Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[CH3:26]
Reactant: O=C1Oc2ccc(Cl)cc2C1c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 42.8 mmol of 5-chloro-2,3-dihydro-2-oxo-3-phenylbenzofuran in 50 ml of anhydrous dimethylformamide is added at room temperature to a suspension of 42.8 mmol of sodium hydride in 20 ml of anhydrous dimethylformamide. The mixture is stirred for one hour at 20° C. and 42.8 mmol of ethyl bromoacetate are added. The mixture is stirred for 12 hours at 20° C., the medium concentrated under vacuum, the residue taken up in 200 ml of 1% strength hydrochloric acid solution, the aqueous phase extracted with benzene, the organic phase dried over anhydrous sodium sulfate, the solvent evaporated off and the crystalline residue washed with a solution of ethyl ether and acetone (90:10). After filtration, 25.8 mmol of crystals are collected.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.F[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].C([O-])([O-])=O.[K+].[K+].[ClH:25]>CS(C)=O.CCOC(C)=O.CO.CCOC(C)=O.CCCCCC>[ClH:25].[CH:14]([C:13]1[CH:12]=[C:11]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH:18]=[CH:17][CH:16]=1)=[O:15]
Reactant: O=Cc1cccc(F)c1
Reactant: c1ccc2[nH]cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O=Cc1cccc(-n2cnc3ccccc32)c1

Procedure:
A solution of benzimidazole (VIII: R=H) (1.00 g, 8.47 mmol) and 3-fluorobenzaldehyde (IX: R1′=3—CHO; halogen=F) (1.08 mL, 10.2 mmol) in DMSO (30 mL) was heated with anhydrous K2CO3 (2.34 g, 16.9 mmol) for 24 hours at 100° C. to give, after column chromatography on silica gel eluting with EtOAc/hexane (1:1) to EtOAc/hexane (3:1), Example 4 as the HCl salt, mp (EtOAc/MeOH) 196-201° C.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]2[CH2:12][C@H:11]2[C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH:4]=1)[NH2:2].CN(C)[C:25](=[N:27][C:28](=O)[CH2:29][O:30][CH3:31])[CH3:26]>C(O)(=O)C>[CH3:31][O:30][CH2:29][C:28]1[N:1]([C:3]2[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]3[CH2:12][C@H:11]3[C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH:4]=2)[N:2]=[C:25]([CH3:26])[N:27]=1
Reactant: Cc1nc(NN)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Reactant: COCC(=O)N=C(C)N(C)C
Solvent: CC(=O)O
Product: COCc1nc(C)nn1-c1cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)nc(C)n1
Temperature: 25 °C

