Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:20]=[C:19]([S:21](C)=O)[CH:18]=[CH:17][C:16]=1[NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28]>>[Cl:14][C:15]1[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:16]=1[NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:28])[F:29]
Reactant: CS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@@](O)(C(=O)Nc1ccc(S)cc1Cl)C(F)(F)F
Yield: 103.6 %

Procedure:
Trifluoroacetic anhydride (5 ml) was added to (R)-N-(2-chloro-4-methylsulphinyl-phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 92) (0.188 g). The mixture was stirred and heated under reflux for 45 minutes then cooled and evaporated to dryness. A mixture of triethylamine (5 ml) and methanol (5 ml) was added to the residue. This mixture was stirred for a further 45 minutes then evaporated to dryness. The residue was dissolved in chloroform (50 ml), washed with saturated aqueous ammonium chloride solution (50 ml), dried and concentrated by evaporation to give the title compound (0.177 g) as a gum which was used without purification. MS (ESP−): 298.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:17][CH:18]=2)[C:13]1=[O:29].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:17][CH:18]=2)[C:13]1=[O:29]
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(N4CCN(C)CC4)cc3c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To a stirred solution of methyl 4-methyl-3-[7-(4-methylpiperazin-1-yl)-1-oxoisoquinolin-2(1H)-yl]benzoate (272 mg) in methanol was added 1N NaOH solution (0.85 ml) and the reaction mixture was stirred at 65° C. for 30 minutes and then neutralized with 1N HCl. After cooling to room temperature the resulting precipitate was collected by filtration and washed with water, ethyl acetate, methanol and then air-dried to yield 4-methyl-3-[7-(4-methylpiperazin-1-yl)-1-oxoisoquinolin-2(1H)-yl]benzoic acid (166 mg) as a pale yellow solid; NMR Spectrum: (DMSOd6) 2.12 (s, 3H), 2.25 (s, 3H), 2.50 (m, 4H), 3.27 (m, 4H), 6.64 (d, 1H), 7.12 (d, 1H), 7.56 (m, 2H), 7.60 (s, 1H), 7.63 (d, 1H), 7.75 (s, 1H), 7.94 (d, 1H); Mass Spectrum: M+H+ 378.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=O>C1COCC1>[N:11]1([CH2:9][CH:8]([NH2:7])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NC(C(=O)N1CCOCC1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CN1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of LAH (6.1 mmol) in THF (25 mL) is added dropwise a solution of 2-amino-1-morpholin-4-yl-2-phenylethanone (670 mmol) in THF (5 mL) at 0° C. The reaction mixture is refluxed for 2 hr, and then the reaction is quenched by the addition of Na2SO4-10H2O at 0° C. After stirring at room temperature for 0.5 h, the resulting mixture is filtered through celite, and the filtrate is concentrated in vacuo to give the title compound, which is directly used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCN2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1-[2-(3-fluoro-4-nitro-phenoxy)-ethyl]-pyrrolidine (1.96 g, 7.7 mmol) and 10% palladium on carbon (0.2 g) in MeOH (40 mL) is stirred for 0.5 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to provide the title compound. ESI-MS: 225.1 [MH]+; tR=0.95 min (system 1).
Reaction SMILES: C([C:3]1([OH:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=C.O=[O+][O-].O=O.OS([O-])=O.[Na+].S(=O)(O)[O-]>CO.O>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][C:3]1=[O:12]
Reactant: C=CC1(O)Cc2ccccc2C1
Agent: O=O
Agent: O=S([O-])O
Agent: O=[O+][O-]
Solvent: O
Solvent: CO
Product: O=C1Cc2ccccc2C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
(The following representative procedure is taken from Ragan et al., Org. Process Res. Dev. 2003, 7, 155–160). 2-Vinyl-indan-2-ol (15.0 g, 93.6 mmol) was dissolved in 150 mL MeOH, cooled to −78° C., and treated with a stream of ozone generated from O2. The dark solution became lighter in color after ca. 15 min, and HPLC analysis indicated consumption of starting material. Oxygen was bubbled through the solution for 5 min, then a stream of nitrogen was bubbled through for 30 min. A slurry of NaHSO3 (19.5 g, 187 mmol) in 15 mL water was then added, and the mixture was allowed to gradually warm to room temperature. After 30 min, a starch-Kl strip tested negative for peroxides. The slurry was then heated to 60° C. for 30 min to complete formation of the bisulfite adduct. After cooling to room temperature and stirring for 2 h, the resulting solids were collected and rinsed with methanol (2×30 mL), to provide the desired product as a while powder (16.2 g, 61% yield from 2-indanone). Combustion analysis of this material indicated 56% purity (Anal. Calcd for C10H11SO5Na: C, 45.1; H, 4.2. Found: C, 25.2; H, 2.6). Recrystallization from 10 volumes of water provided analytically pure material in 47% recovery (8.01 g recrystallized from 80 mL water, isolated 3.75 g analytically pure 2):
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH2:6][CH:5]([S:8][C:9]2[CH:15]([CH3:16])[CH:14]3[N:11]([C:12](=[O:20])[CH:13]3[CH:17]([OH:19])[CH3:18])[C:10]=2[C:21]([OH:23])=[O:22])[CH2:4]1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Cl.[C:33](=[NH:38])(OCC)[CH3:34]>>[OH:19][CH:17]([CH:13]1[C:12](=[O:20])[N:11]2[CH:14]1[CH:15]([CH3:16])[C:9]([S:8][CH:5]1[CH2:4][CH:3]([CH2:2][NH:1][C:33](=[NH:38])[CH3:34])[O:7][CH2:6]1)=[C:10]2[C:21]([OH:23])=[O:22])[CH3:18]
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(=N)NCC1CC(SC2=C(C(=O)O)N3C(=O)C(C(C)O)C3C2C)CO1
Yield: 77.3 %

