Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:16])[C:10](N(OC)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])(O)(=O)=O.[K+].[CH3:29][O:30][C:31]([CH2:33]P(OC)(OC)=O)=[O:32].[H-].[Na+]>C(OCC)C.O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:16])/[CH:10]=[CH:33]/[C:31]([O:30][CH3:29])=[O:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)/C=C/[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.7 %

Procedure:
A solution of (2S)-2-[(tert-butoxy)carbonylamino]-N-methoxy-N-methylpropanamide (13.05 g, 56.18 mmol) in ethyl ether (560 mL) was chilled with an ice water bath and then 95% lithium aluminum hydride (2.80 g, 70.23 mmol) was added. The reaction was stirred at room temperature for 20 minutes and then a solution of aqueous potassium hydrogen sulfate (300 mL, 0.33M) was added. The resulting mixture was extracted three times with ethyl ether. The combined organic layers were washed three times with 1N hydrogen chloride, three times with saturated aqueous sodium hydrogen carbonate, and once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting solid was dissolved in anhydrous tetrahydrofuran (430 mL) then added to a cold solution of trimethyl phosphonoacetate (27.3 mL, 168.5 mmol) and sodium hydride (112 mmol) in anhydrous tetrahydrofuran (130 mL) that had been previously stirred at room temperature for 30 minutes. The reaction was stirred for 5 minutes in a ice water bath, at room temperature for 20 minutes, and then water (500 mL) was added. The reaction mixture was diluted with brine and ethyl acetate, stirred, and the layers separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 0-30% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (8.85 g, 69%): ES-MS (m/z) 230.4 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]([CH3:20])[CH:12]=3)[O:10][C:3]=12.[CH3:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[CH3:19][O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:31][C:30]3[C:22]([CH3:21])=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)[CH:8]=2)=[CH:12][C:13]=1[CH3:20]
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: COc1c(C)cc(-c2cc3nccc(Cl)c3o2)cc1C
Product: COc1c(C)cc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1C

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(4-methoxy-3,5-dimethylphenyl)furo[3,2-b]pyridine (28.90 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.42 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a white solid (22 mg, 56%). (HPLC (method F): 99%, RT: 4.37 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.15 (s, 1H), 8.51 (s, 1H), 7.94 (d, J=5.5, 1H), 7.54 (s, 2H), 7.38 (t, J=2.7, 1H), 7.30 (d, J=8.3, 1H), 7.25 (s, 1H), 7.00 (d, J=8.4, 1H), 6.52 (s, 1H), 6.14 (d, J=5.5, 1H), 3.69 (s, 3H), 2.35 (s, 3H), 2.25 (s, 6H); MS (m/z) 398 [M+H]+, RT: 4.2 min.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][CH:12]=[CH:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:16]1(=[O:23])O[C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1.C(N(CC)CC)C>[NH2:1][C:2]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][CH:12]=[CH:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:16]1(=[O:23])[NH:1][C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC(=O)O1
Agent: Nc1cc2cccnc2c2ncccc12
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C1CCCC(=O)N1

Procedure:
5-Amino-1,10-phenanthroline (350 mg, 1.8 mmol) was refluxed with glutaric anhydride (2.0g, 17.5 mmol) in pyridine (3 mL) and triethylamine (3 mL) for 2 hours. The reaction mixture was reduced to a viscous oil by rotary evaporation. Column purification on silica with 10% methanol in methylene chloride (product produced bright red spots with Fe(II) on TLC) gave the crude product (320 mg 1.1 mmol). Further purification of the crude product was by recrystallization once from 30 mL boiling water to give the title compound (250 mg, 0.85 mmol) as centimeter long transparent needles.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.C(N(CC)C(C)C)(C)C.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCCl>[C:17]1([S:23][C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]2[OH:7])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1CCC2OC2C1
Reactant: Sc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O[C@@H]1CCCC[C@H]1Sc1ccccc1
Reaction time: 16 h