Procedure:
A solution of 2-((1R,2R)-2-(6-hydrazinyl-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (4-7, 25.0 mg, 0.0850 mmol, 1.0 eq) in acetic acid (3 mL) was added to a round bottom flask containing N-(1-(dimethylamino)ethylidene)-2-methoxyacetamide (200 mg, 1.26 mmol, 14.9 eq; prepared according to procedure 2-1). The acetic acid solution was heated at 100° C. for 30 minutes, allowed to cool to room temperature and concentrated to dryness. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by reverse phase liquid chromatography (H2OCH3CN gradient w/ 0.1% NH4OH present) to afford 2-((1R,2R)-2-(6-(5-(methoxymethyl)-3-methyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (4-8) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.69 (m, 2H), 7.24 (m, 3H), 5.11 (s, 2H), 3.81 (s, 3H), 3.57 (s, 3H), 2.83 (m, 2H), 2.69 (s, 3H), 2.56 (s, 3H), 2.04 (m, 1H), 1.98 (m, 1H). HRMS m/z (M+H) 390.2039 found, 390.2037 required.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:7]([NH:9][CH2:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:8])(=[O:3])[CH3:2].[NH2:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34]>>[C:1]([S:4][CH2:5][CH:6]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:7]([NH:9][CH2:10][C:11]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Product: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
As described in Example 7 of U.S. Pat. No. 4,235,885, this compound can be prepared by reacting (±)-N-[2-[(acetylthio)methyl]-4-methyl-1-oxopentyl]glycine, 4-nitrophenyl ester with (L)-arginine to give (±)-N-[N-[2-[(acetylthio)methyl]-4-methyl-1-oxopentyl]glycyl]-L-arginine. An aqueous chilled solution of this product is then treated with concentrated ammonia to give (±)-N-[N-[2-(mercaptomethyl)-4-methyl-1-oxopentyl]glycyl]-L-arginine; m.p. 132°-146°.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.BrCC1C=CC(C2C=CC=CC=2C#N)=CC=1>C1(C)C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:7][CH:8]=1
Reactant: N#Cc1ccccc1-c1ccc(C(Br)Br)cc1
Agent: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
After the dropwise addition of the solution prepared by dissolving the mixture of 4'-dibromomethyl-2-cyanobiphenyl and 4'-bromomethyl-2-cyanobiphenyl in toluene was terminated, the mixture was allowed to react up to a point where the above suspension no longer absorbs hydrogen gas. After the reaction was terminated, Raney catalyst and sodium carbonate were filtered off, and the reaction mixture was then concentrated to distill off methanol and toluene. The resulting crude 4'-methyl-2-cyanobiphenyl was purified by distillation, to give 7.4 g of 4'-methyl-2-cyanobiphenyl having an LC purity of 98.2%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]CC2C=CC(OC)=CC=2)[CH:5]=[C:4]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:3]=1
Reactant: COc1ccc(COc2cc(Br)cc(S(C)(=O)=O)c2)cc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc(O)cc(Br)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
Bromo-3-methanesulfonyl-5-(4-methoxy-benzyloxy)-benzene (5.7 g) was dissolved in glacial acetic acid (80 mL) and stirred at 100° C. for 5 h. The solvent was removed under reduced pressure and the crude material was purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (3.4 g, 88% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[O:23][N:22]=[C:21]([O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[OH-].[Na+]>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[O:23][N:22]=[C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cc(OCC(=O)O)no2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A mixture of tert-butyl [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}isoxazol-3-yl)oxy]acetate obtained in Example 215 (0.99 g, 2.23 mmol) and trifluoroacetic acid (8 mL) was stirred at room temperature for 3 h. The reaction mixture was neutralized with 1 M sodium hydroxide solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a solid (0.74 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)c1ccccc1CBr
Yield: 102.6 %

