Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:34])[C@H:7]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH2:19]2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])C.Cl.CCOCC>O1CCOCC1>[CH3:24][CH:22]([N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C@H:7]([C:6]([OH:34])=[O:5])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=3)(=[O:11])=[O:10])=[CH:13][CH:14]=2)[CH2:19]1)[CH3:23]
Reactant: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C(C)C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)N1CCc2ccc(S(=O)(=O)N[C@@H](Cc3cccc(C#N)c3)C(=O)O)cc2C1
Reaction time: 2.5 h
Yield: 83.3 %

Procedure:
1M Aqueous sodium hydroxide solution (6.0 ml, 6 mmol) was added to a stirred solution of N-[2-(2-propyl)-1,2,3,4-tetrahydroisoquinoline-7-sulphonyl]-3-cyano-(S)-phenylalanine ethyl ester (Preparation 25; 1.0 g, 2.19 mmol) in 1,4-dioxan (6.0 ml). After 2.5 hours at room temperature, the reaction mixture was neutralised using 1M hydrochloric acid (6.0 ml) and evaporated to dryness under reduced pressure. The residue was extracted successively with dichloromethane and a mixture of dichloromethane:2-propanol (9:1), then the combined extracts evaporated under reduced pressure to provide a material which, on trituration with ether, gave the title compound as a white powder (780 mg). Rf 0.06 (SS 3). m/e 428 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]3[N:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]3=[N:13][C:12]=2[C:26]#[C:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)=[CH:7][CH:6]=1.[CH3:40][Mg]Br>C1COCC1>[O:23]1[CH2:22][CH2:21][N:20]([C:19]2[C:14]3[N:15]([C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:4](=[O:38])[CH3:40])=[CH:10][CH:9]=4)=[C:12]([C:26]#[C:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[N:13]=3)[N:16]=[CH:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of compound 65a (140 mg, 0.270 mmol) in 10 mL of THF at 0° C. was added methylmagnesium bromide (0.270 mL, 0.810 mmol, 3.0 M in Et2O) dropwise under an Argon atmosphere. After stirring at 0° C. for 1 h, the reaction was quenched with 2 mL of saturated NH4Cl. The mixture was treated with 50 mL of EtOAc and washed with water (25 mL), brine (25 mL) and then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0:1-1:4 EtOAc/DCM) to afford the title compound 159 as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.09-8.22 (m, 2H), 8.00 (s, 1H), 7.77-7.93 (m, 3H), 7.44-7.59 (m, 2H), 6.43 (d, J=5.6 Hz, 1H), 5.99 (d, J=6.1 Hz, 2H), 5.81 (s, 1H), 5.71 (s, 1H), 4.06 (br. s., 4H), 3.99 (s, 3H), 3.86 ppm (br. s., 4H). Mass spectrum (ESI, m/z): Calcd. for C29H25N5O4, 508.2 (M+H). found 508.5.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19]1[C:24]([C:25]#[C:26][CH3:27])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.[ClH:29]>C(Cl)Cl>[ClH:29].[C:25]([C:24]1[C:19]([C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)[NH2:7])=[N:20][CH:21]=[CH:22][CH:23]=1)#[C:26][CH3:27]
Reactant: CC#Cc1cccnc1[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Product: CC#Cc1cccnc1[C@@H](N)c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a round bottom flask containing (S)-tert-butyl((3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate (400 mg, 1.025 mmol) was added DCM (8 mL). The resulting mixture was stirred at 23° C. for 2 min. Hydrogen chloride (4 mL, 4 N in 1,4-dioxane) was then added via syringe. The reaction was then stirred for 3 h and then the volatiles were removed via rotary evaporator. The solid was placed on high vacuum overnight to give (S)-(3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([S:7]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: CN1CCN(S(=O)(=O)c2ccc(Cl)s2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.8 %

Procedure:
To a stirred solution of commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) in pyridine (10 mL) was added at room temperature commercially available 1-methylpiperazine (0.46 g, 4.61 mmol). The reaction mixture was stirred at room temperature for 1 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/methanol) to yield the title compound (0.92 g, 63%) as an off-white solid. MS (ISP) 280.9 [(M+H)+], mp 242° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:26][CH2:25]C2[C:19](=CC=CC=2)[CH2:18]1.Cl.CC1N(C2N=CC=CN=2)N=CC=1/C=C/CN1CCC2C(=CC=CC=2)C1.Cl.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[N:62]1CCNCC1>>[ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[F:55])[CH2:25][CH2:26]1
Reactant: Cc1c(C(=O)CCN2CCc3ccccc3C2)cnn1-c1ncccn1
Reactant: Fc1ccccc1N1CCNCC1
Agent: Cc1c(/C=C/CN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: Cl
Product: Cc1c(/C=C/CN2CCN(c3ccccc3F)CC2)cnn1-c1ncccn1