Procedure:
The title compound is prepared by the procedure of Example 47 using 0.052 g of product from Example 46, 5 ml of sodium phosphate buffer (pH 7) adjusted to pH 8.5 and 0.097 g of ethyl acetimidate hydrochloride to give 0.045 g of the desired product.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[SiH:17]([Cl:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:20][Si:17]([CH3:19])([CH3:18])[CH:2]([CH3:3])[CH2:1][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: C[SiH](C)Cl
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: Cc1ccccc1
Product: Cc1cc(=O)oc2cc(OCC(C)[Si](C)(C)Cl)ccc12

Procedure:
To a solution of 2.16 g of 7-allyloxy-4-methylcoumarin and 5×10-6 mols chloroplatinic acid hydrosilylation catalyst in 20 ml toluene was slowly added 2.0 g of Me2SiHCl and the mixture was heated at 40°-42° for 6 hrs. Toluene and unreacted silane were then removed at reduced pressure to yield 7{2-(chlorodimethylsilyl)propoxy}-4-methylcoumarin. The 1H-NMR spectrum (ppm) contained signals at 0.2(s) for SiCH3, (6H); 2.4(s) for CH3,(3H); 4.0(t) for CH2O, (2H) and no signal for the allyl moiety.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](=O)[CH2:24][CH2:25][CH:26]=[CH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:27]([N:16]1[C:10]2[C:11](=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]=2)[CH2:13][CH2:14][CH2:15]1)[CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Reactant: C=CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C=CCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Ex. 4.1 step 1) (2 g, 6.96 mmol) in DCE (35 ml) was added pent-4-enal (2.061 ml, 20.88 mmol) and the mixture was stirred at RT overnight. A further portion of sodium triacetoxyborohydride (4.43 g, 20.88 mmol) was added and the mixture was stirred at RT for 2.5 hours under an atmosphere of nitrogen. Water was added and the mixture was extracted with EtOAc (3×60 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1)(=[O:8])[O:5]CC)[CH3:2]>N1CCCC1>[CH2:1]([O:3][P:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1)(=[O:5])[OH:8])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccc(N2CCCC2)c2ccccc12
Solvent: C1CCNC1
Product: CCOP(=O)(O)c1ccc(N2CCCC2)c2ccccc12
Temperature: 80 °C
Yield: 59.6 %

