Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]=1[C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>C1COCC1>[CH3:23][NH:24][C:20]([C:10]1[N:11]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2)nc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CNC(=O)c1nc(-c2ccccc2)sc1NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A solution of 5-tert-butoxycarbonylamino-2-phenyl-thiazole-4-carboxylic acid (138 mg, 0.43 mmol) in THF (2.5 ml) was treated with HATU (187 mg, 0.49 mmol), N-methylmorpholin (0.25 ml, 2.24 mmol) and methylamine (0.29 ml, 2M THF solution) and stirred at 75° C. for 6 h. The reaction mixture was partitioned between potassium hydrogen sulfate (10% aqueous solution) and ethyl acetate and extracted. The organic layer was washed with water, sodium bicarbonate and brine. The combined organic phases were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (98 mg, 65%).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:51])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])=[CH:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:51])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])=[CH:22][CH2:23][CH2:24][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=CCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.49 mL (3.5 mmol) of triethylamine was added and dissolved in a suspension of 0.56 g (3.2 mmol) of ascorbic acid in acetonitrile (7 mL). After the above crude product of (4,8,12,16-tetramethylheptadec-3-enyl)tosylate was added at room temperature, the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCc1ccccc1
Product: CCCCN1C(=O)C(NCCc2ccccc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-phenylethanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (500 MHz CDCl3): δ 7.58-7.52 (m, 2H), 7.50-7.42 (m, 2H), 7.30-7.20 (m, 4H), 6.88 (dd, 2H), 5.38 (t, 1H), 3.70 (t, 2H), 3.18 (dt, 2H), 2.62 (t, 2H), 1.88-1.78 (m, 2H), 1.50-1.40 (m, 2H), 0.98 (t, 2H); 13C NMR (125 MHz CDCl3): δ 159.4, 137.8, 137.5, 131.8, 130.0, 129.0, 128.9, 128.7, 127.1, 125.2, 107.2, 45.1, 40.4, 36.0, 30.4, 20.3, 13.8; Mass-Spectrum M+H+ 385.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=[O:23])[CH2:19][C:20](O)=[O:21].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:18](=[O:23])[CH2:19][C:20](=[O:21])[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)Nc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=O)N(c2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 50 °C
Yield: 70.7 %

Procedure:
In a 300-ml glass flask equipped with a thermometer, a reflux condenser and a stirrer, 5.0 g of N-benzyl-N′-phenylurea synthesized in Exemplary Synthesis 1, 2.5 g of malonic acid, 20 ml of toluene, and 5.6 g of acetic anhydride were put, the content was heated under stirring so as to adjust the inner temperature to 80° C., and kept under stirring at 80° C. for 3 hours. The content was then cooled to 50° C., washed with 15 ml of water, and the aqueous phase was discarded. The organic layer was kept under stirring at room temperature, and 5 ml of isopropanol was dropped therein. The content was further stirred at 10° C. or below for 0.5 hours, filtered under suction to collect a deposited crystal, the crystal was washed with cold isopropanol, and dried, to thereby obtain 4.6 g of 1-benzyl-3-phenylbarbituric acid as an intermediate.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1O)[CH3:17].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH3:17]
Reactant: CCOC(=O)/C(C)=C/c1ccc(O)c(OCC)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(C)=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(OCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
0.8 mL (4.8 mmol) of triflic anhydride is added to a solution of 1.5 g (4 mmol) of ethyl (E)-3-(3-ethoxy-4-hydroxyphenyl)-2-methylacrylate and 1.6 mL (12 mmol) of triethylamine in 20 mL of dichloromethane at 0° C. The reaction mixture is stirred at room temperature for 1 hour. The medium is hydrolyzed in sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and 1.65 g (100%) of ethyl (E)-3-(3-ethoxy-4-trifluoromethanesulfonyloxyphenyl)-2-methylacrylate are obtained in the form of a brown oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][NH:16][CH:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH:20]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[OH:30])[C:14]3=[O:31])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][CH2:42][Cl:43]>C(#N)C.O>[Cl:43][CH2:42][CH2:41][CH2:40][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:15]1[C:14](=[O:31])[N:13]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=2[CH3:12])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:32])[CH:18]=[CH:17][N:16]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N1C=CNC(N2CCCC2c2ccccc2O)C1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N2CCCC2c2ccccc2OCCCCl)c1=O
Temperature: 83 °C
Reaction time: 10 h