Procedure:
To a solution of methyl-2-methylbenzoate (3.00 g, 20.0 mmol) in carbon tetrachloride (15 mL) was added N-Bromosuccinimide (3.55 g, 20.00 mmol). The reaction was allowed to stirr at reflux for 3 h. The mixture was cooled and then partioned between 1:1 ethyl acetate/hexane and the combine organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure afforded the title compound as a yellowish liquid (4.70 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H), 7.54-7.35 (mm, 3H), 4.98 (s, 2H), 3.98 (s, 3H).
Reaction SMILES: [C:1]([O:6][CH:7]1[CH:11]2[O:12][C:13](=[O:23])[CH:14]3[CH:15]([C:16]([O:18]C(C)(C)C)=[O:17])[CH:8]1[CH2:9][CH:10]23)(=[O:5])[C:2]([CH3:4])=[CH2:3]>C(O)=O>[C:1]([O:6][CH:7]1[CH:11]2[O:12][C:13](=[O:23])[CH:14]3[CH:15]([C:16]([OH:18])=[O:17])[CH:8]1[CH2:9][CH:10]23)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Solvent: O=CO
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
Dissolved into 810 g of formic acid was 202.2 g of the methacrylate ester (25) obtained in Synthesis Example 1-1-1; and then, the resulting mixture was stirred at 25° C. for 16 hours. After formic acid was removed by distillation under reduced pressure, recrystallization was made from ethyl acetate to give 135.1 g of the intended product (Yield 81%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)([OH:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
3-Methyl-4-oxo-piperidine-1,3-dicarboxylic acid-1-tert-butyl ester 3-methyl ester (1.1 g, 4.07 mmol) was dissolved in tetrahydrofuran and cooled to 0° C. To the solution was added 4-chlorophenyl magnesium bromide (12.2 mL, 12.2 mmol) dropwise over ˜½ h and then stirred at 0° C. for 1 h. The reaction was quenched with saturated solution of NH4Cl and extracted with ethyl acetate (3×). The organics were collected, dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (10% ethyl acetate/90% hexane to 20% ethyl acetate/80% hexane) to yield the title compound (1.1 g, 70%). 1H-NMR (CDCl3): δ 1.17 (s, 3H), 1.44 (s, 9H), 1.55 (m, 1H), 1.96 (d, 1H) 3.00 (m, 1H), 3.37 (m, 2H), 3.53 (s, 3H), 3.91 (m, 2H), 4.07 (d, 1H), 7.27 (d, 2H), 7.43 (d, 2H). ESI-MS m/z: 384.1 (M+1), retention time 2.95.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].Cl.[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([OH:38])=[O:37].C[O-].[Na+]>CCO.C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:31][CH2:32][C:33]3[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=3)[C:36]([OH:38])=[O:37])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCc1cccc(C(=O)O)c1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: O=C(O)c1cccc(CNC(=O)c2ncc3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 17.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (63 mg, 0.16 mmol), 3-aminomethyl-benzoic acid HCl salt (306 mg, 1.6 mmol) and NaOMe (167 mg, 3.1 mmol) in EtOH (6 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in a 1:1 mixture of THF and MeOH (6 mL). 2 M NaOH (3 mL) was added, and the mixture was stirred at r.t. for 16 h. The mixture was concentrated to approximately one-third of its original volume, and 1 M HCl was added until pH was about 2. The resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as a yellow solid. MS: (+) m/z 506.29 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]([OH:15])=O)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][C:6]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=4)=[N:7][C:8]=23)=[O:15])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 574.5 [(M+H)+]; mp 228-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH2:33]([O:35][C:36]([C:38]1([NH2:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([C:38]1([NH2:44])[CH2:39][CH2:40][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=3[C:29]([F:31])([F:32])[F:30])[N:8]=[CH:9]4)[C:18](=[O:26])[N:19]=2)[CH2:42][CH2:43]1)=[O:37])[CH3:34]
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CCOC(=O)C1(N)CCNCC1
Product: CCOC(=O)C1(N)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
4-Amino-1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid ethyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-amino-piperidine-4-carboxylic acid ethyl ester following General Procedure B.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH:8]1[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]1>Br>[NH:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)N1CCC(Nc2ccccn2)CC1
Agent: Br
Product: c1ccc(NC2CCNCC2)nc1
Yield: 166.4 %

Procedure:
6 g of ethyl 4-(pyridin-2-ylamino)piperidine-1-carboxylate (23a) were refluxed in 30 ml of 47% HBr for 6 h. Evaporation of the mixture, trituration of the resulting crude product with ethyl acetate/CH3OH (9:1) and renewed drying afforded 7.1 g of white solid; ESI-MS [M+H+]=178.15.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:6](O)=[O:7])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>CN(C)C=O>[CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:6]([Cl:19])=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,6-diisopropylbenzoic acid (12.8 g, 0.062 mol), oxalyl chloride (25 mL), and dimethylformamide (2 drops) was stirred overnight at room temperature. The volatiles were removed on the rotary evaporator and the residue dried to yield an orange oil, 12.65 g, 90.9%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2[CH2:23][OH:24])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.CCOCC>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2[CH:23]=[O:24])=[CH:16][CH:17]=1
Reactant: OCC1=C(c2ccc(Cl)cc2)CCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC1=C(c2ccc(Cl)cc2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.1 g) in dichloromethane (30 ml) at −78° C. was added dimethylsulfoxide (6.12 ml). The mixture was stirred at −78° C. for 30 minutes, and then a solution of EXAMPLE 143C (1.2 g) in dichloromethane (10 ml) was added. The mixture was stirred at −78° C. for 2 hours before the addition of triethylamine (10 ml). The mixture was stirred overnight and the temperature was allowed to rise to room temperature. The mixture was diluted with ether (300 ml) and washed with water, brine and dried over Na2SO4. Evaporation of solvent and column purification (5% ethyl acetate in hexane) to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-])=O)[CH:22]=3)[C:17]2=[O:29])=[O:8])=[CH:5][CH:4]=1.C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH2:26])[CH:22]=3)[C:17]2=[O:29])=[O:8])=[CH:30][CH:31]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3ccc(N)cc3C2=O)cc1
Yield: 58 %

