Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCO1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCO4)c23)C1
Temperature: 160 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (225 mg, 0.686 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (412 mg, 2.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (239 μL, 1.37 mmol) in n-BuOH (5 mL) was purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (101 mg, 0.199 mmol, 29.0% yield) as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:11]2[C:15]([CH3:16])=[C:14]([CH:17]([F:19])[F:18])[O:13][N:12]=2)=[CH:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1>[F:19][CH:17]([F:18])[C:14]1[O:13][N:12]=[C:11]([C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=2)[C:15]=1[CH3:16]
Reactant: CCOC(=O)c1ccc(-c2noc(C(F)F)c2C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)F
Reaction time: 20 h
Yield: 99.8 %

Procedure:
A solution of 5-(5-Difluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid ethyl ester (Preparative Example 25, 1.0 g, 3.48 mmol) in THF (20 mL) was treated with an aqueous solution (5 mL) of lithium hydroxide monohydrate (292 mg, 6.96 mmol) and allowed to stir for 20 hr. The reaction was then evaporated to a small volume and treated with a 1 N aqueous hydrochloric acid solution to a pH of ˜2 and the resulting solids filtered, washed with water and air dried to afford product as a colorless solid (900 mg, 99%). 1H NMR (DMSO-d6) 2.29 (s, 3H), 7.44 (t, J=51.9, 1 H), 7.66 (d, J=2.6, 1 H), 7.78 (d, J=2.6, 1 H). 13C NMR 7.7, 108.1 (t, J=236), 115.0, 130.3, 134.3, 134.5, 137.4, 157.8, 159.6 (t, J=26), 163.1. 19F NMR −118.8 (J=51.5). LC/MS 5.41 min, [M+1]+ 260.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[CH3:17][O:18][CH2:19][CH2:20]Cl>>[CH3:1][C:2]1[N:3]([CH2:20][CH2:19][O:18][CH3:17])[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: COCCCl
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: COCCn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-chloroethyl methyl ether: MS (ES) m/z 283 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35]O.[K+].[Br-].Cl>>[O:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][O:24][C:23]([C:18]1([C:20]([O:22][CH2:35][CH:31]2[CH2:32][CH2:33][CH2:34][O:30]2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: OCC1CCCO1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1CCCO1)(C(=O)OCC1CCCO1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and tetrahydrofuran-2-ylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 1.1 (d, J=6.37 Hz, 3H, CH3), 1.43-1.6 (m, 2H, CH2) 1.65-1.8 (m, 4H, CH2), 1.98-2.0 (m, 2H, CH2), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 3.57-3.7 (m, 4H, CH2), 4.05 (m, 2H, CH2), 4.2 (m, 2H, CH2), 4.3 (m, 2H, CH2), 5.04 (m, 1H, CH), 6.34 (d, J=3.95 Hz, 1H, OH), 6.84 (dd, J=8.13, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.36-7.44 (m, 3H, Ar--H), 7.48 (s, 1H, Ar--H), 8.77 (brs, 1H, NH), 9.2 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 590 (M+H)+ ; Analysis for: C30H36ClNO9 ×HCl: Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 56.37; H, 5.90; N, 2.20.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3=[CH:13][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][C:16](=[O:17])[N:11]3[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH2:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>C1(C)C=CC=CC=1>[CH2:76]([NH:84][C:2]1[N:7]=[C:6]([N:8]2[C:12]3=[CH:13][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][C:16](=[O:17])[N:11]3[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1)[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCN2c1cncc(Cl)n1
Reactant: NCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccccc2)cc2n1CCN2c1cncc(NCCc2ccccc2)n1
Temperature: 70 °C

Procedure:
To a mixture of 1-(6-chloro-pyrazin-2-yl)-7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (85 mg, 0.26 mmol), sodium tert-butoxide (70 mg, 2.8 eq), BINAP (24 mg, 15% eq), and Pd (OAc)2 (9 mg, 15% eq) was added toluene (5 mL) and phenethylamine (39 μL, 1.2 eq). After purged with N2 for 10 min, the overall mixture was heated at 70° C. for 3 h prior to being cooled to room temperature. The resulting material was filtered through Celite and the filtrated cake was washed with DCM/MeOH (98:2) and the filtrates were concentrated. The residual material was purified by a preparative thin-layer chromatography (2% MeOH in DCM) to provide the title compound as a pale yellow solid. MS m/e 410 (M+H)+. Biological Assays
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][OH:22])[C:9](=[O:19])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([Br:17])[C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[C:9](=[O:19])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([Br:17])[C:11]=2[O:22][CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c(F)ccc(Br)c1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2c(F)ccc(Br)c2OCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of N-benzyl-3-bromo-2,6-difluoro-N-(2-hydroxyethyl)benzamide (1.50 g, 4.05 mmol) in N,N-dimethylformamide (30 ml) under ice-cooling, 60% sodium hydride (210 mg, 5.27 mmol) was added, and the mixture was stirred for 1 hr under ice-cooling. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product (1.40 g, 98.6%) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[C:7]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.O.[C:23](=O)([O:29]C(C)(C)C)[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:23]([N:1]1[CH2:2][CH2:3][C:4](=[C:7]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:5][CH2:6]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=C2c3ccccc3CCc3cccnc32)CC1

