Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:23])=[CH:25][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1cc2c(o1)CCNC2
Reactant: CCCCCCCc1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCc1ccc(C(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.264 g (1.2 mmol) of 4-heptylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added under ice-cooling, followed by overnight stirring at room temperature. This solution was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18]C(=O)C)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO>O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)[CH3:22])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
To a cooled (˜15° C.) and stirred solution of 18 g (57.4 mmol) of trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester in 135 mL of dioxane was added within 5 min 63.2 mL (63.2 mmol, 1.1 eq) of aqueous 1M NaOH. The reaction was homogenised with 13 mL of MeOH and 28.7 mL (28.7 mmol, 0.5 eq) of aqueous 1M NaOH after 3 h, then stirred for additional 1.5 h. The reaction was evaporated to remove the dioxane, partitioned between Et2O (×3)/H2O, dried over Na2SO4 and evaporated to yield 17.13 g (quantitative) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester, MS: 272 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[N:18]=[N:17]2)=[N:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+].Cl>O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[N:18]=[N:17]2)=[N:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2cc(C(=O)O)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of ethyl 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-1H-1,2,3-triazole-4-carboxylate (0.20 g, 0.54 mmol) in a 1:1 mixture of tetrahydrofuran:water (20 mL) was added lithium hydroxide (0.11 g, 2.69 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, acidified with 10% HCl solution and extracted with dichloromethane (2×50 mL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford the title compound as a white solid in 53% yield (0.27 g): 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 9.03 (t, J=6.0 Hz, 1H), 7.35-7.22 (m, 5H), 4.46 (d, J=6.0 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 344.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14]CC)=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC)cc(F)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
To a solution of ethyl 2-(4-fluoro-1-hydroxy-6-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (134 mg, 0.50 mmol) in THF (2 mL) was added dropwise an aqueous solution of lithium hydroxide (102 mg, 2.5 mmol) in water (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified to pH=2 with diluted hydrochloride acid. The resulting mixture was extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (43 mg, Yield: 36%). 1H NMR (400 MHz, DMSO-d) δ 12.20 (s, 1H), 9.45 (s, 1H), 7.09-7.09 (d, J=1.6 Hz, 1H), 6.91-6.95 (m, 1H), 5.51-5.55 (m, 1H), 3.80 (s, 3H), 2.91-2.97 (m, 1H), 2.27-2.33 (m, 1H). MS (ESI) m/z=481 [2M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][CH:6]=[CH:5][N:4]=1)=O.Cl.[C:15]([NH:19][NH2:20])([CH3:18])([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[C:15]([N:19]1[C:9](=[O:11])[C:8]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[CH:1]=[N:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)c1cccnc1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)n1ncc2ncccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In acetic acid-water (1:1) (5 ml) was dissolved ethyl 2-formyl-3-pyridinecarboxylate (1.3 g) followed by addition of t-butylhydrazine hydrochloride (1.8 g), and the mixture was refluxed with stirring for 1 hour. This reaction mixture was cooled to room temperature, adjusted to pH 5.0 with saturated aqueous NaHCO3 solution, and extracted with dichloromethane. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in acetic acid (2 ml) and refluxed for 1 hour. This reaction mixture was cooled, adjusted to pH 5.0 with saturated aqueous NaHCO3 solution, and extracted with dichloromethane. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (n-hexane: ethyl acetate =1:1). White powder, 1.2 g. 1H-NMR (CDCl3) δ: 1.73(9H,s), 7.64(1H,dd,J=8.2&4.4Hz), 8.38(1H,s), 8.69(1H,d,J=8.2Hz), 9.03(1H,d,J=4.4Hz).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc2nc(Cl)ncc2c1
Reactant: Nc1ccc(Br)cc1
Solvent: CCO
Product: COc1ccc2nc(Nc3ccc(Br)cc3)ncc2c1

Procedure:
2-chloro-6-methoxyquinazoline (1eq) and 4-bromoaniline (2 eq) in ethanol was heated at 80° C. for 16 h. The mixture was concentrated and passed through a plug of silica to yield (4-bromophenyl)(6-methoxyquinazolin-2-yl)amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[NH:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1.[C:17]([S:20][CH2:21][CH:22]([CH3:26])[C:23](Cl)=[O:24])(=[O:19])[CH3:18].O>CC(N(C)C)=O>[C:17]([S:20][CH2:21][CH:22]([CH3:26])[C:23]([N:12]([CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1)[CH2:13][C:14]([OH:16])=[O:15])=[O:24])(=[O:19])[CH3:18]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: COc1ccc2c(c1)C(NCC(=O)O)CC2
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)C(N(CC(=O)O)C(=O)C(C)CSC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
N-(6-Methoxy-1-indanyl)glycine (2.0 g) is suspended in 20 ml of dimethylacetamide, then 2.2 g of 3-acetylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and thereafter stirring is continued at room temperature for 2 hours. The reaction mixture is poured into 200 ml of water, and extracted with 200 ml of ethyl acetate. The extract is washed with 20 ml of 10% hydrochloric acid and with water, and dried over anhydrous sodium sulfate. After ethyl acetate is distilled off under reduced pressure, the residue is subjected to silica gel column chromatography, eluted with acetone-benzene (1:9). The oily substance obtained is crystallized from an ethyl ether-petroleum ether mixture, to give 1.8 g of N-(3-acetylthio-2-methylpropionyl)-N-(6-methoxy-1-indanyl)glycine, colorless needles showing a melting point of 106°-110° C.
