Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:4]=[N:3]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:5]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:4]=[N:3]1
Reactant: CCOC(=O)CCc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ncc(CCC(=O)O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 77.8 %

Procedure:
To a solution of ethyl 3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propionate (22 g, 50 mmol) in methanol (60 ml) was added 10% aqueous sodium hydroxide solution (60 ml), and the mixture was stirred under reflux for 2 hours. The reaction mixture was acidified with 10% aqueous citric acid solution, and the mixture was extracted with a mixed solvent of chloroform and methanol. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propionic acid (16 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[OH:12].[CH2:14]([Mg]Cl)[CH2:15][CH3:16]>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:14][CH2:15][CH3:16])=[CH:6][C:5]=1[OH:12]
Reactant: CCC[Mg]Cl
Reactant: COC(=O)c1ccc(C=O)cc1O
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(=O)OC)c(O)c1
Temperature: -78 °C

Procedure:
4-Formyl-2-hydroxy-benzoic acid methyl ester (360 mg, 2 mmol) is dissolved in THF (anhydrous, 10 mL). The solution is cooled to −78° C. and stirred under nitrogen. To this solution is added n-propyl-magnesium chloride (2M in THF, 2 mL, 2 mmol) dropwise via syringe. The reaction mixture is stirred at −78° C. for 1 hour, then gradually warmed to room temperature over 1 hour after which point, the reaction is quenched by adding saturated aqueous ammonium chloride. The resulting mixture is extracted with EtOAc (3×15 mL). The combined organic phase is washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the crude product is purified with silica gel flash column chromatography (10-20% ethyl acetate in hexanes gradient) to afford 2-hydroxy-4-(1-hydroxy-butyl)-benzoic acid methyl ester as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 10.74 (s, 1H), 7.79 (d, 1H, J=8.4 Hz), 6.95 (d, 1H, J=1.2 Hz), 6.86 (dd, 1H, J=1.6, 8 Hz), 4.67 (t, 1H, J=6.8 Hz), 3.94 (s, 3H), 1.82 (br, 1H), 1.80-1.62 (m, 1H), 1.46-1.28 (m, 2H), 0.93 (t, 3H, J=7.2 Hz).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=O>C1COCC1>[CH3:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:9][NH:8][CH3:7])=[CH:12]1
Reactant: CNC(=O)c1cn(C)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cn(C)c2ccccc12
Reaction time: 23 h
Yield: 66.2 %

Procedure:
A solution of LiAlH4 in THF (1.0 M, 5.20 mL, 5.2 mmole) was slowly added via syringe to a solution of N,1-dimethyl-1H-indole-3-carboxamide (0.50 g, 2.6 mmole) in anhydrous THF (15 mL). Gas was evolved during the addition of the first 2 mL of LiAlH4 solution. When the addition was complete, the resulting light yellow solution was heated at gentle reflux. After 23 hr, the reaction was cooled in ice and quenched by the sequential dropwise addition of H2O (0.5 mL), 1.0 N NaOH (0.5 mL), and H2O (0.5 mL). The mixture was stirred for 15 min, then was filtered through celite®, and the filter pad was washed thoroughly with THF. The filtrate was concentrated and the residue was flash chromatographed on silica gel (10% MeOH/CHCl3 containing 0.5% conc. NH4OH) to afford the title compound (0.30 g, 67%) as a light yellow oil: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCO
Reactant: O=C1CCC(O)N1
Product: CCCCCCCOC1CCC(=O)N1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 8 g of 5-hydroxy-pyrrolidin-2-one, 100 cm3 of n-heptanol and 4 g of Amberlite IR 120 H is agitated at 60° C. for 4 hours. After filtering and distilling to dryness, 11.9 g of the expected product is obtained, m.p. 52°-54° C., crystallized from hexane.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:11][CH2:10][CH2:9][S:8][C:7]=1[CH3:12])=[O:5])C.[OH-].[K+].Cl>CO>[C:4]([C:6]1[S:11][CH2:10][CH2:9][S:8][C:7]=1[CH3:12])([OH:5])=[O:3]
Reactant: CCOC(=O)C1=C(C)SCCS1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)SCCS1

Procedure:
3-Ethoxycarbonyl-2-methyl-5,6-dihydro-1,4-dithiin (10.0 g.) is heated at reflux for eight hours in a solution of potassium hydroxide (85%; 3.60 g.) in methanol (40 ml.). The cool solution is acidified wth 10% aqueous hydrochloric acid and the precipitate is removed by filtration and dried (8.1 g.). The crude product is recrystallized from ethanol to afford 2-carboxy-3-methyl-5,6-dihydro-1,4-dithiin, m.p. 179°-180° C., dec.
