Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH:9]([C:12]1[CH:20]=[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1)([CH3:11])[CH3:10].C([O-])(O)=O.[Na+]>ClCCl.CCOC(C)=O>[CH:9]([C:12]1[C:20]([C:5](=[O:7])[CH3:6])=[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1)([CH3:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: CC(C)c1cc2ccccn2n1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 46 %

Procedure:
Solid aluminum chloride (0.82 g, 2 equivalents) was added to a solution of acetyl chloride (0.24 mL, 1.1 equivalents) in 1 mL of dichloromethane and the solution was stirred at room temperature for 40 minutes. Neat 2-isopropylpyrazolo[1,5-a]pyridine (0.5 g, 1 equivalent) was added dropwise to this solution at room temperature (exotherm was observed), and the resulting solution was stirred at room temperature for 20 hours and worked up with EtOAc and saturated NaHCO3. The crude product was purified by silica gel flash column chromatography to give 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone (0.29 g, 46% yield) as a solid. Compound 1080.
Reaction SMILES: [F:1][C@@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[F:1][C@@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1
Reactant: C[C@@H]1C[C@H](F)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](F)c2ncnc(N3CCNCC3)c21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.725 g, 2.155 mmol) was dissolved in dioxane (5 mL) and cooled to 0° C. A solution of HCl in dioxane (13.47 mL, 53.88 mmol; 4M) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. A white precipitate had formed after about 8 hours. The reaction mixture was concentrated in vacuo, re-suspended in MeOH, and re-concentrated (3×). The residue was dissolved in MeOH (about 2 to 3 mL) and added dropwise to a rapidly stirring flask containing ether (80 mL). The white solid was filtered under a blanket of nitrogen gas and dried under nitrogen gas to give (5R,7S)-7-fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine di-hydrochloride a white solid (555 mg, 83%). LCMS (ESI+) m/z 237.2 [M+H]+; Rf: 1.70 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[CH2:20]([OH:23])[C:21]#[CH:22]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:22]#[C:21][CH2:20][OH:23]
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1Br
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OCc2ccccc2)ccc1C#CCO
Temperature: 50 °C
Yield: 72.2 %

Procedure:
To a solution of 5-Benzyloxy-2-bromo-benzoic acid methyl ester (120 g, 374 mmol) and prop-2-yn-1-ol (41.9 g, 747 mmol) in triethylamine (1 L), copper(I) iodide (0.712 g, 3.74 mmol) and bis(triphenylphosphine)palladium(II) chloride (26.2 g, 37.4 mmol) at RT under N2. The mixture was heated at 50° C. reflux under N2 for 12 hr. The reaction was cooled to room temperature, concentrated to dryness, diluted with H2O (50 mL) and extracted with ethyl acetate (500 mL*3), The organic phase was washed with saturated sodium bicarbonate solution 500 mL, dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography eluted with PE:EA=10:1˜4:1 to give title product (80 g, 72%) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[C:5]([O:10][CH3:11])[N:4]=[CH:3][C:2]=1[O:1][CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:9]
Reactant: COc1cc(C=O)c(O)cn1
Reactant: CCOC(=O)Cn1nccc1-c1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nccc1-c1ncccc1COc1cnc(OC)cc1C=O
Temperature: 70 °C
Yield: 94.1 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (107 mg, 0.70 mmol, 1 eq.), ethyl 2-(5-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate hydrochloride (220 mg, 0.70 mmol, 1 eq.), and K2CO3 (386 mg, 2.8 mmol, 4 eq.) in DMF (6.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give ethyl 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (261 mg, 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.69 (d, J=3.8 Hz, 1H), 8.02 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.40 (dd, J=7.6, 4.0 Hz, 1H), 7.13 (s, 1H), 6.53 (d, J=1.6 Hz, 1H), 5.30 (s, 2H), 5.28 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 1.18 (t, J=7.1 Hz, 3H). LRMS (M+H+) m/z 397.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:4]([OH:21])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=3)[O:21][C:4]=2[CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1O)c1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: FC(F)(F)c1ccc(-c2nc3ccc(Br)cc3o2)cc1
Temperature: 160 °C
Yield: 73.1 %

Procedure:
Intermediate 53 (940 mg, 2.6 mmol) was dissolved in xylene (25 ml) and added p-Toluenesulphonic acid (991 mg, 5.22 mmol). This mixture was refluxed to 160° C. for 12 h under a dean-stork condenser. Xylene removed from the reaction mixture and basified the residue with aq. NaHCO3 (30 ml). Work up (EtOAc/H2O) followed by purification with combiflash using a gradient mixture of EtOAc and Petether (5:95) as eluent to afford the titled compound (650 mg) as an Off-White solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(OCCN3CCCCC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin- 1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.4 g, 10 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 g (77%); off white powder, mp 174° C.; MS: 517.6 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:11][CH2:10][C:9]([O:13][CH3:14])=[O:12])[CH:2]=1
Reactant: NCc1cccnc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
3-Pyridylmethylamine (10.81 g) is dissolved in methanol (50 ml), and thereto is added dropwise methyl acrylate (8.60 g) under ice-cooling. The mixture is stirred at room temperature for 18 hours. The mixture is distilled to remove the solvent, and then the residue is distilled under reduced pressure to give methyl 3-(3-pyridylmethylamino)propionate (16.02 g, 82.5%), b.p. 119°-120° C./0.4 mmHg.
