Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])=[O:8].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>O.C(O)C>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:15][C:16]([OH:18])=[O:17])=[O:12])=[O:8]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(N)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH x H2O (648 mg) was added to a solution of ethyl 3-{2-[(3-(amino)-benzoyl)amino]acetamido}-3-phenyl-propanoate from II.3b (1.5 g) in 300 ml of water and the mixture was stirred at room temperature for 24 h. It was then neutralized with trifluoroacetic acid and concentrated. After chromatographic purification (methylene chloride/methanol (2:1)), a solid was isolated. This was taken up in ethanol, filtered and a white solid was obtained after concentration of the filtrate (yield: 1.4 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:38]4[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Reactant: OC1CCNCC1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCC(O)CC4)c23)ccc1OCc1ccccc1
Yield: 60 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and 4-hydroxypiperidine to give the title compound in 60% yield; NMR Spectrum: 1.34-1.40 (m, 2H), 1.66-1.69 (m, 2H), 2.16 (t, 2H), 2.22 (s, 3H), 2.75-2.81 (m, 4H), 3.40-3.43 (m, 1H), 4.39 (t, 2H), 4.53 (d, 1H), 5.13 (s, 2H), 7.01 (d, 1H), 7.32-7.48 (m, 7H), 8.19 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 475 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[N:3]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[O:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1>C(Cl)Cl>[O:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[N:8][CH:9]=2)=[O:15])[CH2:39][CH2:38]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(-c2ncc(C(=O)O)cn2)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1nc(-c2ncc(C(=O)NC3CCOCC3)cn2)no1
Reaction time: 0.17 h
Yield: 47.5 %

Procedure:
To a solution of 2-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid (50 mg, 0.24 mmol) in DCM (10 mL) is added 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (50 mg, 0.26 mmol) and N-hydroxybenzotriazole (35 mg, 0.26 mmol) at room temperature. The mixture is stirred for 10 min, and tetrahydro-pyran-4-ylamine (27 mg, 0.26 mmol) is added. The mixture is stirred overnight, washed with 2N HCl (1×5 mL), saturated NaHCO3, (1×5 mL), water (lx 5 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 5% MeOH in DCM to afford 2-(5-methyl-[1,2,4]oxadiazole-3-yl)-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide (33 mg) as a solid. MS: 290 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.70 (m, 2H), 2.04 (m, 2H), 2.76 (s, 3H), 3.59 (m, 2H), 4.06 (m, 2H), 4.28 (m, 1H), 9.26 (s, 2H); IC50=513.5 nM.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:17]([S:22](=[O:31])(=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]1[CH3:32].[OH-].[Na+]>CO>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]([CH3:32])=[C:7]2[CH2:15][C:16]1[C:17]([S:22](=[O:31])(=[O:30])[NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)Nc2ccccc2)c2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Cc2cccnc2S(=O)(=O)Nc2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
A mixture of [5-fluoro-2-methyl-3-(2-phenylsulfamoylpyridin-3-ylmethyl)indol-1-yl]acetic acid methyl ester (0.20 g), 1.0 M aqueous sodium hydroxide solution (0.50 mL) and methanol (10 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue was diluted with 1.0 M aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration and purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (3:7 to 9:1 by volume) to afford the title compound (0.020 g).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH:31]([NH:34][CH2:35][CH2:36][CH2:37][NH2:38])([CH3:33])[CH3:32]>>[CH:31]([NH:34][CH2:35][CH2:36][CH2:37][NH:38][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29])([CH3:33])[CH3:32]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CC(C)NCCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCNC(C)C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-isopropyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 460 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]>C(O)C.[OH-].[Na+]>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=1)[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1cc(OC)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude material from Example 44b (23.3 g) is dissolved in 110 ml ethanol and 44 ml of 4N NaOH. The mixture is stirred at rt for 18 h. After that time, the ethanol is evaporated. To the residue, water is added and the mixture is washed twice with dichloromethane. To the water phase, conc. HCl is added until pH=1 is reached. The title compound is obtained by extraction with ether. Purification follows by crystallization from ethyl acetate-hexane. mp: 131-134° C.; MS: 196 (M+−1); HPLC: tret=7.90 min (Grad 1).
Reaction SMILES: [I-:1].[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][N+](C)(C)C.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[I-:1].[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cn1cccc1C[N+](C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CC#N
Product: Cn1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.8 %

