Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[OH-].[Na+]>CCO.O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COCc1cc(C(=O)OC)ccc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of methyl 2-(methoxymethyl)-2′-methylbiphenyl-4-carboxylate (40.0 g, 148.0 mmol) in EtOH (1.2 L) at RT was treated with a 5N aqueous solution of NaOH (90 mL, 450 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to RT and concentrated to give a yellow solid which was taken up in water (800 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with a concentrated aqueous solution of HCl (40 mL, pH˜2) and it was extracted with EtOAc (2×400 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated affording the title compound as a yellow solid (35.1 g, 92%). 1H NMR (DMSO-d6, 300 MHz) δ 12.99 (br s, 1H), 8.09 (s, 1H), 7.91 (m, 1H), 7.33-7.22 (m, 4H), 7.09 (m, 1H), 4.11 (m, 2H), 3.18 (s, 3H), 1.99 (s, 3H). LC/MS (Method B): 255.2 (M−H)−. HPLC (Method A) Rt 4.52 min (Purity: 96.4%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7])=[CH2:2].[CH2:12]([O:19][C:20]1[CH:25]=[C:24](I)[CH:23]=[CH:22][C:21]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH:2]=[CH:1][C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([NH2:8])=[O:7])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][C:29](=[O:34])[NH:30][S:31]1(=[O:33])=[O:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=Cc1cccc(C(N)=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(C=Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Temperature: 120 °C

Procedure:
A mixture of 3-vinylbenzamide (32 mg, 0.22 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), Pd(OAc)2 (20 mg, 0.09 mmol) and triethylamine (0.256 mL, 1.84 mmol) in MeCN (2 mL) is heated in a microwave apparatus at 120° C. for 25 min. The mixture is filtered over Celite and washed with MeCN. The filtrate is evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Al+3].[Cl-].[Cl-].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCc1ccc(F)cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCc2ccc(F)cc2)cc1
Yield: 100 %

Procedure:
A procedure similar to step 2 of Example 1 was used. 3-(4-fluoro-phenyl)-propionyl chloride prepared in the step 1 and methylphenyl ether were used as starting materials, and anhydrous AlCl3 was used as catalyst. The obtained product was a white solid in a yield of 100%, mp: 80-81 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.05 (2H, t, J=7.84 Hz, ArH), 3.23 (2H, t, J=7.84 Hz, ArH), 3.87 (3H, s, OCH3), 6.92 (2H, d, J=8.68 Hz, ArH), 6.97 (2H, t, 3JFH=3JHH=8.72 Hz, ArH), 7.21 (2H, dd, 3JHH=8.68 Hz, 4JFH=5.60 Hz, ArH), 7.93 (2H, d, J=8.68 Hz, ArH); EI-MS m/e (%): 258.0 (M+, 27), 135.0 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH:27][C:24]4[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=4)[N:30]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: COc1ccc(NC(=N)N)cc1
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(4-methoxyphenyl)guanidine were converted to I-14 (39%): HRMS Calcd. for C19H11ClN4O2: 367.0960, Found 367.0975.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=1.[C:23](=[O:25])=[O:24].Cl>C1COCC1>[Br:13][C:14]1[C:19]([C:23]([OH:25])=[O:24])=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(Br)cc(F)c(F)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of i-Pr2NH (3.65 mL, 25.8 mmol) in THF (50 mL) was added n-BuLi (10.3 mL, 25.8 mmol, 2.50 M solution in hexanes) at 0° C. After stirring for 15 minutes, the reaction mixture was cooled to −78° C. A solution of 5-bromo-1,2,3-trifluorobenzene (5.00 g, 23.7 mmol) in THF (5 mL) was added. The resulting mixture was stirred for 2 hours at −78° C., poured into an excess of freshly crushed dry ice, and stirred for 30 minutes To this mixture was added 10% aqueous HCl to adjust its pH to 1. The resulting mixture was extracted with ether (3×). The combined organic layers were washed with 5% aqueous NaOH (2×). The combined basic aqueous layers were acidified to pH 1 with concentrated HCl, and extracted with ether (2×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (5.06 g, 84%) that was used directly without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.C([Sn](CCCC)(CCCC)[C:26]1[O:30][N:29]=[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=1)CCC>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:26]1[O:30][N:29]=[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)no1
Product: CCOC(=O)c1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)on1