Procedure:
A room temperature solution of cyclohexene oxide (9.81 g, 100 mmol) and N,N-diisopropylethylamine (2.60 g, 20.0 mmol) in 1,2-dichloroethane (200 mL) was treated with thiophenol (11 g, 100 mmol), stirred for 16 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=1[CH3:31])=O)C>O1CCCC1>[CH3:30][S:27]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:14][OH:13])=[C:17]1[CH3:31])(=[O:29])=[O:28]
Reactant: CCOC(=O)c1c(C)n(S(C)(=O)=O)c2ccc(OC)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CO)c(C)n2S(C)(=O)=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Diisobutylaluminum hydride (6 ml, 6 mmol, 1M in dichloromethane) was added slowly at −78° C. under N2 to a solution of 1-methanesulfonyl-5-methoxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.4 g, 1.29 mmol) in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred at −78° C. for 1.5 hours and then kept at 4° C. for 16 hours. The reaction was quenched with water and stirred for 0.5 hour. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel eluting with 50 to 70% ethyl acetate in hexane to give (1-methanesulfonyl-5-methoxy-2-methyl-1H-indol-3-yl)-methanol as a white solid, (0.26 g, 75.2%). 1H NMR (CDCl3) δ: 2.59 (s, 3H), 3.00 (s, 3H), 3.87 (s, 3H), 4.79 (bs, 2H), 6.91 (dd, 1H, J=9.1 Hz, 2.6 Hz), 7.11 (d, 1H, J=2.6 Hz), 7.89 (dd, 1H, J=9.1 Hz, 0.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][CH2:12][C:13]2([CH:18]([CH3:20])[CH3:19])OCC[O:14]2)[CH3:9])=[CH:4][CH:3]=1.CO.Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:10][CH2:11][CH2:12][C:13](=[O:14])[CH:18]([CH3:20])[CH3:19])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(NCCC1(C(C)C)OCCO1)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: CC(C)C(=O)CCNC(C)c1ccc(Br)cc1
Temperature: 65 °C
Yield: 82.2 %

Procedure:
To a solution of [1-(4-bromo-phenyl)-ethyl]-[2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl]-amine (14.5 g, 0.042 mol) in MeOH (70 mol) was added HCl (36%, 70 mol). The mixture was stirred at 65° C. till the reaction was over. The mixture was cooled to 0° C. The pH of the mixture was adjusted to 7. The mixture was condensed, and the residue was extracted with EtOAc. The organic phase was dried over Na2SO4, and concentrated to give the crude 1-[1-(4-bromo-phenyl)-ethylamino]-4-methyl-pentan-3-one (10.3 g, crude), which was used for the next step without further purification. 1H NMR (CDCl3): 1.08 (m, 6H), 1.35 (m, 3H), 2.51-2.70 (m, 6H), 3.72 (m, 1H), 7.19 (m, 2H), 7.42 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:19][CH2:18][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20])=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCNc1ccc(C#N)cn1
Reaction time: 24 h

Procedure:
A solution of 6-chloronicotinonitrile (1.0 g, 7.2 mmol), beta-alanine tert-butyl ester hydrochloride (2.0 g, 11.0 mmol) and DIEA (4.9 mL, 28.9 mmol) in anhydrous dioxane (20 mL) was heated at reflux. After 24 hours, an additional amount of beta-alanine tert-butyl ester hydrochloride (0.5 g, 2.75 mmol) was added. After 24 additional hours at reflux, the reaction mixture was concentrated under reduced pressure. The residue was taken up with EtOAc (50 mL) and washed with water (2×20 mL) and brine (20 mL). The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. After precipitation from MTBE/pentane, the title compound was obtained as an off-white powder (1.28 g, 72%). HPLC (Method A), Rt: 2.7 min (purity: 99.9%). UPLC/MS, M+(ESI): 248.1, M−(ESI): 246.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.40 (d, J=2.0 Hz, 1H), 7.67 (m, 2H), 6.56 (d, J=8.9 Hz, 1H), 3.50 (td, J=6.8, 6.0 Hz, 2H), 2.48 (t, J=6.8 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1.[CH3:36][O:37][C:38]1[CH:50]=[CH:49][C:41]([CH2:42][NH:43][C:44]2[CH:48]=[CH:47][O:46][N:45]=2)=[CH:40][CH:39]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:43]([C:44]4[CH:48]=[CH:47][O:46][N:45]=4)[CH2:42][C:41]4[CH:40]=[CH:39][C:38]([O:37][CH3:36])=[CH:50][CH:49]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1
Reactant: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: COc1ccc(CNc2ccon2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(Br)ccc3OC)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70.1 %

