Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(Br)cc2)nc(N)n1
Yield: 84 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-bromoaniline provided the title compound (84% yield). 1H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3), 6.10 (s, 1H, Ar), 6.45 (s, 2H, NH2), 7.31 (d, 1H, J=8.3 Hz, Ar), 7.37 (dd, 1H, J=8.2 Hz, J=2.3 Hz, Ar), 7.41 (d, 1H, J=2.3 Hz, Ar), 7.43-7.45 (m, 2H, Ar), 7.78-7.75 (m, 2H, Ar), 9.35 (s, 1H, NH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=2)[CH:2]=1>CCO.[Rh]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH2:8]2)[CH:2]=1
Reactant: O=C1C=C(c2cccnc2)CCC1
Agent: [Rh]
Solvent: CCO
Product: O=C1CCCC(c2cccnc2)C1
Temperature: 25 °C

Procedure:
A mixture of 8b (275 mg, 1.59 mmol) and rhodium (325 mg, 0.158 mmol, 5% wt. on activated basic alumina) in EtOH (16.0 mL) was hydrogenated at atmospheric pressure while stirring at rt. After the reaction was deemed to be complete, the reaction mixture was filtered through a short column of Celite®, eluting copiously with EtOAc, and the combined organics were concentrated in vacuo to afford the title compound, 8c. m/z (ES) 176 (MH)+
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([C:14]1([C:17]([O:19]C)=[O:18])[CH2:16][CH2:15]1)=[O:13].[Li+].[OH-].Cl>O1CCOCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([C:14]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15]1)=[O:13]
Reactant: COC(=O)C1(C(=O)N2CCCc3c(Br)cccc32)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1(C(=O)N2CCCc3c(Br)cccc32)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.2 %

Procedure:
A mixture of methyl 1-(5-bromo-1,2,3,4-tetrahydroquinoline-1-carbonyl)cyclopropanecarboxylate (500 mg, 1.478 mmol) and LiOH (1.478 mL, 5.91 mmol) in 1,4-dioxane (5 mL) was stirred at room temperature for 2 d, and then adjusted to pH 1-3 with 3 N HCl. The resulting mixture was extracted with ethyl acetate (3×15 ml). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (0.37 g, 37%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:38]1[C:42]2[CH:43]=[C:44]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])[CH:45]=[CH:46][C:41]=2[CH2:40][CH2:39]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:49]3[C:48](=[O:53])[C:47]([C:44]4[CH:45]=[CH:46][C:41]5[CH2:40][CH2:39][O:38][C:42]=5[CH:43]=4)([CH3:54])[NH:51][C:50]3=[O:52])[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2ccc3c(c2)OCC3)NC(=O)NC1=O
Reactant: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)C[C@@H]1C
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCC4)C2=O)C[C@@H]1C

Procedure:
(S)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}-3-methylpiperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydrobenzofuran-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[C:13](N)=[C:12]([C:15]([O:17][CH3:18])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.N(OCCC(C)C)=O>O1CCCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)ns1
Yield: 66 %

Procedure:
A solution of 4.5 g. of methyl 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylate and 5.1 g. of isoamyl nitrite in 50 ml. of tetrahydrofuran was heated to reflux for one-half hour. The reaction mixture then was cooled, and the solvent was removed by evaporation under reduced pressure to provide a solid product which was crystallized from ethanol and water to give 2.8 g. (66% yield) of methyl 3-(3-trifluoromethylphenyl)-5-isothiazolecarboxylate. M.P. 82°-83° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:2]1.[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>C1COCC1>[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[NH:13][N:12]=[CH:11]4)[CH2:2]2)=[CH:21][CH:20]=1
Reactant: c1cc2[nH]ncc2cc1N[C@H]1CCCNC1
Reactant: CSc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CSc1ccc(CN2CCC[C@H](Nc3ccc4[nH]ncc4c3)C2)cc1

