Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([OH:40])=O)[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:75][CH:76]([CH3:79])[CH2:77][NH2:78]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([NH:78][CH2:77][CH:76]([OH:75])[CH3:79])=[O:40])[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCC(CC(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)CNC(=O)CC1CCN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of rac {1-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (77 mg, 0.28 mmol) and DIPEA (94 uL, 0.54 mmol) were added followed by 2-hydroxy-2-methyl-ethylamine (Aldrich, 20 mg, 0.27 mmol) and the mixture was stirred at rt for hers. The reaction was quenched with water and the mixture was extracted with methylene chloride (3×10 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 48 mg.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7]([CH3:26])=[C:6]2[CH2:27][C:28]([OH:30])=[O:29].[CH2:31](OC(=O)CC1C2C(=CC=C(OC)C=2)N(CCCCCCCCCCCCCC)C=1C)C.[OH-].[Na+].Cl>CO>[CH3:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7]([CH3:26])=[C:6]2[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCCCCCCCCCCCCCn1c(C)c(CC(=O)OCC)c2cc(OC)ccc21
Reactant: CCCCCCCCCCCCCCn1c(C)c(CC(=O)O)c2cc(OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCn1c(C)c(CC(=O)O)c2cc(C)ccc21
Yield: 90 %

Procedure:
5-Methoxy-2-methyl-1-tetradecyl-1H-indole-3-acetic acid. A solution of 1.60 g (3.6 mmol) of 5-methoxy-2-methyl-1-tetradecyl-1H-indole-3-acetic acid ethyl ester and 10 mL of 1N NaOH in 25 mL of MeOH was stirred 16 hours, made acidic with 1N HCl, and the precipitate filtered valve 1.36 g (90% yield) of 5-methyl-2-methyl-1-tetradecyl-1H-indole-3-acetic acid, mp, 105-107° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])[CH:8]=[C:7]2[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)c1c[nH]c2ccc(Br)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cn([Si](C)(C)C(C)(C)C)c2ccc(Br)cc12
Yield: 88.9 %

Procedure:
0.50 g (12.6 mmol) of 60% strength sodium hydride in paraffin oil is introduced under argon into 20 ml of THF at room temperature. A solution of 2.0 g (8.40 mmol) of 5-bromo-3-isopropyl-1H-indole (Example X) in 20 ml of THF is added dropwise and the mixture is stirred until evolution of gas can no longer be detected. 2.03 g (13.44 mmol) of tert-butyl(chloro)dimethylsilane are subsequently added dropwise. After a short reaction time a precipitate deposits. The batch is stirred for 3 h at room temperature. It is treated with 200 ml of water. The aqueous phase is extracted twice with ethyl acetate, and the combined org. phases are dried and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (eluent: cyclohexane). 2.63 g (89%) of 5-bromo-1-[tert-butyl(dimethyl)silyl]-3-isopropyl-1H-indole are obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=2)[C@@H:11]([C:44]2[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[C:17]([F:43])[CH:16]=2)[C@@H:11]([C:44]2[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](OCc4ccccc4)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 81.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*,4S*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (143 mg, 0.207 mmol) prepared in Example 98b, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (91 mg, 81%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:17])[CH:14]=[CH:15][CH3:16])=[CH:5][CH:4]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:17])[CH2:14][CH:15]([CH3:16])[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: CC=CC(=O)c1ccc(OC)c2c1CCCC2
Reactant: C1CCNC1
Solvent: CCO
Product: COc1ccc(C(=O)CC(C)N2CCCC2)c2c1CCCC2
Yield: 58.8 %

