 hours, and then the reaction mixture was concentrated in vacuo. The resultant yellow residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted again with ethyl acetate (200 mL). The combined organic extracts were washed with brine (1×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield crude product as a yellow oil which crystallized upon standing. Recrystallization of this solid from absolute ethanol afforded 6.00 g (73%) of 2-(4-benzyloxy-5-ethyl-2-methoxy-phenyl)-6-(2,5-dimethyl-pyrrol-1-yl)-pyridine (6) as a tan solid.
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]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:38][C@H:39]1[CH2:43][NH:42][CH2:41][C@@H:40]1[OH:44].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[NH2:38][C@@H:39]1[C@@H:40]([OH:44])[CH2:41][N:42]([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:19]=[CH:20][C:21]([O:24][C:25]([Cl:28])([F:26])[F:27])=[CH:22][CH:23]=3)=[O:16])=[CH:4][N:3]=2)[CH2:43]1
Reactant: N[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncc(F)c2)C[C@@H]1O
Temperature: 80 °C
Reaction time: 44 h

Procedure:
2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide (Stage 266.1, 70 mg, 0.160 mmol) and DIPEA (0.196 mL, 1.121 mmol) were added to a vial containing iPrOH (2 mL). (3S,4S)-4-Aminopyrrolidin-3-ol (30 mg, 0.168 mmol) was added. The mixture was stirred at 80° C. for 44 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced to give the crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/MeOH, from 95:5 to 8:2) to afford the title product as a beige solid. HPLC (Condition 10) tR=5.83 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=494.2/496.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.91 (dd, J=11.53, 2.93 Hz, 1H) 3.22-3.28 (m, 1H) 3.36-3.46 (m, 2H) 3.59-3.66 (m, 1H) 4.02-4.08 (m, 1H) 5.48 (d, J=3.91 Hz, 1H) 7.35 (d, J=8.60 Hz, 2H) 7.87 (m, J=9.00 Hz, 3H) 8.13 (d, J=2.35 Hz, 1H) 8.55 (s, 1H) 8.64 (d, J=2.74 Hz, 1H) 8.79-8.83 (m, 1H) 10.22 (s, 1H).
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][C:11]([F:24])=[C:12]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[CH:13]=2)[N:8]=[C:7]([N:25]2[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]2)[N:6]=1>C1COCC1>[NH2:3][C:5]1[C:14]2[C:9](=[CH:10][C:11]([F:24])=[C:12]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[CH:13]=2)[N:8]=[C:7]([N:25]2[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]2)[N:6]=1
Reactant: CCOC(=O)c1cnn(-c2nc(Cl)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2nc(N)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Reaction time: 6 h
Yield: 63.3 %

Procedure:
A methanol solution of ammonia (7M, 0.39 mL, 2.7 mmol) was added to a solution of the above 1-[4-chloro-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, ethyl ester (120 mg, 0.27 mmol) and THF (2 mL). The mixture was stirred 6 h, then concentrated. The residue was triturated with Et2O, providing the titled compound (72 mg, 64%). 1H NMR (500 MHz, DMSO-d6): 8.96 (d, J=0.8 Hz, 1H), 8.44-8.02 (m, 3H), 7.71 (d, J=11.9 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.17 (dd, J=8.6, 6.2 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.12 (s, 6H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19][CH2:20][C@@H:21]([C:30]([OH:32])=O)[NH:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CN(C=O)C>CCOC(C)=O>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([O:23][NH:22][C@@H:21]1[C:30](=[O:32])[NH:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[S:19][CH2:20]1)=[O:29]
Reactant: CC(C)(C)C(=O)ON[C@@H](CSc1cccc(F)c1N)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)ON[C@H]1CSc2cccc(F)c2NC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
0.366 mL of diethyl cyanophosphonate (0.393 mg, 2.41 mmol) is placed in a 25 mL three-necked flask containing 670 mg of 49 (2.028 mmol) and 10 mL of DMF, at 0° C., followed by addition, after 10 minutes, of 0.273 mL of TEA (1.943 mmol). The reaction medium is stirred at 0° C. for 2 hours. 30 mL of EtOAc are added and the mixture is then washed with twice 30 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (70 g) with a heptane/EtOAc eluent (as an EtOAc gradient: 8% to 50%). 68.4 mg of expected product 50 are obtained (white solid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]([CH3:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>>[CH3:38][N:27]([CH3:26])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:30][CH:29]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Product: CN(C)c1ccc(CC(=O)Nc2cccc(-c3n[nH]c4ccc(C(N)=O)cc34)c2)cc1
