Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[OH:5][CH:6]1[CH2:29][CH2:28][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH:16]=[N:17][C:18]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.C(Cl)(=O)C(Cl)=O.Cl>ClCCl.C(N(CC)CC)C>[F:26][C:23]([F:24])([F:25])[C@H:22]([CH3:27])[O:21][C:18]1[N:17]=[CH:16][C:15]([N:12]2[CH2:11][CH2:10][C:9]3([CH2:8][CH2:7][C:6](=[O:5])[CH2:29][CH2:28]3)[C:13]2=[O:14])=[CH:20][CH:19]=1
Reactant: C[C@H](Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cn1)C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H](Oc1ccc(N2CCC3(CCC(=O)CC3)C2=O)cn1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
DMSO (16.3 ml) was added dropwise over a period of 5 minutes to a solution of 8-hydroxy-2-[6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one (39.3 g) in dichloromethane (400 ml) that was cooled down to −78° C. in a CO2/acetone-bath. After 5 minutes, oxalylchloride (15.6 ml) was added dropwise over a period of 15 minutes and stirring was continued for 30 minutes at −78° C. Then, triethylamine (42.7 ml) was added dropwise over a period of 15 minutes to the reaction mixture and after 5 minutes, the mixture was allowed to warm to 20° C. and stirred further 2 h at R.T. The reaction mixture was poured into ice/water and was acidified with 2M aqueous HCl solution to pH 3. The aqueous phase was extracted two times with dichloromethane and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient 20% to 60 of AcOEt in hexane) to give the title compound as an off white solid (23.96 g). MS (m/e): 357.2 (MO.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:14])=[C:5]([C:10]([O:12]C)=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([C:3]1[C:4]([I:14])=[C:5]([C:10]([OH:12])=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2]
Reactant: COC(=O)c1sc(SC)c(C#N)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1sc(C(=O)O)c(I)c1C#N
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of methyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (3.40 g, 10 mmol) in tetrahydrofuran (80 mL) and water (16 mL) was added a solution of 1.00M sodium hydroxide in water (30 mL). The solution was allowed to stir overnight. The reaction was quenched with a solution of 1N hydrogen chloride in water (50 mL) and diluted with water (400 mL). The resultant precipitate was filtered, washed with water (2×100 mL) and dried in a vacuum oven to give 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylic acid (2.6 g, 79%) as a white solid. LCMS: (FA) ES+ 326.
Reaction SMILES: [N:1]([CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[OH:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH2:16]>CN(C=O)C>[OH:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]([NH:1][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]([CH3:11])[CH3:12])=[O:3]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCOC(=O)C(N=C=O)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1O)C(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
To a solution of ethyl 2-isocyanato-3-methybutyrate (333 mg, 1.95 mmol) in DMF (1.0 ml), 2-hydroxy-4-nitroaniline (300 mg, 1.95 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. Chromatography of the resulting liquid on silica gel gave desired product (420 mg, 66%). EI-MS m/z 326 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:21])=O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:21][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 3-[(3-nitroquinolin-4-yl)amino]propan-1-ol (20.75 g, 83.93 mmol), thionyl chloride (15.0 g, 125.89 mmol), and dichloromethane (420 mL). The bright yellow, homogeneous solution was stirred at ambient temperature for 2 hours at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and he resulting solid stirred in water (400 mL) made basic (pH 10) with solid sodium carbonate. A bright yellow solid was collected by filtration to afford N-(3-chloropropyl)-3-nitroquinolin-4-amine (21.63 g, 81.41 mmol) which was used without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([O:14][CH3:17])=[O:13])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96.6 %