Reaction SMILES: C([Al])C.[CH:4]([OH:7])([CH3:6])[CH3:5].[C-:8]#[N:9].[CH2:10]([Al+:12][CH2:13][CH3:14])[CH3:11]>C1COCC1>[Al:12]([C:8]#[N:9])([CH2:13][CH3:14])[CH2:10][CH3:11].[CH3:5][CH:4]([OH:7])[CH3:6]
Reactant: CC[Al+]CC
Reactant: [C-]#N
Agent: CC[Al]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC[Al](C#N)CC

Procedure:
The sulfinimine-mediated asymmetric synthesis involves addition of ethylaluminium cyanoisopropoxide generated in situ by addition of isopropanol (i-PrOH) to diethylaluminium cyanide (Et2AlCN) to the compound VIIa. Thus treatment of compound VIIa (1.0 mmol) at −78° C. in THF with 1.5/1.0 equiv of Et2AlCN/i-PrOH gave amino nitrile VIII in good yield (50-70%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[O:16]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](Cl)=O)=[CH:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:23](/[CH:22]=[CH:21]/[C:18]3[CH:19]=[CH:20][O:16][CH:17]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccoc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Fc1ccc2c(c1)nc(/C=C/c1ccoc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-furyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=3[N:6]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc(C(Br)c2cccc(F)c2)c1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3cccc(F)c3)c3cccc(F)c3)nc1-2
Yield: 47 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]acetate and bis (3-fluorophenyl)methylbromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 47%.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:30]3[CH2:29][CH2:28][NH:27][CH:26]([CH3:25])[CH2:31]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC1CNCCN1
Solvent: CCCCO
Product: Cc1nc(N2CCNC(C)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 112 mg of 2-methylpiperizine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 422.3 (M)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:26](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:44][S:45]([C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1)(=[O:47])=[O:46].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:26]([C:51]2[CH:52]=[CH:53][C:48]([S:45]([CH3:44])(=[O:47])=[O:46])=[CH:49][CH:50]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C4COC(C)(C)O4)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OCC(c2cnc3c(c2)cc(C(=CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)O1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-[1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-vinyl ester (1.7 g, 2.7 mmol), bis(triphenylphosphine)palladium(II) chloride (190 mg, 0.27 mmol) and 4-(methanesulfonyl)phenylboronic acid (1.1 g, 5.5 mmol) in dioxane (10 mL) was added a 2M sodium carbonate solution (3.4 mL) at 25° C. The mixture was subjected to microwave irradiation for 1.5 h at 100° C. The mixture was cooled to 25° C., extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (1.1 g, 67.2%) as a yellow solid: LC/MS m/e calcd for C32H35N2S2O6 [M+H]+ 607.77, observed 607.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.47-1.62 (m, 4H), 1.52 (s, 3H), 1.60 (s, 3H), 1.71-1.98 (m, 4H), 2.68 (m, 1H), 3.07 (s, 3H), 3.80 (m, 1H), 4.40 (dd, J=6.3 Hz, 8.3 Hz, 1H), 5.22 (m, 1H), 6.35 (d, J=10.1 Hz, 1H), 6.58 (s, 1H), 7.29 (m, 2H), 7.37, 7.39 (2d, J=8.6 Hz, 2H), 7.49 (t, J=7.5 Hz, 1H), 7.74 (m, 2H), 7.78, 7.79 (2d, J=8.6 Hz, 2H), 7.96, 7.97 (2d, J=2.1 Hz, 1H), 8.50, 8.51 (2d, J=2.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:36]([O:38][C:39]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)=[O:40])[CH3:37].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:45][C:44]3[CH:46]=[CH:47][C:41]([C:39]([O:38][CH2:36][CH3:37])=[O:40])=[CH:42][CH:43]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
To a solution of 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol) and triethylamine (140 μL, 1 mmol) in DMF (5 mL) was added isobutyl chloroformate (130 μL, 0.9 mmol) at -10° C. After being stirred for 15 min, p-ethoxycarbonylaniline (200 mg, 1.2 mmol) was added. The mixture was stirred overnight at room temperature and 0.2N hydrochloric acid was added. The precipitates formed were collected by filtration, washed with water, and dried in vacuo. The crude product was rinsed with methanol-water, and dried in vacuo to give 230 mg of the title compound (46%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.35 (s, 1H), 7.92 (d, 2H, J=9 Hz), 7.70 (d, 1H, J=9 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 2H, J=9 Hz), 5.16~5.28 (m, 1H), 4.28 (q, 2H, J=7.2 Hz), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=16.8 Hz), 2.65 (d, 2H, J=7.6 Hz), 2.10 (dm, 1H, J=13.5 Hz), 1.80~1.97 (m, 1H), 1.31 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH:6]([O:60][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:71])[CH3:2].F>C(#N)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH:6]([OH:60])[CH2:5][C:4]1=[O:71])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(Oc4ccccc4)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(Oc4ccccc4)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
