Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:34])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>>[CH3:11][NH:10][C:8](=[O:9])[C:4]1[CH:3]=[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:17][CH:18]=2)[CH:7]=[CH:6][N:5]=1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1Nc1ccccc1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)c3ccccc3Nc3ccccc3)cc2)ccn1
Reaction time: 16 h

Procedure:
4-Chloro-N-methylpicolinamide (70 mg, 410 μmol), N-(4-hydroxyphenyl)-2-(phenylamino)benzamide (150 mg, 492 μmol), cesium carbonate (267 mg, 821 μmol), and DMSO (410 μl 410 μmol) were added into a screw-capped test tube. The tube was sealed and placed in a preheated oil bath at 130° C. After 16 h, LC-MS showed mainly desired product. Water was added, and a gray solid precipitated out of the solution. The solid was filtered off and rinsed with water. The product was purified by reverse phase preparative HPLC. Fractions containing the product were combined, neutralized with sat NaHCO3 (aq), washed with brine, dried over MgSO4, and concentrated in vacuo. The product, N-methyl-4-(4-(2-(phenylamino)benzamido)phenoxy)picolinamide was collected as a black solid. MS Calcd for C26H22N4O3: [M]+=438. Found: [M+H]+=439.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9][CH2:10][CH2:11][F:12])[S:8][C:4]=2[CH:3]=1.[CH3:15][N:16]([C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.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>[F:12][CH2:11][CH2:10][S:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([N:16]([CH3:15])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:29][CH:28]=3)[CH:14]=[CH:13][C:5]=2[N:6]=1
Reactant: FCCSc1nc2ccc(Br)cc2s1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc3nc(SCCF)sc3c2)cc1
Temperature: 95 °C

Procedure:
A mixture of 6-Bromo-2-(2-fluoroethylthio)benzo[d]thiazole (60 mg, 0.2 mmol), tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (68 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol) in 2 mL dioxane and 0.5 mL of a 1 M Na2CO3 aqueous solution was heated at 95° C. in a microwave reactor for 10 min. After cooling to rt, it was diluted with EtOAc (30 mL) and washed with brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (5% to 30% EtOAc in hexane) to afford tert-butyl 4-(2-(2-fluoroethylthio)benzo[d]thiazol-6-yl)phenyl(methyl)carbamate as a clear wax (15 mg, 18%). MS (ESI) m/z 419 (M+H+).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([F:37])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:35][CH3:36])=[C:21]([O:24][CH:25]4[CH2:34][CH2:33][C:28]5(OCC[O:29]5)[CH2:27][CH2:26]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>O1CCCC1>[Cl:6][C:7]1[C:8]([F:37])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:35][CH3:36])=[C:21]([O:24][CH:25]4[CH2:34][CH2:33][C:28](=[O:29])[CH2:27][CH2:26]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCC2(CC1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
25 ml of 4M sulphuric acid are added to 9.0 g 4-[(3-chloro-2-fluoro-phenyl)amino]-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazoline in 110 ml of tetrahydrofuran and the mixture is stirred for 18 hours at ambient temperature. The mixture is made alkaline with 4M sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried, evaporated down and stirred with diethyl ether. The solid is suction filtered and dried.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:52])[C:4]([NH:7][CH2:8][CH2:9][CH:10]([CH2:42][CH2:43][NH:44][C:45]([CH3:51])([CH3:50])[C:46](=[N:48][OH:49])[CH3:47])[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:41]=[CH:40][C:19]([CH2:20][N:21]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24])=[CH:18][CH:17]=1)=[O:15])([CH3:6])[CH3:5].CN1CCOCC1.C1CN([P+]([O:76][N:77]2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Si](ON)(C(C)(C)C)(C)C>CN(C)C=O>[OH:76][NH:77][C:23]([CH:22]([N:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:14]([NH:13][CH2:12][CH2:11][CH:10]([CH2:42][CH2:43][NH:44][C:45]([CH3:50])([CH3:51])[C:46](=[N:48][OH:49])[CH3:47])[CH2:9][CH2:8][NH:7][C:4]([CH3:5])([CH3:6])[C:3](=[N:2][OH:1])[CH3:52])=[O:15])=[CH:41][CH:40]=1)[S:29]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCC(CCNC(C)(C)C(C)=NO)CCNC(C)(C)C(C)=NO)cc2)C(C(=O)O)C(C)C)cc1
Agent: CC(C)(C)[Si](C)(C)ON
