Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]#[N:9])[CH3:5].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18]>CO>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8](=[NH:9])[NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=1)[CH3:5]
Reactant: CCOC(C#N)OCC
Reactant: NCc1cccc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1cccc(F)c1
Temperature: 25 °C
Yield: 108.1 %

Procedure:
A solution of sodium methoxide (23%, 4.1 mL, 16 mmol) in MeOH was added to a solution of diethoxyacetonitrile (22 g, 86 mmol) in MeOH (400 mL) with stirring. The solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. The residue was dissolved in diethyl ethyl (200 mL) and washed with washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was dissolved in MeOH (100 mL), and m-fluorobenzylamine (10 g, 80 mmol) was added. Then this solution was heated under reflux overnight. After cooled to room temperature, the solvent was distilled off under reduced pressure to give the crude title compound (22 g).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7](C(=O)C(F)(F)F)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[ClH:16].CC(O)C>>[ClH:16].[ClH:16].[CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C(N1CCN(C2CC2)CC1)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Product: C1CN(C2CC2)CCN1
Reaction time: 5 h

Procedure:
To 1-(4-cyclopropyl-piperazin-1-yl)-2,2,2-trifluoro-ethanone (444.4 mg, 2 mmol) was added a mixture of HCl/IPA (5-6N, 2 mL). Solids were observed to precipitate immediately after the HCl/IPA was added. The resulting suspension was stirred for 5 h. Heptane (2 mL) was then added to the reaction mixture, followed by addition of IPA (2 mL). The resulting suspension was stirred for 0.5 h at ambient temperature. The solids were filtered off using a medium glass sintered funnel with a filter paper on the top. The reaction flask was rinsed with IPA (3 mL) and the rinse was used to wash the solids. The solid was washed a second time with fresh IPA (2 mL). The solids were dried at ambient temperature and house vacuum to yield the title compound as a white crystalline solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: CNc1nc(SC)ncc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CNc1nc(SC)ncc1C=O
Reaction time: 2 h
Yield: 30.2 %