Procedure:
The procedure is identical to that used in Example 1 except (5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 6, 582 mg, 1.50 mmol) and ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (Sakamoto, T. et al., Tetrahedron, 1991, 47, 5111–5118); 806 mg, 1.87 mmol) were used as starting materials. The crude product was purified by chromatography on silica gel using EtOAc, followed by recrystallization from acetone/hexanes to give 175 mg of the title product.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([C:11]([O:26][CH2:27][C@@:28]23[CH2:41][O:40][C@@H:30]([C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[OH:39])[O:32]2)[C@@H:29]3[OH:42])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C@@H:31]1[O:32][C@:28]2([CH2:27][O:26][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C@@H:29]([OH:42])[C@H:30]1[O:40][CH2:41]2)[CH:2]=[CH2:3]
Reactant: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](c4ccccc4O)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1[C@@H]1O[C@@]2(COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)CO[C@@H]1[C@@H]2O
Temperature: 25 °C
Reaction time: 40 h
Yield: 86.1 %

Procedure:
Allyl bromide (0.017 ml, 0.20 mmol) was added to an anhydrous acetone (16 ml) solution of the compound (28) (96 mg, 0.18 mmol), whereafter potassium carbonate (27 mg, 0.20 mmol) was added, and the mixture was stirred for 40 hours at room temperature. After the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate 3 times. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain a colorless oily substance (29) (90 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Cl-].[Cl-].[Cl-].[Al+3].O>CO>[OH:10][C:11]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[C:6]=1[CH2:7][CH2:8][C:9]2=[O:12]
Reactant: Cc1cccc2c1OC(=O)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1O)CCC2=O
Temperature: 177.5 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
The mixture of 8-Methyl dihydrocoumarin (20 gm, 0.123 mole) and Aluminum trichloride (49.3 gm, 0.370 mole) was stirred for 2 hours at 175-180° C. To the reaction mixture, water (250 ml) was added slowly and stirred for an hour. Further it was filtered and obtained solid was stirred in Methanol (60 ml). Finally the suspension was filtered and obtained solid was dried under vacuum to give 13.5 gm of desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:17])[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH2:10][CH:9]2[OH:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].N1C=CN=C1.[C:27]([Si:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)Cl)([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[Si:31]([O:15][CH2:14][CH:12]1[CH2:11][CH2:10][CH:9]([OH:16])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:18]([F:19])([F:20])[F:21])[CH:4]=2)([CH3:17])[CH2:13]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(CO)CCC1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCC1O
Temperature: 25 °C
Reaction time: 29 h
Yield: 73.4 %

Procedure:
A solution of (1RS,2RS,4RS)-2-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methylcyclohexanol (1.253 g, 3.88 mmol) in DMF (15 mL) was treated with imidazole (0.581 g, 8.54 mmol) followed by tert-butyldiphenylchlorosilane (1.097 mL, 4.27 mmol). The resulting mixture was stirred at rt for 29 h. After this time, the solution was diluted with ethyl acetate (150 mL), washed three times with water, once with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel, eluting with 5-25% ethyl acetate-hexanes, to provide (1RS,2RS,4RS)-4-((tert-butyldiphenylsilyloxy)methyl)-2-(4-chloro-3-(trifluoromethyl)phenyl)-2-methylcyclohexanol as a colorless gummy glass (1.599 g, 73%). 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1 H), 7.82 (dd, J=8.5, 1.6 Hz, 1 H), 7.63 (t, J=6.6 Hz, 4 H), 7.40 (m, 7 H), 3.72 (dt, J=12.0, 3.5, 3.4 Hz, 1 H), 3.42 (m, 2 H), 2.43 (m, 1 H), 1.69 (m, 5 H), 1.33 (s, 3 H), 1.12 (m, 2 H), 1.06 (s, 9 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[O:15])=[CH:11][C:10]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][C:38](Cl)=[O:39].CCN(CC)CC>C1COCC1>[C:30]([C:10]1[CH:11]=[C:12]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)=[O:15])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:38](=[O:39])[CH2:37][CH2:36][O:35][CH3:34])=[CH:3][CH:4]=2)[N:9]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COCCC(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(N)cc2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCC(=O)Nc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 21.4 %

