Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][N:10]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([CH3:22])[CH:21]=2)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)[CH:11]=1.[I:24]I.[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[I:24][C:9]1[N:10]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([CH3:22])[CH:21]=2)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)[CH:11]=[C:7]([CH3:6])[N:8]=1
Reactant: II
Reactant: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)c(I)n1
Temperature: 25 °C

Procedure:
n-Butyllithium (2.94 cm3 of a 1.43M solution in n-hexane) was added dropwise to a stirred suspension of 6-(4-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.45 g) (see Example 6) in tetrahydrofuran (THF) (25 cm3) at -70° C. under nitrogen. After one hour iodine (0.51 g) was added and the mixture warmed to room temperature over 1.5 hours. Ammonium chloride solution was added (5 cm3), and the mixture was poured into water (20 cm3). The aqueous mixture was extracted with dichloromethane (3×50 cm3) and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]). Elution with chloroform followed by combination and evaporation of appropriate fractions gave a solid which was recrystallised from ethyl acetate to afford 6-(2-iodo-4-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone, m.p. (d) 260° (0.22 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([NH:28][C:6]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1)=[O:8])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CC(C(=O)NCc2ccccc2)C1
Reaction time: 1.5 h

Procedure:
To a solution of 3-oxocyclobutanecarboxylic acid (13.5 g) in tetrahydrofuran (135 mL), 1,1′-carbonyldiimidazole (23.0 g) was added under cooling with ice. The mixture was brought to room temperature and stirred for 90 minutes. Benzylamine (15.5 mL) was added and the mixture was stirred at that temperature for 14 hours. The crude product was adsorbed on diatomaceous earth with the solvent being distilled off under reduced pressure. The crude product adsorbed on the diatomaceous earth was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to give N-benzyl-3-oxocyclobutanecarboxamide as a colorless solid (16.9 g).
Reaction SMILES: [OH:1][C:2]1([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:23]=[C:18]([C:2]2([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]2)[CH:19]=[N:20][CH:21]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2cncc(C(F)(F)F)c2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: OC1(c2cncc(C(F)(F)F)c2)CCNCC1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
Benzyl 4-hydroxy-4-[5-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxylate (1.30 g, 3.42 mmol), 5% palladium on activated carbon (50 mg) and ammonium formate (2.0 g) in ethanol (20 mL) were stirred and heated under reflux for 1 hour then cooled to ambient temperature and filtered through diatomaceous earth. The filtrate was applied to an SCX column and eluted with methanol followed by 2M ammonia in methanol. Fractions containing product were combined and evaporated then purified by flash silica chromatography, elution gradient 10 to 20% 2M ammonia in methanol in DCM. Pure fractions were evaporated to dryness to afford 4-[5-(trifluoromethyl)pyridin-3-yl]piperidin-4-ol (0.417 g, 50%) as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([C:20]1[CH:21]=[C:22]([C:25]([O:27]C)=[O:26])[NH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O>[CH2:6]([C:20]1[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[NH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Yield: 89.6 %

Procedure:
A solution (1 ml) of 2N sodium hydroxide was added to an ethanol solution (5 ml) of 0.22 g (0.69 mmol) of methyl 4-tetradecylpyrrole-2-carboxylate prepared in Example 9 and heated under reflux for 13 hours. Water was added to the resulting mixture, and then washed with ether. After acidifying the aqueous layer with hydrochloric acid, the mixture was extracted with ether and dried over anhydrous magnesium sulfate. The removal of the solvent afforded 0.19 g (95% yield) of 4-tetradecylpyrrole-2-carboxylic acid, m.p. 148°-150 ° C.
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:20](=[N:22]O)[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([CH:20]([NH2:22])[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: CC(=NO)c1nccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)N)nccc32)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
A mixture of 1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone oxime (1.29 g, 3.92 mmol), zinc (2.55 g, 39.2 mmol), and NH4Cl (2.10 mg, 39.2 mmol) in MeOH (5 mL) and HOAc (3 mL) was stirred at 80° C. for 4 h. The mixture was cooled to RT and the solid filtered. The filtrate was concentrated under reduced pressure. To the residue was added ammonia solution (50 mL) and the reaction mixture was extracted with DCM (3×50 mL). The combined organic extracts were concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH/TEA (15:1:0.2) to afford 1.08 g (87.4%) (±)-1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanamine as a yellow solid: MS (ESI) m/z: 316.2 [M+1]+.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].C(=O)=O.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O-:20].[K+]>O>[OH:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:1]([OH:2])=[O:4])[CH:15]=2)[CH:10]=1
Reactant: [O-]c1ccc2ccccc2c1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 280 °C
Yield: 67 %

