Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].I[C:15]1[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:20]([N:18]1[CH:19]=[C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH:16]=[N:17]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCn1cc(I)cn1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCn1cc(-c2ccc(C(=O)OC)cc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a suspension of 4-Methoxycarbonylphenyl boronic acid (648 mg) and 4-iodo-1-heptylpyrazole (876 mg) and Pd(PPh3)4 (173 mg) in 1,2-dimethoxyethane (10 ml) was added 2M Na2CO3 aq. (3.6 ml). The reaction mixture was stirred at 80° C. for 2 hours under N2 atmosphere, and poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over MgSO4. The solvent was removed under pressure. The residue was subjected to column-chromatography on silica gel 60 (Merk) and eluted with n-hexane/ethyl acetate (80:20). The fractions containing the object compound were combined and evaporated under reduced pressure to give 1-heptyl-4-(4-methoxycarbonylphenyl)pyrazole (0.20 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][S-:11].[Na+]>CN(C=O)C>[CH3:10][S:11][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[S-]
Reactant: N#Cc1ccncc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cnccc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a mixture of 2.0 g of 3-chloroisonicotinonitrile and 8 ml of DMF, 1.02 g of sodium thiomethoxide was added while ice-cooling. The reaction mixture was stirred at 0° C. for one hour. The reaction mixture was concentrated under reduced pressure, to which ethyl acetate was added for filtering out insoluble matters. Filtrates were concentrated under reduced pressure, and the resultant residue was subjected to silica gel column chromatography to give 2.11 g of 3-methylthioisonicotinonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]=[C:6]1[CH2:10][C@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1([CH2:17][N+:14]([O-:16])=[O:15])[CH2:7][C@@H:8]([CH3:12])[C@H:9]([CH3:11])[CH2:10]1)[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1C[C@@H](C)[C@@H](C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
The unsaturated ester (2) (1.384 g, 7.60 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 70° C. with nitromethane (0.82 mL, 15.2 mmol) and tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 11.4 mL, 11.4 mmol). After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with 2N HCl (30 mL) followed by brine (50 mL). The organic phase was collected, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane 5:95) to give 0.837 g (45%) of a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1.O1CCOCC1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.Cl[C:53]1[N:58]=[C:57]([NH2:59])[C:56]([N+:60]([O-:62])=[O:61])=[C:55]([NH2:63])[N:54]=1>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.O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:53]3[N:54]=[C:55]([NH2:63])[C:56]([N+:60]([O-:62])=[O:61])=[C:57]([NH2:59])[N:58]=3)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Reactant: Nc1nc(Cl)nc(N)c1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under argon, 860 mg (2.32 mmol) of the compound from Example 6A were introduced into 1,4-dioxane (86 ml), and the reaction mixture was flushed with argon for 10 min. Then 3.51 ml (6.95 mmol) of hexabutylditin and 483 mg (2.55 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine (prepared by the method of Helvetica Chimica Acta (1951), 34, 835-40) were added. Subsequently 860 mg (0.744 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the reaction mixture was heated at reflux overnight. The mixture was then cooled to RT, water was added and the mixture was extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulphate, filtered and concentrated. The residue was subjected to extractive stirring in ethyl acetate, and the solid was isolated by filtration and dried under high vacuum. This gave 355 mg (62% purity, 24% of theory) of the desired compound. The crude product was reacted without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])=[CH2:2].I[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:16][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9]
Reactant: C=Cc1ccc(O)c(C(=O)OCC(C)C)c1
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: CC(C)COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O

Procedure:
Palladium (II) acetate (0.15 g, 0.67 mmol) was added to a stirred solution of isobutyl 5-ethenyl-2-hydroxybenzoate (6.6 g, 30 mmol) and 4-iodo-N-2-pyridinylbenzenesulfonamide (10.8 g, 30 mmol) in dimethylacetamide (40 ml) and tributylamine (10 ml, 42 mmol) at 95° C. After 100 min. the solution was filtered and evaporated at 50°-60° C. (bath temp.) until solid material appeared. The mixture was diluted with isopropanol (0.5 l) and chilled in a freezer. The product was filtered off to yield 7.1g (52%).
Reaction SMILES: C(C1C=CC2N=C(N[C:16]([NH:18][CH2:19][CH3:20])=[O:17])SC=2C=1)C1C=CC=CC=1.[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][C:27]=2[N:28]=1.C(N(CC)CC)C.C(N=C=O)C>C1(C)C=CC=CC=1>[CH2:36]([O:35][C:33]([C:31]1[CH:30]=[CH:29][C:27]2[N:28]=[C:24]([NH:23][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[S:25][C:26]=2[CH:32]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)c1ccc2nc(N)sc2c1
Reactant: CCNC(=O)Nc1nc2ccc(Cc3ccccc3)cc2s1
Agent: CCN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2ccc(C(=O)OCC)cc2s1
Yield: 82 %

