Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:44])([O:6][CH2:7][CH2:8][N:9]([C:41](=[O:43])[CH3:42])[C:10]1[C:15]([I:16])=[C:14]([C:17]([N:19]([CH:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)[CH3:20])=[O:18])[C:13]([I:28])=[C:12]([C:29]([N:31]([CH:33]2[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34]2)[CH3:32])=[O:30])[C:11]=1[I:40])[O:2][CH:3](Cl)[CH3:4].[C:45]([NH:48][C:49]1[C:50]([I:65])=[C:51]([N:60]([C:62](=[O:64])[CH3:63])[CH3:61])[C:52]([I:59])=[C:53]([C:56]([O-:58])=[O:57])[C:54]=1[I:55])(=[O:47])[CH3:46].[K+].[I-].[K+]>CN(C=O)C>[C:45]([NH:48][C:49]1[C:50]([I:65])=[C:51]([N:60]([C:62](=[O:64])[CH3:63])[CH3:61])[C:52]([I:59])=[C:53]([C:56]([O:58][CH:3]([O:2][C:1]([O:6][CH2:7][CH2:8][N:9]([C:41](=[O:43])[CH3:42])[C:10]2[C:15]([I:16])=[C:14]([C:17]([N:19]([CH:21]3[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]3)[CH3:20])=[O:18])[C:13]([I:28])=[C:12]([C:29]([N:31]([CH:33]3[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34]3)[CH3:32])=[O:30])[C:11]=2[I:40])=[O:44])[CH3:4])=[O:57])[C:54]=1[I:55])(=[O:47])[CH3:46]
Reactant: CC(=O)N(CCOC(=O)OC(C)Cl)c1c(I)c(C(=O)N(C)C2COC(C)(C)O2)c(I)c(C(=O)N(C)C2COC(C)(C)O2)c1I
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)OCCN(C(C)=O)c2c(I)c(C(=O)N(C)C3COC(C)(C)O3)c(I)c(C(=O)N(C)C3COC(C)(C)O3)c2I)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl 2-(N-(3,5-bis-((2,2-dimethyl-1,3-dioxolan-4-yl)-methylaminocarbonyl)-2,4,6-triiodophenyl)-acetylamino)ethyl carbonate (3.1 g, 3.3 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (2.00 g, 3 mmol) and potassium iodide (50 mg, 0.3 mmol) in dry DMF. After stirring at 50° C. for 18 hours and at room temperature for one day the solvent was removed at reduced pressure. The residue was suspended in chloroform (50 ml) and DMF (5 ml) and washed twice with a sodium hydrogen carbonate solution and twice with water. After treatment of the organic phase with magnesium sulfate and charcoal the solution was evaporated to dryness. Yield: 2.65 g. FAB-MS: M+1=1528.
Reaction SMILES: CO.[CH3:3][S:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OCCC(C)(C)C)=O)[C:13]([C:27]([O-:29])=[O:28])=[CH:12]2.[Li+].[OH-]>C1COCC1>[CH3:3][S:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:27]([OH:29])=[O:28])=[CH:12]2
Reactant: CSCCCOc1ccc2c(c1)cc(C(=O)[O-])n2C(=O)OCCC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSCCCOc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 70 °C
Yield: 79.9 %

Procedure:
A methanol solution of 1-(1,1-dimethylethyl)2-ethyl 5-{[3-(methylthio)propyl]oxy}-1H-indole-1,2-dicarboxylate (0.488 g, 1.24 mmol) was treated with 1 N LiOH (4 mL). The reaction mixture turned cloudy, THF was added to redissolve the precipitate and the mixture was heated to 70° C. When no starting material remained as evident by TLC the reaction mixture was partitioned between EtOAc and water. The aqueous layer was separated and acidified with conc. HCl. The aqueous layer was extracted with EtOAc and the organic layer was evaporated to afford the title compound (0.263 g, 80%). 1H NMR (400 MHz, Acetone-d6) δ ppm 10.73 (br. s., 1H), 7.43 (d, 1H), 7.14 (d, 1H), 7.09-7.13 (m, 1H), 6.96 (dd, 1H), 4.09 (t, 2H), 2.68 (t, 2H), 2.08 (s, 3H), 2.04 (t, 2H). LCMS: m/z=264.1 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](OC(=NC(C)C)NC(C)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)N=C(NC(C)C)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A neat solution of 18.6 mL (15 g, 118.8 mmol) of 1,3-diisopropylcarbodiimide and 60 mg (0.6 mmol) of cuprous chloride was placed under a blanket of argon and then cooled to 0° C. in an ice bath. To this reaction mixture was added dropwise (via syringe) 12.9 mL (13.5 g, 124.7 mmol) of benzyl alcohol. The resultant green reaction mixture was allowed to stir at 0° C. overnight, filtered through celite (rinsing with hexane) and the filtrate then Kugelrohr distilled (105° C., 2 mm Hg) to give 2-benzyl-1,3-diisopropyl isourea as a clear, colorless oil. To a solution of 650 mg (4.7 mmol) of 4-hydroxybenzoic acid in 20 mL of tetrahydrofuran was added 1.1 g (4.7 mmol) of 2-benzyl-1,3-diisopropyl isourea. The reaction mixture was allowed to stir at ambient temperature overnight, filtered (rinsing with tetrahydrofuran) and then concentrated in vacuo. Purification by flash chromatography (silica, 3 25% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][C:27]#[N:28]>C1COCC1>[C:27]([CH2:26][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([NH:16][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=2)[NH:22][CH:21]=1)#[N:28]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#CCc1c[nH]c2ccc(NC(=O)c3ccccc3)cc12
Reaction time: 18 h