Procedure:
To a solution of 1-[2-(4-aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (200 mg, 0.45 mmol) and 3-methoxypropionyl chloride (55 mg, 0.45 mmol) in anhydrous THF (5 mL) was added Et3N (69 mg, 0.68 mmol). The reaction was stirred at room temperature for 7 h, and then partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (1:1 hexanes/EtOAc) to give 51 mg (21%) of the desired product. 1H-NMR (DMSO-d6) δ 10.16 (s, 1H), 9.14 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 7.74 (d, J=6.9 Hz, 2H), 7.48 (d, J=6.9 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.08 (d, J=6.6 Hz, 2H), 6.88 (d, J=5.4 Hz, 2H), 6.35 (s, 1H), 3.63 (t, J=6.0 Hz, 2H), 3.33 (s, 3H), 2.57 (t, J=6.0 Hz, 2H), 1.27 (s, 9H); MS LC-MS [M+H]+=529, RT=2.20 min.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])[CH2:26][CH2:25]1>>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([N:27]5[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]5)[CH:31]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CC(C)(C)OCc1cccc(-c2ccc3cnc(O)nn23)c1
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cccc(COC(C)(C)C)c5)n4n3)c2)CC1
Yield: 44.8 %

Procedure:
Analogous to Example 1510b, 7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (109 mg, 0.37 mmol) and 3-(4-Methylpiperazin-1-yl)aniline (0.0878 g, 0.459 mmol) were reacted to afford [7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (78 mg, 45%). LCMS: 471 (M+H); 1H-NMR (DMSO-d6): 9.26 (s, 1H), 9.26 (s, 1H), 8.97 (s, 1H), 8.08 (s, 1H), 7.99 (d, 1H, J=7.83 Hz), 7.46 (t, 1H, J=7.83 Hz), 7.35 (d, 1H, J=7.83 Hz), 7.27 (m, 2H), 7.13 (m, 2H), 6.95 (d, 1H, J=4.38 Hz), 6.57 (d, 1H, J=8.50 Hz), 4.48 (s, 2H), 3.01 (s, 4H), 2.40 (s, 4H), 2.22 (s, 3H), 1.22 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Cl[CH2:16][C:17]1[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1>>[S:20]1[CH:21]=[C:17]([CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]1=2
Reactant: ClCc1csc2ccccc12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: O=C(O)c1cc2ccccc2n1Cc1csc2ccccc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-chloromethyl-benzo[b]thiophene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 306.4 ([M−H]−).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cc1ccc(C(=O)CCCCCBr)cc1C
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)c(C)c2)CC1
Yield: 42.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound, potassium carbonate (3.0 g) and 6-bromo-1-(3,4-dimethylphenyl)-1-hexanone (1.1 g) were reacted and treated in the same manner as in Example 172 to give 0.82 g of 4-amino-5-chloro-N-((1-(6-(3,4-dimethylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C:11]([CH3:14])([OH:12])[CH2:13][N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=3)[CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: FC(F)(F)Oc1ccc(NC2CCNCC2)cc1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(CN1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 56.1 %