Procedure:
Reaction of (S)—N-(piperidin-3-yl)-1H-indazol-5-amine and 4-(methylthio)-benzaldehyde using the method of Example 8 and using THF as the reaction solvent afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(C)c2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)c1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 2) 30.0 mg (0.071 mmol) in 3 ml of EtOH and 2 ml of THF was added 28.0 mg (0.70 mmol, 0.7 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCI. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ7.90 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.46 (2H, s), 7.32-7.13 (4H, m), 7.10 (1H, s), 6.98 (1H, t, J=4.5 Hz), 2.34 (3H, s), 2.31 (2H, d, J=4.5 Hz), 1.30 (6H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33]([NH:37][S:38](Cl)(=[O:40])=[O:39])(=[O:36])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:38]([NH:37][C:33](=[O:36])[CH2:34][CH3:35])(=[O:40])=[O:39])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CCC(=O)NS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC(C)C)C1=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
A mixture of Example 34B (52.2 mg, 0.110 mmol) and the product of Example 100A (94.6 mg, 0.55 mmol) in dichloromethane (5 mL) was treated with triethylamine (66.5 mg, 0.658 mmol). The mixture was stirred at rt for 15 minutes. The reaction mixture was partitioned between dichloromethane and 1N hydrochloric acid, and the aqueous phase extracted with additional dichloromethane. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by HPLC to give the title compound (36.3 mg, 57%). 1H NMR (300 MHz, DMSO-d6) δ 0.41 (s, 2 H) 0.69 (d, J=6.62 Hz, 3 H) 0.72 (d, J=6.62 Hz, 3 H) 0.88 (t, J=7.54 Hz, 3 H) 1.33 m, 2 H) 1.57 (s, 3 H) 2.04 m, 1 H) 2.14 (q, J=7.35 Hz, 2 H) 2.25 (m, J=13.97, 3.31 Hz, 1 H) 7.48 (dd, J=9.01, 2.39 Hz, 1 H) 7.54 (m, J=8.27, 3.86 Hz, 1 H) 7.59 (d, J=2.21 Hz, 1 H) 7.71 (d, J=8.82 Hz, 1 H) 7.76 (d, J=3.68 Hz, 2 H) 8.16 (d, J=8.09 Hz, 1 H) 10.94 (s, 1 H) 11.98 (s, 1 H) 13.80 (s, 1 H).). MS (ESI+) m/z 575.2 (M+H)+, 592.2 (M+NH4)+, (ESI−).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][C:15]=4[C:16]=3[OH:17])=[N:9]2)=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][C:15]=4[C:16]=3[O:17][CH3:26])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)c(O)c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)c(OC)c2c1
Yield: 49.1 %

Procedure:
A mixture of 7-chloro-2-(5-methoxycarbonyl-3-hydroxybenzofuran-2-yl)quinoline (1.0 g), potassium carbonate (0.39 g), and methyl iodide (0.40 g) in a mixture of tetrahydrofuran (20 ml) and N,N-dimethylformamide (8 ml) was stirred under reflux. After being cooled, the appeared precipitates were collected by filtration and washed with acetone to give 7-chloro-2-(5-methoxycarbonyl-3-methoxybenzofuran-2-yl)quinoline (0.51 g).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][C@H:5]([NH:18][C:19](=[O:24])OC(C)=C)[CH2:6][N:7]([CH3:17])[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9].[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]([C@@H:43]2[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]2)[O:35][CH2:36][CH2:37][NH:38][C:39](=[O:42])[O:40][CH3:41])[CH:31]=[CH:32][CH:33]=1>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]([C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:19](=[O:24])[NH:18][C@@H:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:25])[CH3:26])[CH2:6][N:7]([CH3:17])[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])=[O:9])[CH2:44]2)[O:35][CH2:36][CH2:37][NH:38][C:39](=[O:42])[O:40][CH3:41])[CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: C=C(C)OC(=O)N[C@@H](CCC(C)(C)C)CN(C)C(=O)OCC[Si](C)(C)C
Solvent: C1CCOC1
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CCC(C)(C)C)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 50 °C

