Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:23]=2[CH3:38])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:37])[C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:23]=2[CH3:38])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3cccc(NC(=O)c4ccc(F)cc4)c3C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)O)ccc3c12
Temperature: 92.5 °C
Yield: 97.1 %

Procedure:
A suspension of ethyl 8-carbamoyl-5-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-2-carboxylate (Intermediate 3-100, 1.63 g, 3.20 mmol) in ethanol (12 mL) was treated with 1 M aqueous sodium hydroxide (1.5 mL, 1.500 mmol), forming a yellow suspension which was heated at 90-95° C. for 30 min. The mixture was cooled to rt and acidified with 1 M hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to provide 8-carbamoyl-5-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-2-carboxylic acid as an off-white solid (1.496 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 12.76 (br. s., 1 H) 11.84 (s, 1 H) 10.15 (s, 1 H) 8.38 (s, 1 H) 8.24 (br. s., 1 H) 8.03-8.13 (m, 3 H) 7.56 (br. s., 1 H) 7.46-7.54 (m, 2 H) 7.42 (t, J=7.7 Hz, 1 H) 7.35 (t, J=9.0 Hz, 2 H) 7.23 (dd, J=7.5, 1.3 Hz, 1 H) 7.04 (d, J=7.5 Hz, 1 H) 7.01 (d, J=8.3 Hz, 1 H) 1.88 (s, 3 H). Mass spectrum m/z 482.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:34][C:35]([F:42])([F:41])[C:36](OCC)=[O:37]>C(#N)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:36](=[O:37])[C:35]([F:42])([F:41])[F:34])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(NC(=O)C(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (600 mg, <1.46 mmol) and triethylamine (0.41 mL, 2.94 mmol) in acetonitrile (10 mL) was added ethyl trifluoroacetate (0.35 mL, 2.94 mmol) at room temperature. The mixture was stirred at room temperature for 3 hr. Ethyl trifluoroacetate (0.35 mL, 2.94 mmol) and triethylamine (0.5 mL, 3.59 mmol) were added to the reaction mixture at room temperature. The mixture was stirred at room temperature for 18 hr and at 60° C. for 20 hr. The reaction mixture was concentrated in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound (611.7 mg, 1.21 mmol, 83%) as a pale yellow solid.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1([CH2:21][CH2:22][OH:23])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:7].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(N(CC)CC)C>[C:6]([C:8]1([CH2:21][CH2:22][O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9]1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCOS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
To 10 mL of a tetrahydrofuran solution containing 1.0 g of tert-butyl 4-cyano-4-(2-hydroxyethyl)piperidine-1-carboxylate, 0.77 mL of triethylamine was added at room temperature, thereto was added 0.37 mL of methane sulfonyl chloride under cooling with ice, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. The reaction mixture was added with an aqueous saturated sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.3 g of a brown oily substance, tert-butyl 4-cyano-4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6](O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.P(Br)(Br)[Br:14].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([Br:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2O
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cnc2c(c1)CCCC2Br

Procedure:
1.50 Grams of 3-methyl-8-hydroxy-5,6,7,8-tetrahydroquinoline was dissolved in 20 ml of chloroform, to this solution was added dropwise a solution consisting of 1.35 g of phosphorus tribromide and 5 ml of chloroform under ice-cooled condition, then the mixture was stirred under ice-cooled condition for 2 hours, next was stirred at room temperature overnight. To the reaction mixture was added 5%-sodium hydroxide aqueous solution, then was extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain 1.80 g of 3-methyl-8-bromo-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [C:1]([CH:4]1[CH:8]2[CH2:9][C:10](=[O:13])[CH:11]=[CH:12][C:7]2([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)OC1=O)(=[O:3])[CH3:2].[Cl-].[NH+]1C=CC=C[CH:25]=1>CO>[CH3:25][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([CH2:4][C:1](=[O:3])[CH3:2])[CH:9]=1
Reactant: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Reactant: c1cc[nH+]cc1
Agent: [Cl-]
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)c(CC(C)=O)c1
Yield: 50.4 %