Yield: 14.3 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-(dimethylamino)phenyl acetic acid (0.13 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 33 mg (13% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.15 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (t, 1H), 7.35 (br s, 1H), 7.18 (m, 2H), 6.68 (d, 2H), 3.5 (s, 2H), 2.9 (s, 6H); ES-MS (m/z) 414 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].C(O)C.C(O[C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:13]([C:16]#[N:17])[C:14]#[N:15])C>O>[NH2:15][C:14]1[O:3][N:2]=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[C:16]#[N:17]
Reactant: CCOC(=C(C#N)C#N)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)noc1N

Procedure:
Hydroxylamine hydrochloride was suspended in water (30 ml) and added sodium hydroxide (4.4 g, 0.11 mole), then ethanol (40 ml) followed by batchwise addition of 2-(Ethoxy-phenyl-methylene)-malononitrile(21.7 g, 0.11 mole). Heated reaction mixture to 50° C. for 2 hours. Removed ethanol under vacuum and filtered precipitate. Redissolved precipitate in 50% ethyl acetate/hexanes and chromatographed on silica gel to give 8.2 g product after removal of solvent (yield: 40%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:16])[C:14]=2[OH:15])=[CH:6][CH:5]=1.S(OC)(O[CH3:23])(=O)=O>O>[CH3:23][O:15][C:14]1[C:13]([CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:18][CH:17]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(Oc2ccc(Cl)cc2)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cccc1Oc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
An aqueous solution (25 ml) of potassium hydroxide (7.5 g) was added to a mixture of 6-(4-chlorophenoxy)-o-cresol (10.5 g) and dimethyl sulfate (8.6 ml) with stirring at room temperature, and refluxed under heating for an hour. After cooling, water was added to the reaction mixture and extracted with n-hexane. The extract was washed with water, dried over magnesium sulfate and evaporated to give oily 4-chlorophenyl 2-methoxy-3-methylphenyl ether (10.7 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]=[C:29]1[O:33][C:31](=[O:32])[CH2:30]1>C1(C)C=CC=CC=1>[O:33]=[C:29]([CH3:28])[CH2:30][C:31]([O:20][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:32]
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OC(COCc1ccccc1)COCc1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
1.00 g (3.67 mmol) 1,3-dibenzyloxy-2-propanol is dissolved in 10 ml toluene, 3.72 mg (0.04 mmol) triethylamine are added, and the mixture is stirred at 90° C. 401 mg (4.77 mmol) diketene are added, and stirring is continued for 1 h. The mixture is cooled to room temperature, diluted with ice-water and extracted with toluene. The organic layer is dried over magnesium sulfate and evaporated to dryness. The crude product is purified by column chromatography on silica gel (eluent: cyclohexane/ethylacetate 2:1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3)[CH3:2].[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CS(C)=O.[NH4+].[OH-]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:25][CH2:24][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3cc(Br)ccc3nc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(Br)ccc3nc21
Temperature: 110 °C
Yield: 98.4 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-bromo-1H-pyrazolo[3,4-b]quinoline (6.5 g, 0.021 mol), cyclohexanemethylamine (5.46 g, 0.042 mol) and DMSO (20 ml) was heated at 110° C. overnight. The reaction mixture was cooled, poured into water and basified with NH4OH. The mixture was extracted with CH2Cl2 (2×100 ml) and the combined CH2Cl2 extracts were washed with brine, then evaporated to about 20 ml. The solution was purified by column chromatography on silica gel eluting with ethyl acetate to afford 8.0 g (98.8%) of 1-ethyl-6-bromo-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 158°-160° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH3:29])[C:17]=3[CH3:30])=[C:12]([C:31]([CH3:33])=[CH2:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH3:29])[C:17]=3[CH3:30])=[C:12]([CH:31]([CH3:33])[CH3:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=C(C)c1snc(-c2ccc(CC)cc2)c1COc1ccc(CCC(=O)OCC)c(C)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(CC)cc3)nsc2C(C)C)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of ethyl 3-(4-[[3-(4-ethylphenyl)-5-(prop-1-en-2-yl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoate (76.3 mg, 0.16 mmol, 1.00 equiv) in ethanol (5 mL) and palladium on carbon (10%, 76 mg). The mixture was then subject to an atmosphere of hydrogen and stirred for 12 h at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 73.1 mg (95%) of ethyl 3-(4-[[3-(4-ethylphenyl)-5-(propan-2-yl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoate as white oil.