Procedure:
(4-Pyrrolidin-1-ylnaphthalen-1-yl)phosphonic acid diethyl ester 139MBT64-B (40 mg, 0.11 mmol) was dissolved in pyrrolidine (0.5 mL) and the mixture was heated to 80° C. for 20 hours. The mixture was concentrated and the crude product was purified by preparative TLC (0-10% methanol in dichloromethane) to give the title compound (20 mg, 55%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:29].[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:36]1([NH:41][C:33]([C:30]2([C:28]([NH:27][C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[O:17])[CH:10]=4)=[CH:7][C:2]=3[F:1])=[O:29])[CH2:32][CH2:31]2)=[O:34])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NC1CCCC1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)NC5CCCC5)CC4)c(F)c3)ccn2)CC1
Reaction time: 25 h
Yield: 51 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added cyclopentylamine (0.0163 ml), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 25 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (23.2 mg, 51%).
Reaction SMILES: CC(C)([O-])C.[Na+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Br:13][CH:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCCCCC(Br)Br
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCCCCN1CCOCC1
Temperature: 50 °C

Procedure:
Under nitrogen 250 ml anhydrous THF were added to 37 g (1.1 eq, 385 mmol) sodium tert-butoxide. Then 30.45 g (1 eq, 350 mmol) morpholine were added neat. The suspension was heated to 50° C. for 1 h. After cooling to RT, 1.21 anhydrous THF and 85.29 g (1 eq, 350 mmol) dibromohexane in ˜150 ml anhydrous THF were added. After 1 h at RT the mixture was heated to 85° C. over night. The overstanding solution was decanted and all volatiles removed in vacuo. The residue was dissolved in ether and water and the organic layer extracted with 2M hydrochloric acid. After dilution with water and ether, KOH flakes were added under vigorous stirring and cooling until pH=10. After phase separation, the aqueous layer was extracted with ether. The combined organic layers were dried over brine and MgSO4 and all volatiles removed to yield 40 g. Further purification by column chromatography (70% hexane, 30% ethyl acetate, 5% triethylamine) yielded 14.56 g, 99% by GCMS. 1H-NMR (400 MHz, CDCl3): [ppm]=3.71 (t, J=4 Hz, 4H), 3.41 (t, J=6.8 Hz, 2H), 2.42 (t, J=4 Hz, 4H), 2.32 (t, J=7.6 Hz, 2H), 1.48 (m, 4H), 1.34 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.O>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:12][CH:11]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CC(c3ccc(OC)cc3)C2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(C2CC(c3ccc(O)cc3)C2)cc1
Temperature: 210 °C

Procedure:
A mixture of 1,3-bis-(p-methoxyphenyl)cyclobutane (13.57 g., 0.051 mole) and pyridine hydrochloride (46.8 g., 0.41 mole) is heated at 210° C. under a nitrogen atmosphere for 30 minutes and then poured into 500 ml. of water. Several ethyl acetate extracts are taken, combined, washed (dilute HC1, water), dried (MgSO4), and evaporated. The desired product after recrystallization from benzene weighs 8.1 g. (67%), m.p. 148°-163.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]([F:49])([F:48])[CH:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:30]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:37])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([C:16]([NH:47][CH:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:39]([F:38])([F:48])[F:49])=[O:17])[CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Reactant: NC(c1ccccc1)C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)NC(c2ccccc2)C(F)(F)F)c1)S(C)(=O)=O
Reaction time: 4 h

Procedure:
To a solution of 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI, 10.0 mg, 0.019 mmol) and (2,2,2-trifluoro-1-phenylethyl)amine (7.6 mg, 0.056 mmol) in DMF (500 μL) were added BOP reagent (10.0 mg, 0.022 mmol), ethyl(diisopropyl)amine (5.0 μL, 0.028 mmol). After sitting at rt for 4 hr, the reaction was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl {1-benzyl-1-methyl-2-[(3-[(methylsulfonyl)(propyl)amino]-5-{[(2,2,2-trifluoro-1-phenylethyl)amino]carbonyl}benzyl)oxy]ethyl}carbamate which was taken up in HCl(g) saturated EtOAc (1 mL). After 15 hr, it was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to provide 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(methylsulfonyl)(propyl)amino]-N-(2,2,2-trifluoro-1-phenylethyl)benzamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.61-7.55 (m, 2H), 7.46-7.40 (m, 3H), 7.34-7.24 (m, 3H), 7.20-7.15 (m, 2H), 6.04-5.96 (m, 1H), 4.72 (A of AB, d, J=13.8 Hz, 1H), 4.68 (B of AB, d, J=13.8 Hz, 1H), 3.71 (t, J=7.1 Hz, 2H), 3.45 (A of AB, d, J=10.0 Hz, 1H), 3.40 (B of AB, d, J=10.0 Hz, 1H), 3.08 (A of AB, d, J=13.4 Hz, 1H), 2.96 (s, 3H), 2.87 (B of AB, d, J=13.4 Hz, 1H), 1.51-1.41 (m, 2H), 1.25 (s, 3H), 0.90 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8](=[O:13])[CH:9]([CH3:12])[CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[OH:14].[CH:15]1C(O)=CC=CC=1C.C[C@@H](CC)C(Cl)=O>>[CH3:15][C:7]1[CH:2]=[C:3]([OH:14])[CH:4]=[CH:5][C:6]=1[C:8](=[O:13])[CH:9]([CH3:12])[CH2:10][CH3:11]
Reactant: CCC(C)C(=O)c1ccc(O)c(Cl)c1
Reactant: Cc1cccc(O)c1
Agent: CC[C@H](C)C(=O)Cl
Product: CCC(C)C(=O)c1ccc(O)cc1C