Procedure:
4-Methylamino-2-methylsulfanyl-5-pyrimidine-methanol (2.40 g, 13.0 mmol) in 7 mL of acetic acid was added to a solution of sodium dichromate-dihydrate (1.30 g, 4.4 mmol) in 6 mL of acetic acid. After 2 hours at room temperature, additional sodium dichromate-dihydrate (0.3 g, 1.0 mmol) in 1 mL of acetic acid was added. After a total reaction time of 3.5 hours, the bright yellow solid was removed by filtration. Water (30 mL) was added to the filtrate, followed by aqueous ammonium hydroxide until basic (pH 9.0). The mixture was cooled in the refrigerator for 30 minutes. The precipitate was collected and dissolved in ethyl acetate, and the solution was dried over MgSO4. Filtration and concentration in vacuo gave 0.72 g (30%) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxaldehyde, mp 99°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10]([OH:12])=O)[CH:7]=1.O=S(Cl)Cl.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:12])[CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 3-(5-fluoro-2-methylphenyl)-3-methylbutyric acid (3.80 g, 18.0 mmol) in 15 mL of dichloromethane was treated with SOCl2 (1.98 mL, 27.1 mmol) at 0° C. After 30 minutes, a mixture of morpholine (2.36 mL, 27.1 mmol) and pyridine (4.4 mL, 54.2 mmol) in 10 mL of dichloromethane was added to the reaction mixture at 0° C. After an additional 90 minutes, 60 mL of 2 M aqueous HCl solution was added, phases were separated and the aqueous layer was extracted with three 50 mL portions of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5.03 g of 3-(5-fluoro-2-methylphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one as an oil, which was used without further purification (quantitative yield).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[O:7]=[C:8]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:9][CH2:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@@H:12]1[CH2:24][CH:25]=[O:26].S([O-])([O-])=[O:40].[Na+].[Na+]>O.CC(C)=O>[O:7]=[C:8]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:9][CH2:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][C@@H:12]1[CH2:24][C:25]([OH:40])=[O:26]
Reactant: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CC=O)c2c1
Reactant: O=S([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CC(=O)O)c2c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
A solution of 0.85 g of potassium permanganate in 25 cm3 of water and 120 cm3 of acetone was added over approximately 1 hour, with stirring and at a temperature in the region of 25° C., to a solution of 1.2 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetaldehyde in 60 cm3 of acetone. The mixture was stirred for 3 hours at this same temperature and then cooled to approximately 10° C. A solution of 5 g of sodium sulfite in 200 cm3 of water was added to the reaction mixture and then the mixture obtained was filtered through celite. The acetone of the filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then the evaporation residue was taken up in 200 cm3 of water and washed with 200 cm3 of diethyl ether. The aqueous phase was separated by settling, acidified with citric acid in the solid state to a pH in the region of 3-4 and extracted with 200 cm3 of diethyl ether. The ethereal solution, separated by settling, was dried over magnesium sulfate, filtered, and evaporated under the above conditions. 0.74 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetic acid was obtained in the form of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydro-quinolin-2(1H)-one (1.50 g) in N,N-dimethylformamide (10 ml), potassium carbonate (1.85 g) and methyl iodide (0.63 ml) were added and stirred overnight at room temperature. Insoluble materials were filtered off and the filtrate was concentrated. The resulting residue was diluted with ethyl acetate and then washed sequentially with water, saturated aqueous sodium thiosulfate:brine (1:1) and brine, followed by distilling off the solvent under reduced pressure. The resulting residue was diluted with n-hexane, and the crystal was collected by filtration to give 7-methoxy-3,4-dihydroquinolin-2(1H)-one (1.38 g) as a colorless crystal. To a solution of 7-methoxy-3,4-dihydroquinolin-2(1H)-one thus obtained (1.38 g) in tetrahydrofuran (30 ml), lithium aluminum hydride (592 mg) was added under ice cooling, heated under reflux for 4.5 hours, and then stirred overnight at room temperature. The reaction mixture was diluted with 28% aqueous ammonia under ice cooling and filtered to remove insoluble materials. The filtrate was evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 9:1) to give the titled compound, i.e., 7-methoxy-1,2,3,4-tetrahydroquinoline (1.18 g) as a yellow oil.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:31][C:32]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:33]=1[CH2:34]Br.Cl>CC(N(C)C)=O>[Br:31][C:32]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:33]=1[CH2:34][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:24]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2cc(F)ccc2Br)c1=O
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2-bromo-5-fluorobenzyl bromide (375 uL, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (160 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.10 (br. s., 1 H), 7.69 (dd, J=8.59, 5.31 Hz, 1 H), 7.11 (ddd, J=8.53, 3.16 Hz, 1 H), 7.05 (dd, J=9.60, 2.78 Hz, 1 H), 4.95 (s, 2H), 4.63 (t, J=12.38 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.24 (q, 2 H), 1.79 (d, J=13.14 Hz, 2 H), 1.52-1.74 (m, J=27.54, 11.62 Hz, 3 H), 1.28 (q, J=12.88 Hz, 2 H), 1.10 (q, J=12.97 Hz, 1 H).
Reaction SMILES: Br.[Br:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C1COCC1.C(Cl)Cl>[Br:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:6][CH:5]=1
Reactant: BrCc1ccc2cn[nH]c2c1
Reactant: C1=COCCC1
Agent: Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: BrCc1ccc2cnn(C3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
A yellow suspension of 6-(bromomethyl)-1H-indazole hydrogen bromide (9.0 g, 43 mmol) (5) and 3,4-dihydro-2H-pyran (7.2 g, 86 mmol) in THF (200 mL) was heated at reflux for 2 hours. The reaction mixture was additionally stirred at room temperature for 12 hours under nitrogen. The reaction solution was diluted with methylene chloride (500 mL), washed with saturated NaHCO3, water and brine. After drying (MgSO4), the solvent was removed under vacuum to give a yellow oil. Flash chromatography yielded the title compound (6.6 g, 72%). TLC Rf 0.52 (80:20 of hexane-ethyl acetate); MS (electrospray) 295, 297 (M+1); 1H N MR (CDCl3) δ 1.57-1.84 (m, 3H), 2.16 (m, 2H), 2.55 (m, 1H), 3.75 (m, 1H), 4.01 (m, 1H), 4.65 (s, 2H), 5.71 (d, 1H, J=9.2 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.59 (d, 1H, J=8.8 Hz), 7.73 (s, 1H), 8.00 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1