Procedure:
Subsequently, to a suspension of (1-methylpyrrol-2-yl)methyl trimethylammonium iodide (55.34 g, 197.5 mmol) obtained above in acetonitrile (400 ml) was added triphenylphosphine (62.20 g, 237.1 mmol) with stirring, and the resulting mixture was stirred at 80° C. for 10 hours. After cooling, the reaction mixture was concentrated to about one-half of its initial volume, to which was added ethyl acetate (200 ml). The crystals precipitated were collected by filtration, washed with ethyl acetate and dried in vacuo to afford the title compound (77.14 g, yield: 81%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([OH:24])(=[O:23])[CH:20]([CH3:22])[CH3:21].Br[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1.Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.O.C(OCC)(=O)C>[CH3:21][C:20]([CH3:22])([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[C:19]([OH:24])=[O:23]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CC(C)(Cc1ccc2ccccc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (576 ml) in tetrahydrofuran (3.5 L) was cooled to −68° C., and a 2.6M n-butyllithium-n-hexane solution (1.5 L) was slowly added under an argon atmosphere. After addition of a solution of isobutyric acid (181 ml) in hexamethylphosphoramide (340 ml), the reaction mixture was stirred at room temperature for 30 min. After ice-cooling the mixture, a solution of 2-bromomethylnaphthalene (392 g) in tetrahydrofuran (1 L) was added dropwise, and the obtained solution was stirred at room temperature for 1 day. The reaction mixture was ice-cooled, 6N hydrochloric acid (665 ml) was added thereto, and the organic layer was separated from the aqueous layer. The separated organic layer was concentrated under reduced pressure to yield a residue. On the other hand, ethyl acetate and water were added to the aqueous layer and the organic layer was separated from the aqueous layer. The organic layer and the aforementioned residue were combined and washed three times with water. The organic layer was extracted with a solution of sodium hydroxide (80 g) in water (600 ml), and then extracted three times with a 4N aqueous sodium hydroxide solution (200 ml). The aqueous layer was washed with ethyl acetate, acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (177.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.[W].CC(N=NC(C#N)(C)C)(C#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][Br:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(F)c1
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(F)c1
Yield: 80 %

Procedure:
A mixture of methyl 3-fluoro-4-methylbenzoate (4.3 g), N-bromosuccinimide (4.5 g) and AIBN (20 mg) in carbon tetrachloride was irradiated with a 100 W Tungsten lamp at reflux for 1 hour. The mixture was filtered through diatomaceous earth, and evaporated to give methyl 3-fluoro-4-(bromomethyl)benzoate (5.0 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH:4]=[C:5]([CH3:7])[N:6]=1.[Br:19]Br.[OH-].[Na+]>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:19][C:16]1[CH:17]=[C:8]([N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[CH3:1])[CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2
Reactant: Cc1cn(-c2ccc3c(c2)CCC(=O)N3)c(C)n1
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Cc1cn(-c2cc(Br)c3c(c2)CCC(=O)N3)c(C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6-(2,4-dimethylimidazol-1-yl)-3,4-dihydro-2-(1H)-quinolone (0.2 g) in concentrated sulphuric acid (5 cm3) was added bromine (0.045 cm3) and silver sulphate (0.186 g). The mixture was stirred at room temperature for 16 hours, poured onto ice (20 g.) and the mixture brought to pH 10 with aqueous 5M sodium hydroxide solution and extracted with dichloromethane (100 cm3). The organic extract was dried (MgSO4), filtered and evaporated in vacuo to yield a white solid. This solid was recrystallised from ethyl acetate to give 8-bromo-6-(2,4-dimethylimidazol-1-yl)-3,4-dihydro-2-(1H)-quinolone (0.15 g), m.p. 242°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 4-(4-benzyl-morpholin-2-yl)-benzaldehyde (1.19 g; 4.23 mmol) in MeOH (25 mL) was added NaBH4 (0.16 g; 4.23 mmol), in small portions, at 0° C. After the addition was complete the mixture was allowed to warm to RT and stirred for one hour. Subsequently, the mixture was cooled to 0° C., water was added, and the MeOH evaporated in vacuo. To the aqueous solution was added a 5% aqueous NaHCO3 solution and EtOAc. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-methanol (1.16 g) which was used as such.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.C([Mg]Br)C.Br[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[N:35][CH:36]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:34]1[CH:33]=[CH:32][C:31]([C:2]2[N:3]=[CH:4][NH:5][CH:6]=2)=[CH:36][N:35]=1
Reactant: Fc1ccc(Br)cn1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: Fc1ccc(-c2c[nH]cn2)cn1
Reaction time: 1.5 h
Yield: 46 %