Reaction SMILES: [CH:1]1([N:4]([S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH2:5][CH2:6][O:7]C(=O)C)[CH2:3][CH2:2]1.[OH-].[K+]>CO>[CH:1]1([N:4]([CH2:5][CH2:6][OH:7])[S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)N(CCOC(C)=O)C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)N(CCO)C1CC1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
A mixture of acetic acid 2-[cyclopropyl-(propane-1-sulfonyl)-amino]ethyl ester (1.7 g, 6.8 mmol) and KOH (0.57 g, 10.2 mmol) in 30 ml Methanol was stirred over night at room temperature. The solvent was evaporated the residue dissolved in ethyl acetate and subsequently extracted with water and 1 M KOH, dried over Na2SO4 and the solvent evaporated to obtain 0.46 g of product which was used purified by chromatography (253.5 mg of colorless oil)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:38])[N:26]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[N:25]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][N:26]([CH2:39][C:40]([CH3:41])([OH:42])[CH3:43])[C:27]=3[CH3:38])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Reactant: Cc1nn(CC(C)(C)O)c(C)c1B1OC(C)(C)C(C)(C)O1
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: C1COCCO1
Solvent: O
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c(C)nn(CC(C)(C)O)c3C)cc12

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (20.0 mg, 0.0521 mmol), 1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-2-methylpropan-2-ol (30.7 mg, 0.104 mmol), Pd(PPh3)4 (3.01 mg, 0.00261 mmol), K2CO3 (21.6 mg, 0.156 mmol) and 4:1 dioxane:water was microwaved at 100° C. for 45 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.23 (s, 3H), 1.24 (s, 3H), 1.80 (d, J=7.3 Hz, 3H), 2.07 (s, 3H), 2.17 (s, 3H), 3.65 (br. s., 3H), 4.01 (s, 2H), 5.06-5.15 (m, 1H), 6.89 (dd, J=9.1, 4.0 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.32 (s, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H). MS (ES+): m/z=471.03/473.01 (100/50) [MH+]. HPLC: tR=3.47 min (polar—5 min, ZQ3).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[NH:8][CH2:7][C:6]=2[N:5]=[CH:4]1.C(N(CC)CC)C.[Se](=O)=O>O1CCOCC1>[NH:3]1[C:11]2[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[N:8]=[CH:7][C:6]=2[N:5]=[CH:4]1
Reactant: COC(=O)[C@@H]1Cc2[nH]cnc2CN1
Agent: Cl
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2[nH]cnc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
68.5 g methyl (6S)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate dihydrochloride, 81.8 g triethylamine and 63.3 g selenium dioxide were suspended in 1.1 l anhydrous 1,4-dioxane. The mixture was refluxed for 2 h. 26.3 g triethylamine were added and the mixture was allowed to cool down to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue was suspended in 300 ml methanol. 46.8 g triethylamine were added to adjust to pH 8-9. The resulting precipitate was filtered and washed with 70 ml methanol. The precipitate was treated with 500 ml N,N-dimethylformamide, stirred at 140° C. for 30 minutes and filtered hot. Upon cooling to room temperature, precipitation takes place. The precipitate was filtered, washed with 80 ml cold methanol and dried under vacuum to yield the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].FC(F)(F)S(O[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=2)[N:27]=1)(=O)=O.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([N:15]1[CH2:16][CH2:17][CH:12]([N:5]3[C:6]4=[N:7][CH:8]=[CH:9][N:10]=[C:11]4[C:3]([CH3:19])([CH3:2])[C:4]3=[O:18])[CH2:13][CH2:14]1)[CH:35]=[CH:34]2
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Reactant: O=S(=O)(Oc1ccc2cc(F)ccc2n1)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1(C)C(=O)N(C2CCN(c3ccc4cc(F)ccc4n3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.117 g, 0.414 mmol), 6-fluoroquinolin-2-yl trifluoromethanesulfonate (0.134 g, 0.455 mmol), and DIEA (0.253 ml, 1.448 mmol) in DMSO (3 mL) was heated at 110° C. in 1 h. The reaction mixture was cooled, H2O was added, and the mixture was extracted with DCM (3×). The organic extracts were dried over Na2SO4, filtered, concentrated, and purified by ISCO (0-30% EtOAc/DCM) to give the title compound (81 mg, 50%). MS (M+1): 392.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11-8.13 (1 H, m), 8.08-8.10 (1 H, m), 8.05 (1 H, d, J=9.2 Hz), 7.60 (1 H, dd, J=9.2, 5.3 Hz), 7.52 (1 H, dd, J=9.4, 2.9 Hz), 7.40-7.45 (1 H, m), 7.35-7.40 (1 H, m), 4.71 (2 H, d, J=13.5 Hz), 4.48-4.63 (1 H, m), 3.02 (2 H, t, J=12.1 Hz), 2.36-2.48 (2 H, m), 1.79 (2 H, d, J=9.8 Hz), 1.27-1.36 (6 H, m).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][CH2:8][O:9][C:10]([CH2:12][C:13]([CH2:15][C:16](OCC)=[O:17])=O)=[O:11].Cl>C(O)(=O)C>[CH2:8]([O:9][C:10]([CH2:12][C:13]1[CH:15]=[C:16]([OH:17])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1)=[O:11])[CH3:7]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: Nc1nc[nH]n1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(O)n2ncnc2n1