Procedure:
A solution of N-cyclopropyl-3-{3-[2-(2-hydroxyphenyl)pyrrolidin-1-yl]-2-oxo-3,4-dihydropyrazin-1(2H)-yl}-4-methylbenzamide (Example 324a, 0.2 g) in acetonitrile (5 mL) was treated with potassium carbonate (0.642 g) and 1-bromo-3-chloropropane (0.459 mL) under nitrogen. The resulting suspension was stirred at 83° C. for 10 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to give the subtitle compound (0.23 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCN1CCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCCN1CCCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(1-pyrrolidinyl)ethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.61 (1H, br), 8.28 (1H, br s), 7.36 (1H, s), 7.30 (2H, m), 7.14 (2H, t, J=8.8 Hz), 4.04 (2H, s), 3.41 (2H, m), 2.56 (2H, t, J=6.4 Hz), 2.54-2.48 (4H, m), 1.68 (4H, m); ES+ MS: 411 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][NH:21][C:29](=[O:31])[CH3:30])=[CH:16][CH:17]=1)[CH2:6][CH2:5]2
Reactant: N#CCCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Reaction time: 3 h
Yield: 33.7 %

Procedure:
To a solution of 4-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]benzenepropanenitrile (0.50 g, 1.7 mmol) in tetrahydrofuran (25 mL) was added lithium aluminum hydride (77 mg, 2.0 mmol) under ice-cooling, and the mixture was stirred in an ice bath for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The obtained oil was dissolved in pyridine (20 mL), acetic anhydride (0.18 mL, 0.95 mmol) was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.11 g, yield 18%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>C(Cl)Cl>[Cl:20][C:19]1[C:14]([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)=[N:15][CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl)S(C)(=O)=O
Reaction time: 15 h

Procedure:
2.4 g (21.0 mmol) of methanesulfonyl chloride were slowly added dropwise to a mixture of 3.0 g (9.77 mmol) of 2-(3-amino-4-chlorophenyl)-3-chloro-5-trifluoromethylpyridine, 2.2 g (22.4 mmol) of triethylamine and 50 ml of anhydrous methylene chloride at 0°-5° C. The mixture was stirred at 20°-25° C. for about 15 hours and then washed twice with water, dried over sodium sulfate and finally concentrated. The residue was stirred with ether, filtered off with suction and dried under reduced pressure. Yield: 3.6 g (87%) of colorless crystals of melting point 230°-231° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4]([F:17])[C:5]([F:16])=[C:6]([CH:15]=1)[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[CH:19](OCC)(OCC)[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:3]([F:18])=[C:4]([F:17])[C:5]([F:16])=[C:6]([CH:15]=1)[C:7]([C:9](=[CH:19][O:20][CH2:21][CH3:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8]
Reactant: CCOC(=O)CC(=O)c1cc(Cl)c(F)c(F)c1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(Cl)c(F)c(F)c1F
Yield: 92.3 %

Procedure:
103 g (0.37 mole) of the ester obtained and 83 g (0.56 mole) of triethyl orthoformate are heated with 95 g of acetic anhydride at 150°-160° for 2 hours and then concentrated at 120°-130° under atmospheric pressure and thereafter under high vacuum. 115 g (92% of theory) of ethyl 2-(5-chloro-2,3,4-trifluorobenzoyl)-3-ethoxyacrylate are obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CI
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (300 mg, 1.80 mmol) in 3.6 mL of dry N,N-dimethylformamide was added sodium hydride (94 mg, 55%, 2.1 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, methyl iodide (0.17 mL, 2.7 mmol) was added with additional stirring for 30 min. After the reaction mixture was quenched with saturated NH4Cl aqueous solution at 0° C., the solution was extracted with ether. The extract was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 70/30) to obtain the title compound as a slightly yellow powder (298 mg, 91%).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH3:22].O>CN(C)C=O>[CH3:22][C:10]1[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][S:2][CH3:1])[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=1
Reactant: C[S-]
Reactant: Cc1nc2cnc3ccccc3c2n1CCCCCl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCCCn1c(C)nc2cnc3ccccc3c21
Yield: 95.9 %

