Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([S:11]([CH3:13])=[O:12])[CH:3]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.O>[CH3:13][S:11]([C:4]1[CH:3]=[C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of the product of Example 14B (45 mg, 0.17 mmol), tert-butyl piperazine-1-carboxylate (38 mg, 0.2 mmol), tetrabutylammonium bromide (6 mg, 0.02 mmol) and potassium carbonate (35 mg, 0.26 mmol) in dry DMSO (5 mL) was heated under nitrogen at 120° C. for 3 hours. The mixture was added to water (20 mL) and aqueous hydrogen chloride solution (20 mL) and washed with ethyl acetate. The aqueous phase was basified with 2.5N sodium hydroxide solution and extracted with ethyl acetate (3×20 mL). The combined organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40/1 dichloromethane/methanol to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:10][C@H:11]([OH:37])[C@@H:12]([NH:26]C(=O)OCC1C=CC=CC=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH2:26][C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[C@@H:11]([OH:37])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
Method 1 A solution containing the product from Example 23J (0.568 g, 0.95 mmol) in a mixture of ethyl acetate (5 mL) and methanol (5 mL) was treated with Pd(OH)2 on carbon (0.2 g, 20% Pd by wt.) and HCl solution (0.25 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) for 16 hours at 25° C., filtered through a bed of celite®, rinsed with a mixture of 50% ethyl acetate in methanol, and concentrated. The residue was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.442 g), which was used without further purification.
Reaction SMILES: [CH:1]([CH:5]([CH2:11][CH:12]=[CH2:13])[C:6](OCC)=[O:7])([CH2:3][CH3:4])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[F-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH:1]([CH:5]([CH2:11][CH:12]=[CH2:13])[CH2:6][OH:7])([CH2:3][CH3:4])[CH3:2]
Reactant: C=CCC(C(=O)OCC)C(C)CC
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(CO)C(C)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (50 mL) solution of ethyl 2-sec-butylpent-4-enoate was added dropwise over 30 minutes to a tetrahydrofuran (120 mL) solution of lithium aluminum hydride (4.79 g, 126.3 mmol) cooled to 0° C., and the mixture was then stirred at 0° C. for 1 hour and then stirred at room temperature for 2 hours. The mixture was cooled again to 0° C. Ethyl acetate (55.4 mL), water (44.7 mL), tetrahydrofuran (83.1 mL), and sodium fluoride (53.0 g) were added thereto, and the mixture was stirred for 1.5 hours. The mixture was filtered through Celite to remove insoluble matter. Then, the solution was concentrated, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (12.20 g, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Br)n[nH]c2c1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of 5.0 g of 6-nitro-1H-indazole in 50 ml dimethylformamide was added 5.73 g of N-bromosuccinimide at room temperature, and the mixture was stirred at the same temperature for 1 hour. After removing the solvent by distillation, the residue was added with 250 ml of ethyl acetate. The mixture was sequentially washed with half-saturated aqueous sodium hydrogencarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. After filtrating the organic layer through a silica gel pat, the solvent was evaporated and the resulting crystals were suspended in toluene, to give 6.59 g of the title compound as light brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14]O)[C:5]2([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16].S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][Cl:25])[C:5]2([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]
Reactant: O=S(Cl)Cl
Reactant: OCCCNC1=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Product: OC1(c2ccccc2)C(NCCCCl)=Nc2ccc(Cl)cc21