Procedure:
The procedures of Example 6 (1) and (2) were repeated but substituting the 1,2,3,4-tetrahydroisoquinoline hydrochloride employed in Example 6 (1) by 1-(2-fluorophenyl)piperazine hydrochloride. After the completion of the post treatment, the title compound was obtained.
Reaction SMILES: C([NH:3][CH:4]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)=O.S(=O)(=O)(O)O>C(O)C.O1CCCC1.O>[NH2:3][CH:4]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)COc1ccc(CCC(NC=O)c2cccnc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COc1ccc(CCC(N)c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
In a mixed solvent of 4 ml of ethanol, 4 ml of tetrahydrofuran, and 4 ml of water was dissolved 150 mg of ethyl 4-[3-formamido-3-(3-pyridyl)propyl]phenoxyacetate, followed by addition of 0.15 ml of conc. sulfuric acid, which was then heated to 60° C. and stirred for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, followed by addition of methanol-methylene chloride (5:95 v/v) and water. While stirring, the property of the solution was adjusted to weak alkalinity with gradual addition of saturated aqueous sodium hydrogencarbonate solution. After separation of the organic phase, which was then extracted with methanol-methylene chloride (5:95 v/v) from the aqueous phase and washed in saturated aqueous sodium chloride followed by drying over magnesium sulfate and distillation of the solvent, 50 mg of ethyl 4-[3-amino-3-(3-pyridyl)propyl]phenoxyacetate was obtained.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=[C:30]=[O:31])=[CH:26][CH:25]=1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:30]([NH:29][CH2:28][C:27]4[CH:32]=[CH:33][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[O:31])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: COc1ccc(CN=C=O)cc1
Product: COc1ccc(CNC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1

Procedure:
The title compound, MS: m/e=439.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 4-methoxybenzyl isocyanate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=[C:13]([NH2:24])[N:12]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][OH:34]>CN(C=O)C>[NH2:24][C:13]1[N:12]=[C:11]([C:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:10][N:9]=2)[N:16]=[C:15]([N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:32][CH2:33][OH:34])[N:14]=1
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3ccco3)n2)n1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2noc(-c3ccco3)n2)nc(N(CCO)c2ccccc2)n1
Reaction time: 18 h
Yield: 12 %

Procedure:
6-(5-Furan-2-yl-[1,2,4]oxadiazol-3-yl)-N-phenyl-[1,3,5]triazine-2,4-diamine (prepared in an analogous manner to Example 2, 100 mg, 310 μmol) and potassium carbonate (86 mg, 620 μmol) were stirred together in a sealed tube in DMF (5 ml). 2-Bromoethanol (26 μL, 310 μmol) was added and the reaction was heated at 110 C for 18 h. Potassium carbonate (43 mg, 310 μmol) and 2-bromoethanol (26 μL, 310 μmol) were added and the reaction stirred at 110 C for a further 18 h. After cooling and evaporation of the solvent the crude residue was dissolved in water (30 mL) and extracted twice with DCM (30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was purified using prep HPLC method B to give the desired title compound (14 mg, 12%).
Reaction SMILES: C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH:8]([C:11]1[C:16]2[C:17](=[O:32])[N:18]([C:22]3[C:27]([F:28])=[C:26]([F:29])[N:25]=[C:24]([F:30])[C:23]=3[F:31])[S:19](=[O:21])(=[O:20])[C:15]=2[CH:14]=[C:13]([O:33]C)[CH:12]=1)([CH3:10])[CH3:9].Cl>C(Cl)(Cl)Cl>[CH:8]([C:11]1[C:16]2[CH2:17][N:18]([C:22]3[C:27]([F:28])=[C:26]([F:29])[N:25]=[C:24]([F:30])[C:23]=3[F:31])[S:19][C:15]=2[CH:14]=[C:13]([OH:33])[CH:12]=1)([CH3:10])[CH3:9].[S:19]1(=[O:20])(=[O:21])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:16]=2[C:17](=[O:32])[NH:18]1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(c1c(F)c(F)nc(F)c1F)C2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCS
Product: CC(C)c1cc(O)cc2c1CN(c1c(F)c(F)nc(F)c1F)S2
Product: O=C1NS(=O)(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.7 %