Procedure:
A flask containing perfluorophenyl 1-(5-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (3.65 g, 6.33 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine (1.358 g, 6.65 mmol) was flushed with nitrogen and then charged with THF (63.3 ml) and cooled to 0° C. Lithium bis(trimethylsilyl)amide (1.0M in THF) (6.97 ml, 6.97 mmol) was added slowly, and the solution was stirred at 0° C. for 45 minutes until complete consumption of starting material. The reaction was quenched with water and extracted (×3) with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was triturated in IPA and filtered, washing well with IPA, to yield 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.65 g, 4.44 mmol, 70.1% yield) as a white solid. m/z (ESI) 596.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:40]([O:44]C)(=[O:43])[CH:41]=[CH2:42]>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[NH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH2:42][CH2:41][C:40]([OH:44])=[O:43])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)c2ccccc12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CCC(=O)O)c2ccccc12
Temperature: 100 °C
Yield: 58.1 %

Procedure:
To a mixture of 4-bromo-1-naphthylamine (4.44 g, 20.0 mmol), potassium acetate (6.28 g, 64.0 mmol), tetrabutylammonium chloride hydrate (6.1 g, 22 mmol), palladium(II)acetate (224 mg, 1.0 mmol) and tri-o-tolylphosphine (1.22 g, 4.0 mmol) was added DMF (60 mL) and methyl acrylate (2.3 mL, 25 mmol). The reaction was heated to 100° C. under N2 for 2 hours, poured into water (300 mL) and extracted with diethyl ether (3×50 mL). The combined ether layers were washed with brine (1×50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The product was purified on silica gel eluting with 30% ethyl acetate/hexanes to provide the titled compound 2.5 g, 55%).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CO.ClCCl>[CH3:28][O:27][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[OH:26])[C:20]([N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:21]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1O
Reaction time: 18 h

Procedure:
Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.50 g, 2.7 mmol) (prepared by extraction from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and dichloromethane (25 mL). Add 3,5-dimethoxy-4-hydroxybenzoic acid (0.55 g, 2.78 mmol), 1-hydroxybenzotriazole hydrate (0.4 g, 2.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g, 2.9 mmol). After 18 hours, dilute the reaction mixture with dichloromethane and extract with saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with methanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1 to give the title compound; Rf=0.74 (silica gel, methanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([C:37](O)=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])([CH3:25])[CH3:24]>>[C:23]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:37](=[O:38])[N:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:25])([CH3:22])[CH3:24]
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1C
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)cn2)C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)cc1C

Procedure:
In analogy to the procedure described for the synthesis example 21, step 3, the title compound was prepared from (3,4-dimethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine and boc-L-alpha-phenylglycine. MS (m/e): 528.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].O[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:24][CH2:25][NH:26][C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33]
Reactant: CCOC(=O)C(Cc1ccc(O)c(Br)c1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)c(Br)c1)Oc1ccccc1
Yield: 89.5 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(3-bromo-4-hydroxyphenyl)-2-phenoxypropionate (374 mg), which is the product of Reference example 52(a), t-butyl 2-hydroxyethylcarbamate (403 mg), triphenylphosphine (672 mg) and a solution of diethylazodicarboxylate in toluene (40%, 1.16 ml) and the reaction mixture was treated to afford the desired compound (466 mg) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:4]=1.[CH:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][CH:21]=1>CCOCC.CC(C)=O.CCOCC.C(Cl)Cl>[C:19]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[O:7][N:6]=[C:5]([C:8]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:9])[CH:4]=3)[CH2:24][CH2:23]2)[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(c1ccccc1)c1cc(CBr)on1
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(CN2CCN(c3ccccc3)CC2)on1
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.9 %

