Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nc(Cc2ccccc2)c(-c2ccccc2)s1
Product: O=C(Nc1nc(Cc2ccccc2)c(-c2ccccc2)s1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-benzyl-5-phenylthiazole as the raw materials, the same operation as the example 195(3) gave the title compound. (2-Amino-4-benzyl-5-phenylthiazole: refer to Chem. Pharm. Bull., 1962, 10, 376.)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[S:14][CH:13]=[N:12][CH:11]=1.[CH3:15][C:16]([S:19]([N:21]=[C:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:20])([CH3:18])[CH3:17].C[Al](C)C.CCCCCCC>C1COCC1.C1(C)C=CC=CC=1>[CH3:18][C:16]([S:19]([NH:21][C:22]1([C:13]2[S:14][C:10]([CH3:9])=[CH:11][N:12]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:20])([CH3:15])[CH3:17]
Reactant: Cc1cncs1
Reactant: CC(C)(C)S(=O)N=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: C[Al](C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cnc(C2(NS(=O)C(C)(C)C)CCOCC2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A 2.0M solution of lithium diisopropylamide in THF (492 μl, 984 μmol) was added dropwise to a solution of 5-methylthiazole (97.5 mg, 984 μmol) in dry THF (0.3 ml) cooled to −78° C. and once the addition was complete the reaction was stirred for 30 minutes at −78° C. followed by addition of dry toluene (0.6 ml). To a solution of 2-methyl-N-(2H-pyran-4(3H,5H,6H)-ylidene)propane-2-sulfinamide (CAN 861857-62-7, 100 mg, 492 μmol) in dry toluene (1 mL) was added a 2.0M solution of trimethylaluminum in heptane (271 μl, 541 μmol). The former solution was then added to the reaction mixture cooled at −78° C. The reaction was allowed to warm up to room temperature overnight. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and was then diluted with ethyl acetate. The bi-phasic mixture was poured into a separatory funnel and extracted. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane-methanol gradient to yield the title compound (102 mg, 69%). MS (ESI, m/z): 303.5 (M+H+).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C:4]1[C:5]([Cl:33])=[N:6][C:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)=[O:22])=[CH:16][CH:15]=2)=[N:8][C:9]=1[N:10]([CH3:12])[CH3:11].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Cl:33][C:5]1[C:4]([CH2:3][C:2]#[N:1])=[C:9]([N:10]([CH3:12])[CH3:11])[N:8]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[N:6]=1
Reactant: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC(N)=O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
To a solution of N-(4-{[5-(2-amino-2-oxoethyl)-4-chloro-6-(dimethylamino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide (0.360 g, 0.76 mmol) in pyridine (15 mL) at rt was added trifluoroacetic anhydride (0.161 mL, 1.14 mmol) dropwise and the resulting reaction mixture was stirred at room temperature for 15 hours. The volatiles were removed in vacuo and the remaining residue was partitioned between EtOAc and saturated aqueous ammonium chloride solution. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the resulting crude product by silica gel chromatography eluting with 20% EtOH in CHCl3 gave N-(4-{[4-chloro-5-(cyanomethyl)-6-(dimethyl-amino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide as an amorphous solid (0.345 g, 100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)[CH2:2][CH3:3].[C:14]([O:18][C:19]([C:21]1[C:22]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33]Br)=[C:29]([F:35])[CH:28]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:11][C:9]([C:7]1[CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:20])=[CH:28][C:29]=2[F:35])[N:6]=1)=[O:10])[CH3:13]
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 65 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
Ethyl 3-n-propylpyrazole-5-carboxylate (1.05 g, 5.8 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (2.0 g, 5.8 mmol), and potassium carbonate (1.6 g, 11.5 mmol) were dissolved in DMF (10 mL). The mixture was stirred at 65° C. for 16 hours, then diluted with EtOAc. The organic layer was washed with saturated NaHCO3 and saturated aqueous NaCl, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography (EtOAc in hexanes) to yield 1-(2′-t-butoxycarbonyl-3-fluorobiphenyl-4-ylmethyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (2.7 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20](CC)[CH2:21][C:22]3C=CC(OC)=CC=3)[CH:15]=2)=[CH:11][C:10]=1[F:34].Cl.O>C(Cl)Cl>[NH2:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH3:22])[CH:15]=2)=[CH:11][C:10]=1[F:34]
Reactant: CCN(Cc1ccc(OC)cc1)c1cc(Oc2ccc(N)c(F)c2)ccn1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCNc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 40 °C