Procedure:
Dissolve 13.8 g of 11-(4-piperidylidene)-6,11 dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine (Compound IC) prepared according to Villani et. al., J. Med. Chem. 15, 750 (1972) in 250 ml of dry tetrahydrofuran. With stirring, add in one portion 12 g of di-t-butyl carbonate and stir at room temperature overnight. The mixture is poured into water, is extracted with ether, is washed with water and the solvent removed. Recrystallize the residue from isopropyl ether. The melting point is 144°-145° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42](=[O:55])[C:43](I)=[C:44]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:45]2)=[CH:40][C:39]=1[O:56][CH3:57]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:43]3[C:42](=[O:55])[C:41]4[C:46](=[CH:47][C:38]([Br:37])=[C:39]([O:56][CH3:57])[CH:40]=4)[O:45][C:44]=3[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1cc2c(=O)c(I)c(-c3ccccc3)oc2cc1Br
Product: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1Br
Yield: 52 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-bromo-3-iodo-6-methoxy-2-phenyl-chromen-4-one was reacted to give the title compound as a pale yellow foam (302 mg, 52%). LCMS (Method B): RT=5.02 min, [M+Na]+=598/600.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=CC=1)(=O)C.[CH3:22]O>Cl>[CH2:5]([OH:4])[C:6]#[C:7][CH2:12][CH2:11][CH2:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:22]
Reactant: CO
Reactant: CCCCCCCC(=O)c1ccc(CCOC(C)=O)cc1
Agent: Cl
Product: CCCCCCCCCCCCC#CCO
Temperature: 65 °C

Procedure:
The compound (12,374 g) of (1) above was dissolved in a N solution (230 ml) of hydrochloric acid in methanol and the mixture was heated at 65° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 8.465 g of 2-pentadecynyl alcohol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:22]>Cl.C(Cl)Cl>[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:22][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13]
Reactant: Cc1cccc(O)c1C
Reactant: c1ccc(CN2CC3OC3C2)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(O[C@@H]2CN(Cc3ccccc3)C[C@H]2O)c1C

Procedure:
A mixture of 17.5 g. (0.10 mole) of 1-benzyl-3,4-epoxypyrrolidine, 18.3 g. (0.15 mole) of 2,3-dimethylphenol and 2 drops of concentrated hydrochloric acid was heated at 120° C. under a nitrogen atmosphere overnight. The reaction mixture was dissolved in methylene chloride and washed with four 100-ml portions of 5% sodium hydroxide and once with water. The methylene chloride layer was dried over anhydrous sodium sulfate-potassium hydroxide and concentrated to give 28.6 g. of dark oil as residue. This oil was chromatographed on 600 g. of silica gel and the product was eluted with an acetone-benzene solution. The appropriate fractions were concentrated to give an oil which crystallized upon standing. This solid was recrystallized from ligroin to give 9.1 g. (31%) of white solid, m.p. 100°-4° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[C:2]=1[OH:8].[OH-].[K+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([O:7][C:3]1[C:2]([OH:8])=[N:1][CH:6]=[CH:5][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccnc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ncccc1OCc1ccccc1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
Pyridine-2,3-diol (38 g, 342.04 mmol) was added to a solution of potassium hydroxide (21 g, 374.26 mmol) in methanol (400 mL) in portions while maintaining the reaction temperature below 30° C. Benzyl bromide (64.4 g, 376.53 mmol) was then added dropwise with stirring to the reaction mixture at room temperature. The resulting solution was stirred at 40° C. for 5 hr then concentrated in vacuo. The residue was diluted with water (500 mL) and the mixture was extracted with of dichloromethane (2×500 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Recrystallization from ethanol afforded the title compound (30 g, 43%) as a white solid: 1H NMR (400 MHz, DMSO) delta 11.60 (s, 1H), 7.45-7.28 (m, 5H), 6.96-6.89 (m, 2H), 6.10-6.06 (m, 1H), 5.01 (s, 2H).
Reaction SMILES: B.[Na].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: B
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C