Procedure:
A solution of 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (0.3 g, 1.38 mmol) and N-(piperidin-4-yl)-4-trifluoromethoxyaniline (0.43 g, 1.66 mmol) in DMF (8 ml) was stirred at 80° C. for 2 hours. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford 1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenylamino)piperidin-1-yl]propan-2-ol (0.37 g, yield 56%) as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28]C)[C:8]([O:13]CC2C=CC=CC=2)=[C:9]([CH:11]=O)[CH:10]=1)=[O:4].Cl.[NH2:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[NH2:41])[C:35]([NH2:37])=[NH:36]>>[C:35]([C:34]1[CH:38]=[CH:39][C:40]2[NH:41][C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[OH:28])[C:8]=3[OH:13])=[N:31][C:32]=2[CH:33]=1)(=[NH:36])[NH2:37]
Reactant: COC(=O)c1cc(C=O)c(OCc2ccccc2)c(-c2cc(F)ccc2OC)c1
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: Cl
Product: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)O)cc(-c4cc(F)ccc4O)c3O)nc2c1
Yield: 58.2 %

Procedure:
Proceeding as in Reference 23, but substituting 6-benzyloxy-5′-fluoro-5-formyl-2′-methoxybiphenyl-3-carboxylic acid methyl ester (1.3 g, 3.30 mmol) and 3,4-diaminobenzamidine hydrochloride (0.739 g, 3.96 mmol), gave 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carboxylic acid (0.780 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:15](=[O:24])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)C=Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
m-Toluidine (5 g, 46.64 mmol) and pyridine (3.77 mL, 46.64 mmol) were dissolved in dry dichloromethane (25 mL). To the reaction mixture, cinnamoyl chloride (7.72 g, 46.64 mmol) was added and stirred for 3 h at 0° C. The reaction mixture was extracted with dichloromethane washing with water and 2N HCl. The solvent was removed and the crude product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](C)(C)[CH2:7][CH2:6]2.B(Br)(Br)Br.C(Cl)(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(C)(C)C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
3.69 g of 6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one was dissolved in 70 ml of anhydrous methylene chloride. The obtained solution was cooled in a dry ice-acetone bath. Thereafter, 36 ml of boron tribromide (a 1.0 M methylene chloride solution) was added thereto, and the obtained mixture was stirred at room temperature overnight. Thereafter, the reaction solution was again cooled in a dry ice-acetone bath. 36 ml of boron tribromide (a 1.0 M methylene chloride solution) was added thereto, and the obtained mixture was stirred at room temperature overnight. Thereafter, the reaction solution was poured into ice, and chloroform was then added thereto. An insoluble precipitate was removed by filtration. The organic layer was separated and then dried over anhydrous sodium sulfate. The obtained solution was passed through a glass filter filled with silica gel, and the solvent was removed under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.52 g of the subject compound.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16](Br)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][C:20](=[O:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:16]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][C:20](=[O:26])[CH:19]=[CH:18]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc2[nH]c(=O)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 100 °C

Procedure:
The mixture of (S)-2-(5-bromo-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethyl pivalate (34 mg, 0.078 mmol), Pd(PPh3)4 (9 mg), 4-chlorophenylboronic acid (16 mg, 0.1 mmol), aqueous K2CO3 solution (0.15 mL, 2 M, 0.3 mmol) in 1,2-dimethoxyethane (2 mL) was heated at 100° C. for 90 minutes. The residue was diluted with ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4. Concentration and purification gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): 470.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CCc2ccccc2OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 46.1 %

Procedure:
Following a procedure similar to that described in Example 36(a), 456 mg of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 600 mg of 1-t-butoxycarbonyl-4-hydroxypiperidine and 865 mg of triphenylphosphine were reacted with 575 mg of diethyl azodicarboxylate in 30 ml of methylene chloride. The reaction mixture was worked up as described in Example 6(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 379 mg (yield 46%) of the title compound as a colorless oil.