Yield: 55.7 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of [4-(4-amino-3-fluoro-phenoxy)-pyridin-2-yl]-ethyl-(4-methoxybenzyl)amine (1.2 g, 3.27 mmol) in CH2Cl2 (50 mL) and the resulting solution was heated to 40° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was treated with HCl (5 mL, 12M, 60 mmol) and water (50 mL). The solution was washed with EtOAc (4×50 mL). The aqueous layer was treated with NaHCO3 until pH=8 and then extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (3×50 mL), dried (NaSO4) and concentrated in vacuo to give 4-(4-amino-3-fluorophenoxy)-N-ethylpyridin-2-amine (0.45 g, 67% yield). 1H NMR (300 MHz, DMSO-d6) δ7.79 (d, J=5.7, 1H), 6.85 (dd, J=11.7, 2.4 Hz, 1H), 6.78 (t, J=8.7 Hz, 1H), 6.67 (dd, J=8.7, 2.4 Hz, 1H), 6.39 (m, 1H), 6.05 (dd, J=5.7, 2.1 Hz, 1H), 5.72 (d, J=2.1 Hz, 1H), 5.09 (s, 2H), 3.15 (m, 2H), 1.03 (t, J=7.2, 3H); MS (ESI) m/z: 248.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10](O)=[O:11])[S:9][C:5]=2[CH:4]=1.CN([C:20]([O:24][N:25]1N=NC2C=CC=N[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][O:24][N:25]([CH3:26])[C:10]([C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:14]=[CH:13][C:6]=2[CH:7]=1)=[O:11]
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2ccc(C(F)(F)F)cc2s1
Reaction time: 0.03 h

Procedure:
To 6-(Trifluoromethyl)-1-benzothiophene-2-carboxylic acid dissolved in DMF (0.5 M) was added HATU (1.2 equiv) at 0° C. and the reaction was stirred for 2 min followed by addition of N,O-dimethylhydroxylamine hydrochloride (1.5 equiv). The reaction was stirred for 2 min prior to the addition of iPr2NEt (5 equiv). The reaction was stirred for an additional 20 min at 0° C. The reaction was quenched with equivalent amounts of half-saturated aqueous NaHCO3 and H2O. The title compound was obtained as a solid and filtered on a Büchner funnel before being and air-dried.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[NH:11][CH2:10]1.Br[CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10]1
Reactant: CCCC(Br)C(=O)OCC
Reactant: O=C1NCC(COc2cccc(Cl)c2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)N1CC(COc2cccc(Cl)c2)OC1=O
Yield: 48 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.35 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 6.00 g of 5-(3-chlorophenoxymethyl)oxazolidin-2-one, 100 ml of anhydrous dimethylformamide and 6.48 g of ethyl 2-bromovalerate were used. The resulting crude product was applied to a silica gel chromatography column, and eluted, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give a polar diastereomer and a less polar diastereomer separately. From the polar diastereomer, 4.5 g of the title compound having an Rf value of 0.58 (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent) were obtained, and from the less polar diastereomer, 4.47 g of the title compound, melting at 43° C. to 49° C., were obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=1)[C:11]([CH3:26])=[CH:10]2.CN(C)[CH:29]=[O:30]>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:11]([CH3:26])=[C:10]2[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(-n2c(C)cc3cc(Br)ccc32)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2cc(Br)ccc2n1-c1ccc(O)cc1
Yield: 51 %

Procedure:
Phosphorous oxychloride (2.5 mL) was added to anhydrous dimethylformamide (5 mL) and stirred at room temperature for 15 min whereupon a solution of 5-bromo-1-(4-methoxymethyloxyphenyl)-2-methyl-1H -indole (0.65 g, 1.9 mmol) in dimethylformamide (10 mL) was added. The solution was reacted according to the procedure used in Example 2a to afford a tan solid (51%): mp>250° C.; 1H NMR (DMSO-d6): δ 2.50 (3H, s), 6.95-7.02 (3 H, m), 7.21 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.28 (2H, d, J=8.7 Hz), 8.38 (1H, d, J=2.2 Hz), 9.98 (1H, s), 10.14 (1H, s); MS m/Z (M+H)+ 318/320 (1 Br). Anal. for C16H12BrNO2·0.2H2O: Calc'd: C, 55.99; H, 3.88; N, 4.35. Found: C, 55.69; H, 3.95; N, 4.15.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[F:5][C:6]([F:17])([F:16])[C:7](=O)[CH:8](Cl)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>CCO>[NH2:1][C:2]1[S:3][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:6]([F:5])([F:17])[F:16])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C(F)(F)F
Temperature: 80 °C
Yield: 108.8 %

Procedure:
To a suspension of thiourea (3.3 g, 22.88 mmol) in EtOH (200 mL) was added ethyl 4,4,4-trifluoro-2-chloroacetoacetate (5 g, 22.88 mmol), and the resulting reaction mixture was heated at 80° C. for 24 h. Then, the reaction mixture was cooled to RT and concentrated in vacuo. The product was purified by column chromatography to give ethyl 2-amino-4-trifluoromethylthiazole-5-carboxylate (A-32) as a colorless oil (5.98 g, 85% yield). 1H NMR (500 MHz, CDCl3) δ 4.32 (q, 2H, J=7.0 Hz), 3.56 (m, 4H), 1.70 (m, 6H), 1.36 (t, 3H, J=7.0 Hz); LCMS (ESI) [M+1]+ 309.3.