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[O:3])[CH3:2].O.[CH:9](=[C:11]([C:17](=O)[CH2:18]Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][CH:10]=[C:9](/[C:11](=[CH:17]/[CH3:18])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC=C(C(=O)CCl)C(=O)OCC
Reactant: CC(=O)NC(N)=S
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C(\C(=O)OCC)c1csc(NC(C)=O)n1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
14.6 parts by weight of acetylthiourea, 30 parts by volume of water and 50 parts by volume of N,N-dimethylformamide are heated up to 85° C. under nitrogen. 22.9 parts by weight of ethyl 2-ethylidene-4-chloro-3-oxobutyrate are then added at this temperature in the course of 40 minutes. The mixture is stirred at 80° to 85° C. for 1 hour and then cooled to 15° C., and, after 10 minutes, the precipitate which has separated out is filtered off with suction. The precipitate is suspended once in 34.5 parts by volume of water, filtered off with suction again and washed twice more with water. The crude product is dried and then extracted by stirring once in a mixture of 13.8 parts by volume of water and 41.8 parts by volume of ethanol for 10 minutes, filtered off with suction and rinsed with ethanol/water (3/1). After drying, 8.8 parts by weight of a pure product are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:20][CH:19]4[O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]5[O:44][CH2:43][CH2:42][N:41]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]=5[CH:50]=4)=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CI.[H-].[Na+].[C:55](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:49][O:48][CH2:47][CH2:46][CH2:45][N:41]1[C:40]2[CH:50]=[C:36]([CH2:35][O:34][CH:19]3[CH:18]([C:15]4[CH:14]=[CH:13][C:12]([CH:11]([O:10][C:5]5[CH:6]=[CH:7][CH:8]=[C:9]6[C:4]=5[CH:3]=[CH:2][NH:1]6)[CH3:55])=[CH:17][CH:16]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:20]3)[CH:37]=[CH:38][C:39]=2[O:44][CH2:43][CH2:42]1
Reactant: O=C([O-])O
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4cccc5[nH]ccc45)cc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(C)Oc4cccc5[nH]ccc45)cc3)cc21
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
The solution of 0.100 g of benzyl 4-[4-(1H-indol-4-yloxymethyl)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 346a), 0.0424 g of methyl iodide and 1.5 ml of N,N-dimethylformamide is admixed with stirring at −10° C. with 0.012 g of sodium hydride dispersion (60%). The reaction mixture is stirred at −10° C. for 1.5 hours, then poured onto saturated aqueous sodium hydrogencarbonate solution (45 ml) and extracted with tert-butyl methyl ether (2×75 ml). The combined organic phases are washed with 75 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a violet oil from the residue. Rt=5.90.