Procedure:
9.33 g of sodium boron hydride was suspended in 200 ml of tetrahydrofuran, and added thereto was boron trifluoride diethyl complex under ice-cooling. The mixture was stirred as such under ice-cooling for 30 minutes, and then, 150 ml of a tetrahydrofuran solution containing 40 g of trans-4-(tert-butoxycarbonylamino)cyclohexane carboxylic acid was added thereto under ice-cooling. The mixture was stirred at room temperature for 4 hours, and the reaction mixture was poured into ice water, and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 20 g of N-tert-butoxycarbonyl-trans-4-(hydroxymethyl)cyclohexylamine. (2) By using the compound obtained in the above (1) and corresponding starting materials, compounds of Reference Examples 9-14 to 9-29 in Table 10 were obtained in the same manner as in Reference Example 9-8.
Reaction SMILES: [C:1](=[S:12])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)SC.[CH3:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16].[NH2-].[Na+].Cl>C1(C)C=CC=CC=1.O>[CH3:13][CH:14]([CH3:18])[C:15](=[O:17])[CH2:16][C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[S:12]
Reactant: CC(=O)C(C)C
Reactant: CSC(=S)OCc1ccccc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C(=O)CC(=S)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
A solution of S-methyl O-benzyl dithiocarbonate (6.90 g) and 3-methylbutan-2-one (3.00 g) in toluene (20 mL) was added dropwise to a suspension of sodium amide (2.71 g) in toluene (60 mL) at 0° C. over a 5-minute period. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the mixture was acidified by addition of 1 mol/L hydrochloric acid. The resulting mixture was extracted with diethyl ether, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) to give the title compound (5.90 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([S:18]([CH3:26])(=[N:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:19])[CH:15]=[CH:16][CH:17]=1>C(#N)C>[CH2:24]([O:23][C:21]([N:20]=[S:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:5]2[N:4]=[C:3]([S:9][CH3:10])[C:2]([Br:1])=[CH:7][N:6]=2)[CH:13]=1)([CH3:26])=[O:19])=[O:22])[CH3:25]
Reactant: CSc1nc(Cl)ncc1Br
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(N)c1
Solvent: CC#N
Product: CCOC(=O)N=S(C)(=O)c1cccc(Nc2ncc(Br)c(SC)n2)c1
Yield: 59.9 %

Procedure:
Intermediate 13 was prepared in analogy to GP 2 by reaction of 2.15 g of Intermediate 12 (4.5 mmol, 1 eq.) and 1.09 g of Intermediate 5 (4.5 mmol, 1 eq.) to yield (after crystallization from acetonitrile) 1.2 g of Intermediate 13 (60% yield).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11](O)[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)[S:28](Cl)(=O)=O>CC(C)=O>[CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([SH:28])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(S)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
To a solution of 600 mg of (2RS)-2-cyclopentyl-2-methyl-5-hydroxy-6,7-dichloroindan-1-one (prepared by the method described in European Patent Publication No. 47011) in 6 ml of dry acetone was added 690 mg of potassium carbonate at a time and the mixture was stirred for twenty minutes. The reaction mixture was cooled to 0° C., 0.23 ml of trifluoromethanesulfonyl chloride was dropped thereto and the mixture was stirred for 10 minutes at the same temperature. The solid was filtered out from the reaction mixture and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride and the solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 860 mg of the title compound as crude product having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3ccc(F)cc3)C2=O)cc1
Yield: 29 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-fluorophenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (29%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:15]([OH:17])=[O:16])=[C:8]([C:12]([OH:14])=O)[C:9]([NH:11][C:4]2=[CH:3][CH:2]=1)=[O:10].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:15]1(=[O:16])[C:7]2[C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[NH:11][C:9](=[O:10])[C:8]=2[C:12](=[O:14])[O:17]1
Reactant: O=C(O)c1c(C(=O)O)c2ccccc2[nH]c1=O
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1OC(=O)c2c1c(=O)[nH]c1ccccc21