Procedure:
A solution of 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-2-butene-1-one (3.0 g) and pyrrolidine (1.85 g) in ethanol (100 ml) was stirred for 3 hours at room temperature. The mixture was evaporated in vacuo to give the residue. The residue was partitioned into water and ethyl ether. The ethyl ether was washed with water. The organic layer was extracted with 2N hydrochloric acid. The aqueous layer was neutralized with ammonia water and then extracted with ethyl ether. The ethyl ether was dried over anhydrous magnesium sulfate and then filtered. The filtrate was evaporated in vacuo to give 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-3-methyl-3-pyrrolidino-1-propanone (2.31 g, Yield: 53.6%) as an oil. ##STR341##
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Si](OCCC[C@H:33]1[O:37][C:36](=[O:38])[C@H:35]([S:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:34]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)C>[O:38]=[C:36]1[CH:35]([S:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:9])[CH:34]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:33][O:37]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](OCCC[C@H]1OC(=O)[C@H](Sc2ccccc2)[C@H]1c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1OCC(c2ccccc2)C1S(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
m-Chloroperbenzoic acid (242 mg) was added to a solution of (3R*,4S*,5R*)-5-[3-(t-butyldiphenylsilyloxy)propyl] -2-oxo-4-phenyl-3-phenylthiotetrahydrofuran in dichloromethane (10 ml) at 0° C. and the resulting mixture was stirred at 0° C. for 30 minutes. The resulting mixture was poured into a mixture of diethyl ether, aqueous sodium bisulfite and aqueous sodium bicarbonate. The organic layer was separated, washed with water and brine successively, dried over ( magnesium sulfate, and evaporated in vacuo to give (3R*,4S*,5R*)-5-[3-(t-butyldiphenylsilyloxy)propyl]-2(oxo-4-phenyl-3-phenylsulfinyltetrahydrofuran (537 mg) as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[C:5]([CH3:24])[C:6]([O:22][CH3:23])=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]([F:33])([F:32])[C:27]1[CH:31]=[CH:30][NH:29][N:28]=1.ClC1C(OC)=CC=C2C=1N=C(N1C=CC(C(F)(F)F)=N1)C=C2OCC1C=CC(OC)=CC=1>>[CH3:23][O:22][C:6]1[C:5]([CH3:24])=[C:4]2[C:9]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:11][C:2]([N:29]3[CH:30]=[CH:31][C:27]([C:26]([F:33])([F:32])[F:25])=[N:28]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Agent: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)cc1
Product: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(C)c(OC)ccc23)cc1
Yield: 19 %