Procedure:
A stainless steel pressure autoclave is charged with 100 parts of kerosene and 38 parts of potassium carbonate and heated to 280° C. It is then pressurized with 10 bar of carbon dioxide. Over the course of 5 hours, 50 parts of potassium β-naphtholate are metered in as a suspension in kerosene via a metering pump, part of the kerosene being distilled off, condensed and transferred out of the reaction vessel at reduced pressure. After cooling, the reaction mixture is taken up in water and the kerosene upper phase is decanted off. After acidification with sulfuric acid to a pH of 7, unreacted β-naphthol can be precipitated and separated off. Further acidification to pH 4 precipitates first the 2-hydroxynaphthalene-6-carboxylic acid and at pH 1 finally the remaining acids. The 2-hydroxynaphthalene-6-carboxylic acid is obtained in a yield of 67% based on potassium β-naphtholate used. In addition, 23% of unreacted β-naphtholate and small amounts of 2-hydroxynaphthalene-3-carboxylic acid and 2-hydroxynaphthalene-3,6-dicarboxylic acid are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.C(OCC)(=O)C>C(O)(=O)C.[Pd]>[NH2:26][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13][C:12]=3[CH:25]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Yield: 93.8 %

Procedure:
A solution of 1,1-dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (example 8, step 1) (2.3 g, 6.0 mmol), in acetic acid (20 mL) and ethyl acetate (20 mL) was hydrogenated at 45 psi over 10% Pd—C (1.0 g) for 1 h using a Parr apparatus. The catalyst was filtered off and the filtrate was concentrated to give 1,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.0 g, 94% yield) as a light yellow oil. MS (EI) for C20H25N3O3: 356 (MH+).
Reaction SMILES: [C:1]([CH:5]([CH:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)[C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:7][SiH3:8])([CH3:4])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[C:1]([CH:5]([C@@H:21]1[CH2:22][C@H:23]([OH:25])[CH2:24]1)[C:6]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[O:7][SiH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(C1CC(=O)C1)C(O[SiH3])(c1ccccc1)c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C([C@H]1C[C@@H](O)C1)C(O[SiH3])(c1ccccc1)c1ccccc1
Temperature: -78 °C

Procedure:
In a 50 mL flask with 3-(tert-butyl-diphenyl-siloxyethyl)cyclobutanone (0.48 g, 1.36 mmol) inside, dry THF 10 mL was added under argon to give a light yellow solution. This was cooled to −78° C., after a while, L-selectride (1.0 M in THF, 1.6 mL, 1.63 mmol) was added drop by drop and this was allowed to warm up to room temperature, after which the reaction was quenched with saturated NaHCO3 Then cool the mixture to 0° C., add 30% H2O2 drop by drop, followed by the addition of H2O and EtOAc. The organic phase was separated, washed with H2O twice and brine once, dried over MgSO4 and solvent evaporation gave the crude product, which was purified by silica gel flash chromatography (Hexane:EtOAc=9:1) to give a colorless oil (0.3 g, 61.8%). 1H NMR (CDCl3, 300 MHz): δ 1.04 (s, 9H), 1.40-2.10 (m, 5H), 2.38-2.47 (m, 2H), 3.58-3.62 (t, J=6.3, 2H), 4.04-4.14 (m, 1H), 7.34-7.45 (m, 6H), 7.64-7.67 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:22]=[CH:21][C:10]3[CH2:11][CH2:12][N:13]([CH:16]([CH3:20])[CH2:17][CH2:18]O)[CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:23])=[N:3]1.S(Cl)([Cl:26])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:26][CH2:18][CH2:17][CH:16]([N:13]1[CH2:12][CH2:11][C:10]2[CH:21]=[CH:22][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:23])[CH:5]=3)=[CH:8][C:9]=2[CH2:15][CH2:14]1)[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(-c2ccc3c(c2)CCN(C(C)CCO)CC3)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccc3c(c2)CCN(C(C)CCCl)CC3)n(C)n1