Procedure:
Reaction of 5-chloro-2-(3-hydroxypropylamino)-3-phenyl-3H-indol-3-ol with thionylchloride by a procedure analogous to that described in Example 2 gives 5-chloro-2-(3-chloropropylamino)-3-phenyl-3H-indol-3-ol.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[O-].[Na+].[C:7]([O:14]CC)(=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(=O)(O)(O)O>CO>[CH3:1][N:2]([CH3:3])[C:7](=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CNC
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 1,500 mL reactor, are added at 0° C., 360 g (4 mol) of dimethylamine (DMA) solution at 50% by weight in methanol and 44 g (0.2 mol) of sodium methylate at 25% by weight in methanol. To this mixture are added at 0-5° C. and within 1 hour, 584 g (4 mol) of diethyl oxalate. The mixture is maintained with stirring at 0° C. for 4 hours. The reaction medium is concentrated in vacuo (Pmax=200 mbars) for removing residual DMA and methanol and an 85% orthophosphoric acid solution (23.3 g 0.2 mol) is then added. The salts formed are filtered and the filtrate is then distilled in vacuo (Tbp=77-78° C., P<1 mbar) for recovering the desired product (500 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1.O>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
A solution of 1.48 g of 3-aminobenzene sulfonic acid in 1:1 tetrahydrofuran/water was treated at 0° C. with 1.43 g of sodium bicarbonate. After 5 min, 1.30 g of acetic anhydride was added dropwise and the reaction allowed to warm to ambient temperature under an atmosphere of nitrogen over 14 h. The reaction mixture was passed through a column of Amberlyst 15 ion exchange resin, eluted with water, and concentrated in vacuo to yield an oil which upon treatment with benzene and azeotropic removal of water in vacuo yielded 1.8 g of the title product as a white crystalline solid. (1H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH:16]([CH2:18][CH:19]=[O:20])[C:15](=[O:21])[C:14]([CH3:22])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:23]COC)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl>CO.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH:16]([CH2:18][CH:19]=[O:20])[C:15](=[O:21])[C:14]([CH3:22])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(CC=O)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(CC=O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A solution of (2RS,9aSR)-9a-butyl-7-methoxymethoxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (85 mg) in methanol (1 mL) was diluted with 2N HCl (0.36 mL, 0.72 mmol). The resulting mixture was stirred at room temperature for 30 minutes followed by heating in an oil bath at 80° C. for 40 minutes. On cooling to room temperature, crystals formed. The mixture was diluted with EtOAc and washed with 5% NaHCO3 and 1N HCl. The aqueous washes were back-extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by PLC on a 0.1×20×20 cm silica gel GF plate, using 2:1 hexanes-EtOAc as developing solvent, to afford (2RS,9aSR)-9a-butyl-7-hydroxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (50 mg).
Reaction SMILES: [H-].[Li+].C([Al+]CC(C)C)C(C)C.[H-].C([O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[O:25][CH:26]([CH3:28])[CH3:27])(C)C>C1COCC1>[Cl:24][C:20]1[C:19]([O:25][CH:26]([CH3:28])[CH3:27])=[C:18]([CH2:17][OH:16])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)OC(=O)c1cccc(Cl)c1OC(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1c(Cl)cccc1CO
Temperature: 25 °C
Reaction time: 120 h
Yield: 89.2 %

Procedure:
Diisobutylaluminum lithium hydride (26.8 mL of a 1.0 M in hexanes, 26.8 mmol) was added dropwise to a solution of 3-chloro-2-isopropoxybenzoic acid isopropyl ester (2.29 g, 8.94 mmol) in THF (20 mL) under N2 at 0° C. After the addition was complete, the ice bath was removed, the solution warmed to ambient temperature, and the reaction mixture stirred for 5 d. The reaction was cooled to 0° C. and quenched using 1N HCl (100 mL) until all the solids dissolved. The solution was extracted with Et2O (3×50 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (1.60 g, 89%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 7.41 (d, J=4.5 Hz, 1H), 7.33 (dd, J=8.0, 1.5 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 5.19 (t, J=5.7 Hz, 1H), 4.53 (d, J=5.5 Hz, 1H), 4.44-4.36 (m, 1H), 1.24 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C(N(CC)C(C)C)(C)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:23]1([S:29]([O:13][C:3]2[C:2]([Br:1])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:5][CH:4]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc2ccc(O)c(Br)c2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 0 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
A mixture of 8-bromo-2-methylquinolin-7-ol (1.10 g, 4.62 mmol) and N,N-diisopropylethylamine (1.19 g, 9.24 mmol) were dissolved in anhydrous DCM (10 mL), and the solution was cooled to 0° C. Benzenesulfonyl chloride (0.90 g, 5.10 mmol) in 5 mL DCM was added over 10 min, and the reaction mixture was stirred for 14 h at room temperature under argon. Solvent was removed in vacuo, and residue was dissolved in EtOAc and washed twice with saturated aq. NaHCO3 and then dried over anhydrous Na2SO4. Solvent was removed in vacuo, and the residue was purified by SiO2 column chromatography (Hexanes/EtOAc=1/1) to yield SO185 as a white solid (1.70 g, 4.49 mmol, 97% yield). 13CNMR (ppm, 500 MHz, CDCl3, 298 K) δ 161.588, 148.067, 145.802, 136.573, 135.924, 134.834, 129.444, 128.907, 128.029, 126.122, 123.236, 121.950, 118.038, 25.922. 1HNMR (ppm, 400 MHz, CDCl3, 298 K) δ: 8.049 (d, 1H, J=8.4 Hz), 7.976 (m, 1H), 7.958 (m, 1H), 7.758 (d, 1H, J=8.8 Hz), 7.701-7.657 (m, 1H), 7.599 (d, 1H, J=8.8 Hz), 7.554-7.507 (m, 2H), 7.346 (d, 1H, J=8.0 Hz), 2.785 (s, 3H). MS-ESI (m/z): [M+H]+ calculated for C16H13BrNO3S, 378.0 (79Br) and 380.0 (81Br); found 378.0 (79Br) and 379.9 (81Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15]S(C(F)(F)F)(=O)=O)[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:36]2[CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=[C:34]([C:33]([F:32])([F:48])[F:47])[CH:35]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 38 %

