Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.CC(C)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=3)[CH:8]=2)[N:3]=1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: COc1cccc(CBr)c1
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(COc2ccc3nc(Cl)ccc3c2)c1
Yield: 44.5 %

Procedure:
To a stirred solution of 2-chloro-6-hydroxy-quinoline (0.6 g, 3.0 mmol) in aceton (15 ml) potassium carbonate (0.55 g, 4.0 mmol) and 3-methoxybenzylbromide (0.8 g, 4.0 mmol) were added at ambient temperature. Then the reaction mixture was heated to reflux for 3 h. Upon cooling to ambient temperature water was added and the whole mixture extracted twice with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane, ethyl acetate 1:0=>1:4) yielded 2-chloro-6-(3-methoxy-benzyloxy)-quinoline as a white solid (0.4 g, 40%), MS 300.8 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([CH2:16]Cl)[N:13]=[C:12]([NH2:18])[N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:14]2[CH:15]=[C:10]([Cl:9])[N:11]=[C:12]([NH2:18])[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)cc(CCl)n1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(COc2ccc(Br)cc2)n1
Temperature: 100 °C

Procedure:
A mixture of 4-bromophenol (173 mg, 1.00 mmol), 4-chloro-6-(chloromethyl)pyrimidin-2-amine (CAS#: 92311-35-8) (178 mg, 1.16 mmol) and K2CO3 (175 mg, 1.00 mmol) in DMF (5 mL) was heated to 100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo, and the residue taken up in and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided 4-((4-bromophenoxy)methyl)-6-chloropyrimidin-2-amine as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1.O.[NH2:24][NH2:25]>CO>[NH:24]([C:3](=[O:2])[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1)[NH2:25]
Reactant: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of benzyl 4-(2-methoxy-2-oxoethoxy)benzoate (1.0 g, 3.33 mmol) in MeOH (15 mL) was added hydrazine hydrate (1.7 mL). After stirring for 1 h at rt, the reaction mixture was filtered. The cake was washed with MeOH (3×4 mL) and dryed under vacuo at 50° C. overnight gave 936 mg of the title compound (94%) as a white solid in 99.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][C@@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:19][CH:20]([CH3:22])[CH3:21])[C@@H:12]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N=C1N[C@@H](CC(C)C)CS1
Reactant: CC(C)CBr
Product: Cc1cc(Br)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Bromo-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-bromo -2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-bromo-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CC[NH:30]C1.[NH:33]1[CH2:41][CH2:40][CH2:39][CH:35]([C:36](O)=[O:37])[CH2:34]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:33]3[CH2:41][CH2:40][CH2:39][CH:35]([C:36]([NH2:30])=[O:37])[CH2:34]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: O=C(O)C1CCCNC1
Reactant: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCCC(C(N)=O)C3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with nipecotic acid. A yellow solid 107 was obtained (0.0283 g, 59%). 1H-NMR (CDCl3, 400 MHz) δ 1.64–1.74 (m, 1H), 1.90–1.98 (m, 1H), 2.06–2.12 (m, 2H), 2.84–2.92 (m, 1H), 3.52–3.59 (m, 1H), 3.72–3.93 (m, 2H), 3.83 (s, 3H), 4.22–4.27 (m, 1H), 6.96 (d, J=5.9 Hz, 1H), 7.00–7.08 (m, 4H), 7.45–7.52 (m, 3H), 7.84 (s, 1H), 8.31 (d, J=6.5 Hz, 1H); MS (APCI) m/z 489 (M+H)+.
Reaction SMILES: [CH2:1](N)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15].C([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])C.ClC1C=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35]>CCO>[N+:34]([C:26]1[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:23][C:22]=1[NH:19][CH2:20][CH2:21][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15])([O-:36])=[O:35]
Reactant: C#CCOCCOCCOCCOCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Solvent: CCO
Product: C#CCOCCOCCOCCOCCOCCOCCOCCOCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 276.2 %