Procedure:
Ethanethiol (0.82 ml, 11.26 mmol) was added to a suspension of aluminium chloride (0.99 g, 7.42 mmol) in chloroform (20 ml) at 0° C. The mixture was stirred for 10 minutes then a solution of 4-isopropyl-6-methoxy 2-(2,3,5,6-tetrafluoro-4-pyridyl) 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (0.5 g, 1.73 mmol) in chloroform (10 ml) was added. The mixture was stirred at room temperature for 2-3 hours, then at reflux for 48 hours. The mixture was then cooled, poured over ice-water, acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water, then brine, and then was dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 40% ethyl acetate/hexane to afford 0.3 g (62%) of 4-isopropyl-6-hydroxy-2-(2,3,5,6-tetrafluoro-4-pyridyl)-1,2-benzisothiazol-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, m.p. 164.5°-165.5° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22].[Li]CCCC.CCCCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1.[NH4+].[Cl-]>C(OCC)C.C1(C)C=CC=CC=1>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[F:50])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Br)c(C)nc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3F)c(C)nc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 9.2 %

Procedure:
50 mg of 3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.11 mmol) is dissolved in 4 ml of diethylether and cooled to −78° C. and 0.1 ml of n-BuLi 1.6M in hexane (0.16 mmol) is added at −78° C. and stirred at −78° C. for 20 min. 104 mg of N-fluorobenzene sulfonimide (0.33 mmol) in 2 ml of toluene is added at −78° C. and stirred at room temperature for 1 h. sat. NH4Cl is added, and the mixture is extracted with Et2O, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 4.1 mg of the title compound. Yield 10%. Mass spectrum (m/e): 404 (M+1). 6.71 (s, 1H), 3.87 (t, J=4.6 Hz, 4H), 3.55 (t, J=5.0 Hz, 4H), 3.34 (m, 1H), 2.58 (s, 3H), 2.54 (s, 3H), 1.84 (m, 4H), 0.88 (t, J=7.4 Hz, 6H).
Reaction SMILES: C(O)(C)C.[NH3:5].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=4)=[CH:20][CH:21]=3)[N:16]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](S(C)=O)[N:33]=3)[CH:15]=2)=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=4)=[CH:20][CH:21]=3)[N:16]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH2:5])[N:33]=3)[CH:15]=2)=[CH:10][CH:9]=1
Reactant: N
Reactant: COc1ccc(-c2cn(-c3ccnc(S(C)=O)n3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1
Solvent: CC(C)O
Product: COc1ccc(-c2cn(-c3ccnc(N)n3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2.0 M ammonia isopropanol solution (2 mL) was added to 3-(4-methoxyphenyl)-1-(2-(methylsulfinyl)pyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (90 mg) and then stirred at 100° C. for 3 hours in a sealed state. After cooling to room temperature, thus produced solid was filtered. After washing with isopropanol and then drying, the target compound (50 mg) was obtained as white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][C:14](O)=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12].C(OCC)(=O)C.O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[C:3]([CH2:13][CH2:14][OH:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12]
Reactant: COc1c(F)c(CC(=O)O)cc2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1c(F)c(CCO)cc2ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
In 8.1 mL of tetrahydrofuran is dissolved 1.42 g of 2-(6-fluoro-7-methoxybenzo[b]thiophen-5-yl)-acetic acid. At an ice-cooled temperature, 4.8 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is added to the solution obtained above, and the resulting mixture is stirred at ambient temperature for 2 hours. Ethyl acetate and water are added to the reaction mixture, pH is adjusted to 10 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.72 g of 2-(6-fluoro-7-methoxybenzo[b]thiophen-5-yl)-1-ethanol is obtained as an oily product.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1[F:40]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1[F:40])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(O)c1ccc(CBr)c(F)c1
Product: O=C(O)c1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(F)c1

Procedure:
The title compound was prepared from 3-(3-Benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 4-Bromomethyl-3-fluoro-benzoic acid following the procedure of Example 478: MS m/z 532; MS m/z 530; HRMS: calcd for C31H21F4NO3+H+, 532.15303; found (ESI, [M+H]+), 532.153;
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O-:16].[Na+].CO>O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:16][CH3:15])=[N:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2nccnc2Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nccnc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Next, 3.87 g of 2-chloro-3-(4-fluorophenyl)pyrazine, 2.01 g of sodium methoxide, and 30 mL of methanol were put in a three-neck flask equipped with a reflux pipe, and reacted by being heated and refluxed under a nitrogen atmosphere for three hours. After the reaction, the reaction solution was cooled down to room temperature, water was added thereto, and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated saline and water, and dried with magnesium sulfate. Then, magnesium sulfate was removed by filtration and the solvent was distilled off, so that 2-(4-fluorophenyl)-3-methoxypyrazine was obtained (milky white powder, yield: 96%). A synthetic scheme of Step 2 is shown in the following (a1-2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]([F:37])([F:36])[CH2:34]I.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:34][C:33]([F:37])([F:36])[F:32]
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OCC(F)(F)F
Temperature: 80 °C