Reaction SMILES: C(N([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.[Cl:31][C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1>CN1CCCC1=O>[Cl:31][C:32]1[CH:33]=[C:34]([NH:38][C:15]2[N:16]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:17]=[C:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:35]=[CH:36][CH:37]=1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: Nc1cccc(Cl)c1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2Nc2cccc(Cl)c2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with 3-chloro-phenylamine ([108-42-9]) in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as off-white crystals. MS: m/e=354.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[K+].CN(C=O)C>O>[N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[O:20][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1
Reactant: OC1(CNc2c(Br)cnc3ccccc23)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=Nc2c(cnc3ccccc23)OC12CCCCC2
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A mixture of 5.5 g of 3-bromo-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine, 2.2 g of potassium tert-butoxide and 50 ml of DMF was heated at 130° C. for 1 hour and then poured into 250 ml of water. The product was extracted with dichloromethane and ethyl acetate, dried and concentrated, and the residue was purified by HPLC using dichloromethane:MeOH=95:5 as the eluent. The fractions containing the product were combined and concentrated. The residue was taken up in water and stirred for 1 hour, and the solid was filtered and recrystallized from toluene. The yield was 2.6 g, mp 164°-165° C.
Reaction SMILES: C([C:4]1[NH:5][S:6](=[O:20])(=[O:19])[C:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH3:16])[C:8]=2[C:17]=1[OH:18])(=O)C>C(O)CO.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:16][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:7]2[S:6](=[O:20])(=[O:19])[NH:5][CH2:4][C:17](=[O:18])[C:8]1=2
Reactant: CC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: c1ccccc1
Product: Cn1c2c(c3ccccc31)S(=O)(=O)NCC2=O

Procedure:
The acetyl derivates of the formula XII are treated in the presence of an acid and under anhydrous conditions with ethyleneglycol and form the ketals of the formula ##STR13## wherein R2 and Y have the meanings defined above. For example, 3-acetyl-2,5-dihydro-4-hydroxy-5-methyl-1,2-thiazino[5,6-b]indole-1,1-dioxide is refluxed with ethyleneglycol in benzene as a solvent and in the presence of p-toluenesulfonic acid as a catalyst for 5 days, which yields the ethylene ketal of 2,5-dihydro-5-methyl-1,2-thiazino[5,6-b]indole-4(3H)-one-1,1-dioxide.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:5][C@@H:4]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:43]I>C1COCC1>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([C@H:4]2[CH2:5][C@H:3]2[CH2:2][I:43])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CI)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 4 (2.0 g, 7.8 mmol), PPh3 (2.68 g, 10.2 mmol), imidazole (1.07 g, 15.7 mmol), and iodine (2.98 g, 11.7 mmol) were dissolved in THF (15 mL), and the resulting solution was stirred at RT for 2 h. The solution was quenched with sat. Na2S2O3, and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10/1 hexanes/EtOAc) which provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@@H:9]1[C@@H:14]([OH:26])[C@@H:15]([N+:23]([O-])=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@@H:9]1[C@@H:14]([OH:26])[C@@H:15]([NH2:23])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1[C@@H](O)[C@@H](N)Cc1ccccc1
Reaction time: 0.17 h

Procedure:
