Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14]C)=[O:13].Cl>N1C=CC=CC=1>[C:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])([OH:14])=[O:13]
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(O)c(C(=O)O)c1
Yield: 98 %

Procedure:
A mixture of dimethyl 4-hydroxyisophthalate (10 g) and pyridine (100 ml) was heated at reflux overnight. After cooling, 6 M hydrochloric acid was added to the reaction solution. The thus-precipitated crystals were filtered, thereby giving 9.15 g of methyl 3-carboxy-4-hydroxybenzoate.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17]I)[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][NH:22][CH3:23].C[O-].[Na+]>CN(C)C=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:22]([CH3:23])[CH3:21])[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(CCCCI)CCN1N=Cc1ccccc1
Reactant: CNC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCCN1CCN(N=Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A stirred solution of 1-phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone (prepared as described in Example B, Part II) (7.0 g, 0.0189 mole), dimethylformamide (125 ml), and dimethylamine hydrochloride (6.15 g, 0.075 mole) is heated on a steam bath. Sodium methoxide (4.05 g, 0.075 mole) is added portionwise over approximately 2 hours while heating. After addition, heating is continued 2 hours, then the mixture is cooled to ambient temperature. The mixture is concentrated under reduced pressure to an oily residue. This residue is suspended in saturated NaHCO3 solution. (300 ml) and extracted with CH2Cl2 (3×100 ml). The CH2 Cl2 extract is washed with H2O (2×100 ml), then dried over MgSO4. The filtered solution is concentrated under reduced pressure to an oily-liquid residue, which is triturated in hexane (2×100 ml), decanted, then dried in vacuo, giving 4.6 g (0.016 mole) of 1-phenylmethyleneamino-3-[4-(dimethylamino)butyl]-2-imidazolidinone, as a solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2].[NH2:15]C1C=CC(O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH2:15])=[O:14])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2]
Reactant: Nc1ccc(O)cc1
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc2c(C=O)n[nH]c2c1
Reaction time: 2 h

Procedure:
To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g, 8.4 mmol) and 4-aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide (35 mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4 mL, 10.1 mmol). The reaction was stirred at room and monitored by TLC and LC/MS. After two hours the reaction was complete. The solvent was removed by vacuum and the product was purified by flash column chromatography using ethyl acetate: petroleum ether 1:1 to pure ethyl acetate. N-4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide was isolated as a tan colored solid. 1H NMR (DMSO-d4) δ 6.79 (2H, d, 8.9 Hz), 7.59 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz), 8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([S:27](=[O:34])(=[O:33])[N:28]([CH3:32])[CH2:29][CH2:30][CH3:31])=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]([S:27](=[O:33])(=[O:34])[N:28]([CH3:32])[CH2:29][CH2:30][CH3:31])=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(C)S(=O)(=O)c1cc(C(=O)OC)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(C)S(=O)(=O)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.8 113 g of methyl 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoate are dissolved in 300 ml of methanol and 300 ml of THF, 600 ml of 2 N NaOH are added, and the mixture is stirred at room temperature for 14 hours. Some of the solvent is removed, and the mixture is neutralised using dilute HCl with ice-cooling. The precipitated product is separated off and dried, giving 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoic acid in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:55][C@H:56]1[CH2:60][NH:59][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:57]1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([N:59]1[CH2:60][C@H:56]([OH:55])[CH2:57][C@H:58]1[C:61]([O:63][CH3:64])=[O:62])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoic acid (2 g, 6.6 mmole), synthesized using Scheme 1, in dichloromethane (20 mL) was added DIPEA (11.5 mL, 33.0 mmole), HATU (2.7 g, 7.2 mmole) followed by (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.3 g, 7.2 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude (2S,4R)-methyl 1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate. The crude product was taken to the next step without further purification (2.2 g, 80%). MS: MS m/z 427.2 (M++1).
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+].C(=O)([O-])[NH2:19].[NH4+].O>S1(CCCC1)(=O)=O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:19])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: NC(=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: [NH4+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
Ammonium picrate (0.92 g, 3.7 mmol) and ammonium carbamate (0.59 g, 7.5 mmol) are suspended in sulfolane (3 ml) and stirred for 2 hr with the temperature of the reaction increasing from 25° C. to 177° C. The reaction is continued an additional 6 hr at 177° C. and cooled to ambient temperature. Water (30 ml) is added to the slurry and the product is collected, washed with water and dried to yield 0.75 g (87%) of picramide (Table 1, entry 4).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Brc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.1 %