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCC(CCNC(C)(C)C(C)=NO)CCNC(C)(C)C(C)=NO)cc2)C(C(=O)NO)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The hydroxamic acid was attached via tert-butyldimethylsilyl protected intermediate (Compound 11*). Thus, a mixture of the acid (Compound 10*) (57 mg, 0.76 mmol), 4-methylmorpholine (34 μl, 0.30 mmol), [7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium-hexafluorophosphate] PyAOP, 40 mg, 0.076 mmol) and O-(tert-butyldimethylsilyl)hydroxylamine (12 mg, 0.08 mmol) in dimethylformamide (4 ml) was stirred at ambient temperature and the reaction monitored by HPLC. The reaction was stopped after 3 hours and solvents were evaporated. The residue was re-dissolved in dichloromethane and at ambient temperature, hydrochloric acid gas was bubbled through the mixture for 10 minutes. The mixture was evaporated to dryness and the residue co-evaporated with dichloromethane (5×5 ml). The product was obtained as a white powder after HPLC, M+H, 762. Yield 15 mg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:15].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCCl
Reactant: Oc1ccc(-c2cccc(F)c2)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc(-c2cccc(F)c2)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.6 %

Procedure:
2-Methoxyethoxymethylchloride (0.67 mL, 5.83 mmol) was added dropwise to a solution of 3-bromo-3′-fluoro-[1,1′-biphenyl]-4-ol (˜5.55 mmol) and diisopropylethylamine (1.93 mL, 11.1 mmol) in dry dichloromethane (20 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 3 days, 1.0 M aqueous sodium hydroxide (20 mL) added and the biphasic mixture stirred vigorously for 20 minutes. The reaction mixture was partitioned between ethyl acetate (100 mL) and 1.0 M aqueous sodium hydroxide solution (100 mL), the organic phase separated, washed with water (75 mL) and saturated brine (75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange oil. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 10% ethyl acetate (containing 2% methanol) in hexanes to give 3-bromo-3′-fluoro-4-((2-methoxyethoxy)methoxy)-1,1′-biphenyl (1.57 g, 80% yield) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[OH-].[Na+].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>O1CCOCC1.O>[C:11]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: NCCCS(=O)(=O)O
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C(=O)NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-amino-1-propanesulfonic acid (2.0 g, 14.4 mmol) was dissolved a NaOH (1.2 g, 30.2 mmol) solution in a mixture of 1,4-dioxane (5 mL) and water (15 mL). The mixture was cooled to 0° C. before pivaloyl chloride (2.8 mL, 21.6 mmol) in 1,4-dioxane (5 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature and it was stirred at 65° C. for 4 h. The solvent was evaporated under reduced pressure. The resulting solid was dissolved in water (30 mL), and treated with Dowex 50WX8 resin. The suspension was stirred for 5 minutes and the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The residual material was suspended in 20% EtOH/Acetone. The mixture was stirres at reflux for 30 seconds. The solid product was collected by filtration, and dried in vacuo, to afford compound DT (1.3 g, 41%). 1H NMR (D2O, 500 MHz) δ ppm 3.16 (t, 2H, J=6.8 Hz), 2.75 (t, 2H, J=7.8 Hz), 1.78 (m, 2H), 1.1 (s, 9H). 13C NMR (D2O, 125 MHz) δ ppm 182.75, 48.70, 38.57, 38.18, 26.65, 24.27. ES-MS 222 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:25])[C@H:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:17].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:13][O:14][C:15](=[O:25])[CH:16]([NH:17][C:8](=[O:9])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccccc1)NC(=O)C=Cc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
4-hydroxy cinnamic acid (1.0 g, 6.1 mmol), phenylalanine methyl ester (1.2 g, 6.7 mmol) and 1-hydroxybenzotriazole hydrate (1.0 g, 7.4 mmol) were dissolved in dimethylformamide (25 mL). The resulting solution was then placed in a water bath at 0°0 C. and treated with triethylamine (3.5 mL), followed by stirring for 10 minutes. To the resulting mixture, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.4 g, 7.4 mmol) was added. After removing the water bath, the mixture was stirred for 18 hours at room temperature. The reaction was diluted in water (60 mL), extracted with ethylacetate (EtOAc) (200 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)) to obtain 1.8 g of the title compound. The yield was 91%. The results of analyses of the compound are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:7][C:5]([NH2:6])=[C:4]([F:17])[CH:3]=1.Cl[C:19]([O:21][CH3:22])=[O:20].CN(C)C1C=CC=CC=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([NH:6][C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Temperature: 25 °C

Procedure:
Into a mixture of 4-chloro-2-fluoro-5-(2-hydroxyphenoxy)aniline [Intermediate Compound A3-4], methyl chloroformate and tetrahydrofuran is added dropwise N,N-dimethylaniline, and the mixture is stirred at room temperature. Dilute hydrochloric acid is added to the reaction solution, and this is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 2-(2-chloro-4-fluoro-5-methoxycarbonylaminophenoxy)phenol [Intermediate compound A9-4].
