Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](O)=[O:13])=[N:9][C:8]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:16])=[CH:7]2.CN(C=O)C.C(Cl)(=O)C([Cl:44])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([Cl:44])=[O:13])=[N:9][C:8]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:16])=[CH:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)O)n4)ncnc32)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)Cl)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboxylic acid 10 (160 mg, 0.327 mol, 1 eq) and DMF (0.1 mL) in DCM (10 mL), oxalyl chloride (83.1 mg, 0.654 mmol, 2 eq) was added and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbonyl chloride 11. The product obtained was used directly in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:19]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]2[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8](=[O:14])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC(=O)c1ccccc1O
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: COC(=O)C1C(=O)c2ccccc2OC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 500 mg, 2.56 mmol) and 3,4-dichlorobenzaldehyde (496 mg, 2.83 mmol) in isopropanol (5.0 mL) was treated with piperidine (25 μl, 257 μmol) and acetic acid (15 μl, 257 μmol) and then heated to reflux for 20 h. At the conclusion of this period, the mixture was cooled on ice, causing a gum to separate from the solution. The mixture was treated with a small amount of water and heated until homogeneous. On slow cooling to rt, a solid formed, which was collected by filtration and dried under vacuum to provide racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylate as an off-white powder (496 mg, 55%). An additional sample (57 mg, 6%) was obtained by partial concentration of the filtrate. The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.18 (s, 1 H) 6.81 (dd, J=8.1, 1.0 Hz, 1H) 6.99 (td, J=7.4, 1.0 Hz, 1 H) 7.19 (dd, J=8.4, 1.8 Hz, 1 H) 7.31 (m, 1 H) 7.34 (d, J=8.1 Hz, 1 H) 7.43 (d, J=2.0 Hz, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1H). High resolution mass spectrum m/z found 373.0016, calcd 373.0010 (M+Na)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:13]=[N:14][C:15](C4N=C(CN(CC)CC)ON=4)=[C:11]3[CH2:10][N:9]([CH3:27])[C:8](=[O:28])[C:7]=2[CH:29]=1.[CH3:30][C:31](C)=[O:32]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([C:13]4[N:14]=[C:31]([CH2:30][N:9]([CH2:10][CH3:11])[CH2:8][CH3:7])[O:32][N:12]=4)=[N:14][CH:15]=[C:11]3[CH2:10][N:9]([CH3:27])[C:8](=[O:28])[C:7]=2[CH:29]=1
Reactant: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(Cl)ccc2-3)no1
Reactant: CC(C)=O
Agent: Cl
Product: CCN(CC)Cc1nc(-c2ncc3n2-c2ccc(Cl)cc2C(=O)N(C)C3)no1
Yield: 42 %

Procedure:
A solution of 200 mg (0.54 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 4 ml of N,N-dimethylformamide was treated with 0.17 ml (1.65 mmol) of diethylamine and stirred at room temperature under argon for 1.5 hrs. The solution was evaporated and the residue was triturated in 10 ml of water. The crystals were filtered off under suction, the filtrate was extracted once with ethyl acetate and the extract was evaporated. The combined crude products were chromatographed on 20 g of silica gel (methylene chloride/acetone 4:1, 2:1). There were obtained 124 mg of 8-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted in acetone with ethereal hydrochloric acid into the hydrochloride. By crystallization from acetonitrile there were obtained 108 mg (42%) of 8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1.9) of m.p. 191°-205° (dec.).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH3:10]
Reactant: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)N)C(C)C