Procedure:
A solution of 2.0 g (0.014 mole) of benzoyl chloride in THF was treated with 10 ml pyridine followed by 2.43 g (0.014 mole) of 5-aminoindole-3-acetonitrile, Example 1, and stirred 18 hr. The solvent was removed in vacuo and crude product recrystallized from EtOH to give product used directly in next step below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[BH4-].[Na+]>CO>[NH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Br:1])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N)cc(Br)c1
Reaction time: 0.01 h
Yield: 98.4 %

Procedure:
To a stirred solution of methyl 3-bromo-5-nitrobenzoate (1.0 g, 3.8 mmol) in methanol (30 mL) was added NiCl2-6 H2O (1.8 g, 7.6 mmol) and NaBH4 (430 mg, 11 mmol) successively at 0° C. The reaction mixture was stirred for 30 seconds and was then quenched by the addition of water. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford methyl 3-amino-5-bromobenzoate (860 mg, 97% yield). 1H NMR (400 MHz, d-DMSO) δ 7.14 (dd, J=2.0, 2.4 Hz, 1H), 7.11 (t, J=2.4 Hz, 1H), 6.94 (t, J=2.8 Hz, 1H), 5.72 (brs, 2H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([O:12][CH3:13])[CH:8]=2)[CH2:3]1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:14])=[C:7]([O:12][CH3:13])[CH:8]=2)[CH2:3]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(cc1N)CN(C)CC2
Yield: 77.2 %

Procedure:
A solution of 2-methyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline and Pd(OH)2(1 g) in MeOH(100 mL) was stirred under H2 at room temperature for 5 h. The solution was filtered and all solvents were removed under reduced pressure to give 2-methyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (2 g, 77.2%). 1H NMR (400 MHz, CDCl3) δ ppm 6.51 (s, 1 H), 6.38 (s, 1 H), 3.81 (s, 3 H), 3.64 (s, 2 H), 3.43 (s, 2 H), 2.81 (t, J=5.77 Hz, 2 H), 2.64 (t, J=5.90 Hz, 2 H), 2.42 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1>CN(C=O)C>[CH:25]1([S:28]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[N:11]4[C:12]5[CH:18]=[CH:17][NH:16][C:13]=5[N:14]=[CH:15][C:10]4=[N:9][N:8]=3)[CH2:5][CH2:6]2)(=[O:30])=[O:29])[CH2:27][CH2:26]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: c1cc2c(ncc3nnc(C4CCNCC4)n32)[nH]1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=S(=O)(C1CC1)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Reaction time: 3 h
Yield: 6.2 %

Procedure:
To a suspension of 1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.090 g, 0.37 mmol, Example #2) and pyridine (0.12 mL, 1.5 mmol) in DMF (5 mL) was added cyclopropanesulfonyl chloride (0.060 g, 0.41 mmol). After about 3 h at ambient temperature, the reaction mixture was quenched with MeOH (0.5 mL) and then purified by RP-HPLC (Table 2, Method b). The appropriate fractions were concentrated and lyophilized to afford 1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazine as a white solid (0.008 g, 6%): LC/MS (Table 2, Method a) Rt=1.52 min; MS m/z: 347 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])CCC.[F-].[K+]>CN(C)C=O.O>[O:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:3][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCC[Sn](/C=C/C(=O)OCC)(CCCC)CCCC
Reactant: Brc1ccc(OCc2ccccc2Oc2ccccc2)cn1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2Oc2ccccc2)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-5-((2-phenoxybenzyl)oxy)pyridine (1.0 g) in dimethylformamide (7 ml), 1.26 g of ethyl (2E)-3-(tributylstannyl)acrylate and 350 mg of tetrakis triphenylphosphine palladium were added, and the reaction solution was stirred overnight at 100° C. under nitrogen atmosphere. The reaction solution was cooled, then 15 ml of a saturated aqueous potassium fluoride solution was added, and the reaction solution was stirred for 1 hour, followed by removing insoluble matters by filtration through Celite and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water, extracted with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-25:75-30:70)) to afford the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH:12]([C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1>>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][C:23]([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(NCC(c1ccc(F)cc1)c1ccc(Br)cc1)OCc1ccccc1
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(-c2cn[nH]c2)cc1)OCc1ccccc1