Temperature: 25 °C
Yield: 96 %

Procedure:
A suspension of 3-amino-s-triazole (28 g) and diethyl acetonedicarboxylate (100 g) in 100 ml of acetic acid was refluxed for six hours. After cooling to room temperature, 150 ml of concentrated hydrochloric acid was added under ice cooling, the crystals thus formed were collected by filtration, and washed twice with 100 ml of ethanol, then once with 100 ml of ether, affording 71 g of the objective compound as colorless crystals.
Reaction SMILES: C([O:4][B:5](OC(C)C)[O:6]C(C)C)(C)C.[Cl:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[O:22][C:23]([F:26])([F:25])[F:24]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([B:5]([OH:6])[OH:4])[CH:18]=[CH:17][C:16]=1[O:22][C:23]([F:26])([F:25])[F:24]
Reactant: FC(F)(F)Oc1ccc(I)cc1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Triisopropylborate (0.76 mL, 3.29 mmol) and iodide 54 (815 mg, 2.53 mmol) were successively added via syringe to a mixture of anhydrous toluene (4 mL) and anhydrous distilled THF (1 mL) under N2 and the mixture was cooled to −78° C. n-Butyllithium (1.08 mL of a 2.5 M solution in hexanes, 2.70 mmol) was added drop-wise over 75 min to the stirred solution (at −78° C.), and the mixture was stirred at −78° C. for an additional 3 h, and then slowly warmed to −20° C. (over 1.5H). 2N HCl (2.6 mL) was added and the mixture was stirred at room temperature for 30 min, and then diluted with water (40 mL) and extracted with EtOAc (5×50 mL). The extracts were washed with brine (50 mL) and then evaporated to dryness. The residue was triturated in pentane (˜3-4 mL), cooled to −78° C., and rapidly filtered cold (washing with pentane cooled to −78° C.) to give 3-chloro-4-(trifluoromethoxy)phenylboronic acid (55) (459 mg, 76%) as a white solid (a 1:1 mixture of the trimeric boroxine and the boronic acid by NMR): mp 202-204° C.; 1H NMR (CDCl3) δ 8.26 (d, J=1.5 Hz, 3H, boroxine), 8.12 (dd, J=8.2, 1.5 Hz, 3H, boroxine), 7.85 (d, J=1.5 Hz, 1H, boronic acid), 7.65 (dd, J=8.2, 1.6 Hz, 1H, boronic acid), 7.48 (dq, J=8.2, 1.5 Hz, 3H, boroxine), 7.35 (dq, J=8.2, 1.5 Hz, 1H, boronic acid), 4.57 (s, 2H, boronic acid).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[S:7])=[CH:4][CH:3]=1.[CH2:11]([NH2:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].[OH-].[K+]>C(Cl)CCl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:19][C:6](=[S:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[S:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=S)Cl)cc1
Reactant: NCCCCCCCN
Agent: [K+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1ccc(C(=S)NCCCCCCCNC(=S)c2ccc(C)cc2)cc1

Procedure:
m.p. 181°-182° C., 25.8 g., was prepared as in Example 1 using 4-methylthiobenzoyl chloride (prepared from 31 g. of 4-methylthiobenzoic acid as in Example 6) in 100 ml. of ethylene dichloride, 11.9 g. of 1,7-heptanediamine, 200 ml. of 10% aqueous potassium hydroxide solution, 500 ml. of ethylene dichloride and recrystallization from acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[CH:8]=[CH:7][C:6]=2[CH:12]=1.[OH-:13].[Na+]>[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[CH2:8][CH:7]([OH:13])[C:6]=2[CH:12]=1
Reactant: O=S1(=O)C=Cc2cc(Br)ccc21