Procedure:
N-(tert-butoxycarbonyl)-L-alanyl-N1-isobutyl-L-valinamide (247 mg, 0.72 mmol) is stirred for 30 min under nitrogen with 1 mL of trifluoroacetic acid and 3 mL of dichloromethane. It is concentrated on a rotary evaporator. To the residue is added 2 mL of saturated sodium bicarbonate (pH=8). The product is diluted with 100 mL of ethyl ether. The aqueous salt is siphoned out and anhydrous sodium sulfate is added. The solution is filtered through glass wool and concentrated to 136 mg of the title compound as an off-white solid. NMR (MeOD)-d3 δ 4.66 (bs) 4.16 (d, J=8 Hz, 1H), 4.00 (q, J=7 Hz, 1H), 3.07 (dd, 1H), 2.98 (dd, 1H), 2.05 (m, 1H), 1.79 (m, 1H), 1.49 (d, J=7 Hz, 3H), 0.99 (d, J=7 Hz, 6H) 0.93 (d, J=7 Hz, 6H). HRMS (ESI) calcd for C12H25N3O2+H1 244.2025, found 244.2023.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[C:12]([O:14][CH3:15])=[O:13].Cl.C[O-].[Na+]>CO>[SH:10][C:7]1[CH:8]=[CH:9][C:4]([NH:3][C:12](=[O:13])[O:14][CH3:15])=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(S)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Nc1ccc(S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
17.4 ml of a 10% aqueous sodium hydroxide solution were carefully added to 2.40 g of 4-aminothiophenol at room temperature and 3.27 ml of methyl chloroformate were added dropwise to the resulting mixture. The reaction mixture was then stirred at room temperature for 2 hours, at the end of which time the reaction mixture was acidified with 1.5 ml of 4N hydrochloric acid, and the resulting mixture was extracted with methylene: chloride. The resulting extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid. 4 ml of methanol and 10 ml of a 2M solution of sodium methoxide in methanol were added to the crude crystalline solid at room temperature. The resulting mixture was then stirred at room temperature for 1.5 hours, at the end of which time the reaction mixture was acidified with 2 ml of 4N hydrochloric acid, and the resulting mixture was extracted with methylene chloride. The resulting extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline residue which was recrystallised from a mixed solvent of methylene chloride and hexane to give 1.135 g (yield 32%) of the title compound as a solid having a melting point of 94° to 96° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[Cl:11])C=O.C[O-].[Na+].[CH:15](OC)([O:18][CH3:19])[O:16][CH3:17]>CO>[CH3:17][O:16][CH:15]([O:18][CH3:19])[C:8]1[CH:5]=[CH:4][C:3]([Cl:2])=[C:10]([Cl:11])[CH:9]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.1 %

Procedure:
Concentrated hydrochloric acid (1.0 ml) was added to a stirred suspension of 3,4-dichlorobenzaldehyde (140 g) in a mixture of trimethyl orthoformate (94 g) and dry methanol (400 ml). After stirring for 24 hours at laboratory temperature (about 25° C.), the reaction solution was adjusted to pH 7-8 by the addition of a solution of sodium methoxide in methanol and concentrated on a rotary evaporator. The residual oil was then dissolved in diethyl ether (600 ml). The ethereal solution was washed with water until the washings were neutral and then dried over anhydrous sodium sulphate, filtered and distilled to give 3,4-dichlorobenzaldehyde dimethyl acetal (157.5 g). b.p. 137°-140° C./25 mm Hg, as a clear mobile oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2].[Br:24]Br>>[Br:24][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[Cl:10])=[O:3]
Reactant: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(C(C)=O)c2)c1
Reactant: BrBr
Product: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(C(=O)CBr)c2)c1