Procedure:
3-Acetyl-3a,7a-dihydro-7a-(phenylethynyl)benzofuran-2,5(3H,4H)dione, (1.75 g 6 mmole), pyridinium chloride (1.5 g, 13 mmole) and MeOH (50 mL) were placed in a 100 mL round bottomed flask and heated at reflux for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between Et2O and water. The ether phase was washed with 3N hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was recrystallized from ethanol (10 mL) to give 0.8 g (50%) of the title compound as a light yellow solid, m.p. 63°-65° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[CH3:12][NH:13][C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2Cl)[CH:17]=1)=[O:15]>>[CH3:12][NH:13][C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:17]=1)=[O:15]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CNC(=O)c1cc2nccc(Cl)c2s1
Product: CNC(=O)c1cc2nccc(Nc3ccc4[nH]c(C)cc4c3)c2s1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid methylamide by a procedure analogous to Example 1C. MS: 337 (MH+); HPLC Rf: 3.86 min.; HPLC purity: 98%.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=1.BrB(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(NS(C)(=O)=O)c(C)c1
Agent: BrB(Br)Br
Product: Cc1cc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)ccc1NS(C)(=O)=O
Yield: 38.6 %

Procedure:
Following General Procedure F, N-[4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)-2-methylphenyl]methanesulfonamide (47 mg, 0.11 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 3.0 mL, 3.0 mmol) to afford the desired product (17 mg, 39%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.58 (d, J=5.4 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 7.21 (s, 1H), 7.17-7.14 (m, 2H), 6.10 (d, J=5.4 Hz, 1H), 3.40 (s, 3H), 2.43 (s, 3H); ESI MS m/z 401 [C19H6N2O4S2+H]+; HPLC 96.4% (AUC), tR=10.23 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([OH:23])=O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O>CN(C)C(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[CH:20][C:21]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:23])=[CH:24][CH:25]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C=CC(=O)O)cc2)CC1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C=CC(=O)N3CCOCC3)cc2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
The 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-cinnamic acid (870 mg, 2.5 mmol) obtained in Example 11(1) was dissolved in N,N-dimethylacetamide (hereinafter referred to as DMA) (15 ml), and HOBt (423 mg, 2.8 mmol), WSCD (530 mg, 2.8 mmol), morpholine (241 mg, 2.8 mmol) were added thereto, followed by stirring at 80° C. for 16 hours. After cooling to room temperature, water was added to the mixture, and the precipitate was collected by filtration, thereby obtaining (3-(4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-phenyl)-1-oxo-2-propen-1-yl)-morpholine (836 mg, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH2:15][CH2:16][OH:17])[C:13]3[C:18]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=[CH:21][C:12]=3[N:11]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:17][CH2:16][CH2:15][N:14]1[C:13]2[C:18]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=[CH:21][C:12]=2[N:11]=[C:10]1[NH:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[O:30][CH3:31])(=[O:34])[CH3:33]
Reactant: CCCC(O)(CCC)c1cccc2nc(Nc3c(C)cc(Cl)cc3OC)n(CCO)c12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCC(O)(CCC)c1cccc2nc(Nc3c(C)cc(Cl)cc3OC)n(CCOC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of 4-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazol-7-yl]heptan-4-ol (100 mg, 0.22 mmol) in pyridine (5 mL) was treated with acetic anhydride (1 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, diluted with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel to give 97 mg (0.20 mmol, 89%) of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)c(Cl)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, grey solid (46 mg, 50%), MS (ISP) m/z=370.3 [(M+H)+], mp 245° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)=[C:7]([F:29])[CH:6]=1.[Li+].[OH-].ClCCl.CO.CCCCCC.C(OCC)(=O)C>O1CCCC1>[F:29][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:30])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCc3ccc4ccccc4n3)cc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)Cc1ccc(-c2ccc(OCc3ccc4ccccc4n3)cc2)c(F)c1
Yield: 101.2 %