Procedure:
A mixture of 31.4 g (0.080 mole) of 1,2-diphenyl-4-p-bromophenylbutane-1,4-dione, 100 ml of xylene, 16 g (0.036 mole) of phosphorus pentasulfide and 125 g (3.67 mole) of hydrogen sulfide was heated in a 1-liter stainless steel autoclave with stirring for four hours at 156°-176° C. (1140-1320 psig). The reactor was cooled to room temperature and the hydrogen sulfide was led into a sodium hydroxide solution. Treatment of the residue with 150 ml of absolute ethanol gave 18.5 g (59.1%) of crude solid, m.p. 135°-137°. Recrystallization from 20 ml of dioxane and 60 ml. of absolute ethanol gave 16.5 g (52.7%) of pure 2,3-diphenyl-5-p-bromophenylthiophene.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH:15]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH:16][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:25]#[N:26])[CH3:24])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:15]2[N:16]=[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[C:25]#[N:26])[O:27][C:14]=2[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)C(NC(=O)CCCCCC(C)C#N)c2ccc(OC)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(CCCCCC(C)C#N)oc2-c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 93.9 %

Procedure:
15 g of phosphorus oxychloride is added with stirring to a solution of 13.8 g of (RS)-1,2-bis(4-methoxyphenyl)-2-(7-cyanooctanamido)ethanone in 65 cm3 of toluene, and the mixture is heated to 80° C. for 4 hours. The solution is poured onto 50 g of ice, the toluene phase is separated after settling has taken place and the aqueous phase is extracted with twice 50 cm3 of ethyl acetate. The combined organic extracts are washed with water (3 times 20 cm3) and with 30 cm3 of saturated aqueous sodium chloride solution. After drying over-sodium sulphate, the solvent is evaporated off under reduced pressure. The residue is chromatographed on a column 2.8 cm in diameter containing 100 g of silica gel (50 to 200). The column is eluted, collecting 50 cm3 fractions, with 1.8 liters of diisopropyl ether. The fractions emerging at between 0.3 liter and 1.8 liters are concentrated under reduced pressure (0.2 kPa). 12.4 g (93%) of (RS)-7-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]-2-methylheptanenitrile are obtained in the form of a yellowish oil, which is used directly in the subsequent reaction.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][OH:23].[CH2:24](N(S(F)(F)F)CC)C.CO>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][O:23][CH3:24]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2CO
Reactant: CCN(CC)S(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2COC
Reaction time: 4 h

Procedure:
65 mg of the compound (177) obtained in Example 54 was suspended in 5 ml of tetrahydrofuran, and 270 μl of diethylaminosulfurtrifluoride was added to the solution. The solution was stirred for 4 hours, and 1 ml of methanol was added to the solution. The deposited solid matter was filtered off and washed with ether to obtain 34 mg of the subject compound (180).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:10][CH2:11][CH2:12][OH:13].C>C(OC(C)C)(C)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)c(Cl)c1
Solvent: CC(C)OC(C)C
Product: NS(=O)(=O)OCCOc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared by the procedures of Example 16 from sulfamoyl chloride and to 2-(3,4-dichlorophenoxy)ethanol. The tan colored solid obtained was dissolved in isopropyl ether and the solution treated with charcoal and filtered through Celite®. The filtrate was evaporated under reduced pressure and the solid residue was recrystallized from isopropyl ether to give the title compound, mp 84°-85° C., in 19% yield.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:29][C:30]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:17])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Product: O=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=O)Nc1ccccc1