Procedure:
According to the General Procedure for 1-(6-substituted-2-benzothiazolyl)-3-ethylurea compounds, and similar to the synthesis of 1-(6-benzyl-2-benzothiazolyl)-3-ethylurea, a mixture of 2-amino-6-ethoxycarbonyl-benzothiazole, triethylamine and ethyl isocyanate in toluene was reacted to give the desired compound 2.40 g (82%). LC/MS 294.0 (M+1); LC retention time 4.29 min.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[F:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[C:13]([CH3:32])([CH3:31])[CH2:12][C:11]=2[C:10]=1[C:33](O)=[O:34].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH:20]=3)[C:13]([CH3:31])([CH3:32])[CH2:12][C:11]=2[C:10]=1[C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2c(ccc(F)c2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(ccc(F)c2C(=O)NS(C)(=O)=O)NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (102 mg, 2.5 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (247 mg, 2.6 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (100 mg, 0.26 mmol) and 1,1′-carbonyldiimidazole (106 mg, 0.65 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-methanesulfonamide (36 mg, 30%) as a white solid: LC/MS m/e calcd for C23H28FN3O4S (M+H)+: 462.56, observed: 462.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7](C1C=CC=C(O)C=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S([O:39][CH2:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:43][CH2:42]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([C:47]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[O:48])[CH2:45][CH2:46]1)=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a stirred solution of tert-butyl(3-hydroxyphenyl)(phenyl)methylcarbamate. (the second eluting isomer from Chiral Example 1 Step 4, 1.00 g, 3.34 mmol) in DMF (15 mL), was added potassium carbonate (0.554 g, 4.01 mmol). The reaction mixture was stirred for 10 minutes, and benzyl 4-((tosyloxy)methyl)piperidine-1-carboxylate (prepared according to Bioorganic & Medicinal Chemistry Letters, 20(1), 380-382; 2010, which is incorporated herein by reference in its entirety, 1.48 g, 3.67 mmol) added. The reaction mixture was heated at 60° C. for 2 days followed by 80° C. for 5 days. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine (×2). The organic phase was dried with anhydrous magnesium sulfate, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 50% ethyl acetate in iso-hexane to afford the title compound (1.12 g, 63%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>CN(C)C=O.C(OCC)(=O)C>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][S:15][C:13]1[O:14][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccc3[nH]ncc3c2)o1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(CSc2nnc(-c3ccc4[nH]ncc4c3)o2)c1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol (218 mg, 1.00 mmol) and 1 M aqueous sodium hydroxide solution (1.00 mL, 1.00 mmol) in N,N-dimethylformamide (5 mL) was added 3-(trifluoromethyl)benzyl chloride (0.155 mL, 1.00 mmol) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from methanol to give the title compound (279 mg, yield 74%) as colorless crystals.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[N:37]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[NH:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]3[N:33]=[CH:34][CH:35]=[CH:36][N:37]=3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Yield: 58.2 %

Procedure:
This compound was prepared according to the general methods described in Example 1 using 2,2'-dithiobisbenzoyl chloride (3.0 g, 8.7 mmol) in 30 mL dichloromethane and 4-amino-N-(2-pyrimidinyl) benzenesulfonamide (5.3 g, 21.7 mmol) in 100 mL pyridine. The crude product was recrystallized from a mixture of dimethylformamide, ethanol, and water to yield 3.9 g of the title compound, mp 280° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH:13]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc(F)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
To a solution of 4-fluoroaniline (3.85 g, 34.7 mmol) in tetrahydrofuran (100 mL) were added 2,4-dimethoxybenzaldehyde (6.34 g, 38.2 mmol) and acetic acid (11.9 mL, 208 mmol). After stirring at room temperature for 15 min, sodium triacetoxyborohydride (22.1 g, 104 mmol) was added thereto and the mixture was stirred at the same temperature for 15 hr. The mixture was concentrated under reduced pressure, diluted with ethyl acetate, and then washed with 2 mol/L aqueous sodium hydroxide solution and brine successively. The organic layer was dried over anhydrous sodium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to afford the title compound as a pale yellow solid (7.37 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[C:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18](O)=O)#[CH:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[C:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)#[CH:15]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: C#Cc1cnccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: C#Cc1cnccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
A mixture of 0.29 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.27 g of 3-ethynylisonicotinic acid, 0.35 g of WSC and 8 ml of pyridine was stirred for 2 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 2-(3-ethynylpyridin-4-yl-)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 211).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>O1CCCC1>[CH:15]1([CH:11]([C:10]2[CH:13]=[CH:14][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=2)[OH:12])[CH2:17][CH2:16]1
Reactant: CCCS(=O)(=O)c1ccc(C=O)cc1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CCCS(=O)(=O)c1ccc(C(O)C2CC2)cc1
Temperature: 25 °C