Procedure:
Sodium thiomethoxide (2.02 g of 95%, 27.40 mmol) was added in a single portion to a solution of 1-(4-chlorobutyl)-2-methyl-1H-imidazo[4,5-c]quinoline (5.0 g, 18.26 mmol) in anhydrous N,N-dimethylformamide (91 mL). After 30 minutes the reaction mixture was poured with rapid stirring into water (500 mL). The resulting solution was extracted with chloroform (2×200 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (100 mL) then with brine (100 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide 5.0 g 2-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinoline as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[C:21]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(C)=O)cc1OC
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred solution of β-(3,4-dimethoxyphenyl)ethylamine (100 g, 0.552 m) and triethylamine (66.6 g, 0.66 m) in CHCl3 (1 liter) was added acetyl chloride (47.1 g, 0.60 mole) dropwise over a period of 30 min. and the mixture stirred overnight. The mixture was washed with 3×500 ml H2O, dried over MgSO4 and evaporated to a solid. The solid was dissolved in 500 ml hot CCl4, 300 ml cyclohexane added and allowed to cool slowly. The crystallized solid was collected by filtration and dried to afford N-acetyl-3,4-dimethoxyphenethylamine as a white solid, 112.1 g (91% yield). m.p. 99°-100°.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:10]([C:12]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[C:37](=[O:42])[C:38](=[O:41])[C:39]=3[OH:40])=[CH:26][CH:25]=2)[C:15]2=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]2[N:13]=1)[CH3:11].[I-].[K+].C(OCC)C>CN(C)C(=O)C>[C:1]([O:7][CH2:8][O:42][C:37]1[C:38](=[O:41])[C:39](=[O:40])[C:36]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:15]3=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]3[N:13]=[C:12]2[CH2:10][CH3:11])=[CH:25][CH:26]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(O)c(=O)c2=O)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(OCOC(=O)C(C)(C)C)c(=O)c2=O)cc1
Reaction time: 48 h

Procedure:
Chloromethyl pivalate (3.22 g) was added, dropwise, at ambient temperature, to a stirring suspension of 3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl -2-yl]-4-hydroxycyclobut-3-ene-1,2-dione (4.21 g; preparable as in Example 4) in dry N,N-dimethylacetamide (40 ml). Potassium iodide (2.5 g) was added to the resulting mixture and stirring was continued am ambient temperature for 2 days. More chloromethyl pivalate (3.7 g) was added and stirring was continued for an additional 2 days. The mixture obtained was poured into diethyl ether (500 ml) to give a gum which was separated and then dissolved in a mixture of acetone (100 ml) and ethyl acetate (300 ml). The resulting solution was washed with saturated aqueous sodium bicarbonate solution (2×400 ml) then water (2×400 ml) and dried over magnesium sulphate. The solvents were evaporated under reduced pressure and the residue obtained was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give 2-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-3,4-dioxocyclobut-1-en-1-yloxymethyl pivalate, an active compound of the present invention, as a fellow foam (0.54 g) which melted slowly at 60°-80° C.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH2:6][C@@H:5]1[CH2:14][C:15]1[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1.Cl[CH2:30][C:31]1[S:32][C:33]2[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:34]=2[N:35]=1.O>CN(C=O)C>[F:41][C:37]1[C:38]([F:40])=[CH:39][C:33]2[S:32][C:31]([CH2:30][O:13][C:10]3[CH:11]=[C:12]4[C:7]([CH2:6][CH:5]([CH2:14][C:15]5[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=5)[CH:4]4[OH:3])=[CH:8][CH:9]=3)=[N:35][C:34]=2[CH:36]=1
Reactant: O=S(=O)(Nc1cccc(C[C@H]2Cc3ccc(O)cc3[C@H]2O)c1)C(F)(F)F
Reactant: Fc1cc2nc(CCl)sc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cccc(CC2Cc3ccc(OCc4nc5cc(F)c(F)cc5s4)cc3C2O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 127.4 %