Procedure:
The compound is prepared by a method analogous to that of Example 20 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carboxamide and phenyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.[CH3:23][N:24]=[C:25]=[O:26]>C(Cl)Cl>[CH3:23][NH:24][C:25](=[O:26])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=NCc2ccccc2)CC1
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a stirred solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (2.0 g) in CH2Cl2 (40 ml) was added 1,8-diazabicyclo[5.40]undec-7-ene (0.16 g) followed by the dropwise addition of methyl isocyanate (0.39 g) in CH2Cl2 (10 ml). The reaction was monitored via TLC and after 3 hours the solution was concentrated and the precipitate was collected and recrystallized from acetonitrile to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate (1.85 grams).
Reaction SMILES: [C:1]1([N:7]=[C:8]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]([C:12]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:16](=[O:22])[N:15]([CH3:23])[C:14](=[O:24])[CH:13]=1)[NH2:11]>CN(C=O)C>[CH2:18]([N:17]1[C:12]2=[N:10][NH:11][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]1=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: S=C=Nc1ccccc1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)[nH]nc21
Temperature: 120 °C
Yield: 13.6 %

Procedure:
Phenyl isothiocyanate (0.17 mL, 1.4 mmol) is added to a solution of 6-hydrazinyl-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (31 mg, 0.47 mmol) in DMF (10 mL). The reaction mixture is heated at 120° C. for 6 hours, and then evaporated to remove solvent under reduced pressure. The residue is further purified by silica-gel flash chromatography to give 20 mg of product (Yield: 41%). 1H NMR (400 MHz, DMSO-d6) 50.95 (s, 3H), 0.97 (s, 3H), 2.30 (m, 1H), 3.37 (s, 3H), 3.77 (d, 2H), 7.16-7.43 (m, 5H), 7.61 (s, 1H). MS (FAB) m/z 314.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][N:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=3)[CH2:15][CH2:16]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: c1ccc(CN2CCC3(CCNC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCC3(CCN(Cc4ccccc4)C3)C2)nc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-benzyl-2,7-diazaspiro[4.4]nonane (1.00 g, 4.68 mmol), methyl 6-chloronicotinate (800 mg, 4.68 mmol) and K2CO3 (700 mg, 5.07 mmol) in 5 mL of DMSO was stirred under microwave irradiation for 20 min at a temperature of 150° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (Na2SO4), filtered and concentrated, giving methyl 6-(7-benzyl-2,7-diazaspiro[4.4]non-2-yl)nicotinate. A bottle containing a suspension of the benzyl amine and 20% Pd(OH)2/C (600 mg, 0.857 mmol) in 20 mL of EtOH was evacuated and purged with H2 gas three times. Using a Parr shaker apparatus, the suspension was agitated under 50 psi of H2 for 20 h. The pressure was released and the mixture filtered through a pad of Celite and concentrated, giving methyl 6-(2,7-diazaspiro[4.4]non-2-yl)nicotinate: 1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J=2.1 Hz, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 7.27 (d, J=4.4 Hz, 1H), 6.44 (d, J=8.8 Hz, 1H), 3.74 (s, 3H), 3.13 (br s, 4H), 2.89 (t, J=7.3 Hz, 2H), 2.72 (AB, J=7.6 Hz, 2H), 1.92 (br m, 2H), 1.69 (AB, J=7.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17]Cl)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cc2cc(OCCCCl)cnc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Yield: 75 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from 5-(3-chloro-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium carbonate, potassium iodide and pyrrolidine to give the desired product as light yellow solid (75%).
Reaction SMILES: O[C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([NH:22][CH3:23])=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1.Cl.[H][H]>CO.[C].[Pd]>[CH:8]1[N:7]=[CH:6][N:5]2[CH2:4][CH2:3][CH:2]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:20]([NH:22][CH3:23])=[O:21])[CH:14]=[CH:13]4)[C:9]=12
Reactant: [H][H]
Reactant: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC(=O)c1ccc2cc(C3CCn4cncc43)ccc2c1
Yield: 72.6 %