Procedure:
The resulting (S)-prop-1-en-2-yl 5,5-dimethyl-1-(N-methyl-N-(2-trimethylsilylethoxycarbonyl)amino)hexan-2-ylcarbamate was dissolved in THF (5 mL) and methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (40 mg, 0.1227 mmol, 1.1 equiv) added and the mixture heated to 50° C. overnight. After completion of the reaction, the solution was washed with 0.5 M HCl, brine, then dried over Na2SO4, filtered, and evaporated to afford crude methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-5,5-dimethyl-1-(N-methyl-N-(2-trimethylsilylethoxycarbonyl)amino)hexan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate which was taken directly to the next step.
Reaction SMILES: [CH:1]1([C:8](O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1>C1COCC1>[CH:1]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCCC1
Agent: B
Solvent: C1CCOC1
Product: OCC1CCCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of cycloheptane carboxylic acid (83 g, 0.58 mol) in THF (350 mL) was added BH3-THF (700 mL of a 1M solution in THF, 0.70 mol) dropwise. The reaction mixture was stirred at 0° C. for 30 min. After warming to room temperature, the reaction was quenched with the addition of MeOH (300 mL) initially dropwise then more quickly. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and aqueous NaHCO3, washed with brine, dried over MgSO4 and concentrated under reduced pressure. Purification by distillation (96° C. at 19 Torr) gave pure cycloheptylmethanol. Yield (58.3 g, 78%). 1H NMR (DMSO-d6) δ 4.36 (dt, J=3.5, 1.9 Hz, 1H), 3.13 (t, J=6.0 Hz, 2H), 1.34-1.69 (m, 11H), 1.02-1.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18](OC(NC(=NC(OC(C)(C)C)=O)SC)=O)(C)(C)C.C(O)(=O)C>CO>[NH2:1][C:2]1[C:6]([CH3:18])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)cc1N
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1[nH]c(-c2ccccc2)c(C)c1N
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a 25-mL, round-bottomed flask was added ethyl 3-amino-5-phenylpyrrole-2-carboxylate (Example 66 (b)) (1.1 g) and MeOH (5 mL). To the reaction flask was added 1,3-bis(tertbutoxycarbonyl)-2-methyl-2-thiopseudourea (Aldrich Chemical Company) (1.6 g, 5.5 mmol), followed by glacial acetic acid (1.43 mL, 25 mmol). The reaction mixture was stirred at room temperature under N2 for 28 h. A heavy precipitate formed and was collected by filtration, washed with H2O (3×10 mL) and dried in a vacuum oven overnight to give 0.71 g (32% from Example 66 (a)) of the title compound as an off-white solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.38 (t, 3, J=7.00), 1.44 (s, 9), 1.46 (s, 9), 4.38 (q, 2, J=6.97), 7.31-7.46 (m, 3), 7.76 (d, 2, J=7.86), 11.06 (br s, 1), 11.25 (s, 1), 11.61 (s, 1), 11.95 (br s, 1); MS m/z: 473 (M+1), 471 (M−1).
Reaction SMILES: [CH2:1]([C:5]1(Cl)[S:9][C:8]2[C:10]([Cl:17])=[C:11]([Cl:16])[C:12]([O:14][CH3:15])=[CH:13][C:7]=2[C:6]1(Cl)O)[CH2:2][CH2:3][CH3:4].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:16][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:7]2[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:9][C:8]=2[C:10]=1[Cl:17]
Reactant: CCCCC1(Cl)Sc2c(cc(OC)c(Cl)c2Cl)C1(O)Cl
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Temperature: 0 °C
Yield: 59.8 %

Procedure:
To a solution of 5.0 g of 2-n-butyl-6,7-dichloro-2,3-dichloro-3-hydroxy-5-methoxybenzo[b]thiophene in 25 ml of glacial acetic acid is added 6.5 ml of boron trifluoride etherate, with stirring. The mixture is heated on a steam bath until dissolution occurs and is stirred at room temperature for one hour. A mixture of 20 ml of 10% sodium hydroxide solution and 50 mg of ice is added followed by 50% sodium hydroxide solution to pH 7. The mixture is extracted with 3×100 ml-portions of ether. The ether extracts are washed with water, dried and concentrated to give an oil. The oil is chromatographed on 100 g silica gel column using a 9:1 hexane dichloromethane system as the eluant. Evaporation of the eluant gives 2.3 g of 6,7-dichloro-2-n-butyl-5-methoxybenzo[b]thiophene or an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH:15]([C:17](=[O:19])[NH2:18])[F:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[Li+].[OH-].Cl>CO.C1COCC1>[C:17]([CH:15]([F:16])[C:12]1[CH:13]=[CH:14][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=2[CH:11]=1)(=[O:19])[NH2:18]
Reactant: CCOC(=O)c1cc2ccc(C(F)C(N)=O)cc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)C(F)c1ccc2cc(C(=O)O)sc2c1