Procedure:
3,6,9,12-tetraoxapentadec-14-yn-1-amine (815 mg, 2.27 mmol, 1 equiv.) was dissolved in EtOH (10 mL), and triethylamine (666 μL, 0.726 mmol, 1.5 equiv.) and 1-chloro-2,4-dinitrobenzene (505 mg, 2.5 mmol, 1.5 equiv.) were added. The reaction flask was fitted with a reflux condenser and the reaction was heated to reflux for 48 h, cooled, and concentrated to a yellow oil. The crude mixture was purified by flash chromatography (3 cm×20 cm Silica, 3% MeOH:CH2Cl2) to yield N-(2,4-dinitrophenyl)-3,6,9,12,15,18,21,24-octaoxaheptacos-26-yn-1-amine (10) as a yellow solid (1.15 g, >95% yield). IR (thin film/NaCl) 3363 (w), 2871 (s), 1621 (s), 1337 (m), 1103 (s) cm−1; 1H-NMR (500 MHz, CDCl3) δ 9.08 (d, 1H, J=2.6 Hz), 8.77 (bs, 1H), 8.21 (dd, 1H, J=2.6, J=9.5 Hz), 6.94 (d, 1H, J=9.5 Hz), 4.16 (6, 2H, J=2.4 Hz), 3.78 (t, 2H, J=5.0 Hz), 3.64 (m, 32H), 3.58 (q, 2H), 2.41 (t, 1H, 2.38 Hz); 13C-NMR (125 MHz, CDCl3) δ 148.5, 136.1, 130.5, 130.29, 124.3, 114.3, 79.8, 74.6, 70.7, 70.6, 70.5, 69.2, 68.7, 58.5, 43.3; HRMS (EI) calc'd for C25H39N3O12 (M+H) m/z 574.260650. Found 574.26106.
Reaction SMILES: C([C:3](CC)(CC)[CH:4](P(O)(O)=O)[C:5]([OH:7])=[O:6])C.[H-].[Na+].[Br:18][C:19]1[CH:26]=[C:25]([F:27])[C:22]([CH:23]=O)=[C:21]([F:28])[CH:20]=1.Cl.[CH2:30]1COC[CH2:31]1>>[Br:18][C:19]1[CH:26]=[C:25]([F:27])[C:22]([CH:23]=[C:4]([CH3:3])[C:5]([O:7][CH2:30][CH3:31])=[O:6])=[C:21]([F:28])[CH:20]=1
Reactant: C1CCOC1
Reactant: CCC(CC)(CC)C(C(=O)O)P(=O)(O)O
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)=Cc1c(F)cc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a THF (100 mL) solution of triethyl-2-phosphonopropionic acid (33.8 mL) was added sodium hydride (8.4 g) under ice-cooling. After the reaction mixture was stirred for 1 h, to the reaction mixture was added a THF solution of 4-bromo-2,6-difluorobenzaldehyde (2) (23.2 g) dropwise under ice-cooling. After the reaction mixture was stirred under ice-cooling for 2 h, to the reaction mixture were added ice-water, 2N hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=15:1) to obtain the compoumd (3) 32.08 g.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C@@H:4]2[CH2:3]1.CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[N:29][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:27][N:26]=1>O1CCCC1>[CH:31]1([C:28]2[N:29]=[CH:30][C:25]([O:1][C@@H:2]3[CH2:17][N:5]4[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:9][C@@H:4]4[CH2:3]3)=[N:26][CH:27]=2)[CH2:33][CH2:32]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](O)C[C@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (7S,8aS)-tert-butyl 7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Wuxi Pharma, 0.485 g, 2 mmol) in tetrahydrofuran (0.3 mL) was added potassium tert-butoxide (2.8 mL, 1 M in tetrahydrofuran, 2.8 mmol) followed by a solution of 2-bromo-5-cyclopropylpyrazine (446 mg, 2.24 mmol) in tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by chromatography on silica gel (ethyl acetate) to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.39 (s, 9H), 1.90 (m, 2H), 2.09 (m, 1H), 2.40 (m, 3H), 2.90 (m, 2H), 3.08 (m, 1H), 3.28 (m, 1H), 3.86-4.08 (m, 2H), 5.27 (m, 1H), 8.11 (m, 2H); MS (ESI) m/z 361 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([OH:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-(4-fluorophenoxy)benzaldehyde (9.00 g, 41.63 mmol) in CHCl3 (75 mL) was treated with m-chloroperbenzoic acid (46-85%, 15.80 g, 52.00 mmol) and stirred for 3 h at room temperature. The reaction was washed with sat. aq. NaHSO3, sat. aq. NaHCO3, and water. The organic layer is concentrated and the residual oil taken up in MeOH (10 mL) containing a few drops of conc. HCL and stirred for 1 h at room temperature. The solvent is removed in vacuo and the resulting oil was chromatographed on silica gel (20% ethyl acetate/hexane) to afford the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:15])=[C:10]2[O:14][CH:13]=[CH:12][C:11]=12)=[O:5])C.[OH-].[Na+]>CO.O>[F:15][C:9]1[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:11]2[C:10]=1[O:14][CH:13]=[CH:12]2
Reactant: CCOC(=O)c1ccc(F)c2occc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(F)c2occc12
Temperature: 55 °C