Procedure:
To a solution of BOC-isonipecotic acid (45.0 g, 0.20 mol) dissolved in a 3:1 solution of dichloromethane/methanol (1200 mL) at 0° C. was added a solution of trimethylsilyldiazomethane (147 mL, 0.29 mol, 2.0M in hexane) over 30 min via an addition funnel. The reaction mixture was then concentrated to afford the title compound (47 g) as a light yellow oil. This was used directly in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]([CH3:37])[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=3)=[C:28]([I:29])[C:22]=2[C:21]1=[O:38])=[O:19])([CH3:16])([CH3:15])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26]([CH3:37])[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([N:36]4[C:4](=[O:5])[C:3]5[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:1]4=[O:11])[N:31]=3)=[C:28]([I:29])[C:22]=2[C:21]1=[O:38])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cn1c2c(c(I)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c2c(c(I)c1-c1ccnc(N3C(=O)c4ccccc4C3=O)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
Pthaloyl chloride (0.089 g, 0.437 mmol) was added to a cold (0° C.) solution of 2-(2-Amino-pyrimidin-4-yl)-3-iodo-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo-[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester (prepared as described in Example 1) (0.158 g, 0.337 mmol) and pyridine (0.069 g, 0.875 mmol) in dry DCM (1.5 ml) and the reaction mixture was stirred at room temperature in argon atmosphere for 4 h. The organic layer was washed with a saturated solution of NaHCO3 (1×2.0 ml), brine (1×2.0 ml), and it was dried over Na2SO4. The filtrate was evaporated to dryness to give the crude product, which was purified by flash chromatography, over silica gel (DCM/MeOH (9.8:0.2) as eluent), to afford 2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyrimidin-4-yl]-3-iodo-1-methyl-4-oxo-1,4,6,7-tetra-hydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.150 mg, 0.25 mmol, 74%).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].O[CH2:9][NH:10][C:11](=[O:13])[CH3:12]>FC(F)(F)C(O)=O>[C:11]([NH:10][CH2:9][S:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5])(=[O:13])[CH3:12]
Reactant: CC(=O)NCO
Reactant: CC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCSCC(C)C(=O)O
Reaction time: 1 h

Procedure:
3-Mercapto-2-methylpropanoic acid (2.4 g.) and N-hydroxymethylacetamide (1.8 g.) are dissolved in trifluoroacetic acid and the solution is stored at room temperature for one hour. The trifluoroacetic acid is removed in vacuo and the residue is dried in vacuo over potassium hydroxide to yield 3-acetamidomethylthio-2-methylpropanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12](F)=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:9]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1.C[O-].[Na+].CO.[C:31](O)(=[O:33])C>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:33][CH3:31])=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:9]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1
Reactant: COCCOc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COCCOc1cc(OC)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-methoxyethoxy)-3H-quinazolin-4-one (0.42 g, 1.22 mmol) in DMF (10 mL) was added a solution of sodium methoxide in methanol (25 wt %, 2.8 g, 12.8 mmol) and the reaction mixture was stirred at 70° C. for 16 hours, then cooled to room temperature. Water (1 mL) was added, the mixture was neutralized to pH approximately 6 with acetic acid, diluted with water (50 mL), and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo, to give 0.30 g of crude compound. Further purification by crystallization in acetone:Et2O (1:3) gave the title compound as a white solid. Yield: 91 mg (15%). 1H NMR (400 MHz, CDCl3): δ 10.08 (br s, 1H), 7.60 (br s, 2H), 6.87 (d, J=1.95 Hz, 2H), 6.55 (d, J=1.95 Hz, 2H), 4.25 (t, J=4.88 Hz, 2H), 3.93 (s, 3H), 3.83 (d, J=4.29 Hz, 2H), 3.44 (s, 3H), 2.64 (s, 6H). MS (ES+) m/z: 356.11 (M+1)+
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.O>CN(C)C=O>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: ClCc1cccs1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1csc(Cn2cnc3ccccc32)c1
Reaction time: 0.5 h