Procedure:
4-Nitrobenzylbromide (E.0) is treated with morpholine and potassium carbonate in acetone to give 4-(4-nitrobenzyl)morpholine (E.1) of Chart E. The nitro group is reduced with platinum on carbon and hydrogen gas to afford the aniline E.2. lodination employing ICI or NIS provides the amine E.3 which is then treated with diethyl ethoxymethylenemalonate to give the enamine E.4. Cyclization with phosphorous pentoxide in methanesulfonic acid affords the quinoline ester E.5. Aminolysis with p-chlorobenzylamine at elevated temperatures gives the arnide E.6. Coupling with an acetylene employing PdCl2(PPh3)2 and copper iodide and subsequent cyclization provides the desired pyrroloquinolones E.7.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:46])[C:27]4[CH:36]=[CH:35][C:34]([O:37]CC5C=CC=CC=5)=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)=[CH:18][CH:17]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].Cl>O1CCCC1.O.[Pd].C(#N)C>[C:1]1([C:7]2[CH:8]=[C:9]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:46])[C:27]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)=[CH:20][CH:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(OCc4ccccc4)c4[nH]c(=O)ccc34)cc2)cc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)cc2)cc1-c1ccccc1

Procedure:
To a solution of N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine (PP) (4.0 g, 6.5 mmol) in tetrahydrofuran (100 mL) and water (16 mL) was added 10% palladium on carbon (800 mg). The reaction was stirred vigorously under one atmosphere of hydrogen for 6.5 h. The solids were filtered off and washed with tetrahydrofuran (4×25 mL) and then 50% methanol/tetrahydrofuran (2×25 mL). The combined filtrates were evaporated to dryness and the crude product was purified by reverse-phase HPLC. Fractions containing pure product were combined and lyophilized. The product from several runs was combined to give 4.68 g which was dissolved in acetonitrile (200 mL) and water (200 mL). 1.0 N HCl (18.7 mL) was added, and the solution was lyophilized. The residue was again dissolved in acetonitrile (125 mL) and water (125 mL). 1.0 N HCl was added and the solution was lyophilized to give a hydrochloride salt of compound 9 as an off white powder. 1H NMR (300 MHz, DMSO-d6) δ 10.55 (br s, 1H), 9.40 (br s, 1H), 8.80, (br s, 1H), 8.26 (d, 1H), 7.60, (br s, 2H) 7.25-7.45 (m, 5H), 6.92-7.16 (m 10H), 6.55 (d, 1H), 5.45 (d, 1H), 3.69 (s, 3H) 2.80-3.15 (m, 6H); m/z: [M+H+] calcd for C32H31N3O4 522.24; found 522.4.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:36]([F:39])([F:38])[F:37])[C:15]3[CH:16]=[C:17]([N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])[CH:18]=[CH:19][C:14]=3[N:13](CC3C=CC(OC)=CC=3)[C:12](=[O:35])[O:11]2)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>C1(OC)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:36]([F:37])([F:38])[F:39])[C:15]3[CH:16]=[C:17]([N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:35])[O:11]2)=[O:7])=[CH:40][CH:41]=1
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(N4CCCC4=O)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Solvent: O
Product: O=C1Nc2ccc(N3CCCC3=O)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 25 °C