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.O[CH2:14][C:15](CO)(C)[C:16](=[O:18])[CH3:17].C1COCC1>C(N(CC)CC)C>[C:16]([C:15]1([CH3:14])[CH2:7][O:6][C:5](=[O:11])[O:4][CH2:2]1)(=[O:18])[CH3:17]
Reactant: CC(=O)C(C)(CO)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)C1(C)COC(=O)OC1
Temperature: -78 °C

Procedure:
In a one liter three neck flask equipped with a mechanical stirrer and under nitrogen were added triphosgene (37.0 g), 3,3-dihydroxymethyl-2-butanone (50 g) and THF (300 mL). The resulting mixture was stirred until a homogeneous solution resulted. This homogeneous solution was cooled to -78° C. Triethylamine (75.0 g) was added to the this solution over 30 min. The cold bath was removed and the reaction allowed to warm to room temperature. After stirring for one hour at room temperature the triethylamine/HCl salt was removed by filtration and the filtrate pass through a silica gel plug. The solvent was removed under reduced pressure resulting in an off white product. This product was then washed with hot ether giving a white solid. NMR analysis indicated that the product contained a small amount of triethylamine/HCl salt, thus the material was dissolved in dichloromethane and washed with water affording 15.02 g of material. 1H NMR (CDCl3) ppm: 4.70 (ab doublet, 2H), 4.20 (ab doublet, 2H), 2.3 (S, 3H), 1.25 (S, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1C(OC)=O.CN1CCNCC1.CN1CCCC1=O>O>[C:7]1([C:5]2[S:4][CH:3]=[C:2]([NH2:1])[CH:6]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1csc(-c2ccccc2)c1
Temperature: 160 °C
Yield: 45.3 %

Procedure:
A mixture of methyl 3-amino-5-phenylthiophene-2-carboxylate (2.50 g, 10.7 mmol), 3.5 mL of N-methylpiperazine and 12 mL of N-methylpyrrolidinone is heated at 160° C. for 4 hours. The reaction mixture is cooled to room temperature and poured into 100 mL of water. The solids are collected by filtration washing with 50 mL of water. Ethyl acetate and hexane are added and the filtrate is decanted off from the gummy black residue. The filtrate is concentrated to provide 850 mg of 5-phenyl-3-thienylamine as a yellow solid, mp 76–78° C.; 1H NMR (DMSO-d6) δ 4.87 (s, 2H), 5.98 (d, J=1.5 Hz, 1H), 6.95 (d, J=1.5 Hz, 1H), 7.28 (m, 1H), 7.37 (t, J=7 Hz, 2H), 7.53 (d, J=7 Hz, 2H); MS 176.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[S:12][N:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:9]=1[C:16]#[N:17]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH:1]1([C:4]([NH:7][C:8]2[S:12][N:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:9]=2[C:16]#[N:17])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)c1nsc(N)c1C#N
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)c1nsc(NC(=O)C2CC2)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.5 g of cyclopropanecarbonyl chloride in 30 ml of toluene are added dropwise to a solution of 16.7 g of 5-amino-4-cyano-3-isopropylisothiazole and about 0.5 g of DMAP (N,N-dimethylaminopyridine) in 200 ml of toluene and 200 ml of pyridine. The solution is stirred for 16 hours at room temperature and then evaporated to dryness, and the residue is taken up in ethyl acetate. The organic phase is extracted with aqueous sodium bicarbonate solution and 10% strength hydrochloric acid and is dried and evaporated down.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.C=O.[C:20](O)(=O)C.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][N:13]([CH3:20])[CH2:12]3)[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: Brc1ccc2c(c1)CCCCN2C1CCNC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(N2CCCCc3cc(Br)ccc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
A solution of compound 4 (0.79 g, 2.68 mmol) in anhydrous methanol (10 mL) was treated with formaldehyde (37% in H2O, 0.26 g, 3.22 mmol) followed by acetic acid (0.38 mL, 6.707 mmol) and NaCNBH3 (0.20 g, 3.22 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight (16 h). The reaction was basified with 2 N NaOH (50 mL) and the product extracted into CH2Cl2 (2×25 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (CH2Cl2, followed by 2 N NH3 in MeOH:CH2Cl2, 5:95) to give compound 5 (0.74 g, 90%) as a brown solid. 1H NMR (DMSO-d6) δ 1.48-1.49 (m, 2H), 1.59-1.72 (m, 3H), 2.22 (s, 3H), 2.54-2.66 (m, 5H), 2.89-2.90 (m, 2H), 3.33 (brs, 2H), 3.90-3.94 (m, 1H), 6.78 (d, 1H, J=8.5 Hz), 7.20 (dd, 1H, J=2.5, 8.5 Hz), 7.26 (d, 1H, J=2.5 Hz); ESI-MS (m/z, %): 311 (MH+, 97), 309 (100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[CH2:21]([N:24]=[C:25]=[O:26])[CH:22]=[CH2:23]>CN(C=O)C>[CH2:21]([NH:24][C:25]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:26])[CH:22]=[CH2:23]
Reactant: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: C=CCN=C=O
Solvent: CN(C)C=O
Product: C=CCNC(=O)NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
A solution of 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (50 mg, 0.16 mmol) in anhydrous DMF (1 mL) was treated with allyl isocyanate (21 mg, 0.25 mmol), shaken at room temperature for 4 h, treated with tris-(2-aminoethyl)amine polystyrene (0.20 g, 0.75 mmol), shaken at 35° C. for 16 h, treated with polystyrene methylisocyanate (0.22 g, 0.32 mmol) and DMF (2 mL) and shaken for a further 6 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound (55 mg, 86%) as a yellow solid.