Reaction SMILES: C(O[C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:24][NH2:25]>CCO>[CH3:6][CH:5]1[N:7]2[C:8]([CH2:9][O:10][C:11]3[C:12]2=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=3)=[N:25][NH:24][C:4]1=[O:22]
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(C)c([N+](=O)[O-])cc21
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1[N+](=O)[O-])N1C(=NNC(=O)C1C)CO2
Temperature: 120 °C
Yield: 76.9 %

Procedure:
To a solution of 2-(7-methyl-6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.130 g, 0.40 mmol) in EtOH (8 mL) was added hydrazine hydrate (98%, 1.4 mmol, 0.070 g) and the reaction mixture was heated at 120° C. for 4 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give 4,7-dimethyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.085 g, 75%) as yellow solid, which was used directly in the next step. TLC (eluting with 25% EtOAc in petroleum ether) Rf=0.4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Br.[Br:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[Br:14][CH2:15][CH2:16][CH2:17][NH:18][S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: NCCCBr
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)NCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyanobenzenesulfonyl chloride (5 g, 0.0248 mol) was added dropwise to a solution of 3-bromopropylamine hydrobromide (6.61 g, 0.0302 mol) and triethylamine (6.26 g, 0.062 mol) in dry dichloromethane (50 ml) at 0° C. and stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over sodium sulfate.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](Cl)=[CH:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([O:1][C:2]3[C:3]([C:12](=[O:14])[CH3:13])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: CC(=O)c1nc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
(3-Hydroxy-quinolin-2-yl)-ethanone (878 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (7.03 g), and 4-dimethylaminopyridine (3.44 g) were suspended in o-dichlorobenzene (20 ml), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-acetone to give 1-[3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (758 mg, yield 36%).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[N:23]([CH2:24][CH2:25][O:26][CH2:27][CH:28]=[CH2:29])[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:10][CH2:9]2)C=CC=CC=1.CC1C=CC=CC=1.[C:37](Cl)(=[O:41])[O:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:27]([O:26][CH2:25][CH2:24][N:23]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:37]([O:38][CH2:39][CH3:40])=[O:41])[CH2:13][CH2:12]1)[CH:28]=[CH2:29]
Reactant: C=CCOCCn1c(CC2CCN(Cc3ccccc3)CC2)nc2cccnc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOCCn1c(CC2CCN(C(=O)OCC)CC2)nc2cccnc21
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a stirred and refluxed mixture of 13.5 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-3-[2-(2-propenyloxy)ethyl)-3H-imidazo[4,5-b]-pyridine and 90 parts of methylbenzene were added dropwise 5.4 parts of ethyl carbonochloridate. Upon complete addition, stirring was continued for 1 hour at reflux temperature. After cooling, the reaction mixture was diluted with water and the whole was treated with potassium carbonate. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 14 parts (75.1%) of ethyl 4-[[3-[2-(2-propenyloxy)ethyl]-3H-imidazo[4,5-b]pyridine-2-yl]methyl]-1-piperidinecarboxylate as a residue (compound 43).