To a stirred solution of 17-ethyl-1-hydroxy-12-[2'-(3"-phenoxy-4"-oxocyclohexyl)-1'-methylvinyl]14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in acetonitrile was added hydrofluoric acid at room temperature. The reaction progress is monitored by tlc analysis and then the reaction mixture is quenched with sat'd aqueous sodium bicarbonate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate three times. Combined organic layers are washed (sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography, 50% ethyl acetate/hexane) gives the title compound.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCCC1.[NH2:17][C:18]1[C:25]([OH:26])=[C:24]([F:27])[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([CH3:34])[C:19]=1[C:20]#[N:21].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:20]([C:19]1[C:22]([CH3:34])=[C:23]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:24]([F:27])=[C:25]([OH:26])[C:18]=1[NH:17][C:1](=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:21]
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C#N)c(NC(=O)/C=C/c2ccccc2)c(O)c(F)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Under nitrogen atmosphere, cinnamoyl chloride (378 mg, 2.27 mmol) was dropwise added to a tetrahydrofuran solution (10 ml) of 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (500 mg, 2.06 mmol) and sodium hydrogencarbonate (399 mg, 4.75 mmol) cooled with ice, followed by stirring at room temperature for 17 hours and stirring at 60° C. for 1 hour. After cooling, ethyl acetate was added to the reaction liquid, followed by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[H-].[Na+].[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18](=[O:21])[CH2:19][O:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[I:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cccc(CO)c1I
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(COCC(=O)OC(C)(C)C)c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
(2-Iodo-3-methyl-phenyl)-methanol (1608 mg, 6.8 mmol, Example 131: step b) was dissolved into DMF (10 mL). The solution was cooled to 0° C. To this was added sodium hydride in one portion and the reaction continued to stir at 0° C. for 30 minutes. To the cooled solution was added t-butylbromoacetate (1.3 mL, 8.9 mmol) and then the reaction was warmed to RT and then heated to 50° C. for 4 hours. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) and the solvent was removed in vacuo resulting in the title compound (1.29 g, 53%) that was used with out further purification. 1H-NMR (CDCl3): δ 7.28–7.13 (m, 3H), 4.63 (s, 2H), 4.07 (s, 2H), 2.44 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:18](O)=O>>[CH3:16][N:15]([CH2:14][CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:18]1)[CH3:17]
Reactant: O=CO
Reactant: CN(C)CCNc1c(N)cnc2ccccc12
Product: CN(C)CCn1cnc2cnc3ccccc3c21

Procedure:
Using the method of Example 137, 3-amino-4-[2-(N,N-dimethylamino)ethylamino]quinoline (from Example 46) was reacted with formic acid to provide 1-[2-(N,N-dimethylamino)ethyl]-1H-imidazo[4,5-c]quinoline. The product was dissolved in ethanol and hydrogen chloride was bubbled into the solution. The precipitate was separated by filtration, washed with ethanol and recrystallized from ethanol. The product was 1-[2-(N,N-dimethylamino)ethyl]-1H-imidazo[4,5-c]quinoline trihydrochloride hydrate, m.p. >250° C. Analysis: Calculated for C14H16N4.3 HCl.H2O: %C, 45.8; %H, 5.5; %N, 15.3: Found: %C, 46.0; %H, 5.2; %N, 15.5.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:25]([OH:27])=O)[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])([CH3:15])([CH3:14])[CH3:13].[NH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[NH2:39])[C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>CN(C)C=O.O>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:36]=[CH:37][C:38]([NH2:39])=[C:29]([NH:28][C:25](=[O:27])[CH:20]([NH:19][C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])[CH2:21][CH:22]([CH3:23])[CH3:24])[CH:30]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N)c(NC(=O)C(CC(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
Hydroxybenzotriazole monohydrate (760 mg, 5.62 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (973 mg, 5.07 mmol) were added to a dimethyl formamide (30 mL) solution of N-tert-butoxycarbonyl-L-leucine (1.06 g, 4.57 mmol). The mixture was stirred until all 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride had dissolved. Methyl 3,4-diaminobenzoate (759 mg, 4.57 mmol) in dimethyl formamide (10 mL) and triethyl amine (0.68 mL, 4.89 mmol) were added sequentially. The reaction was stirred at room temperature over night and poured into water. This mixture was extracted with ethyl acetate three times. The organic portion was extracted with a saturated solution of sodium bicarbonate, water (2×) and brine. The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with ethyl acetate/hexanes (2:3) which yielded the title compound (690 mg, 40%). MS (CI) m/z 380.0 (M+1), 378.2 (M−1).