Procedure:
4-Fluoro-N-{[1-(4-methoxybenzyl)-2-oxo-6-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}benzamide (30 mg, 0.0525 mmol), aluminum trichloride (70 mg, 0.525 mmol) were mixed in anisole (0.5 mL), and the mixture was stirred at room temperature. After all the ingredients were dissolved, the temperature of the solution was raised to 100° C. and the solution was stirred for 4 hours. The temperature of the solution was brought to room temperature and the solution was diluted with ethyl acetate and then water was added thereto. Then, the organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/0), and a crude product was crystallized from ethyl acetate-diisopropyl ether, whereby the objective compound (10.1 mg, 43%) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Br:29])=[CH:27][C:26]([S:30][CH2:31][CH2:32][CH2:33][NH:34][CH3:35])=[CH:25][C:24]=1[Br:36]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:34]([CH3:35])[CH2:33][CH2:32][CH2:31][S:30][C:26]3[CH:27]=[C:28]([Br:29])[C:23]([NH2:22])=[C:24]([Br:36])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCSc1cc(Br)c(N)c(Br)c1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCN(C)CCCSc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-propyl chloride and N-[3-(4-amino-3,5-dibromo-phenylthio)-propyl]-methylamine analogously to Example 1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:11][N:12]=[C:13]2[C:17]([CH3:18])=[N:16][N:15]=[C:14]2[NH2:19])=[N:8][NH:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[NH2:19][C:14]1[C:13](=[N:12][NH:11][C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][NH:9][N:8]=2)[C:17]([CH3:18])=[N:16][N:15]=1
Reactant: CCOC(=O)c1c[nH]nc1NN=C1C(C)=NN=C1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=NN=C(N)C1=NNc1n[nH]cc1C(=O)O
Reaction time: 8 h

Procedure:
3-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-1H-pyrazole-4-carboxylic acid was prepared by dissolving 3-[N′-(3-amino-5-methylpyrazol-4-ylidene)hydrazino]-1H-pyrazole-4-carboxylic acid ethyl ester (0.2 g, 0.8 mmol) in ethanol containing sodium hydroxide (0.2 g, 5 mmol) and the solution was stirred overnight. The mixture was then acidified to pH 1 with 1N hydrochloric acid and the resulting solid was isolated by filtration. The crude material was purified by preparative TLC eluting with (CHCl3:MeOH:H2O=4:1:0.005) to yield 39 mg (22%) of the compound as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: Oc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccc3)C3CCCCC3)c2cc1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 0.2 g (0.51 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 4 mL tetrahydrofuran were added 53 mg (0.56 mmol) phenol and 124 mg (0.61 mmol) tri-n-butylphosphin. The reaction mixture was cooled down to 0° C. and 106 mg (0.61 mmol) N,N,N′,N′-tetramethylazodicarboxamide were added. After stirring for 18 h at room temperature the reaction mixture was evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:Ethyl acetate (100:0 to 60:40). MS (Turbo Spray): m/z=467.2 [M+H].
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[N:32]1([CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:35]5[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])[CH2:33][CH2:34]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: OCCOCCN1CCNCC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCN(CCOCCO)CC5)c4)cc23)CC1
Yield: 24.9 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-{[2-(1-piperazinyl)ethyl]oxy}ethanol (150 mg, 0.87 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (16.7 mg, 25%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[N:11]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][NH2:22]>O1CCCC1.C(O)C.O.NN>[NH:21]1[C:2]2=[N:3][CH:4]=[CH:5][C:6]([C:10]3[N:11]=[C:12]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[CH:13]=[CH:14][CH:15]=3)=[C:7]2[CH:8]=[N:22]1
Reactant: NN
Reactant: CC(C)(C#N)c1cccc(-c2ccnc(Cl)c2C=O)n1
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C#N)c1cccc(-c2ccnc3[nH]ncc23)n1
Temperature: 140 °C
Yield: 22 %

Procedure:
A mixture of 2-(2′-chloro-3′-formyl-2,4′-bipyridin-6-yl)-2-methylpropanenitrile (71 mg, 0.25 mmol) and 1M solution of hydrazine in tetrahydrofuran (3 ml) was heated under microwave irradiation at 140° C. for 20 minutes. The mixture was cooled down to room temperature, diluted with ethanol (1 ml) and hydrazine hydrate (1 ml) was added. The reaction mixture was heated under microwave irradiation at 160° C. for 30 minutes. The mixture was cooled down to room temperature, partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (14.6 mg, 22% yield).