Procedure:
To a stirred solution of 3-[7-(1,3-dimethyl-1H-pyrazol-5-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]-1-butanol (0.25 g) (intermediate 9) in chloroform (8 ml), at room temperature, thionyl chloride (0.11 ml) was added dropwise. After 2h, saturated aqueous sodium hydrogencarbonate (5 ml) was added, the reaction mixture was extracted with dichloromethane (15 ml), the organic phase dried with sodium sulphate and the solvent evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with 80% cyclohexane-ethyl acetate to give the title compound (0.23 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4][N:3]=1.B([C:23]1[CH:34]=[CH:33][C:26]([CH2:27][C@@H:28]([C:30]([OH:32])=[O:31])[NH2:29])=[CH:25][CH:24]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:29][CH:28]([CH2:27][C:26]1[CH:33]=[CH:34][C:23]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1)[C:30]([OH:32])=[O:31]
Reactant: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(Cc1ccc(-c2cc(OC(c3ccccc3)C(F)(F)F)ncn2)cc1)C(=O)O
Temperature: 120 °C
Yield: 11500.3 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with 4-chloro-6-(2,2,2-trifluoro-1-phenyl-ethoxy)-pyrimidine (30 mg, 0.1 μmol), 4-borono-L-phenylalanine (32 mg, 0.16 mmol), 1 ml of acetonitrile and 0.6 ml of water. Aqueous sodium carbonate (0.42 ml, 1M) was added to above solution followed by 10 mol percent of POPd2 (dihydrogen di-μ-chlorodichlorobis(di-tert-butylphosphinito-κP) dipalladate. The reaction vessel was sealed and heated to 120° C. for 30 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 4.8 mg of 2-amino-3-{4-[6-(2,2,2-trifluoro-1-phenyl-ethoxy)-pyrimidin-4-yl]-phenyl}-propionic acid, yield 11%. 1H-NMR (400 MHz, CD3OD): δ 3.20(m, 1H), 3.40(m, 1H), 4.25(t, 1H), 6.82(dd, 1H), 7.43(m, 5H), 7.57(s, 1H), 7.60(m, 2H), 8.10(d, 2H), 8.75(s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[N:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH2:17][CH2:16][N:6]2[C:7]=1[C:8](O)([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:4]=[C:5]2[N:18]([C:19]3[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])[CH2:17][CH2:16][N:6]2[C:7]=1[C:8]([CH2:12][CH2:13][CH3:14])=[CH:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCC(O)(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC=C(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 25 °C

Procedure:
A mixture of 4-[2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-yl]-heptan-4-ol (0.0444 g, 0.000120 mol) and p-toluenesulfonic acid-H2O (15 mole %) in toluene (3 mL) was heated at reflux for 1 h. Upon cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was partitioned between ether and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give the desired product in quantitative yield. LC-MS indicated the presence of two regioisomers in an approximate ratio of 2:1.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:30])[NH:15][C:16]([N:20]4[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[CH:22]=[N:21]4)=[N:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:30])[NH:15][C:16]([N:20]4[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[N:21]4)=[N:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)c4ccccc4)ccc3c(=O)[nH]2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc(S(=O)(=O)c4ccccc4)ccc3c(=O)[nH]2)c1
Reaction time: 16 h
Yield: 14.7 %

Procedure:
A mixture of 1-(7-benzenesulfonyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid, ethyl ester (50 mg, 0.12 mmol), THF (2 mL) and aqueous 1M LiOH (0.6 mL, 0.6 mmol) was stirred for 16 h. The THF was removed under reduced pressure and aqueous 1M HCl (3 mL, 3 mmol) was added. The crude product was collected by filtration and purified by HPLC to afford the titled compound (7.0 mg, 14%). MS (ESI): mass calcd. for C18H12N4O5S, 396.1; m/z found, 397.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.43-12.81 (m, 2H), 8.99 (s, 1H), 8.34-8.25 (m, 2H), 8.18 (s, 1H), 8.05 (d, J=7.6, 2H), 7.96 (dd, J=8.3, 1.5, 1H), 7.78-7.71 (m, 1H), 7.71-7.63 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].Cl.Cl[CH2:15][CH2:16][CH2:17][NH2:18]>N>[N:1]1[C:10]2[CH:9]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CCCC2
Reactant: NCCCCl
Agent: Cl
Agent: N
Agent: [NH2-]
Product: NCCCC1CCCc2cccnc21
Reaction time: 2 h
Yield: 26.5 %