Procedure:
To 11.81 g of benzimidazole in 50 ml of dimethylformamide was added 4.8 g of 50% sodium hydride in oil over 30 minutes. After stirring 30 minutes, 13.25 g of 2-chloromethylthiophene was added over a period of 30 minutes, and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the pH adjusted to 1.5. After extracting with ether, the pH was raised to 11 and precipitated product was filtered and dried, 19.9 g.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[CH:34]=[N:35][CH:36]=[N:37][CH:38]=1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[CH:34]=[N:35][CH:36]=[N:37][CH:38]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Brc1cncnc1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cncnc1)OCC2c1ccc(C(C)C)cc1
Yield: 77 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 5-bromopyrimidine, the title compound was obtained in the same manner as in Example 107. Yield: 77%. Melting point: 167-169° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:15].[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:15])[CH2:4][CH2:5]2
Reactant: CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1C(=O)CCc2cc(N)ccc21
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a stirred suspension of 1-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 2, 1.04 g, 5.05 mmol) in EtOH (10 mL) and water (5 mL) is added ammonium chloride (2.70 g, 10.0 equiv.). To this mixture is added iron powder (0.85 g, 3.0 equiv.) in 3 portions. The resulting mixture is heated at reflux for 2 h and then is cooled to room temperature. The resulting mixture is filtered through celite and the filtrate is further diluted with water (100 mL). The filtrate is extracted with ethyl acetate (2×50 mL) and washed with saline (100 mL). The organic layers are combined, dried over MgSO4 and concentrated under reduced pressure to yield the title compound as a yellow solid (0.86 g, 97%), MS (m/z): 177.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][CH3:19])[CH:12]=2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:3]=1[CH3:32].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([CH3:35])[CH3:19])[CH:12]=2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:3]=1[CH3:32]
Reactant: CNCc1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
A stirred solution of benzyl 2-[3-chloro-2-methyl-5-(3-[(methylamino)methyl]phenethylamino)-6-oxo-1(6H)-pyrazinyl]acetate (preparation 19) (0.38 g, 0.83 mmol) in CH2Cl2 (10 ml) was treated with formaldehyde (0.31 ml). After stirring at room temperature for 45 mins, the resultant cloudy mixture was treated with sodium triacetoxyborohydride (253 mg, 1.19 mmol) and stirred at room temperature for a further 2 days. The reaction mixture was diluted with CH2Cl2 (200 ml) and washed with sat. aq NaHCO3, sat aq brine and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a crude solid which was purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 95:5 CH2Cl2:MeOH; 90:10 CH2Cl2:MeOH) to give the desired product (0.30 g, 77%). 1H NMR (CDCl3) δ 2.20 (s, 3H), 2.25 (s, 6H), 2.90 (t, 2H), 3.40 (s, 2H), 3.70 (m, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10-7.20 (m, 3H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z=469.2, 471.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.O[CH2:74][CH2:75][CH2:76][N:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>C1COCC1>[CH3:83][N:80]1[CH2:81][CH2:82][N:77]([CH2:76][CH2:75][CH2:74][O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])[CH2:78][CH2:79]1
Reactant: CN1CCN(CCCO)CC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCN(CCCOc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)CC1
Yield: 57.9 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0817 g, 0.177 mmol) was dissolved in THF (4.0 mL), and the solution was treated with triphenylphosphine (0.0930 g, 0.354 mmol), 40% DEAD-toluene solution (0.161 mL, 0.354 mmol) and 1-(3-hydroxypropyl)-4-methylpiperazine (0.140 g, 0.855 mmol), followed by purification by flash column chromatography (chloroform/methanol=7/3) to obtain 4-[3-(4-methylpiperazin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0617 g, yield 58%).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([NH:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:12]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)nc1NC1CCCCC1

Procedure:
By allowing ethyl 2,6-dichloronicotinate and cyclohexanamine to undergo the reaction at 50° C. for 1 hour in DMF in the presence of potassium carbonate, ethyl 6-chloro-2-(cyclohexylamino)nicotinate was obtained. By carrying out hydrolysis of an ethanol solution of this at 70° C. for 18 hours in the presence of 1 M sodium hydroxide, 6-chloro-2-(cyclohexylamino)nicotinic acid was obtained.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[CH2:32][O:33]C(/N=N/C(OCC)=O)=O.O>C1COCC1>[CH3:32][O:33][C:3]1[CH:2]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: Oc1cccc2ncccc12
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an oven dry three neck flask was added 5-hydroxy-quinoline (5 g, 34.5 mmol), and triphenylphosphine. The solids were dissolved in THF (100 mL) and DEAD (8.19 mL, 51.7 mmol) was added slowly. The maroon reaction mixture was stirred at room temperature overnight and then poured into H2O (100 mL) and extracted into EtOAc (3×150 mL). The combined organic fractions were dried over Na2SO4, filtered, concentrated, and purified by column chromatography using 20% EtOAc/hexanes as the eluent. The title compound was isolated as 3.5 g (64%) of a white solid.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1N=CS[C:16]=1C=O.O(C)[Na].[CH2:22]1[CH2:26]O[CH2:24][CH2:23]1>>[C:22]1([CH:26]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:16]=[CH:12][CH:11]=[CH:24][CH:23]=1
Reactant: Cc1ncsc1C=O
Reactant: O=C(CO)c1ccccc1
Reactant: C1CCOC1
Agent: CO[Na]
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 5.2 %