Reaction SMILES: [O:1]=O.[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=C)=[CH:8][C:7]=1[OH:14].CSC>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:1])=[CH:8][C:7]=1[OH:14]
Reactant: C=Cc1ccc(C(=O)OC)c(O)c1
Reactant: O=O
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A steady stream of O2 (g) is passed through a cold (−78° C.) solution of 2-hydroxy-4-vinyl-benzoic acid methyl ester (3.28 g, 0.0184 mol) in CH2Cl2 (50 ml). After 5 minutes, O3 (g) is bubbled into the solution until the solution's color turns blue/gray. The solution is then purged with O2 (g) for 5 minutes, treated with DMS (4.05 ml, 0.0552 mol) and allowed to warm to room temperature overnight. All volatiles are removed in vacuo and the crude product is purified with silica gel column chromatography (0-100% ethyl acetate in hexanes gradient) to afford 4-formyl-2-hydroxy-benzoic acid methyl ester: ESMS m/z 181.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](F)=[CH:9][CH:8]=3.[Li]CCCC.[CH:28](N1CCOCC1)=[O:29]>C1COCC1>[Br:1][C:2]1[CH:14]=[C:13]2[C:5](=[CH:4][CH:3]=1)[N:6]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:7]1[CH:8]=[CH:9][C:10]([CH:28]=[O:29])=[CH:11][C:12]2=1
Reactant: COCCOCCn1c2ccc(F)cc2c2cc(Br)ccc21
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCn1c2ccc(Br)cc2c2cc(C=O)ccc21
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 65 %

Procedure:
To a solution of 3-bromo-6-fluoro-9-(2-(2-methoxyethoxy)ethyl)-9H-carbazole (3.4 g, 9.3 mmol) in dry THF (50 ml) was added n-BuLi (1.6 M, 8.7 ml, 13.9 mmol) at −78° C. The resulting mixture was stirred for 50 min at −78° C. and then added with N-formylmorpholine (1.86 ml, 18.6 mmol). The reaction mixture was allowed to warm to rt and stirred for 2 h before quenched with ammonia chloride solution. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to give compound 7 in 65% yield. 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.53 (s, 1H), 8.02-8.00 (m, 1H), 7.80-7.77 (m, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.45 (dd, J=4.0 Hz, J=9.2 Hz 1H), 7.28-7.23 (m, 1H), 4.52 (t, J=5.6 Hz, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.52-3.50 (m, 2H), 3.40 (d, J=2.8 Hz, 2H), 3.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 191.8, 159.3, 156.9, 145.2, 137.8, 128.8, 127.5, 124.4, 123.7, 123.7, 123.7, 122.8, 114.8, 114.5, 110.6, 110.5, 109.8, 106.7, 106.4, 72.1, 71.0, 69.5, 59.2, 43.9. HRMS (MALDI-TOF) m/z Calcd for C18H18FNO3 316.1343. Found 316.1340[M]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25](O)=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CCC(NC2CCCCC2)CC1.ClC(OCC(C)C)=O.[N+:76](=[CH2:78])=[N-:77]>>[C:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:25](=[O:26])[CH:78]=[N+:76]=[N-:77])=[CH:19][CH:18]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: C=[N+]=[N-]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)C=[N+]=[N-])cc1

Procedure:
In a manner analogous to that described in Example 19(i), N-(benzyloxycarbonyl)-3-(4-tert.butoxyphenyl)-L-alanine (prepared from 7.45 g of the dicyclohexylammonium salt) was treated with isobutyl chloroformate followed by reaction with diazomethane to give 3.58 g of benzyl [2-(4-tert.butoxyphenyl)-1(S)-(2-diazoacetyl)ethyl]carbamate as a yellow solid of melting point 80°-82° C.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[N:34]([C:40]1[C:41]([CH2:55][OH:56])=[C:42]([C:46]3[N:50]([CH3:51])[C:49]([C:52](O)=[O:53])=[CH:48][CH:47]=3)[CH:43]=[CH:44][CH:45]=1)[N:33]=[CH:32]2)([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[N:34]([C:40]1[C:41]([CH2:55][OH:56])=[C:42]([C:46]3[N:50]([CH3:51])[C:49]([C:52]([NH2:2])=[O:53])=[CH:48][CH:47]=3)[CH:43]=[CH:44][CH:45]=1)[N:33]=[CH:32]2)([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1c(C(=O)O)ccc1-c1cccc(-n2ncc3cc(C(C)(C)C)ccc3c2=O)c1CO
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1c(C(N)=O)ccc1-c1cccc(-n2ncc3cc(C(C)(C)C)ccc3c2=O)c1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
HATU (110 mg, 0.288 mmol) was added to a solution of 5-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid (113 mg, 0.262 mmol) in dry THF (15 mL). Ammonia gas was bubbled through the solution. The mixture was stirred at room temperature under NH3 (g) for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 5-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide (25 mg, yield 22%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.02-7.90 (m, 2H), 7.54-7.35 (m, 2H), 7.24-7.13 (m, 2H), 7.02 (d, J=1.9 Hz, 1H), 4.37 (s, 2H), 3.87 (s, 3H), 1.37 (s, 9H). LC-MS calcd for C25H26N4O3 (m/e) 430.20, obsd 883 [2M+Na]+.