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.[C:13](=[O:16])([O-])[O-:14].[K+].[K+].[N:19]1(C(Cl)=O)[CH2:23][CH2:22][CH2:21][CH2:20]1>CC(C)=O>[CH3:8][C:6]1[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=[C:2]([C:13]([O:14][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:16])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: O=C(Cl)N1CCCC1
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)ON2CCCC2)nc(C(Cl)(Cl)Cl)n1
Yield: 125.8 %

Procedure:
A mixture of 5.8 g (0.027 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 3.3 g (0.024 mole) potassium carbonate, 3.2 g (0.024 mole) pyrrolidinecarbonyl chloride, and 100 ml acetone was refluxed 5.3 hours. A precipitate was filtered out and the filtrate rotary evaporated to give 9.8 g residue. This was taken up in chloroform, the solution washed with 1% sodium hydroxide, water, and dried over anhydrous magnesium sulfate. Rotary evaporation yielded 4.4 g residue which was recrystallized from petroleum ether to give 2.2 g (28% yield; mp 93°-95° C.) of product. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([CH2:11][CH2:12][CH2:13][OH:14])(O)[CH2:6][CH2:5]2)[O:3]C1.C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[O:14]1[C:7]2([CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)[CH2:11][CH2:12][CH2:13]1
Reactant: OCCCC1(O)CCC2(CC1)OCCO2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC2(CCCO2)CC1

Procedure:
A mixture of 4-(3-Hydroxypropyl)-4-hydroxy-cyclohexanone ethylene ketal (1.4 g) and diisopropylethylamine (3.37 mL) in methylene chloride (100 mL) at -78° C. was treated with triflic anhydride (1.64 mL). After 30 min the reaction mixture was washed with water, the solvent was dried over magnesium sulfate and removed in vacuo. The residue was dissolved in 30 mL of tetrahydrofuran and 15 mL of 3% HCl. After 5 h at room temperature the reaction mixture was diluted with water and the product was extracted with ether. After drying over magnesium sulfate the solvent was removed in vacuo to afford 1-Oxaspiro[4,5]decan-8-one as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31].CCOCC.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)([OH:14])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 120 mg (0.278 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanone (Example 19, Step 4) in 3 mL of THF, 0.35 mL (0.69 mmol) of tert-butyl magnesium chloride (2M in THF) was added and stirred for 1 h at −78° C. Then to the reaction mixture was added 30 μL of ether and 5 mL of 7 mL of qNaHCO3. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford of the title compound as a white solid; 1H-NMR (CDCl3) δ 0.88 (s, 9H), 2.46 (t, J=7.2 Hz, 1H), 2.97 (s, 1H), 3.05 (t, J=7.6 Hz, 1H), 3.31-3.39 (m, 2H), 3.42 (m, 1H), 4.25 (s, 1H), 6.56 (m, 2H), 6.68 (m, 1H), 7.24-7.36 (m, 8H); Mass Spectrum m/e=490 (M+1 35Cl, 35Cl) and 492 (M+1 35Cl, 37Cl).