Procedure:
Procedure C was performed using N-(3-acetyl-4-chlorophenyl)-3,5-dimethoxybenzamide (0.1 g, 0.3 mmol) and Br2 (0.017 ml, 0.33 mmol to afford N-(3-(2-bromoacetyl)-4-chlorophenyl)-3,5-dimethoxybenzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[N:28]1([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([C:43]3[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=3)=[O:42])=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]3[CH:22]=[CH:23][C:24]4[NH:25][C:47]([C:46]5[CH:49]=[CH:50][C:43]([C:41](=[O:42])[NH:40][C:37]6[CH:38]=[CH:39][C:34]([N:28]7[CH2:29][CH2:30][O:31][CH2:32][CH2:33]7)=[CH:35][CH:36]=6)=[CH:44][CH:45]=5)=[N:1][C:4]=4[CH:5]=3)=[O:21])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 195 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholin-4-ylbenzoyl)aniline and 4-(4-morpholinylphenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C35H34N6O4: 603.26; found: 603.36.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1(c2ccc(COc3cccc(C(=O)c4ccccc4)c3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccc(COc3cccc(C(O)c4ccccc4)c3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a stirred solution of methyl 1-(4-((3-benzoylphenoxy)methyl)phenyl)-cyclopropanecarboxylate (1.85 g, 4.787 mmol) in methanol (22.6 mL) at 0° C. under an atmosphere of nitrogen, was added sodium borohydride (0.181 g, 4.787 mmol) in one portion. The reaction mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. After stirring for 40 minutes, the reaction was cooled to 0° C., and additional sodium borohydride (0.091 g, 2.380 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction was quenched with water (3.5 mL), filtered to remove insoluble material, and then concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate (×2). The combined organic extracts were washed with 10% aqueous potassium carbonate (×2), brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford the title compound as a red oil (1.824 g, 98%). The material was used directly in the next step with no further purification.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([N+:13]([O-:15])=[O:14])[C:7]([N+:16]([O-:18])=[O:17])=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[N+:22]([O-:24])=[O:23])([O-:3])=[O:2].[N-:25]=[N+:26]=[N-].[Na+]>C1C=CC=CC=1>[N+:1]([C:4]1[C:9]([N:10]=[N+:25]=[N-:26])=[C:8]([N+:13]([O-:15])=[O:14])[C:7]([N+:16]([O-:18])=[O:17])=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[N+:22]([O-:24])=[O:23])([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: [N-]=[N+]=Nc1c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
The reaction is conducted by stirring a benzene solution of hexanitrobenzene with a slight excess of sodium azide (aqueous solution) at 25° C. After separating and drying the benzene solution, the solvent is removed leaving pure pentanitrophenyl azide. Recrystallization from carbon tetrachloride gives either long, flat yellow prisms (α-form) or chunky, orange-yellow rosettes (β-form) of pentanitrophenyl azide.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29](O)=[O:30]>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:29]([C:19]3[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:21][O:22][C:18]=3[CH3:17])=[O:30])[C:7]=2[CH:8]=1)#[N:13]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1C(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 5-methyl-3-phenylisoxazole-4-carboxlic acid by the same method as described for the title compound of Example 2 to afford a white solid, m.p. 235°-236° C. [α]D =-29.6° (c=0.46, MeOH).
Reaction SMILES: C([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:29])[CH2:17][CH:18]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][CH2:20][CH:21]([O:23][CH3:24])[CH3:22])=[CH:12][CH:11]=1)CCCCCCCC.OC(CCC(CC(C1C=CC=CC=1)=O)CCCC)C.COC(OC)=O>>[CH3:24][O:23][CH:21]([CH2:20][CH2:19][CH:18]([CH2:17][C:16]([C:13]1[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=1)=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH3:22]
Reactant: CCCCCCCCCc1ccc(C(=O)CC(CCCC)CCC(C)OC)cc1
Agent: CCCCC(CCC(C)O)CC(=O)c1ccccc1
Solvent: COC(=O)OC
Product: CCCCC(CCC(C)OC)CC(=O)c1ccccc1
Yield: 88 %

Procedure:
A mixture of the above anisole (31 g) and glacial acetic acid (15 g) was heated to 70° C. for five hours, during which time a steady stream of BF3 was added. After cooling the reaction mixture, it was dissolved in 200 mL methylene chloride and washed with 200 mL water. The organic layer was dried (MgSO4) and the solvent was removed under vacuum to give 32.5 g of a red oil identified as a mixture of p-nonyl 2-methoxy-5-nonylacetophenone (major product) and 2-hydroxy-5-nonylacetophenone. To ensure complete conversion to the methoxyketone, the product mixture was re-alkylated by the phase transfer reaction described above. Work-up of the reaction mixture yielded 31.5 g (88%) of 2-methoxy-5-nonylacetophenone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][NH2:13].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:13][CH3:12])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccccc1Br
Temperature: 0 °C