Procedure:
6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide (77 mg) was dissolved in methanol (5 ml). 1 N Hydrochloric acid (0.5 ml) and 10% palladium carbon (50% wet, 39 mg) were added, and the mixture was vigorously stirred for 12 h under 4 kg/cm2 hydrogen atmosphere. The catalyst was filtered off and the residue was washed with methanol. The filtrate and the washing were combined and aqueous potassium carbonate solution (0.25 M; 1 ml) was added. After neutralization, the solvent was evaporated under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluent, chloroform/methanol containing ammonia (7%); 19/1). The eluate was recrystallized from chloroform-ether to give the title compound (53 mg) as colorless crystals.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1.Cl[CH2:10][C:11]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:18]2[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=2)[N:12]=1.O>CN(C)C=O>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C:19]2[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=3)[N:12]=[C:11]([CH2:10][N:3]3[CH2:8][CH2:7][S:6][CH2:5][CH2:4]3)[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: C1CSCCN1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CN2CCSCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
Oily sodium hydride (60%, 0.753 g) was added to a solution of thiomorpholine (1.8 g) in N,N-dimethylformamide (50 ml), and the mixture was stirred at room temperature for 15 minutes. Then ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (6.0 g) was added. The resulting mixture was stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (7/3, v/v) gave ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-thiomorpholinomethylquinoline-3-carboxylate (1.4 g, 42%) which was then recrystallized from ethanol. Colorless prisms. mp. 148°-149° C.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[S:20]([O:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])([CH3:19])(=[O:22])=[O:21]
Reactant: CCCCCCC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To 130 g (0.995 mol) of 2-octanol and 207 ml (1.19 mol, 1.2 equiv) of diisopropylethylamine in 1.5 L dichloromehane at 0° C. under a CaSO4 drying tube was added dropwise 84.4 ml (1.09 mol, 1.1 equiv.) of methanesulfonyl chloride over 1 hour while keeping the internal temperature at less than 5° C. The faintly yellow solution was stirred at 0° C. for an additional 1.5 h. The cold reaction solution was then washed with 2×1 L ice-cold 1M HCl and 1 L of ice-cold H2O and brine and dried over MgSO4. The residue was filtered through Celite and concentrated in vacuo below 35° C. to afford 208 g of a yellow oil. The yellow oil was placed under high-vacuum for 2 h at 25° C. to give 205 g of yellow oil. NMR spectra confirmed the desired title-product having only trace amounts of solvents present.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:2]1.[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1>>[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([N:10]4[CH2:9][CH2:8][N:7]([CH2:6][C:3]5[CH:4]=[CH:5][S:1][CH:2]=5)[CH2:12][CH2:11]4)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1
Reactant: c1cc(CN2CCNCC2)cs1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCN(Cc2ccsc2)CC1

Procedure:
Reaction of N-(3-thienylmethyl)piperazine and 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid (2g) analogously to the procedure of Example 4 gave the title compound after crystallization from methanol/diethyl ether as the dihydrochloride salt; yield 3.35 g (91%), m.p. indistinct, decomposed at 245°-250° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>>[CH3:1][C:2]1[N:3]([S:32]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1[nH]ccc1C=O
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)ccn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 146 and using 2-methyl-1H-pyrrole-3-carbaldehyde (1.10 g), sodium hydride (60% in oil, 1.20 g), 15-crown-5 (6.0 mL) and pyridin-3-ylsulfonyl chloride (3.22 g), the title compound was obtained as white crystals (yield 1.10 g, 44%).