Procedure:
A mixture of 7-fluoro-benzofuran-4-carboxylic acid ethyl ester (1.54 mmol) and sodium hydroxide (2.31 mmol) in MeOH (1.7 mL) and water (1.7 mL) is heated to 55° C. for 90 min. The mixture is concentrated in vacuo and made acidic by addition of hydrochloric acid (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. 1H-NMR (DMSO-d6): δ=13.19 (bs, 1H); 8.25 (s, 1H); 7.89-7.94 (m, 1H); 7.41 (s, 1H); 7.36 (t, J=9.5 Hz, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[CH3:21].CCN(C(C)C)C(C)C>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[CH3:21])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)CCCCCBr)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.14 g (10 mmol) 6-bromo-hexanoylchloride in 5.0 ml THF is slowly added dropwise with stirring at ambient temperature to 1.65 g (10 mmol) methyl 4-amino-3-methyl-benzoate in 50 ml THF with 2 ml DIPEA. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is dissolved in dichloromethane, washed twice with water and dried over sodium sulphate. The residue remaining after evaporation i. vac. is further reacted without any more purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[N:1]=2)[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(N)cc(Br)cn12
Yield: 39.1 %

Procedure:
A mixture of 2,3-diamino-5-bromopyridine (2.5 g, 13.31 mmol) and ethyl 2-chloroacetoacetate (2.41 g, 14.64 mmol) in 35 ml abs. Ethanol was refluxed for 14 h. The ethanol was evaporated under reduced pressure. The residue was dissolved in methylene chloride and neutralized by aqueous NaHCO3. The organic layer was separated, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride:methanol (100:3.5) as eluent to give 1.55 g (39%) of the title compound.
Reaction SMILES: [CH:1]1[C:2]2[C@H:15]3[C@@H:16]([OH:26])[C@H:17]([OH:25])[C@H:18]4[O:23][P:21]([O-:24])(=[O:22])[O:20][C@H:19]4[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([OH:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12.[Na+].[OH2:28]>>[CH:1]1[C:2]2[C@H:15]3[C@@H:16]([OH:26])[C@H:17]([OH:25])[C@@H:18]([OH:23])[C@@H:19]([O:20][P:21]([OH:24])([OH:22])=[O:28])[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([OH:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12
Reactant: O=C1N[C@H]2[C@@H]3OP(=O)([O-])O[C@@H]3[C@@H](O)[C@H](O)[C@@H]2c2cc3c(c(O)c21)OCO3
Reactant: O
Agent: [Na+]
Product: O=C1N[C@H]2[C@H](OP(=O)(O)O)[C@H](O)[C@@H](O)[C@H](O)[C@@H]2c2cc3c(c(O)c21)OCO3

Procedure:
Sodium pancratistatin 3,4-cyclic phosphate (5a, 0.0165 g, 0.04 mmol) was dissolved in water (1 ml) and eluted through a column containing Amberlite IR 120 (H+) resin. The uv active fractions were combined and freeze dried, 0.011 g, 69%, mp. 150° C. (dec). The material was found to be unstable and decomposed over several days. 1H NMR (DMSO-d6, 300 MHz) δ 12.9 (s, 1H), 8.12 (s, 1H), 6.49 (s, 1H), 6.04-6.02 (m, 2H),4.30 (m, 1H), 3.98-3.87 (m, 3H), 3.07-3.01 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:10](N)=[O:11]>>[CH:10]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: NC=O
Product: O=CN[C@@H](CC(=O)O)C(=O)O