Procedure:
2-Bromobenzenesulfonyl chloride (manufactured by Fluorochem Co., 25 g) was dissolved in tetrahydrofuran (40 mL), and under stirring at 0° C., 40% methylamine aqueous solution (TCI, 25 mL) was added dropwise thereto over ten minutes. After stirring the mixture at room temperature for 2 hours and 40 minutes, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. To the residues, hexane and a small amount of ethyl acetate were added, followed by stirring. Solids were filtered to obtain the target compound (23.26 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[C:10][CH3:11].[OH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>CC(=O)CC>[CH2:8]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)[C:9]#[C:10][CH3:11]
Reactant: CC#CCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC#CCOc1ccc(C(=O)OC)cc1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
13.6 g (98.5 mmol) of potassium carbonate then 9.6 g (65.7 mmol) of 1-bromobut-2-yne are added to a solution containing 10 g (65.7 mmol) of methyl 4-hydroxybenzoate diluted in 250 ml of 2-butanone. The reaction medium is stirred at reflux for 5 h then at ambient temperature for 18 h. After filtration of the salts, the filtrate is concentrated under vacuum. 13.4 g (100%) of methyl 4-but-2-ynyloxybenzoate are obtained in the form of a light-yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:45].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:45])[C:6]=2[N:15]=[C:3]1[CH2:1][CH3:2]
Reactant: [NH4+]
Reactant: CCc1nc2cnc3ccccc3c2n1CCOCCON1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCON
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethoxy}-1H-isoindole-l,3(2H)-dione (11.0 g, 25.5 mmol) in chloroform (150 mL) was added mCPBA (11.4 g, 51.1 mmol). The solution was stirred at room temperature for 2 hours. Concentrated ammonium hydroxide (100 mL) was added, followed by p-toluenesulfonyl chloride (5.40 g, 28.1 mmol). The mixture was stirred overnight at room temperature. The mixture was transferred to a separatory fimnel and was washed twice with 5% aqueous ammonium chloride and once with aqueous sodium carbonate solution, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution with 0-5% methanol in dichloromethane) to provide 6 g of 1-{2-[2-(aminooxy)ethoxy]ethyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH:12][C:13]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:9][CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[C:30]1[C:38]2[CH:37]=[C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]3=[CH:34][C:33]=2[C:32](=[O:43])[NH:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:22]([O:21][C:19]([C:13]1([NH:12][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][N:31]2[C:32](=[O:43])[C:33]3[CH:34]=[C:35]4[CH:42]=[CH:41][CH:40]=[CH:39][C:36]4=[CH:37][C:38]=3[C:30]2=[O:29])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Reactant: CC(C)(C)OC(=O)C(CCO)NC1(C(=O)OCc2ccccc2)CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCN1C(=O)c2cc3ccccc3cc2C1=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of benzyl 1-(1-tert-butoxycarbonyl-3-hydroxy-1-propylamino)cyclohexanecarboxylate (466 mg, 1.19 mmol) in dry tetrahydrofuran (12 mL) was added 1,3-dioxo-1,3-dihydrobenzo[f]isoindole (258 mg, 1.31 mmol), triphenylphosphine (344 mg, 1.31 mmol) and diethylazodicarboxylate (0.21 mL, 1.31 mmol). The resulting mixture was stirred at room temperature for 6 days. The solvent was evaporated under vacuum and the residue was chromatographed on silica gel eluting first methylene chloride and then with 2% ethyl acetate in methylene chloride to afford 1-[1-tert-butoxycarbonyl-3-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)propylamino]cyclohexanecarboxylic acid benzyl ester as a white solid, 530 mg (78%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([CH2:21][CH2:22][N:23]([CH2:25][CH2:26][O:27][CH3:28])[CH3:24])[CH:14]=[C:13]2[C:29]1[N:37](S(C2C=CC(C)=CC=2)(=O)=O)[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[CH:30]=1>[OH-].[K+]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([CH2:21][CH2:22][N:23]([CH2:25][CH2:26][O:27][CH3:28])[CH3:24])[CH:14]=[C:13]2[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[CH:30]=1
Reactant: COCCN(C)CCn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)c(OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COCCN(C)CCn1cc(-c2cc3cccnc3[nH]2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
(2-{5,6-Dimethoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]-pyridin-2-yl)indol-1-yl}ethyl)-(2-methoxyethyl)methylamine trifluoroacetate (0.0152 g; 22.46 μmol) is dissolved in a methanolic potassium hydroxide solution (0.5 ml; 0.1 g of potassium hydroxide/ml methanol) and then agitated at ambient temperature for 48 hours. After evaporation, the residue is taken up, with agitation, in 0.7 ml of a dimethyl sulfoxide and 12N aqueous hydrochloric acid (50/50 v/v). After returning to ambient temperature, dimethyl sulfoxide (0.35 ml) is added and then purification is carried out by reverse-phase liquid chromatography mass spectrometry (method B). The fractions containing the expected compound are combined and evaporated. {2-[5,6-Dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]ethyl}-(2-methoxyethyl)methylamine trifluoroacetate (0.0094 g; 80%) is isolated, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:3]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:10][CH:9]=2)[N:3]=1
Reactant: ClCCN1CCCCC1
Reactant: Cc1cc(C)n(-c2ccc(O)cc2)n1
Agent: Cl
Product: Cc1cc(C)n(-c2ccc(OCCN3CCCCC3)cc2)n1
Yield: 44 %

Procedure:
The title compound was prepared from 4-(3,5-dimethyl-pyrazol-1-yl)-phenol (0.1 g, 0.53 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.2 g, 1.1 mmol) using the general procedure C with a yield of 44% (70 mg); 1H NMR (400 MHz, CDCl3) 7.30 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 5.96 (s, 1H), 4.14 (t, J=12, 6 Hz, 2H), 2.78 (t, J=12, 6 Hz, 2H), 2.53 (br, 4H), 2.28 (s, 3H), 2.24 (s, 3H), 1.61-1.47 (m, 6H); LC/MS (ESI): 96%.