Procedure:
2.21 g (16.3 mmol) of 2-hydroxyacetophenone, 1.96 g of 4-methylthiazole-5-carboxaldehyde (7.86 mmol), and 10 ml of 25% NaOCH3 were reacted in 50 ml of dry THF to give 1.59 g (5.2%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.73 (s, 1H), 8.76 (s, 1H), 8.05 (d, d, J=0.9, 15.0 Hz, 1H), 7.82 (d, d, J=1.5, 8.1 Hz, 1H), 7.49 (d, d, d, J=1.5, 7.2, 8.4 Hz, 1H), 7.31 (d, J=15.0 Hz, 1H), 7.00 (d, d, J=0.9, 8.4 Hz, 1H), 6.95-6.93 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.Cl[P:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:30]1([P:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc(-n2c3ccccc3c3ccccc32)c1
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(-n2c3ccccc3c3ccccc32)c1P(c1ccccc1)c1ccccc1
Yield: 72.9 %

Procedure:
Title compound (1-3) (6.1 g) was obtained as a colorless powder by the same procedure as in the second step of Example 1, except that the reaction was conducted by use of the toluene solution of the crude product of N-(3-methoxyphenyl) carbazole (4-1) in an amount equivalent to 18.3 mmol, that chlorodiphenylphosphine was used instead of Cy2PCl, and further that the product was isolated and purified by crystallization from toluene/n-hexane. Two Steps Overall Isolated Yield: 72.9%.
Reaction SMILES: [F:1][C:2]1[CH:7]=CC=C[C:3]=1N1CCNCC1.[CH:14]([N:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH3:19])([CH3:16])C.Cl.[N:24]1([C:29](=[NH:31])[NH2:30])C=CC=N1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:22][C:20]([N:17]2[CH2:18][CH2:19][N:30]([C:29](=[NH:24])[NH2:31])[CH2:16][CH2:14]2)=[CH:21][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: N=C(N)n1cccn1
Reactant: Fc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CC#N
Product: N=C(N)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of 4-(fluorophenyl)piperazine (100 mg, 0.56 mmol) and diisopropylethylamine (106 μL, 0.61 mmol) in ACN (2 mL) was added 1H-pyrazole-1-carboximidamide hydrochloride (89 mg, 0.61 mmol). The reaction stirred at room temperature overnight. A precipitate formed, which was collected via filtration and washed with ACN to obtain 4-(4-fluorophenyl)piperazine-1-carboximidamide as a white solid (119 mg, 97% yield). 1H NMR. (300 MHz, DMSO-d6): δ 7.77 (br s, 3H), 7.10-6.97 (m, 4H), 3.60 (dd, 4H, J=5.3, 4.7 Hz), 3.14 (dd, 4H, J=5.4, 4.7 Hz); 13C NMR (75.5 MHz, DMSO-d6): δ 157.9 (154.8), 156.3, 147.2, 118.0, 115.5 (115.2), 48.3, 44.7; 19F NMR (282.4 MHz, DMSO-d6): δ−124.70−124.78 (m, 1F); HRMS calcd for C11H15FN4: 223.13535 found 223.1353.
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3CCOCC3)=O)C)=CN=2)=CC=1.[NH2:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29].[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](O)=[O:51]>>[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50]([NH:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29])=[O:51]
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Reactant: COc1cccc(C(=O)O)c1
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccc(OC)c3)nn2)cc1
Yield: 26.4 %

Procedure:
In a similar manner as described for Intermediate 50, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 3-methoxybenzoic acid (68 mg, 0.45 mmol) to give 3-(methyloxy)-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (41 mg) as a yellow solid. MS m/z 380 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:4](=[O:13])[CH:3]=1.N1C=CC=CC=1.S(OC)(O[C:24](SC)([S:27][CH3:28])[S:25][CH3:26])(=O)=O>O1CCOCC1>[CH3:26][S:25][C:24]([S:27][CH3:28])=[C:3]1[C:2](=[O:1])[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])[C:4]1=[O:13]
Reactant: CC(C)CCn1ccc(O)cc1=O
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CSC(SC)=C1C(=O)C=CN(CCC(C)C)C1=O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
The product of Example 457B (2.24 g, 12.37 mmol) in pyridine (8.0 mL, 98.96 mmol) and dioxane (50 mL) at 90° C. was treated with excess tris(methylthio)methyl methyl sulfate (prepared using the procedures in Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi), stirred at 90° C. for 1.5 hours and cooled to about 25° C. The reaction solution was decanted from the resulting solids and the solvent was removed under reduced pressure. The residue was dissolved in hexanes and loaded onto a pad of silica gel (300 mL) and eluted with hexane followed by dichloromethane then 25% ethyl acetate in dichloromethane to provide the title compound (2.42 g, 75%).