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:48][CH:49]([CH:76]([CH3:78])[CH3:77])[C:50]([N:52]1[CH2:56][CH2:55][CH:54]2[N:57]([C:70]3[N:75]=[CH:74][CH:73]=[CH:72][N:71]=3)[CH2:58][CH:59]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:53]12)=[O:51]>CN1C(=O)CCC1.C(OCC)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]([C:11](=[O:13])[NH:48][CH:49]([C:50]([N:52]1[CH2:56][CH2:55][CH:54]2[N:57]([C:70]3[N:75]=[CH:74][CH:73]=[CH:72][N:71]=3)[CH2:58][CH:59]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:53]12)=[O:51])[CH:76]([CH3:77])[CH3:78])[CH3:10])[CH3:14])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution containing Boc-N(Me)Ala-OH (75 mg, 0.37 mmol) in anhydrous NMP (3 mL) was cooled to 0° C. HATU (140 mg, 0.37 mmol) and DIPEA (52 mg, 0.42 mmol) were added followed by the addition of 73 (148 mg, 0.35 mmol) in anhydrous NMP (3 mL). The reaction mixture was slowly warmed to ambient temperature. After 4 h, the reaction mixture was diluted with diethyl ether and washed successively with water, aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 202 mg of crude 74 which was used without further purification. Mass spectrum, m/z [608] (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([CH2:32][CH2:33][N:34]([CH3:62])[CH2:35][CH2:36][C:37](=O)[NH:38][C:39]3[CH:40]=[CH:41][C:42]([C:45]4[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH2:54][C:55]([F:58])([F:57])[F:56])=[C:47]([O:59][CH3:60])[CH:46]=4)=[N:43][CH:44]=3)=O)=[CH:25][N:24]=2)[CH:12]=[C:13]([O:21][CH3:22])[C:14]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18].CO>O1CCCC1>[CH3:52][O:51][C:49]1[CH:50]=[C:45]([C:42]2[CH:41]=[CH:40][C:39]([NH:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:62])[CH2:33][CH2:32][CH2:30][NH:29][C:26]3[CH:27]=[CH:28][C:23]([C:11]4[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[C:9]([O:8][CH3:7])[CH:10]=4)=[N:24][CH:25]=3)=[CH:44][N:43]=2)[CH:46]=[C:47]([O:59][CH3:60])[C:48]=1[O:53][CH2:54][C:55]([F:56])([F:57])[F:58]
Reactant: COc1cc(-c2ccc(NC(=O)CCN(C)CCC(=O)Nc3ccc(-c4cc(OC)c(OCC(F)(F)F)c(OC)c4)nc3)cn2)cc(OC)c1OCC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2ccc(NCCCN(C)CCCNc3ccc(-c4cc(OC)c(OCC(F)(F)F)c(OC)c4)nc3)cn2)cc(OC)c1OCC(F)(F)F
Temperature: 65 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Under nitrogen, lithium aluminum hydride (4.28 g, 113 mmol) was added to an ice-cold solution of N,N-bis[2-[N-[2-[3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)phenyl]-5-pyridyl]carbamoyl]ethyl]methylamine (22.50 g, 28.3 mmol) in anhydrous tetrahydrofuran (500 mL). The ice bath was removed, and the reaction mixture was stirred at 65° C. for 1 hour. Methanol (20 mL, 490 mmol) was added to the ice-cold reaction mixture, and the ice bath was removed. Water (20 mL), diethyl ether (2 L), and anhydrous magnesium sulfate (130 g) were added, and the mixture was stirred overnight at room temperature. Insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide N,N-bis[N-[2-[3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)phenyl]-5-pyridyl]-3′-aminopropyl]methylamine as a colorless oil (20.32 mg, yield: 94%).
Reaction SMILES: [C:1]1([CH:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][NH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:22]1[S:23][C:24]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=2[N:26]=1.Cl>C1(C)C=CC=CC=1>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([N:10]3[CH:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8](=[O:18])[NH:9]3)[S:23][C:24]=2[CH:30]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1NN(c2nc3ccc(Cl)cc3s2)C(c2ccccc2)C1c1ccccc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
The reaction was conducted under a dry nitrogen atmosphere. A suspension of 4,5-diphenyl-3-pyrazolidinone (1.19 g, 5.00 mmol) in 35 mL toluene was treated with 0.40 g NaH (60% in mineral oil; hydride content 0.24 g, 10.0 mmol, 2.00 eq.), and the mixture stirred at 45° C. for 2 hours. 2,6-Dichlorobenzothiazole (1.02 g, 5.00 mmol, 1.00 eq.) was added and stirring continued at 80° C. for 20 hours. After cooling, the reaction mixture was poured onto 30 mL ice-cooled 0.5 N HCl, extracted with EtOAc, and the separated organic phase washed twice with brine, dried over Na2SO4, and the solvent evaporated in vacuo. The residue was recrystallized from Et2O:hexane to provide 1.46 g (72%) light tan crystals: mp 170.5°-2.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:11]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.FC(F)(F)S(O[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH:11]1([CH:17]2[O:18][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: c1ccc2ncccc2c1
Reactant: O=CC1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC2OC(C3CCCCC3)c3ccccc3N2c2ccccc21
Yield: 89 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and cyclohexanecarbaldehyde (0.084 g, 91 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-cyclohexyl-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as a yellow solid (0.141 g, 89% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:5]1(=[O:6])[C:4]2[C:3](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][N:7]1[CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C(NCCSc1ccncc1)c1ccccc1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CCSc1ccncc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a solution of 1.153 g (4.0 mmol) of 4-[2-(2-hydroxymethylbenzoyl)aminoethylthio]pyridine and 1.68 ml (12.1 mmol) of triethylamine in 50 ml of methylene chloride, 0.62 ml (8.0 mmol) of methanesulfonyl chloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 623 mg of the desired compound (57.6% yield, colorless crystals), mp. 86°-87° C.