Procedure:
[2-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid benzyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 3.20 [M+H]+ 416.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]1[CH2:9][CH2:8][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:6]1)(=O)=O.Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:42]3[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=3[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:8][CH2:9][CH:5]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[C:42]5[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=5[NH:40][C:39]4=[O:48])[CH2:36][CH2:37]3)[CH2:6]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2)CC1
Temperature: 70 °C
Reaction time: 52 h

Procedure:
A mixture of 13.5 g of 3,3-bis(p-fluorophenyl)cyclopentyl tosylate (nD20 1.5691), 7.5 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone hydrochloride, 8.6 g of potassium carbonate and 70 ml of dimethylformamide is stirred at 70° C for 52 hours. The reaction mixture is poured into ice water, and the aqueous layer is removed by decantation. The precipitated semi-solid is dissolved in chloroform. The solution is washed with water and dried over sodium sulfate, and the solvent is removed. The crude crystals are recrystallized from a mixture of chloroform and ethanol (20:1) to give 1-[1-(3,3-bis(p-fluorophenyl)cyclopentyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystals, melting at 131°-134° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2].C(O)C>CO.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCC#N)c4c21)C(=O)NC3=O
Agent: [Ni]
Solvent: CCO
Solvent: CO
Product: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCCN)c4c21)C(=O)NC3=O
Reaction time: 20 h

Procedure:
760 mg (1.94 mmol) 12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole (Example 1a) in 100 ml methanol are hydrogenated in the presence of 500 mg Raney nickel at 60° C. and 50-65 bar pressure for 20 hours in an autoclave. The reaction mixture is evaporated, the residue is taken up in 100 ml dimethylformamide, filtered off from the catalyst and again evaporated in a vacuum. The residue is chromatographed on silica gel with dichloromethane/methanol saturated with ammonia (95:5 v/v). The fraction with the Rf of 0.1 is isolated, stirred with ethanol and the undissolved product is filtered off. 12-(3-aminopropyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole is obtained as an amorphous yellow powder which decomposes from about 250° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:51]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:51])[C:8]=2[N:17]=1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCC(=O)N1CCOCC1

Procedure:
2-(2-Methoxyethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline (4.7 g, 13 mmol) was treated with mCPBA (5.73 g, 24.9 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (4.23 g, 22.2 mmol) according to the method described in Part D of Example 8. The crude product was recrystallized twice from ethyl acetate to provide 0.233 g of 2-(2-methoxyethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-4-amine as beige needles, mp 125-126° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2].[Cl:24][S:25](O)(=[O:27])=[O:26]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:25]([Cl:24])(=[O:27])=[O:26])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 2.00 g (6.4 mmol) of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are slowly added to 3.83 ml of chlorosulphonic acid. At room temperature, the reaction mixture is stirred overnight, and then poured into ice-water and extracted with dichloromethane. This gives 2.40 g (91%) of a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[CH:27]=[C:26]([C:33](Cl)=[O:34])[CH2:25][CH2:24]2>C(Cl)Cl>[CH3:32][O:31][C:30]1[CH:29]=[C:28]2[C:23](=[CH:22][C:21]=1[O:20][CH3:19])[CH2:24][CH2:25][C:26]([C:33]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:34])=[CH:27]2
Reactant: COc1cc2c(cc1OC)CCC(C(=O)Cl)=C2
Reactant: COC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)C1=Cc2cc(OC)c(OC)cc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of 6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxylic acid (476 mg, 2 mmol) and SOCl2 (1.5 mL, 20 mmol) in toluene (20 mL) was heated at 50° C. for 1 hour. The solvent was then removed under reduced pressure to give 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbonyl chloride which was used directly in the next step without further purification. To a stirred solution of methyl 2-aminobenzoate (332 mg, 2.2 mmol) and Et3N (0.8 mL, 6 mmol) in anhydrous DCM (20 mL) was added 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbonyl chloride in anhydrous DCM (2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The combined organic phase was dried over sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by flash column, eluting with petroleum ether/ethyl acetate (10:1) to give methyl 2-(6,7-dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoate (330 mg, 45%). LC-MS (ES-API); rt 9.27 min; m/z calculated for C21H21NO5 [M+Na]+ 390.1, found 390.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(F)c(C)c1
Temperature: 25 °C