Procedure:
To 4-(propylsulphonyl)benzaldehyde (0.58 g) in dry tetrahydrofuran (5 mL), at −78° C. under nitrogen, was added a 0.5 M solution of cyclopropylmagnesium bromide in tetrahydrofuran (6.0 mL), slowly with stirring. The mixture was stirred for 1.75 h, quenched by addition of acetic acid (0.5 mL), then warmed to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, solvent stripped, and the residue chromatographed on silica gel, eluent 35% to 50% ethyl acetate in isohexane, to give the title compound as a white solid. 1H NMR (360 MHz, CDCl3) δ 7.88 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.4 Hz), 4.10 (1H, m), 3.06 (2K, m), 2.14 (1H, d, J=2.9 Hz), 1.75 (2H, m), 1.18 (1H, m), 0.99 (3H, t, J=7.4 Hz), 0.66 (2H, m), 0.49 (2H, m).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH:19]=[CH:18]1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][C@@H:19]2[C:20](=[O:22])[NH:21][C:17](=[O:23])[C@@H:18]2[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 25 °C
Reaction time: 27 h
Yield: 90.6 %

Procedure:
A solution of N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)amine (76.68 g, 0.29 mol, prepared as in Organic Syntheses (1989), 67, 133-140) in dichloromethane (130 mL) was added to an ice-cooled mixture of maleimide (25.53 g, 0.26 mol) and trifluoroacetic acid (2.2 mL, 0.028 mol) in dichloromethane (350 ml) over 40 min so that the reaction temperature remained between 0-5° C. The resulting bright yellow solution was allowed to warm gradually and stirred at room temperature for 27 h. The mixture was washed with saturated NaHCO3(aq) (80 mL) and the organic phase was dried (MgSO4) and concentrated under vacuum. The residual oil was stirred with 10% EtOAc-heptane (300 mL) for 15 h, and the resulting precipitate was isolated by filtration, washed with 10% EtOAc-heptane (150 mL) and dried under vacuum at 50° C. to provide the crude, title compound as a white solid (54.25 g). This was stirred with methanol (500 mL) and 50% aqueous H2NOH (4.2 mL) at room temperature for 20 h. The mixture was concentrated under vacuum and the residue was taken up in EtOAc (500 mL) and filtered to remove some insoluble material. The filtrate was concentrated under vacuum to leave the pure, title compound as an off-white solid (49.9 g, 83% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.32-2.43 (m, 2H), 3.18 (d, J=9.8 Hz, 2H), 3.20-3.26 (m, 2H), 3.59 (s, 2H), 7.13-7.35 (m, 5H); MS (DCI/NH3) m/z 231 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:29]1[N:34]([CH3:35])[C:33](=[O:36])[CH:32]=[C:31]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[N:30]=1.ClC1C=CNC(=O)N=1>O1CCCC1>[CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:29]4[N:34]([CH3:35])[C:33](=[O:36])[CH:32]=[C:31]([C:37]5[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=5)[N:30]=4)[CH2:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CN(c1ccc([C@H]2CNCCO2)cc1)C1CCCCC1
Agent: O=c1nc(Cl)cc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1)C1CCCCC1
Yield: 75.6 %

Procedure:
To a solution of (2S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)morpholine (4.47 g, 16.30 mmol) and triethylamine (3.1 ml, 22.2 mmol) in tetrahydrofuran (50 ml) was added 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (3.28 g, 14.82 mmol) portionwise. Upon disappearance of the chloropyrimidone, the reaction mixture was condensed under reduced pressure. The residue was partitioned between 1 N sodium hydroxide and dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow solid, which was recrystallized from ethanol to afford 2-((2S)-2-(4-(N-cyclohexyl-N-methylamino)-phenyl)morpholin-4-yl)-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (5.15 g, 75.7%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:13][C:4]1[S:3][C:2]2[N:1]=[C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]3[C:7](=[O:9])[C:6]=2[C:5]=1[CH3:12]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Product: Cc1sc2nc3ccc(C(=O)O)cn3c(=O)c2c1C
Yield: 1.8 %

Procedure:
From 8.0 g (0.04 mol) of 2-amino-4,5-dimethyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol 99, pages 94-100, 1966) and 6.3 g (0.04 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company) following the procedure of Example 3, there is obtained 0.2 g of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid; mp 364°-368° C. after recrystallization from pyridine.