Procedure:
The title compound was prepared in 38% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 15, step (d)) under the conditions described in Example 15, step (e-f) using 3,5-bis-trifluoromethylphenylboronic acid in step (e).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:15][C:16]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45]Br)=[CH:40][C:17]=1[C:18]([NH:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:8]([O:15][C:16]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:40][C:17]=1[C:18]([NH:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(CCBr)ccc1OCc1ccccc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1CCN(CCc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under ice-cooling, 1-methylpiperazine (0.095 mL) was addedd to an acetone (1.5 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethyl)benzamido)-4-phenylbenzoate (0.10 g), followed by stirring at room temperature for 30 minutes. Potassium carbonate (0.035 g) was added thereto, followed by stirring at room temperature for 1 hour. 1-Methylpiperazine (0.095 mL) and potassium carbonate (0.035 g) were added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was left to stand overnight. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.10 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[C@@H:10]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[Pd]>[CH2:24]([C@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[CH3:22])[CH2:25][CH2:26][CH3:27]
Reactant: [H][H]
Reactant: CCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)c1cccc(C)c1C
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H]1CNCCN1C(=O)c1cccc(C)c1C
Yield: 116.9 %

Procedure:
4-Benzyl-2(S)-n-butyl-1-(2,3-dimethylbenzoyl)piperazine (0.93 g, 2.55 mmol) was dissolved in methanol and hydrogenated in a Parr apparatus under 60 psi hydrogen in the presence of 10% Pd/C (0.186 g) for 24 h. The catalyst was removed by filtration through Celite, and the solvent removed in vacuo to obtain the title compound (0.818 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]([CH3:15])[C:12](Cl)=[S:13].[OH-].[K+]>>[CH3:10][N:11]([CH3:15])[C:12](=[S:13])[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1O
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Product: CN(C)C(=S)Oc1ccccc1C#N
Yield: 94 %