Procedure:
A solution of the ester (1.69 g, 4.21 mmole) of Step F, in dry tetrahydrofuran (20 mL) is treated dropwise under nitrogen with 1N-LiOH (12.6 mL) and the mixture is stirred for 3 hours at room temperature (TLC, 19:1 dichloromethane-methanol or 1:1 hexane-ethyl acetate). The solvent is removed, the residue is treated with water and neutralized (to pH 6.5) with 10% acetic acid. The acid is extracted with ethyl acetate (large volume needed) and the extracts are dried (MgSO4) and evaporated to dryness to yield an off-white solid (1.65 g, quantitative yield, m.p. 190°-193° C., dec.). Recrystallization from ethyl acetate provides a white solid (1.32 g, 80%, m.p. 195°-196° C. dec.). The analytical sample is dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:12]=2[N:11]=[CH:10]1)(=[O:4])=[O:3].[NH:21]1[CH:30]2[CH:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl>CN(C=O)C>[CH3:1][S:2]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([N:21]3[CH:30]4[CH:25]([CH2:26][CH2:27][CH2:28][CH2:29]4)[CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:17][C:12]=2[N:11]=[CH:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)COCCn1cnc2cc(C(=O)O)ccc21
Reactant: C1CCC2NCCCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)COCCn1cnc2cc(C(=O)N3CCCC4CCCCC43)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
To a solution of 1-(2-methanesulfonylmethoxyethyl)-1H-benzimidazole-5-carboxylic acid (0.5 g, 1.677 mmol) in DMF (5 mL) was added decahydroquinoline (0.257 g, 1.845 mmol) followed by HOBt (0.25 g, 1.845 mmol) and DIPEA (0.65 g, 5 mmol). The reaction mixture was cooled to 0° C. and EDCl.HCl (0.354 g, 1.845 mmol) was added. It was gradually raised to ambient temperature and stirring continued for 12 h. The solvent was then evaporated, the residue diluted with water (5 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic phases were washed with brine solution, dried (Na2SO4) and the solvent evaporated affording the crude amide which was purified by preparative HPLC to give 0.3 g (43%) of [1-(2-methanesulfonylmethoxy-ethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone. MS-ESI m/z 420 (M+1): 1H NMR (300 MHz, DMSO-d6) δ 1.1-1.9 (br, 13H), 2.8 (s, 3H), 3.0-3.3 (m, 2H), 4.15 (t, 2H), 4.5 (t, 2H), 4.65 (s, 2H), 7.3 (m, 1H), 7.6 (m, 1H), 7.7 (d, 1H), 8.3 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1>CC(O)=O.[Pt](=O)=O>[C:8]([OH:10])(=[O:9])[CH3:7].[CH3:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH:7]1[C:8]([OH:10])=[O:9]
Reactant: Cc1ccncc1C(=O)O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC1CCNCC1C(=O)O
Yield: 195.5 %

Procedure:
4-Methylnicotinic acid (2.00 g, 14.6 mmol) and platinum(IV) oxide (0.30 g, 1.3 mmol) in AcOH (70 mL) were shaken under hydrogen at about 60 psi for about 3 days. The reaction was filtered through Celite® then concentrated under reduced pressure to afford 4-methylpiperidine-3-carboxylic acid acetate as an oil (2.9 g, 98%): LC/MS (Table 2, Method a) Rt=0.55 min; MS m/z: 144 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:4][CH2:3]1)(=[O:37])[CH3:36]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(N)CC3)nc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(NC(C)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-aminopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (100 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of triethylamine (7 mL) and acetic anhydride (1 mL) at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under vacuum. This resulted in 0.1 g (90%) of methyl 3-(4-acetamidopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as light yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].[H-].[Na+].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C1COCC1>[C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH:14][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1c(NC(=O)N(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of the product from Example 2 (70 mg) in THF (1 mL), under nitrogen, was cooled to 0° C. and treated with sodium hydride (60% in mineral oil) (7 mg). The suspension was stirred for 10 min were upon dimethylcarbamyl chloride (15 uL) was added. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification on a preparative silica TLC plate eluted with 50% EtOAc in hexane afforded the title compound. HPLC/MS: 543.0 (M+1), 545.0 (M+3); Rt=4.27 min.
Reaction SMILES: I[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH2:13])[N:3]=1.[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl>>[CH2:14]([S:21][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH2:13])[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCn1cnc2c(N)nc(I)nc21
Reactant: SCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cnc2c(N)nc(SCc3ccccc3)nc21