Procedure:
5.00 g of 4-fluoro-3-methylbenzoic acid was dissolved in 100 mL of ethanol, and 2.59 mL of concentrated sulfuric acid was added thereto, followed by heating under reflux overnight. The reaction liquid was cooled to room temperature, and then concentrated under reduced pressure, and the obtained residue was alkalified (pH=8) by addition of an aqueous saturated sodium hydrogen carbonate solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5.86 g of ethyl 4-fluoro-3-methylbenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[C:19](#[N:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH2:20][C:19]#[N:21])[CH:12]=[CH:13][CH:14]=1
Reactant: CC#N
Reactant: COc1ccccc1COc1cccc(C=O)c1
Product: COc1ccccc1COc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(2-methoxybenzyloxy)benzaldehyde gave 3-(3-(2-methoxybenzyloxy)phenyl)-3-hydroxypropanenitrile as yellow oil. Yield (0.88 g, 47%): 1H NMR (400 MHz, CDCl3) δ 7.42-7.46 (m, 1H), 7.27-7.31 (m, 2H), 6.90-7.06 (m, 5H), 5.12 (s, 2H), 5.01 (m, 1H), 3.87 (s, 3H), 2.76-2.82 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:20]=2[N:19]=[C:18]1[CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:20]=3[N:19]=[C:18]2[CH2:35][CH2:36][CH3:37])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCCSc1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 104.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 4-chlorobenzenethiol (868 mg, 6.00 mmol) in DMF (5 mL) was added to a mixture of sodium hydride (60% dispersion, 240 mg, 6.00 mmol) in DMF (15 mL); the reaction became homogeneous and was stirred for 15 minutes. Solid 1-(5-chloropentyl)-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (1.93 g, 5.00 mmol) was added in small amounts, and the reaction was stirred for 1.5 hours. Water (25 mL) was added, and the resulting solution was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water (5×30 mL) and brine (2×10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a colorless oil, which crystallized overnight. The solid was dried for three hours under high vacuum to provide 2.58 g of 1-[5-(4-chlorophenylsulfanyl)pentyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:25][CH2:26][CH2:27][NH:28][CH2:29][CH:30]([OH:32])[CH3:31])[CH:10]=[CH:11][C:12]=3[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH:22]([OH:24])[CH3:23])[C:7](=[O:33])[C:6]=2[C:5]([OH:34])=[CH:4][CH:3]=1.[C:35](OC)(=[O:40])[C:36](OC)=[O:37]>CS(C)=O>[CH3:31][CH:30]1[O:32][C:36](=[O:37])[C:35](=[O:40])[N:28]([CH2:27][CH2:26][NH:25][C:9]2[C:8]3[C:7](=[O:33])[C:6]4[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=4[OH:34])[C:14](=[O:16])[C:13]=3[C:12]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH:22]([OH:24])[CH3:23])=[CH:11][CH:10]=2)[CH2:29]1
Reactant: COC(=O)C(=O)OC
Reactant: CC(O)CNCCNc1ccc(NCCNCC(C)O)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Solvent: CS(C)=O
Product: CC(O)CNCCNc1ccc(NCCN2CC(C)OC(=O)C2=O)c2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
A solution of 2.60 g of 1,4-dihydroxy-5,8-bis-[2-(2-hydroxypropylamino)ethylamino]anthraquinone (prepared in Example 3) and 0.650 g of dimethyl oxalate in 25.0 ml of dried dimethyl sulfoxide is processed as described in Example 2 to give the desired product as a blue-black solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:19]>>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:23]3[CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21][CH2:22]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(F)ccc2Oc2ccccc21
Reactant: CCN1CCNCC1
Product: CCN1CCN(C2=Nc3cc(F)ccc3Oc3ccccc32)CC1

Procedure:
Prepared in the same manner as Example 1 starting with 8-fluoro-10H-dibenzo[b,f][1,4]oxazepin-11-one (2, X=O, R1=F) with 1-ethyl piperazine. This compound was an oil with 1H NMR (400 MHz, CDCl3), 1.16 (t, 3H, J=7.2 Hz, CH3), 2.55 (q, 2H, J=7.2 Hz, —CH2—), 2.55-2.65 (broad s, 4H, piperazinyl CH2) 3.55-3.65 (broad s, 4H, piperazinyl CH2), 6.64 (ddd, 1H, J=2.4, 6.6 and 7.2 Hz), 6.82 (dd, 1H, J=2.1 and 7.5 Hz), 7.12 (dd, 1H, J=4.2 and 6.2 Hz), 7.21 (doublet of triplets, 1H, J=0.8 and 6.0 Hz), 7.23 (dd, 1H, J=0.9 and 6.3 Hz), 7.34 (dd, 1H, J=1.2 and 5.7 Hz), 7.44 (doublet of triplets, 1H, J=1.2 and 6.0 Hz).