Procedure:
7-Methoxy-4-(4-methoxy-benzyloxy)-8-methyl-2-(3-trifluoromethyl-1H-pyrazol-1-yl)-quinoline 234c was synthesized from compounds 221b and 233a, following the procedure as described for compound 234a, as a white solid in 19% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.64 (s, 3H), 3.86 (s, 3H), 3.99 (s, 3H), 5.33 (s, 2H), 6.75 (d, J=2.58 Hz, 1H), 6.98 (d, J=8.78 Hz, 2H), 7.20 (d, J=9.22 Hz, 1H), 7.48 (d, J=8.78 Hz, 2H), 7.57 (s, 1H), 8.07 (d, J=9.08 Hz, 1H), 8.88 (s, 1H).
Reaction SMILES: C(S([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]2[CH:18]=[C:19]([C:22]3[C:23]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[N:24][N:25]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[CH:20]=[CH:21][C:8]=2[N:7]=1)(=O)=O)C.[H-].[Na+].[CH3:55][C:56]1[C:61]([OH:62])=[CH:60][CH:59]=[CH:58][N:57]=1.O>CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:9]3[CH:18]=[C:19]([C:22]4[C:23]([C:46]5[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=5)=[N:24][N:25]([C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:26]=4)[CH:20]=[CH:21][C:8]=3[N:7]=[C:6]2[O:62][C:61]2[C:56]([CH3:55])=[N:57][CH:58]=[CH:59][CH:60]=2)=[CH:12][CH:13]=1
Reactant: CCS(=O)(=O)c1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Reactant: Cc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
40 mg 2-(ethylsulfonyl)-1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazole obtained in Example 138 was dissolved in 2 mL N,N-dimethylformamide, then 6.8 mg sodium hydride was added thereto and stirred for 20 minutes, and 3 mL 2-methyl-3-pyridinol was added thereto and stirred at 80° C. for 3 hours. Water was added thereto, and the reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-2-[(2-methyl-3-pyridyl)oxy]-1H-benzo[d] imidazole. This product was subjected to deprotection of the trityl group by the same method as in Example 84 and then purified by NAM silica gel chromatography (ethyl acetate/methanol), to give 6 mg of the title compound as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=[C:9]2[CH:8]=1)=[O:6])[CH3:3].C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH2:38]([C:40]1[C:48]2[C:47]([NH2:49])=[CH:46][CH:45]=[CH:44][C:43]=2[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[N:52]=2)[N:41]=1)[CH3:39]>CN1C(=O)CCC1>[CH2:38]([C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][C:47]=2[NH:49][C:16]([C:13]2[N:10]3[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][C:9]3=[N:15][CH:14]=2)=[O:18])[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[N:52]=2)[N:41]=1)[CH3:39]
Reactant: CCOC(=O)c1ccn2c(C(=O)O)cnc2c1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(N)c12
Agent: Cl
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To 7-(ethoxycarbonyl) imidazo[1,2-a]pyridine-3-carboxylic acid hydrochloride (501 mg, 1.85 mmol) in NMP (10 mL) was added triethylamine (468 mg, 4.63 mmol). The suspension turned into a clear solution. 2,4,6-trichlorobenzoyl chloride (474 mg, 1.94 mmol) was added dropwise to the reaction mixture. A milky suspension resulted after 10 minutes. The mixture was stirred for another 30 minutes. 3-Ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (444 mg, 1.67 mmol) was added in one portion to the reaction mixture. The mixture was sealed and heated to 75° C. for 3 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure to remove NMP. The residue was diluted with EtOAc/H2O (20 mL/10 mL). The organic phase was washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. Silica gel chromatography (EtOAc/Hexane 5:1 to 10:1) provided the final product (665 mg). MS (ES+APCI) m/z=483 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])=[O:10])=[C:7]([CH:20]([CH3:22])[CH3:21])[C:6](=[O:23])[NH:5][C:4]1=[O:24])[CH3:2].[H-].[Na+].Br[CH2:28][O:29][C:30](=[O:32])[CH3:31]>CN(C=O)C.O>[C:30]([O:29][CH2:28][N:5]1[C:6](=[O:23])[C:7]([CH:20]([CH3:21])[CH3:22])=[C:8]([C:9](=[O:10])[C:11]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[N:3]([CH2:1][CH3:2])[C:4]1=[O:24])(=[O:32])[CH3:31]
Reactant: CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reactant: CC(=O)OCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)n(COC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 3-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile (778 g, 2.39 mol) in anhydrous DMF (5 L) was added 60% NaH (115 g) portion-wise over 30 min at 0° C. The reaction mixture was stirred at room temperature for 3 hours and then the mixture was cooled to −10° C. Acetic acid bromomethyl ester (321 mL) was dropwise added to the reaction mixture for 2 hours at the same temperature and the reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (10 L). The precipitate was collected by filtration, washed with water (5 L) and then dissolved in dichloromethane (10 L). The organic solution was washed with water (4 L), dried with anhydrous magnesium sulfate (1 kg) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/dichloromethane, 1:20) to give (4-(3-cyano-5-methylbenzoyl)-3-ethyl-5-isopropyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl acetate (745 g, 1.87 mol, 79%) as a white solid.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[N:25][NH:26][CH:27]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC1(C)C
Yield: 45.7 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (291 mg, 1.50 mmol), sodium carbonate (265 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (2.5 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL), and the mixture was shaken well. The insoluble materials were filtered off. From the filtrate, the organic layer was collected, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc, then EtOAc to 90:10 EtOAc/MeOH) to afford a white solid (60 mg). This solid was triturated with EtOAc/hexane and collected by filtration to afford the title compound (50.3 mg, 38%) as a white solid:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]=[CH:7]1)=[O:5])[CH3:2].CCOC(C)=O>[Pd].CO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C=Cc2ccsc2C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2ccsc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A mixture of 6-ethoxycarbonyl-6,7-dihydrobenzo[b]thiophene (1.00 g), 10% palladium on carbon (2.16 g), AcOEt (30 ml) an, MeOH (10 ml) was stirred at r.t. under hydrogen atmosphere for 4 hours. After removal of insoluble solids, the filtrate was concentrated in vacuo to give 6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.96 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]1OC2C=CC(N)=CC=2O1.ClC1N=C(Cl)C2C(=CC=CC=2)N=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: Clc1nc(Nc2ccc3c(c2)OCO3)c2ccccc2n1
Agent: Clc1nc(Cl)c2ccccc2n1
Product: CN(c1ccc2c(c1)OCO2)c1nc(Cl)nc2ccccc12