Procedure:
To a solution of 6-(carbamoyl-fluoro-methyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester (295 mg, 1.05 mmol) in MeOH/THF (1.5/6 mL) was added 1M LiOH (1.16 mL). The resultant solution was stirred overnight and 1N HCl was added dropwise to acidify (˜2 mL). The solvent was removed in vacuo and the solid was used without further purification. cal'd 254 (MH+), exp 254 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:14]=[C:15]([NH2:24])[S:16][C:17]=1[CH2:18][CH2:19][O:20][N+:21]([O-:23])=[O:22]>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([NH:24][C:15]1[S:16][C:17]([CH2:18][CH2:19][O:20][N+:21]([O-:23])=[O:22])=[C:13]([CH3:12])[N:14]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1CCO[N+](=O)[O-]
Yield: 72 %

Procedure:
Pet-161 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using 2,6-difluoro-benzoic acid and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6].ClC1C=CC=C(C(OO)=[O:39])C=1.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)=[O:39])=[N:12][CH:13]=1)=[O:6]
Reactant: COC(=O)CCc1ccc(Sc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCc1ccc(S(=O)c2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-ylsulfanyl]phenyl}propionate (1.00 g, 2.17 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (0.620 g, 2.60 mmol) at 0° C. The resulting solution was stirred for 1 hour at 0° C. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with water, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was recrystallized from ethanol 3 times, to thereby yield 0.790 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[CH:11][C:8]=2C#N)[CH2:3][CH2:2]1>OS(O)(=O)=O.O>[C:15]1([C:13]2[N:14]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=[CH:11][C:12]=2[C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2cc(C#N)c(N3CCOCC3)nc2-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(-c2ccc(N3CCOCC3)nc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 2-morpholino-6-phenyl-5-p-tolylnicotinonitrile (Compound 116,120 mg, 0.3 mmol) in 50% H2SO4 (5 ml) was heated at 140° C. overnight. The mixture was cooled down to room temperature and diluted with water, extracted with CH2Cl2. The organic layer was washed with water and brine, dried over MgSO4, concentrated in vacuo and purified by MPLC column chromatography (silica gel, 25% ethyl acetate in hexane) to provide the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10](O)[CH2:9]2)=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:24])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@@H:10]([F:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CC[C@@H](c2ccc(Br)cc2)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: F[C@@H]1CC[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of (1S,3R)-3-(4-bromophenyl)cyclopentanol (503 mg, 2.09 mmol) in 10 mL of CH2Cl2 at −78° C. was added (bis(2-methoxyethyl)amino)sulfur tri fluoride (Deoxo-Fluor, 462 μL, 2.50 mmol). The mixture was allowed to gradually warm up to rt overnight and then poured into sat'd NaHCO3 (20 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). The organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using hexanes as the eluant afforded 383 mg (76%) of the title compound: 1H NMR δ 1.53-1.78 (m, 2H), 1.95-2.39 (m, 4H), 3.35 (m, 1H), 5.19-5.32 (m, 1H), 7.09 (d, J 8.5, 2H), 7.40 (d, J=8.2, 2H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]([CH3:29])[CH3:30])=[CH:26][CH:27]=2)([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccc(C(C)C)cc1
Agent: [Pd]
Product: CCOC(=O)C(C)(Cc1ccc(OCCN)cc1)Oc1ccc(C(C)C)cc1
Yield: 97.2 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(2-azidoethoxy)phenyl]-2-(4-isopropylphenoxy)-2-methylpropionate (0.56 g), which is the product of Reference example 9(f), and palladium on carbon (5%, 60 mg) and the reaction mixture was treated to afford the title compound (0.51 g) as a syrup.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 64.5 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.500 mmol) and (2-phenylethyl)amine (0.121 g, 1.001 mmol) in MeCN (2 ml) was heated in a the microwave reactor at 120° C. for 15 nm ins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 15-20% EtOAc in petroleum ether 40-60° C. to give the title compound (0.124 g, 65%). 1H NMR (500 MHz CDCl3): δ 7.58-7.51 (m, 2H), 7.51-7.45 (m, 3H), 7.30-7.18 (m, 3H), 6.87 (d, 2H), 5.35 (t, 1H), 3.14 (q, 2H), 2.62 (t, 2H), 1.73 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 137.6, 135.0, 131.8, 129.9, 128.9, 128.7, 127.0, 125.4, 107.5, 61.7, 45.1, 36.0, 27.8; Mass Spectrum M−H+ 384.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzaldehyde (2 g, 12.8 mmol) in N,N-dimethylformamide (25 mL) were added potassium carbonate (3.46 g, 25 mmol) and methyl iodide (large excess) and the mixture was stirred at room temperature for 18 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.55 g, 70%).