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].[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22](O)[CH:21]=[CH:20]2.C(N(CC)CC)C>ClCCl.O>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=2)[CH:23]=1)(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2cc(Br)ccc2c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Temperature: -10 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Triflic anhydride [(CF3SO2)2O, 1.8 ml, 3.03 g, 10.8 mmol] was added to a solution of 6-bromo-2-naphthol (2 g, 9.0 mmol) and triethylamine (NEt3) (1.52 ml, 1.09 g, 10.8 mmol) in dichloromethane (CH2Cl2) (40 ml) and under inert atmosphere at −10° C. After 2 h of stirring at −10° C., the reaction mixture was diluted in H2O (50 ml) and extractions with CH2Cl2 (3×40 ml) were carried out. The joined organic phases were washed with aq HCl (50 ml, 0.1 M), followed with H2O (50 ml) and were dried on Na2SO4. The filtration, evaporation and purification by column chromatography (SiO2, CH2Cl2) gave the title compound (3.25 g) as a colourless oil. IR (KBr) 3090, 1590, 1501, 1425, 1363, 1251, 1212, 1182, 1141, 1111, 1065, 960, 915, 882, 850, 801, 786, 767, 714, 653 y 609. M/Z (IQ, NH3) 356 [M+(81Br), 53%], 354 [M+ (79Br), 63], 223 [M-SO2CF3+ (81Br), 63] y 221 [M-SO2CF3+ (79Br), 100].
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>CN(C=O)C>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][CH3:15]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCN(CCC)CCCCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
The compound (152.5 mg) obtained in Example 24-1 was dissolved in anhydrous DMF (6.1 ml) and added with cesium carbonate (299.0 mg) and 4-bromomethyl-benzonitrile (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (184.0 mg). The whole was stirred overnight at 60° C. and then stirred at 80° C. for additional 24 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with water, subjected to extraction with chloroform, and dried with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (88.8 mg) as a colorless oily substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: c1cnc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2ccc3ncccc32)cc1
Temperature: 60 °C
Yield: 61.2 %

Procedure:
A solution of 1H-pyrrolo[3,2-b]pyridine (1.30 g, 9.42 mmol) in DMF (15 ml) was treated with sodium hydride (60% in mineral oil, 434 mg, 11.3 mmol) at r.t. until effervescence ceased. After cooling to 0° C. benzyl bromide (1.68 ml, 14.1 mmol) was added and the reaction warmed at 60° C. overnight. The reaction mixture was partitioned between water and EtOAc (50 ml each) and extracted with EtOAc (50 ml). The combined organics were washed with brine (20 ml), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a brown oil (1.20 g, 58%). δH (CDCl3) 8.39 (1H, d, J 4.4 Hz), 7.48 (1H, d, J 8.2 Hz), 7.30 (1H, d, J 3.1 Hz), 7.26-7.18 (3H, m), 7.04-6.69 (3H, m), 6.67 (1H, d, J 4.4 Hz), 5.11 (2H, s). LCMS (ES+) RT 1.56 ml 209 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[S:3][CH:4]=[C:5]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH3:23])[N:6]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(Br)n1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 310D using 1-[(2-bromo-1,3-thiazol-4-yl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 311B) and [3,5-difluorophenyl]boronic acid: MS (ES) m/z 434 (M+1).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][N:24]2[C:36]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH:16]=1>CO>[ClH:1].[ClH:1].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][N:24]2[C:36]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccccc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Oc1ccccc1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 91 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 4-tert-butyl 1-phenyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate TFA salt (108.2 mg, 0.205 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 72.3 mg (91%) of the desired product as a white solid. LC-MS: RT=3.89 min, [M+H]+=314.1.