Procedure:
A solution of 3.5 g of (5-bromomethylisoxazol-3-yl)-phenylmethanone in 100 ml of Et2O was added dropwise to a solution of 8.6 g of phenylpiperazine in 375 ml of 20% acetone/Et2O. The resulting mixture was stirred at room temperature for 72 hours. This mixture was washed with water and brine, and dried over MgSO4. Concentration of the product gave an oil, which was taken up in 500 ml of CH2Cl2 and stirred with 20 g of silica gel overnight. The silica was removed by filtration and washed with 500 ml of CH2Cl2. The combined filtrates were concentrated to give 4.7 g of an oil which solidified on standing. Recrystallization from ethanol yielded 3.1 g (69%) of platelets, m.p. 100°-102° C.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[CH:3][C:2]=1[C:6]([OH:8])=O.Cl.Cl.[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(C)(C)C.C(N(CC)CC)C>[CH:1]1[S:5][CH:4]=[CH:3][C:2]=1[C:6]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:21][CH2:22]2)[CH2:15][CH2:16]1)=[O:8]
Reactant: O=C(O)c1ccsc1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccsc1)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 17 h
Yield: 87.5 %

Procedure:
A mixture of 72 mg of 3-thenoic acid, 187 mg of 1-[1-(piperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride, 110 mg of ethyl 3-(dimethylamino)propylcarbodiimide, 110 mg of 1-hydroxy-1,2,3-benzotriazole, 300 mg of triethylamine, 10 ml of CHCl3, and 10 ml of tert-butyl alcohol was stirred for 17 h. The reaction mixture was partitionized between chloroform and aqueous NaHCO3. The organic layer was washed with aqueous NaHCO3, dried over anhydrous Na2SO4, and concentrated. The residue was purified on SiO2 chromatography (chloroform/methanol=30:1-20:1) to afford 180 mg of 1-[1-[1-(3-thenoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one as a colorless amorphous.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-]CC.[Na+].Cl>C(O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(Cl)cc2)noc1/C=C/c1ccccc1
Yield: 52.8 %

Procedure:
To a stirred solution of 3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (9.6 g, 36.1 mmol) and benzaldehyde (3.69 mL, 36.1 mmol) in ethanol (54 mL) was added sodium ethoxide (2.71 M, 14.6 mL, 39.7 mmol) and the reaction was heated under reflux for 10 min. Hydrochloric acid (1 N, 43.4 mL) was added and the resulting mixture was then triturated with dichloromethane and filtered to afford the title compound (6.21 g, 53%) as a light yellow solid. MS: m/e=324.1 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (206 mg, 0.93 mmol) [prepared according to the procedure of Preparation 9], 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (209 mg, 0.60 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (340 mg, 0.73 mmol) in Chloroform (15 mL). DIEA (0.81 mL, 4.65 mmol) was added and the mixture stirred overnight at room temperature. Upon completion, the reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (112 mg, 0.203 mmol, 22%): LC-MS (ES) m/z=553 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([Cl:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.Br[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][N:26]=1>CCOC(C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:3]1[C:2]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][N:26]=2)=[CH:6][S:5][C:4]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3Cl)c(C)nc12
Reactant: Cn1ncnc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3scc(-c4ncnn4C)c3Cl)c(C)nc12
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 8.8 %

Procedure:
To a flask of 3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.20 g, 0.49 mmol) is added 0.5 g/mL Reike® Zn (1.3 mL, 0.97 mmol). The slurry is heated at 65° C. for 1 hour, placed in a centrifuge for 5 minutes, and the solution transferred to a flask containing 5-bromo-1-methyl-1H-[1,2,4]triazole (0.12 g, 0.73 mmol) and PdCl2(dppf) (0.018 g, 0.024 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (20 mL), washed with sat. NH4Cl (15 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO flash chromatography (20%-50% EtOAc gradient) furnish the title compound (0.018 g, 0.043 mmol, 9%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.26-3.37 (m, 1H), 3.95 (s, 3H), 6.72 (s, 1H), 7.82 (s, 1H), 8.01 (s, 1H). LC/MS (m/z): calcd. for C20H23ClN6S (M+H)+: 415.2; found: 415.3.