Procedure:
5,6,7,8-Tetrahydroquinoline (20 g) was added quickly to sodamide (17.6 g) in liquid ammonia (250 ml) to give a dark red coloured solution. 3-Chloropropylamine hydrochloride (28.9 g) was added in portions over four hours when loss of colour was permanent after which the reaction was stirred for a further 2 hours and then quenched with ammonium chloride (20 g). The liquid ammonia was allowed to evaporate and the residues were partitioned between chloroform and water. The pH was lowered to 6 and the chloroform layer was discarded. The aqueous layer was basified (pH 12-14), and extracted with chloroform, the chloroform extracts were dried, combined, evaporated and the residue was vacuum distilled to give 3-(5,6,7,8-tetrahydroquinol-8-yl) propylamine (7.58 g), b.p. 92°-94° C. at 0.1 mm Hg.
Reaction SMILES: O[CH:2]1[C:11]2[CH:10]=[N:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:14][C:15]([O-:17])=[O:16].S(=O)(=O)(O)O.N>>[CH3:13][O:12][C:8]1[N:9]=[CH:10][C:11]2[CH2:2][CH:3]([CH2:14][C:15]([OH:17])=[O:16])[CH:4]=[CH:5][C:6]=2[CH:7]=1
Reactant: COc1cc2c(cn1)C(O)C(CC(=O)[O-])CC2
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cc2c(cn1)CC(CC(=O)O)C=C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11 Parts of 8-hydroxy-3-methoxy-5,6,7,8-tetrahydro-2-azanaphthalene-7-acetate described in Example 1 is added to 110 parts by volumn of sulfuric acid at room temperature and stirred for 15 minutes. 200 Parts of ice water are added and the solution is made basic with 300 parts by volume of aqueous ammonia. The solution is filtered through celite and then extracted three times with chloroform. Removal of the chloroform and crystallization from methanol provides 3-methoxy-7,8-dihydro-2-azanaphthalene-7-acetic acid, melting at 151-152° C and having the following formula ##SPC27##
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(pyridin-3-yl)acetamide (0.052 g, 0.12 mmol), ethanol (3.5 ml), and 4-dimethylaminobenzaldehyde (0.025 g, 0.17 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was heated at 70° C. for 5.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 50% dichloromethane in ethyl acetate and then 3% methanol in ethyl acetate/dichloromethane (v/v; 8:2). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.022 g, 34%); 1H-NMR (500 MHz, DMSO-d6) 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.72 (br s, 4H, piperazine N(CH2)2), 3.27 (s, 2H, NCH2CO), 6.82 (d, J=9.07 Hz, 2H), and 8.01 (d, J=9.41 Hz, 2H) (3,5-C6H4—NMe2 and 2,6-C6H4—NMe2), 7.34 (dd, J=9.41, 4.70 Hz, 1H, pyridyl 5-H), 8.12 (d, J=8.46 Hz, 1H, pyrid-3-yl), 8.16 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.27 (d, J=4.70, 1H, pyrid-3-yl), 8.85 (s, 1H, pyridyl 2-H), 10.04 (s, 1H, CONH), 13.15 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z): Rt=5.30 min—535, 537 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 535.1596, calculated for C25H28BrN8O (M+H)+: 535.1569.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[C:42]([CH3:43])[C:35]=12.C(#N)C>C(Cl)Cl>[Cl:33][C:34]1[C:35]2[C:42]([CH3:43])=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: Cc1cnc2[nH]cnc(Cl)c1-2
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Agent: Br
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product from Step C of Example 2 (1.06 g, 2.1 mmol) in CH2Cl2 (30 mL) was added HBr (5.7 M in acetic acid; 2.2 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h, concentrated in vacuo and co-evaporated with toluene (2×15 mL). The resulting oil was dissolved in MeCN (10 mL) and added dropwise into a solution of the sodium salt of 4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine in acetonitrile [generated in situ from 4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see J. Med. Chem. 33: 1984 (1990)] (0.62 g, 3.7 mmol) in anhydrous acetonitrile (70 mL), and NaH (60% in mineral oil, 148 mg, 3.7 mmol), after 2 h of vigorous stirring at room temperature]. The combined mixture was stirred at room temperature for 24 h and then evaporated to dryness. The residue was suspended in water (100 mL) and extracted with EtOAc (250+100 mL). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (5×5 cm) using hexane/ethyl acetate (9/1, 5/1, 3/1) gradient as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (0.87 g) as a colorless foam.