Dissolve nickel chloride hexahydrate (0.021 g, 0.09 mmol) and 4-(S)-fluoro-2-(R)-(1-(R)-hydroxy-2-(S)-nitro-3-phenylpropyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.33 g, 0.897 mmol) in methanol (5 mL). Cool in an ice bath and add sodium borohydride (0.17 g, 4.485 mmol) portionwise over 1 min. Stir 10 min, then concentrate. Partition in water and ethyl acetate and filter through filter agent. Separate layers and wash organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate), and concentrate to give the title compound as a white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[O:5][C:4](=[O:14])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:14][CH2:4][CH2:3][C:2]([C:11]1[C:10]([CH3:12])=[CH:9][C:8]([CH3:13])=[CH:7][C:6]=1[OH:5])([CH3:15])[CH3:1]
Reactant: Cc1cc(C)c2c(c1)OC(=O)CC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(C)(C)CCO)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
The product of Example 94A (4.00 g, 0.0196 mol) in tetrahydrofuran (75 mL) was added dropwise to a solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 20.6 mL, 0.0206 mol) in tetrahydrofuran (105 mL) at room temperature over a period of 30 minutes then stirred an additional one hour at ambient temperature. The stirred reaction was quenched by dropwise addition of saturated aqueous ammonium chloride (5 mL) after 15 minutes, the precipitate was removed by vacuum filtration. The filtrate was concentrated by rotary evaporation and the residue purified by silica gel flash chromatography eluting with 4:96 methanol/methylene chloride to afford the title compound as a white solid (2.94 g, 0.014 mol, 72%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.44 (s, 6 H) 2.00-2.07 (m, 2 H) 2.08 (s, 3 H) 2.36 (s, 3 H) 3.11-3.28 (m, 2 H) 4.09 (t, J=4.78 Hz, 1 H) 6.29 (s, 1 H) 6.42 (s, 1 H) 8.95 (s, 1 H). MS (ESI+) m/z 209 (M+H)+, 226 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11]CC)=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.C(O)C.O.[OH-].[Li+]>O>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1cncnc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1cncnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of 0.6 g (3 mmol) of ethyl (4-chloro-5-pyrimidinyl)acetate from Step A above in 0.5 mL of water and 1.5 mL of ethanol was added 215 mg (5.11 mmol) of lithium hydroxide hydrate. The reaction mixture was stirred at ambient temperature for 2 h then concentrated in vacuo to remove all volatiles. The residue was diluted with 7 mL of 2.0 M aqueous hydrogen chloride and then concentrated in vacuo to remove all volatiles to yield the title compound (0.43 g, 83%). 1H-NMR (500 MHz, CD3OD) δ: 8.88 (s, 1H), 8.70 (s, 1H), 3.96 (s, 2H). LC-MS: m/z (E/S) 173 (MH)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14](F)[C:13]([N+:17]([O-])=O)=[CH:12][C:11]=2[F:20])=[N:8][N:9]=1.FC1C=C([N+]([O-])=O)C(F)=C[C:34]=1[C:43](O)=[O:44]>>[NH2:1][C@@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]3[C:13](=[CH:12][C:11]=2[F:20])[NH:17][C:43](=[O:44])[CH2:34]3)=[N:8][N:9]=1
Reactant: N[C@H](CNc1nnc(-c2cc(F)c([N+](=O)[O-])cc2F)s1)Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Product: N[C@H](CNc1nnc(-c2cc3c(cc2F)NC(=O)C3)s1)Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described for Example 2 starting with N—((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(2,5-difluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-amine, which was prepared in a similar manner as shown in Scheme 1 with 2,5-difluoro-4-nitrobenzenecarboxylic acid as the starting material. 2,5-Difluoro-4-nitrobenzenecarboxylic acid was purchased from Ryan Scientific Inc. LCMS (API-ES) m/z (%): 452.5 (100%, M++H); 1H NMR (400 MHz, CD3OD): δ ppm 3.13-3.26 (m, 2H), 3.62-3.71 (m, 3H), 3.78-3.84 (m, 1H), 3.85-4.10 (m, 1H), 3.99 (d, J=2.35 Hz, 4H), 6.83-6.89 (m, 1H), 7.61 (d, J=8.02 Hz, 2H), 7.75 (d, J=8.02 Hz, 2H), 7.99 (d, J=6.85 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C@H:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[NH2:13].[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br>C1COCC1>[CH3:9][O:10][C:11](=[O:24])[C@H:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[NH:13][CH2:28][C:27]([O:26][CH3:25])=[O:30]
Reactant: COC(=O)CBr