Procedure:
A mixture of 2(1H)-Oxo-quinoline-3,4-dicarboxylic acid (2 g), phosphorous oxychloride (4 g) and dry chloroform (30 mL) was heated at reflux for 2 h. The solvent and excess reagents are removed in vacuo and the residue was treated with ice water to afford Furo[3,4-c]quinoline-1,3,4(5H)-trione as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[B:11]([OH:13])O)=O.[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][N:22]=[C:21]2[NH:26][NH2:27])=[CH:17][CH:16]=1.NN>C(O)C.CC(O)=O>[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][N:22]=[C:21]2[N:26]2[N:27]=[CH:1][C:3]3[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=3[B:11]2[OH:13])=[CH:17][CH:16]=1
Reactant: NNC1=NCC(=O)N1Cc1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Agent: NN
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)C=NN(C1=NCC(=O)N1Cc1ccc(Cl)cc1)B2O

Procedure:
A mixture of 1 (360 mg, 2.0 mmol) and 3-(4-chlorobenzyl)-2-hydrazino-3,5-dihydroimidazol-4-one (compound 16, commercially available from Maybridge Chemical Co., Ltd., Ryan Scientific #RF03409; 500 mg, 2.1 mmol) in 6 mL of absolute ethanol was treated with 1 drop of AcOH and was warmed on a steam bath until homogeneous. The mixture was allowed to stand at 23 ° C. overnight, whereupon the 137 mg of the starting hydrazine that had separated as crystals (mp 186-188° C.) was removed by suction filtration. The filtrate was rotary evaporated to dryness, and the residue was triturated with Et2O to give 528 mg (69%, 91% based on unrecovered hydrazine) of the methoxy precursor (compound 17) as a pale yellow powder: mp 135-145° C. (EtOH). 1H NMR ((CD3)2SO) δ 9.16 (s, exchanges with D2O, 1, OH), 7.62 (d, J=8.4 Hz, 1), 7.40 (d, J =8.5 Hz, 2, p-CICA), 7.32 (d, J=8.5 Hz, 2, p-ClC6H4), 7.12 (m, 3), 6.97 (d, J=8.0 Hz, 1), 6.85 (d, J =8.0 Hz, 1), 6.68 (s, 1), 4.23 (d, J=5.6 Hz, 2, benzyl-CH2), 3.67 (s, 3, OCH3). Low-resolution DCI mass spectrum, m/z 383 (2%, MH+). Deprotection of 17 can be effected using conventional techniques to form 18.
Reaction SMILES: Br[CH2:2][CH3:3].[Mg].[CH:5]1([N:15]2[C:19]([CH:20]=[O:21])=[CH:18][N:17]=[CH:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[OH-].[Na+]>O.O(CC)CC>[CH2:2]([CH:20]([C:19]1[N:15]([CH:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][CH2:6]2)[CH:16]=[N:17][CH:18]=1)[OH:21])[CH3:3]
Reactant: O=Cc1cncn1C1CCCc2ccccc21
Reactant: CCBr
Agent: [Mg]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCC(O)c1cncn1C1CCCc2ccccc21
Reaction time: 2 h
Yield: 35.8 %

Procedure:
To a stirred and refluxed Grignard complex, previously prepared starting from 9 parts of bromoethane, 2.16 parts of magnesium and 140 parts of 1,1'-oxybisethane were added dropwise 11.3 parts of 1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-carboxaldehyde. Upon complete addition, stirring was continued for 2 hours at room temperature. The reaction mixture was poured into water and treated with a sodium hydroxide solution. The separated organic layer was washed with water, dried, filtered and evaporated, yielding 4.6 parts (35.8%) of α-ethyl-1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazole-5-methanol as a residue (compound 2.06).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:36])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([OH:34])([CH3:33])[CH3:32])[N:26]=3)[CH:22]=[CH:21][C:20]=2[CH3:35])[C:5]([CH3:18])=[N:6][C:7]=1[O:8]CC1C=CC(OC)=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3](=[O:36])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([OH:34])([CH3:32])[CH3:33])[N:26]=3)[CH:22]=[CH:21][C:20]=2[CH3:35])[C:5]([CH3:18])=[N:6][C:7]=1[OH:8]
Reactant: COc1ccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(O)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution 5-chloro-3-{5-[2-(1-hydroxy-1-methyl-ethyl)-pyrimidin-4-yl]-2-methyl-phenyl}-6-(4-methoxy-benzyloxy)-2-methyl-3H-pyrimidin-4-one from Step I (661 mg, 1.31 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The solution was stirred at ambient temperature for one hour. Concentration in vacuo provided the title compound as a yellow solid (assume theoretical yield). MS (M+H): 387