Procedure:
A mixture of 2-iodo-9-ethyl-9H-purin-6-ylamine (0.2 g, 0.69 mmol), 3 mL of benzyl mercaptan, and solid sodium hydroxide (200 mg, 5.0 mmol) was heated in a steel bomb at 100° C. for 24 hours. The reaction mixture was neutralized with 1N HCl and partitioned between water and chloroform. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo, and the residue chromatographed on a silica gel column, eluting with a mixture of chloroform/methanol (97:3), to give 2-benzylthio-9-ethyl-9H-purin-6-ylamine, a compound of formula (4), as a chromatographically pure solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([NH:1][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: Nc1ccc2cc(O)ccc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc3cc(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL round-bottomed flask containing 6-aminonaphthalen-2-ol (0.600 g, 3.8 mmol), in DCM (10 mL), was added p-Anisoyl chloride (0.972 g, 5.7 mmol), along with K2CO3 (1.57 g, 11.4 mmol). The mixture was stirred at ambient temperature overnight and was diluted with DCM and H2., Extraction with DCM (3×10 mL), drying of the organics over sodium sulfate, filtration, and concentration in-vacuo afforded the crude product. Recrystallization of the crude from DCM/Hexanes gave a tan colored amorphous solid, after drying (0.300 g, 1.0 mmol). MS (ESI pos. ion) m/z: 294 (M+H). Calc'd Exact Mass for C18H15NO3: 293.
Reaction SMILES: [N:1]1([C:6]2[C:11](B(O)O)=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)=[C:18]([F:29])[CH:17]=1>>[F:29][C:18]1[CH:17]=[C:16]([C:11]2[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:21]=[CH:20][C:19]=1[C:22]1[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: OB(O)c1cccnc1N1CCCC1
Product: Nc1cnc(-c2ccc(-c3cccnc3N3CCCC3)cc2F)cn1

Procedure:
Title compound was prepared using methods analogous to those described in Example 377 using (2-(pyrrolidin-1-yl)pyridine-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C19H18FN5, 335.15; m/z found, 336.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.61-8.56 (m, 1H), 8.22-8.17 (m, 1H), 8.12 (s, 1H), 7.97-7.88 (m, 1H), 7.45-7.38 (m, 1H), 7.29-7.23 (m, 1H), 7.21-7.14 (m, 1H), 6.75-6.67 (m, 1H), 4.67 (s, 2H), 3.28-3.10 (m, 4H), 1.87-1.73 (m, 4H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]=1)[NH2:3].[C:11]([CH2:14][C:15](=O)[CH3:16])(=O)[CH3:12].[OH-].[Na+]>O>[CH3:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([N:2]2[C:15]([CH3:16])=[CH:14][C:11]([CH3:12])=[N:3]2)[CH:9]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cc1ccnc(NN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccnc(-n2nc(C)cc2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
In a 50 mL recovery flask, 2-hydrazino-4-methylpyridine hydrochloride (0.5 g, 3.13 mmol), acetylacetone (0.376 g, 3.76 mmol), and water (7 mL) were added and stirred at room temperature for 16 hours. Upon completion of the reaction, a 10% aqueous solution of sodium hydroxide was added to the reaction mixture to adjust the pH up to 14. The resulting mixture was extracted with ethyl acetate twice, and the organic phases were combined and washed with saturated brine once, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 0.47 g of the title compound (yield 80%).