Procedure:
382 mg (9.54 mmol) of sodium hydride, 60% oil dispersion, were added in one portion to a room temperature solution of 1.76 g (4.54 mmol) of the product of Example 56 in 30 mL of anhydrous DMF. After 20 minutes, a room temperature solution of 1.40 g (6.36 mmol) of 2-chloromethyl-5,6-difluorobenzothiazole in 10 mL of anhydrous DMF was added over 15-20 minutes. After stirring 18 hours at room temperature, the reaction mixture was poured into 500 mL H2O, acidified to pH 1, and extracted two times with 300 mL ethyl acetate. The ethyl acetate extracts were combined, washed three times with 150 mL H2O, one time with 100 mL brine, and dried over Na2SO4. Filtration, concentration and drying gave 3.3 g of a brown oil, which was purified by silica gel chromatography (15% to 25% ethyl acetate in CH2Cl2) to afford 1.52 g of the title product as an off-white solid. 59% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([CH:34]=[CH:35][CH:36]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:14]([CH3:33])[CH:13]=1)=[O:10].[H][H]>CCO.[Pd]>[CH3:37][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:34]=[CH:35][CH:36]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:14]([CH3:33])[CH:13]=1)=[O:10]
Reactant: [H][H]
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(C#CCN(C)C)c3)cc2C)n1
Agent: [Pd]
Solvent: CCO
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(CCCN(C)C)c3)cc2C)n1
Reaction time: 5 h

Procedure:
To a mixture of 3-(3-(dimethylamino)prop-1-ynyl)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide (0.060 g, 0.12 mmol) in EtOH (4 mL) was added a suspension of 10% Pd/C (0.012 g, 0.012 mmol) in ethanol. The reaction was exposed to approximately 30 psi hydrogen and was shaken in a Parr apparatus for 5 h. The reaction was filtered through celite, and the filtrate was concentrated in vacuo. The resulting yellow oil was purified by reverse-phase HPLC using acetonitrile/water/TFA to give 3-(3-(dimethylamino)propyl)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide as an off-white solid. MS m/z=497 [M+1]+. Calc'd for C29H32N6O2: 496.61.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[N:12]2)=[N:6][CH:7]=1>CCOC(C)=O.CCO.O=[Pt]=O>[NH2:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[CH:15]=1
Reactant: O=[N+]([O-])c1cnn(CCNc2ccc(F)cn2)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnn(CCNc2ccc(F)cn2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-fluoro-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-amine (100 mg, 0.34 mmol) in EtOAc (0.4 mL, degassed) and EtOH (1.2 mL, degassed), PtO2 (12 mg, 0.05 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 6 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound as a red oil, which was used in the next step without further purification. LC-MS conditions A: tR=0.18 min, [M+H]+=222.34.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.1 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (7 g, 0.032 mol) in 3 mL of NMP, KOH (12.7 g, 0.226 mol) was added at RT. The reaction mixture was stirred well at RT for 20 min. Then a solution of 2-bromo-1-(4-fluorophenyl)ethanone (6.5 g, 0.032 mol) in 2 mL NMP was added dropwise into the reaction mixture at RT over 2-4 h. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography, providing the desired product (1.2 g, 11.02%). 1HNMR (CDCl3, TFA salt) d (ppm): 8.18-8.01 (m, 2H), 7.71 (s, 1H), 7.30 (s, 1H), 7.22-7.10 (m, 2H), 7.00 (d, 1H), 3.60-3.31 (m, 4H), 3.20-3.06 (m, 2H), 2.85-2.70 (m, 2H), 2.45 (s, 6H).