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Triethylamine (22 mmol) was added to a suspension of 4-Nitrophenylalanine methyl ester hydrochloride (2) (21 mmol) in THF (50 ml). The mixture was stirred at room temperature for one hour, the triethylamine hydrochloride was filtered off, and the filtrate concentrated to yellow oil. The oil was dissolved in dry THF (50 ml) and to this solution was added triethylamine (60 mmol) and methylbromoacetate (60 mmol), the solution was stirred at room temperature under nitrogen atmosphere for 3 hours, after which the precipitate was filtered off and the filtrate concentrated on vacuum. The residue was dissolved in ethylacetate, washed with H2O, dried (MgSO4) and concentrated on vacuum to give yellow oil. The yield was 92%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:48])[C:29]2[CH:34]=[CH:33][C:32]([CH:35]([O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[NH4+:53].[OH-].[Na+]>O>[NH2:53][C:9]1[C:8]2[N:22]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:48])[C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)[C:7]=2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=1
Reactant: [NH4+]
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 150 °C
Yield: 15.3 %

Procedure:
N-[4-(2-Butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide (101 mg, 0.16 mmol) and ammonium acetate (1.1 g) were placed into a pressure tube along with a stir bar. The tube was sealed and heated at 150° C. for 16 hours. The reaction was cooled to room temperature and diluted with water. The resulting cloudy aqueous mixture was made basic with 10% aqueous sodium hydroxide and extracted with chloroform (3×25 mL). The combined organic fractions were washed with water followed by brine, dried (Na2SO4), decanted and evaporated to provide a yellow oil. Purification by flash column chromatography (silica gel, 95:5 dichloromethane/methanol gradient to 9:1 dichloromethane/methanol and finally 94:5:1 dichloromethane/methanol/triethylamine) provided 14 mg of N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide as a yellow oil. 1H-NMR (500 MHz, DMSO-d6) δ8.41 (t, J=5.5 Hz, 1H), 7.76 (d, J=8.3 Hz, 2H); 7.43 (d, J=8.3, 2H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1H), 5.84 (bs, 2H), 5.52 (s, 1H), 4.22 (t, J=7.7 Hz, 2H), 3.49 (t, J=5.8 Hz, 2H), 3.29 (dd, J=6.4, 12.4 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.58 (t, J=5.7 Hz, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 2.22 (s, 6H), 1.73-1.65 (m, 4H), 1.61-1.55 (m, 2H), 1.35 (sextet, J=7.4 Hz, 2H), 0.86 (t, J=7.4 Hz, 3H); 13C-NMR (125 MHz, DMSO-d6) δ165.9, 153.0, 148.1, 145.4, 142.0, 138.6, 133.5, 128.23, 127.4, 127.3, 127.1, 126.4, 126.1, 124.5, 103.0, 82.0, 66.3, 58.0, 45.2, 43.6, 38.4, 29.3, 28.8, 26.1, 26.0, 21.7, 21.0, 13.6, 12.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24](O)=[O:25]>>[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1cnccn1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cnccn4)cc23)CC1
Yield: 23.6 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 32 mg (0.131 mMol) pyrazine-2-carboxylic acid, 6.9 mg (24%) of the title compound were recovered.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Oc4ccccc4)c3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3[nH]c4cccc(Oc5ccccc5)c4c3CC2)cc1

Procedure:
A solution of 3-benzoyl-10-phenoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.55 g, 1.45 mmol) in tetrahydrofuran (30.0 mL) and lithium aluminum hydride (0.56 g, 14.5 mmol) was reacted in a manner similar to Preparation 11 to afford 0.47 g (87%) of colorless solid as the desired product: mp 168-170° C.(CH2Cl2/hexane); 1H NMR (400 MHz, DMSO-d6) δ 11.0; 7.34-7.21, 7.10, 7.01, 6.94, 6.84, 6.47, 3.69, 2.89-2.87, 2.84-2.81, 2.78-2.75, 2.65-2.62; 13C NMR (100.6 MHz, DMSO-d6) δ 158.5, 147.8, 139.2, 137.4, 136.9, 129.6, 128.4, 128.1, 126.7, 121.8, 120.5, 120.3, 116.4, 110.2, 109.3, 107.4, 60.2, 55.4, 53.3, 27.6, 24.8; MS (EI) m/z 368 (M+); HRMS cacld for C25H24N2O+H: 369.1967, found: 369.1961; Anal. Calcd. for C25H24N2O: C, 81.49; H, 6.57; N, 7.60. Found: C, 81.12; H, 6.70; N, 7.53.