Procedure:
If the procedure described in Preparation XVI is followed starting from 15 g (126.10-3 mol) of 2-hydroxybenzonitrile, 17.9 g (145.10-3 mol) of dimethylthiocarbamoyl chloride and 7.4 g (126.10-3 mol) of potassium hydroxide, 24.1 g (yield: 94%) of the expected product are obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Cl[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[CH:29][CH:28]=2)[CH2:24][NH:25][CH3:26])=[CH:19][CH:18]=1>>[CH3:26][NH:25][CH2:24][CH:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)=[CH:29][CH:28]=1)[C:20]1[CH:19]=[CH:18][C:17]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:22][CH:21]=1
Reactant: CNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: CNCC(c1ccc(-c2cccnc2)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 1 but substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and coupling to {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine*, the title compound was obtained. LC/MS: (PS-B3) Rt 2.42 [M+H]+355. 1H NMR (Me-d3-OD) δ 1.94 (AcOH, s), 2.72 (3H, s), 3.73 (2H, d), 4.46 (1H, t), 7.41 (2H, d), 7.51-7.56 (3H, m), 7.63 (2H, d), 7.70 (2H, d), 7.96 (2H, s), 8.10 (1H, dt), 8.53 (1H, dd), 8.80 (1H, d). *This starting material can be made by the method described in Example 21.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1([OH:10])[CH2:9][O:8][CH2:7]1)([CH3:5])[CH3:4].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:10][C:6]1([CH:3]([CH3:5])[CH3:4])[CH2:9][O:8][CH2:7]1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC(C)C1(O)COC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C1(OC(=O)Oc2ccccn2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (331 mg, 8.26 mmol) in THF (25 mL) was added 3-isopropyloxetan-3-ol (800 mg, 6.89 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (1489 mg, 6.89 mmol) in THF (25 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage eluting with 20% EtOAc in hexanes to afford the desired product 3-isopropyloxetan-3-yl pyridin-2-yl carbonate (320 mg, 20.2% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) d 8.47-8.39 (m, 1H), 7.86-7.78 (m, 1H), 7.31-7.24 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 4.89 (d, J=8.5 Hz, 2H), 4.67 (d, J=8.5 Hz, 2H), 2.53 (dt, J=13.7, 7.0 Hz, 1H), 1.13 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)C>C(O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Solvent: CCO
Product: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Yield: 86.9 %

Procedure:
A mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (7.00 g, 0.0194 mole) sodium hydroxide pellets (0.88 g, 0.0220 mole), and 95% ethanol (100 ml) was refluxed for 1 hr. The reaction mixture was cooled and filtered. The filter cake (7.3 g) was dissolved in warm water, acidified with concentrated hydrochloric acid, and chilled. The precipitated solid was collected by filtration and the filter cake was rinsed with water, giving 5.6 g (87%) of crystals. Recrystallization from tetrahydrofuran-methanol gave 5.4 g of white needles, mp 264°-267° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](OC)=[O:12])=[CH:10][C:5]=2[N:4]=[CH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[OH:12][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[CH:3]=[N:4][C:5]=2[CH:10]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cnc2cc(CO)ccc21
Reaction time: 2 h
Yield: 58.6 %

Procedure:
A solution of methyl 1-methylbenzimidazole-5-carboxylate (1.6 g, 8.42 mmol) in dry THF (80 mL) was treated with LiAlH4 (1.59 g, 42.1 mmol) and the mixture stirred for 2 hours. 1.5 mL of 5% NaOH solution was then added, and the solid which precipitated was filtered through diatomaceous earth. The filtrate was collected and the solvent removed under reduced pressure to give 0.8 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9]([F:19])[C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:20][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9]([F:19])[C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2([CH3:20])[OH:16])=[CH:4][CH:3]=1
Reactant: COc1cc2c(=O)c3cc(Br)ccc3oc2cc1F
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)Oc1ccc(Br)cc1C2(C)O
Yield: 100.4 %

Procedure:
To a suspension of 7-bromo-3-fluoro-2-methoxy-9H-xanthen-9-one (25 g, 73.4 mmol) in THF (500 mL) was added MeMgCl (2.0 equiv. 146.75 mmol, 48.9 mL, 3.0 M solution in THF) at −20° C. (internal temp) slowly over 30 minutes. The resulting mixture was allowed to reach ambient temperature where it was maintained for 12 hours. The reaction was quenched by adding saturated NH4Cl. The phases were separated and the aqueous layer was extracted with EtOAc (2×300 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford 25 g of 7-bromo-3-fluoro-2-methoxy-9-methyl-9H-xanthen-9-ol that was used in the next step without further purification. A solution of the derived alcohol (25 g) was dissolved in DCM (300 mL) and pPTS (250 mg, 0.995 mmol) was added. The mixture was heated to reflux for 2 hours at which time the reaction was cooled to rt and washed with NaHCO3 (100 mL). The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified via chromatography (hexanes/DCM, 3:1) to provide 7-bromo-3-fluoro-2-methoxy-9-methylene-9H-xanthene as an orange solid.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: NCCCC(O)CN1CCCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCC(O)CN3CCCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by the procedure analogous to Example 1. MS (APCI, m/z): 512 [M+H]+.