Procedure:
A solution of N-(4-methoxybenzoyl)-2-(5-nitro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)benzeneamine (1.11 g, 2.66 mmol) and 5% palladium-on-carbon (1.21 g) in 2:1 ethanol:ethyl acetate (200 mL) was placed under 1 atmosphere of hydrogen. After consumption of the starting material (about 2-3 h), the mixture was filtered through diatomaceous earth and the resulting filtrate concentrated in vacuo. Recrystallization from hexanes/ethyl acetate yielded 596 mg (58% of the title-compound.
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C@H:11]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:13][C@@H:12]1[CH2:42][Hg]Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[CH2:26]([O:25][C@H:15]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:12]([CH2:42][I:1])[O:13][C@@H:14]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: II
Reactant: Cl[Hg]C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: ClCCl
Product: IC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.2 %

Procedure:
Iodine (0.36 g, 14.4 mmol, 1.1 equiv) dissolved in dry DCM (20 mL) was added to a solution of (((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)mercury(II) chloride (1.0 g, 12.9 mmol, 1.0 equiv) in dry DCM (30 mL). The reaction mixture was stirred at room temperature for 16 hours and then quenched with saturated aqueous sodium thiosulfate solution (50 mL). The biphasic mixture was separated and then the organic layer was washed with saturated aqueous sodium chloride solution (10 mL) and then with water (10 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material thus obtained was purified by silica gel chromatography, eluting with 30% EtOAc in petroleum ether, to give (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(iodomethyl)tetrahydro-2H-pyran as a colorless oil (0.7 g, 82%). 1H NMR (300 MHz, CDCl3) δ 7.44-7.22 (m, 18H), 7.17 (dd, J=6.6, 3.0 Hz, 2H), 5.09 (d, J=11.3 Hz, 1H), 4.92-4.67 (m, 4H), 4.67-4.47 (m, 3H), 4.21 (dd, J=2.8, 1.1 Hz, 1H), 3.90 (t, J=9.5 Hz, 1H), 3.76 (dd, J=11.0, 1.9 Hz, 1H), 3.71-3.60 (m, 2H), 3.57 (t, J=6.9 Hz, 1H), 3.53-3.45 (m, 1H), 3.35-3.24 (m, 2H). ESI (M+H2O) 682.2; calc for C35H37IO5 664.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:18]1([C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[CH:5]=[CH:4][N:3]=3)[CH2:30][CH2:31]2)=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(N1CCCCC1)N1CCNCC1
Reactant: CCOc1cc2ccnc(Cl)c2cc1OCC
Product: CCOc1cc2ccnc(N3CCN(C(=O)N4CCCCC4)CC3)c2cc1OCC

Procedure:
In like manner, 1-chloro-6,7-diethoxyisoquinoline and 1-(piperidinocarbonyl)piperazine react to afford 1-(4-piperidinocarbonyl-1-piperazinyl)-6,7-diethoxyisoquinoline, while 4-chloro-6,7-dimethoxyquinazoline and 1-(piperidinocarbonyl)piperazine react to afford 4-(4-piperidinocarbonyl-1-piperazinyl)-6,7-dimethoxyquinazoline respectively. The latter compound is, of course, identical in every respect with the product of Example V.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19](N)=[C:18]([CH3:23])[CH:17]=2)=[C:12]([CH:24]([CH3:26])[CH3:25])[CH:11]=[N:10]1.ClC1C=CC=C(Cl)C=1N1C(CO)=C(C(C)C)C=N1.[Br:45]C1C=CC(O)=CC=1C>>[Br:45][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]2[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=[CH:11][C:12]=2[CH:24]([CH3:26])[CH3:25])=[CH:17][C:18]=1[CH3:23]
Reactant: Cc1cc(O)ccc1Br
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N
Agent: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1Br

Procedure:
The title compound is prepared essentially according to the preparation of 4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenylamine using [2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-methanol and 4-bromo-3-methyl-phenol. ES/MS m/e 454.9 (M+1).