Procedure:
(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-amine: The title compound was prepared from 3,4-methylenedioxyphenylamine and 2,4-dichloroquinazoline by a procedure similar to example 1b and was isolated as solids (45% yield). 1H NMR (CDCl3): 7.81-7.83 (m, 3H), 7.51-7.56 (m, 2H), 7.44 (d, 1H, J=2.1), 6.98 (dd, 1H, J=2.1, 8.1), 6.82 (d, 1H, J=8.1), 6.01 (s, 2H).
Reaction SMILES: [CH2:1]=[CH2:2].[CH:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])([CH3:5])[CH3:4]>>[OH:15][C:13]1[CH:2]=[C:1]([C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:7]=2)[O:12][C:10](=[O:11])[C:9]=1[O:8][C:7]1[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=1[CH:3]([CH3:4])[CH3:5]
Reactant: C=C
Reactant: CC(C)c1ccccc1OC(C(=O)O)C(=O)O
Product: CC(C)c1ccccc1Oc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-trimethylsilyloxy)ethylene (2.62 g, 13.6 mmol) and diethyl ester of 2-(isopropyl)phenoxy propanedioic acid (2.0 g, 6.8 mmol). 1 H NMR (250 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.44 (m, 1H), 6.67 (d, 1H), 6.89 (s, 1H), 7.0 (t, 1H), 7.09 (t, 1H), 7.29 (d, 1H), 7.53 (m, 3H), 7.83 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)[N:15]=3)[C:11]([OH:33])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:34]([O:38][C:39](=[O:58])[N:40]([S:46]([C:49]1[CH:54]=[C:53]([Cl:55])[C:52](F)=[CH:51][C:50]=1[F:57])(=[O:48])=[O:47])[C:41]1[N:42]=[CH:43][S:44][CH:45]=1)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[C:34]([O:38][C:39]([N:40]([C:41]1[N:42]=[CH:43][S:44][CH:45]=1)[S:46]([C:49]1[C:50]([F:57])=[CH:51][C:52]([O:33][C:11]2[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]4)[N:15]=3)=[CH:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[C:53]([Cl:55])[CH:54]=1)(=[O:48])=[O:47])=[O:58])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(-c4cccc(F)c4)ncc3O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(-c4cccc(F)c4)ncc3Oc3cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c4cscn4)cc3Cl)n2)CC1
Yield: 53.6 %

Procedure:
10.0 mg (1.0 eq) of the obtained tert-butyl 4-(4-(2-(3-fluorophenyl)-5-hydroxypyridin-4-yl)pyrimidin-2-yl)piperazin-1-carboxylate and 9.1 mg (1.0 eq) of the obtained tert-butyl((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate were dissolved in 0.2 mL of N,N-dimethylformamide 0.2 mL, then 21.6 mg (3.0 eq) of Cs2CO3 was added thereto. The mixture was reacted at room temperature for 16 hours. The solvent was removed by concentrating under reduced pressure. The residue was separated by PLC (developing solvent, hexane:ethyl acetate=2:1) to obtain 10 mg of tert-butyl 4-(4-(5-(4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-2-(3-fluorophenyl)pyridin-4-yl)pyrimidin-2-yl)piperazin-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>C(O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Yield: 87.4 %

Procedure:
A mixture of 4-fluoro-3-nitroaniline (30 g, 0.192 mol), di-t-butylcarbonate (84 g, 0.384 mol) was stirred in ethanol (300 mL) at r.t. for 1 week. The solvents were removed in vacuo and chromatographic purification (ethyl acetate-hexane) of the residue gave tert-butyl 4-fluoro-3-nitrophenylcarbamate (43 g, 88%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.O(CCCCCO)C1C=CC=CC=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>>[O:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCCCCCOc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: OCCCCCOc1ccccc1
Agent: [K+]
Product: c1ccc(OCCCCCOc2cncc(N3CCNCC3)n2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(5-phenoxypentyl)oxy]pyrazine (2.06 g, 7.03 mmol; obtained according to the procedure of example 50, step 1, starting from 5-phenoxy-1-pentanol*), piperazine (1.88 g, 21.8 mmol) and K2CO3 (0.97 g, 7.03 mmol). The yield of the title compound was 1.15 g (48%) which was obtained as a white solid. Purity 100% (HPLC). MS m/z 343 (M+H)+. HRMS m/z calcd for C19H26N4O2 (M)+ 342.2056, found 342.2054.