Reactant: [OH-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=S1(=O)CC(O)c2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-1-benzothiophene 1,1-dioxide (100 mg, 0.41 mmol) was suspended in 1N aqueous sodium hydroxide (2.0 mL), heated to 100° C. in a microwave, and allowed to stir for 15 minutes. The mixture was then allowed to cool to ambient temperature before the mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was used without further purification. LRMS (ESI) calc'd for C8H7BrO3S [M+Na]+: 285. Found: 285.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:10][CH:9]=1.[OH-].[K+]>C(O)C.O>[OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1ccc(OCCSCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1ccc(OCCSCCO)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl]propanoic acid, methyl ester (37.64 g, 0.132 mol) in 80% aqueous ethanol (300 ml) was treated with a solution of potassium hydroxide (17.0 g, 0.257 mol) in water (25 ml) and the resulting mixture was stirred at 22° C. for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (200 ml) and dichloromethane (200 ml). The aqueous phase was then adjusted to pH 2 with 6N hydrochloric acid and extracted several times with dichloromethane. The combined organic extracts were washed with brine, dried (magnesium sulfate) and evaporated to give 35.67 g (100%) of the title material as a white solid: mp 64-65° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH2:15][CH2:16][CH2:17][O:18]C2CCCCO2)=[CH:7][C:6]=1[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:3])[CH3:2]>CO>[C:1]([O:4][C:5]1[C:6]([C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:7][C:8]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][C:10]=1[C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(CCCOC2CCCCO2)cc1C(C)(C)C
Solvent: CO
Product: CC(=O)Oc1c(C(C)(C)C)cc(CCCO)cc1C(C)(C)C
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A solution of 14.6 g (37.38 mmol) of 3-(4-acetoxy-3,5-di-tert-butylphenyl)-l-(tetrahydropyran-2-yloxy)propane in 80 ml of anhydrous methanol is stirred together with 1 g of amberlyst 15 (H+ -form) for 2 hours at 45° C. and maintained at room temperature overnight. After dilution of the suspension with 100 ml of methanol, the catalyst is removed by filtration and the filtrate evaporated at reduced pressure leaving 11.53 g of crude product, which is purified by flashchromatography over silica gel with H/AcOEt 3:1 as the eluent. 6.96 g (61%) of 3-(4-acetoxy-3,5-di-tert-butylphenyl)propanol is isolated from the product-containing fractions as a faintly yellowish oil, which gradually crystallizes upon standing, m.p. 93°-95° C. (C19H30O3 ; F. W. 306.4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: ClCCCBr
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 6-hydroxycarbostyril (50 g) and 1-bromo-3-chloropropane (120 ml) in dimethylformamide (600 ml) is added potassium carbonate (65 g) in portions at room temperature. The mixture is stirred at room temperature for three days, and the insoluble materials are collected by filtration and washed with n-hexane. The resulting crystals are further washed successively with water, acetone and n-hexane, and dried to give 6-(3-chloropropoxy)carbostyril (50.7 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:26]([O:28][C:29]([C:31]1[CH:47]=[CH:46][C:34]2[NH:35][C:36]([NH:38][CH2:39][CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[N:37][C:33]=2[CH:32]=1)=[O:30])[CH3:27].CO>CN(C)C=O.C(O)(=O)C>[CH2:26]([O:28][C:29]([C:31]1[CH:47]=[CH:46][C:34]2[NH:35][C:36]([NH:38][CH2:39][CH:40]3[CH2:41][CH2:42][N:43]([CH2:5][C:4]4[CH:7]=[C:8]([Cl:10])[CH:9]=[C:2]([Cl:1])[C:3]=4[OH:11])[CH2:44][CH2:45]3)=[N:37][C:33]=2[CH:32]=1)=[O:30])[CH3:27]
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: CCOC(=O)c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1ccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 3,5-dichloro-2-hydroxybenzaldehyde (0.3 mmol) and sodium triacetoxyborohydride (0.3 mmol) to a solution of 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acid ethyl ester (0.1 mmol) in dimethylformamide-acetic acid (10:1) (1.0 ml), the mixture was stirred at room temperature overnight. Methanol (1.0 ml) was added to the reaction mixture to suspend the reaction, and after stirring for 1 hour, the solution was passed through SCX (Bond Elute SCX500MG). The SCX was washed with methanol and then with a mixed solution of chloroform/methanol (1/1), and elution was performed with a 0.5N ammonia-dioxane solution. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to preparative HPLC to obtain 2-{[1-(3,5-dichloro-2-hydroxybenzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylic acid ethyl ester. The compound was identified by LC-MS.