Procedure:
To a solution of 4-Iodo-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (10%) and 5-bromo-2-fluoropyridine (1.2 eq) were added to the reaction mixture. Subsequent reaction conditions and work up are as described previously, in Example 73 to afford the solid 2-Fluoro-5-(1H-imidazol-4-yl)-pyridine (46%). MH+(164).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:18][C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Solvent: C1CCOC1
Product: CC1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)CC1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To this solution 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.43 mmol) in THF was added dropwise at 0° C. Then the reaction mixture was stirred for 0.5 h. The solution of 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (89 mg, 0.51 mmol) in THF was added dropwise in reaction mixture. Then the reaction mixture was stirred at RT for 2 h. The reaction monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water. THF was evaporated and aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to gives 95 mg of desired compound, which was stirred with ethanolic HCl to give the HCl salt of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methylpiperidin-1-yl)ethanone.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[O-:10][CH2:11][CH3:12].[Na+]>CO>[CH2:11]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:12]
Reactant: CC[O-]
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOCc1ccccn1

Procedure:
2-(Chloromethyl)pyridine hydrochloride (16.3 g., 0.1 mole) is dissolved in 100 ml. of methanol. Sodium ethoxide (0.22 mole of sodium dissolved in 150 ml. of ethanol) is added dropwise. The resulting mixture is heated at reflux for 18 hours, then filtered. The filtrate is concentrated. Water and ether are added, the aqueous phase is extracted with ether and the combined ethereal phases are washed with water and saturated aqueous sodium chloride, then dried over magnesium sulfate, concentrated and distilled to give 2-(ethoxymethyl)pyridine.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=3)[CH:16]=[CH:17][C:18]=2[CH2:19][CH2:20][CH2:21]Br)=[CH:9][C:8]=1[C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:3])[CH3:2].[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=3)[CH:16]=[CH:17][C:18]=2[CH2:19][CH2:20][CH2:21][NH:41][CH:38]2[CH2:40][CH2:39]2)=[CH:9][C:8]=1[C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCBr)c(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)cc1
Reactant: NC1CC1
Product: CCOC(=O)c1ccc(-c2ccc(CCCNC3CC3)c(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)cc1
Yield: 57.4 %

Procedure:
In a manner similar to that of Example 38b, by reacting 490 mg of ethyl 4″-(acetylethylamino)-4′-(3-bromopropyl)-3″-tert-butyl[1,1′;3′,1″]terphenyl-4-carboxylate (0.87 mmol) with 0.6 mL of cyclopropylamine (9 mmol). 270 mg of ethyl 4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=57%) in the form of an orange-colored oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:4][N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-:44][Si](C)(C)C)(C)C.[NH4+].[Cl-]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:13][N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH2:44])=[N:3][CH:4]=1
Reactant: CN1CCC[C@H]1c1ccc(Cl)nc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC[C@H]1c1ccc(N)nc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
In a 75 mL sealed tube, (S)-2-chloro-5-(1-methylpyrrolidin-2-yl)pyridine (622 mg, 3.16 mmol) and 2-(dicyclohexylphosphino)biphenyl (222 mg, 633 μmol) were combined with THF (15 ml) to give a light yellow solution. The solution was degassed with argon. Tris(dibenzylideneacetone)dipalladium (0) (290 mg, 316 μmol) was added. LiHMDS (9.49 ml of 1M solution in THF, 9.49 mmol) was added. The reaction was placed under an argon atmosphere and sealed. The reaction mixture was heated to 90° C. and stirred for 15 h. The reaction was complete by tlc. The reaction mixture was cooled to room temperature and diluted with EtOAc. The reaction mixture was poured into 150 mL sat NH4Cl and extracted with EtOAc (4×75 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography with stepwise gradient (silica gel, 40 g, 10% to 50% (60:10:1 CH2Cl2:methanol: NH4OH)/CH2Cl2) gradient to afford the desired product (560 mg, 99%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.57-2.03 (m, 3 H) 2.04-2.39 (m and overlapping s, 5 H) 2.92 (t, J=8.12 Hz, 1 H) 3.14-3.29 (m, 1 H) 4.40 (br. s., 2 H) 6.51 (d, J=8.69 Hz, 1 H) 7.47 (dd, J=8.31, 2.27 Hz, 1 H) 7.95 (d, J=2.27 Hz, 1 H)
Reaction SMILES: [CH:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[O:18]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]1=[O:25].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH:1]([C:7]1[N:8]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]([OH:25])=[O:18])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1cc2ccccc2[nH]1
Reactant: O=C1CCCC(=O)O1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCC=Cc1cc2ccccc2n1C(=O)CCCC(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 2-hex-1-enyl-1H-indole in DMSO was added KOH at RT and this was stirred for 30 minutes. Dihydro-pyran-2,6-dione was added to the reaction mixture and stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>C(OCC)C.CCCCCC.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ccccc2s1
Yield: 37.1 %