Procedure:
Under a nitrogen atmosphere, a slurry of 2.7 gm (20 mmol) L-aspartic acid in 4.0 ml (100 mmol) formamide was heated at 95°-100° C. for 2 hours. Examination of the resulting homogeneous mixture by proton NMR showed that the L-aspartic acid had been completely converted to its N-formyl derivative.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([OH:17])=[N:14][C:15]=1[Cl:16]>CO>[Br:9][C:10]1[CH:11]=[C:12]([I:8])[C:13]([OH:17])=[N:14][C:15]=1[Cl:16]
Reactant: Oc1ccc(Br)c(Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Product: Oc1nc(Cl)c(Br)cc1I
Temperature: 45 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
NIS (7.38 g, 32.8 mmol) was added to a stirring solution of commercially available 5-bromo-6-chloropyridin-2-ol (5.70 g, 27.3 mmol) in MeOH (50 ml) at 45° C. The reaction was allowed to stir at 45° C. for 1 h. The amber colored solution was cooled to rt and then concentrated in vacuo. The resulting yellow solids were diluted with 25 mL DCM, triturated for 30 min, then collected filtering with minimal DCM to give 5-bromo-6-chloro-3-iodopyridin-2-ol (7.60 g, 22.7 mmol, 83% yield) as a white solid consistent by LCMS and NMR. LCMS: m/e 335 (M+H)+ LCMS retention time: 2.62 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=4 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, MeOD) δ ppm 8.26 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>>[CH3:11][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c([N+](=O)[O-])cnc(Cl)c1[N+](=O)[O-]
Reactant: Nc1ccc(CCO)cc1
Product: Cc1c([N+](=O)[O-])cnc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-4-methyl-3,5-dinitropyridine. (Czuba, Rocz. Chem., 1967, 41, 479) and 4-aminophenylethyl alcohol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23](NCCO)=[CH:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8]2=[O:31])[C:4]([CH3:32])=[N:3]1.C[OH:34].[CH2:35]1[CH2:39][O:38]CC1>[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([O:38][CH2:39][CH2:35][OH:34])=[CH:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8]2=[O:31])[C:4]([CH3:32])=[N:3]1
Reactant: CO
Reactant: C1CCOC1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(NCCO)nc4)cc3c21
Agent: [Pd]
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(OCCO)nc4)cc3c21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(2-hydroxy-ethylamino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 19, 40 mg, 0.077 mmol) in MeOH/THF=1:1 (4 ml) was added under nitrogen Pd/C 10% (20 mg, 0.026 mmol). The RM was shacked under H2 at rt for 22 h. The reaction was not completed, again Pd/C catalyst (20 mg) was added and the mixture was stirred under H2 at rt for 22 h. This procedure was repeated for a third time. Then the suspension was filtered over celite and washed with MeOH. The filtrate was evaporated. The residue was dissolved in MeOH and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing product were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.32 min (Method A); M+H=431 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.30-8.26 (m, 1H), 8.17-8.06 (m, 2H), 7.93-7.86 (m, 1H), 7.81-7.75 (m, 1H), 7.50-7.46 (m, 1H), 6.97-6.91 (m, 1H), 4.80-4.86 (m, 1H), 4.34-4.28 (m, 2H), 3.92 (s, 31-1), 3.75-3.69 (m, 2H), 3.58 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:17][O:18][CH2:19]Cl.O>CN(C)C=O>[Cl:3][C:4]1[C:14]([O:15][CH2:17][O:18][CH3:19])=[CH:13][CH:12]=[C:11]([Cl:16])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1c(Cl)ccc(O)c1Cl
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)ccc(OCOC)c1Cl
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% in oil, 474 mg) in N,N-dimethylformamide (2 ml) was added a solution of ethyl 2,6-dichloro-3-hydroxybenzoate (2.42 g) in N,N-dimethylformamide (10 ml) under nitrogen at ambient temperature and the mixture was stirred for 1 hour at the same temperature. Chloromethyl methyl ether (1.15 ml) was added thereto and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:8, V/V) to give ethyl 2,6-dichloro-3-(methoxymethoxy)benzoate (2.58 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:36][C:34](=[O:35])[NH:33][CH:24]([C:23]3[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]([OH:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=3)[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccc(F)c(F)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(F)c(F)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 14.4 %

Procedure:
To a solution of 1-(3,4-difluorophenyl)-2-phenylethanone (120 mg, 0.52 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (101.8 mg, 0.52 mmol), and urea (95.1 mg, 1.56 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HCl solution, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 45 (35 mg, yield 14.5%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.27 (s, 1H), 8.81 (s, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.31 (m, 2H), 7.14 (s, 1H), 7.11-6.99 (m, 3H), 6.87 (m, 1H), 6.86 (d, J=7.2 Hz, 2H), 5.24 (d, J=2.0 Hz, 1H), 4.04 (m, 2H), 1.32 (t, J=7.2 Hz, 3H); MS (ESI): m/z 468.0[M+1]+.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Si:17]([O:24][CH2:25][CH:26]=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[Si:17]([O:24][CH2:25][CH2:26][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of benzyl 1-piperazinecarboxylate (1.751 mL, 9.08 mmol) and 2-(tert-butyldimethylsilyloxy)acetaldehyde (1.209 mL, 9.99 mmol), in MeOH (5 mL) and dichloroethane (5 mL) was stirred for 20 minutes with 4 Å molecular sieves. The mixture was added to a solution of sodium triacetoxyborohydride (4.81 g, 22.70 mmol) in tetrahydrofuran (5 mL) and stirred overnight. The reaction mixture was added to sodium bicarbonate (100 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were concentrated under reduced pressure, and the residue purified with silica chromatography (EtOAc/MeOH) to give 2.10 g, (61%) of a clear oil. 1H NMR: 7.34 (m, 5H), 5.05 (s, 2H), 3.67 (t, 2H), 3.36 (m, 4H), 2.40 (m, 6H), 0.84 (s, 9H), 0.02 (s, 6H).