Procedure:
A 0.15 g quantity of the N-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 17 and 0.18 g of potassium carbonate were dissolved in 4 ml of dimethylformamide, and 0.19 g of 1,1,1-trifluoro-2-iodoethane was added thereto. The mixture was stirred with heating at 80° C. overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. The extract was washed with water twice, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.11 g of white powdery N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-methylpicolinamide.
Reaction SMILES: [Mg].Br[CH2:3][CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][N:7]=1.II>O1CCCC1.C(COC)OC.C(N(CC)CC)C>[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([F:13])=[C:8]([CH2:3][CH3:4])[N:7]=1
Reactant: CCBr
Reactant: Fc1cnc(Cl)nc1Cl
Agent: II
Agent: [Mg]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCc1nc(Cl)nc(Cl)c1F
Temperature: 15 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a stirred mixture of magnesium turnings (12.1 kg) in tetrahydrofuran (161 L) was added a solution of bromoethane (54.3 kg) in tetrahydrofuran (53 L) maintaining the reaction temperature below 50° C. during the addition. The solution of the Grignard reagent was cooled to 0° C. and a solution of the compound of part (i) (56 kg) in dimethoxyethane (170 L) added, maintaining the reaction temperature below 15° C. during the addition. The reaction was stirred for 1 hour at 15° C. and cooled to 0° C. A solution of triethylamine (34 kg) in tetrahydrofuran (70 L) was added, maintaining the reaction temperature at about 5° C., followed by a solution of iodine (85 kg) in tetrahydrofuran (256 L), maintaining the reaction temperature below 15° C. The reaction was then quenched with water (840 L), maintaining the reaction temperature below 25° C. The pH was adjusted to 1 using 5N aqueous hydrochloric acid solution (50 L) and the mixture extracted with toluene (1×490 L followed by 1×210 L). The combined organic layers were washed with 2% w/w aqueous sodium metabisulphite solution (700 L) then water (700 L) added and the remaining tetrahydrofuran removed by distillation under reduced pressure. The mixture was cooled, the organic layer separated, washed with water (425 L) and then concentrated under reduced pressure to provide the product as an oil (50 kg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4[CH:36]=[CH:35][C:30]5[N:31]=[C:32]([CH3:34])[NH:33][C:29]=5[CH:28]=4)[N:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.CO.C(OCC)C>[CH3:34][C:32]1[NH:33][C:29]2[CH:28]=[C:27]([NH:26][C:22]3[N:21]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[N:15][CH:16]=4)[CH:25]=[CH:24][N:23]=3)[CH:36]=[CH:35][C:30]=2[N:31]=1
Reactant: Cc1nc2ccc(Nc3nccc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)n3)cc2[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2ccc(Nc3nccc(-c4ccc(N5CCNCC5)nc4)n3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
A solution of 4-(2-(4-tert-butoxycarbonylpiperazin-1-yl)pyrid-5-yl)-N-(2-methylbenzimidazol-5-yl)-2-pyrimidineamine (70 mg, 0.14 mmol) in a mixture of dichloromethane (5 ml) and methanol (3 ml) was treated with hydrogen chloride (5 ml of a 1M solution in diethyl ether, 5.00 mmol) then stirred for 18 h at room temperature. The precipitate which formed was collected by filtration then subjected to column chromatography (silica, 0.88 ammonia solution-methanol-dichloromethane, 1:5:94) to afford the title compound (19 mg) as a yellow solid m.p. 245-250°. δH (d6DMSO) 2.45 (3H, s), 2.80 (4H, m), 3.38 (4H,m), 6.91 (1H, d, J 9.0 Hz), 7.24 (1H, d J 5.2 Hz), 7.35 (2H, s), 8.11 (1H, s), 8.25 (1H, m), 8.39 (1H, d, J 5.2 Hz), 8.93 (1H, d, J 2.2 Hz), 9.41 (1H, br s) and 11.50 (1H, br s).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.ClCCCl>[C:19]([N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:3][C@@H:2]1[CH3:1])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2ccccc2N1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(=O)N1c2ccccc2N(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 50 °C
Yield: 99.6 %

Procedure:
A 40 mL reaction vial was charged with (S)-tert-butyl 3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.3 g, 1.21 mmol) and 1,2-dichloroethane (10 mL). 4-Dimethylaminopyridine (DMAP) (0.030 g, 0.242 mmol) was added as a solid followed by the addition of acetic anhydride (0.456 ml, 4.83 mmol). The reaction mixture was heated to 50° C. for 16 h on a heater shaker. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The organic layer was removed and set aside. The aqueous layer was washed with another portion of ethyl acetate (20 mL) and the organic layers were combined and concentrated under reduced pressure to yield (S)-tert-butyl 4-acetyl-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.35 g) which was used without further purification. MS (ESI, Na+ ion) m/z 313 [M+1]+.