Procedure:
The title compound (1.2 g) after column chromatography (silica gel, 5% diethyl ether/hexane-diethyl ether eluant) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-chlorobenzothiazole (1.58 g) according to the method of D2.
Reaction SMILES: S1C=CC=C1.O1C=CN=C1.S1C=CN=C1.[N:16]1[CH:21]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[CH:19]=[N:18][CH:17]=1.[Br:28]N1C(=O)CCC1=O>C(O)(=O)C.N1C=CC=CC=1>[N:18]1[CH:19]=[C:20]([C:22]2[S:23][C:24]([Br:28])=[C:25]([CH3:27])[CH:26]=2)[CH:21]=[N:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(-c2cncnc2)c1
Agent: c1cocn1
Agent: c1cscn1
Solvent: c1ccncc1
Solvent: c1ccsc1
Solvent: CC(=O)O
Product: Cc1cc(-c2cncnc2)sc1Br

Procedure:
The pyrimidine substituent on the thiophene ring of 3-Methyl-N-[4-(3-methyl-5-pyrimidin-5-yl-thiophen-2-yl)-phenyl]-isonicotinamide was attached using a Suzuki coupling reaction (as describe in Step B of the synthesis of compound 1) by reacting a boric acid derivative of thiophene (o) with 5-bromo-pyridine (p) in the presence of a palladium catalyst to form 2-(pyrimidin-5-yl)-4-methyl-thiophene (q). In general, aromatic substituents such as pyridine, can be added to thiophene, oxazole, thiazole and oxazole ring systems by using a Suzuki coupling reaction. A bromo substituent was added to (q) by reacting it with N-bromo-succinimide in acetic acid to form 2-(pyrimidin-5-yl)-4-methyl-5-bromo-thiophene (r). Compound (r) is then coupled to an amino pyridine using a Suzuki coupling reaction (as describe in Step B of the synthesis of compound 1) to form Compound (s). Compound (s) is then reacted with 2-methyl-isonicotinoyl chloride in a reaction analogous to the reaction described in step A of the synthesis of 4-[4-(2,6-Difluoro-benzoylamino)-phenyl]-5-methyl-thiophene-2-carboxylic acid methyl ester to form 3-Methyl-N-[4-(3-methyl-5-pyrimidin-5-yl-thiophen-2-yl)-phenyl]-isonicotinamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[Cl:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:11][C:8]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1ccc2nncn2c1
Solvent: ClC(Cl)Cl
Product: Fc1ccc2nnc(Cl)n2c1
Yield: 71.2 %

Procedure:
A solution of Intermediate 24a (789 mg, 5.98 mmol) and N-chlorosuccinimide (878 mg, 6.57 mmol) in chloroform (15 mL) was heated at 65° C. overnight. The cooled mixture was washed with sat. aq. NaHCO3 solution (2×15 mL) and dried (Na2SO4). The solvent was evaporated, then the residue suspended in diethyl ether (10 mL) and filtered to give the title compound (730 mg, 76%). LCMS (Method 1): Rt 1.83 min, m/z 172 [MH+].