Procedure:
Generally following to the procedure as described in paragraph (1) of Preparation Example 1, m-cresol and (S)-(+)-2-methylbutanoic acid chloride were reacted to obtain 3-methyl-4-(1-oxo-2-methylbutyl)phenol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N:24]2[C:28](=[O:29])[CH2:27][CH:26]([NH:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:25]2)[CH:20]=[CH:21][C:22]=1[OH:23]>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[CH:21]=[CH:20][C:19]([N:24]2[C:28](=[O:29])[CH2:27][CH:26]([NH:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:25]2)=[CH:18][C:17]=1[F:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(NC1CC(=O)N(c2ccc(O)c(F)c2)C1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N4CC(NC(=O)c5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 160 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.14 g, 0.6 mmol), N-(1-(3-fluoro-4-hydroxyphenyl)-5-oxopyrrolidin-3-yl)benzamide (Step 4, 0.20 g, 0.6 mmol) and DMAP (78 mg, 0.6 mmol) in 2 mL of dioxane (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 160° C. for 1 h. The mixture was cooled to RT and diluted with 50 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% to 100% EtOAc in hexanes then to 5% MeOH/EtOAc) to provide a white solid. MS (ESI pos. ion) m/z: 502.3 (M+H). Calc'd Exact Mass for C28H24FN3O5: 501.51.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18](=[O:20])[NH:17][C:16]=2[CH:21]=1.[H-].[Na+].Cl.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][Cl:30])[CH3:26].C[O-].[Na+]>CN(C)C=O.CO>[ClH:30].[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18](=[O:20])[N:17]([CH2:26][CH2:25][N:27]([CH2:31][CH3:32])[CH2:28][CH3:29])[C:16]=2[CH:21]=1
Reactant: Cc1ccn2c(C)c(-c3ccc4sc(=O)[nH]c4c3)nc2c1
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(=O)sc2ccc(-c3nc4cc(C)ccn4c3C)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26.3 %

Procedure:
A mixture of 5-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)-2-benzothiazolinone (1.77 g) and sodium hydride (50% suspension in oil, 0.788 g) in dry dimethylformamide (24 ml) was stirred at 40° to 45° C. for 20 minutes. To the resultant mixture was added a solution of 2-diethylaminoethyl chloride hydrochloride (1.55 g) and 1.8 ml of a methanolic solution of sodium methoxide (5 mole/ml) in methanol (30 ml) at ambient temperature. The mixture was stirred for 4 hours under the same condition. The reaction mixture was poured into ice-water (300 ml) and extracted with ethyl acetate. The separated organic layer was re-extracted with 1N hydrochloric acid (25 ml) and the aqueous extract was allowed to stand for 2 hours at ambient temperature to give crystals, which was collected by filtration and dried over phosphorus pentoxide to give 5-(3,7dimethylimidazo[1,2-a]pyridin-2-yl)-3-(2-diethylaminoethyl)-2-benzothiazolinone hydrochloride (0.68 g). mp. 272° C. (dec.).
Reaction SMILES: [CH2:1]([C@:4]1([C:43]2[CH:48]=[C:47]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:58])=[CH:45][C:44]=2[OH:59])[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:5]1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:65]>C(Cl)Cl>[CH2:11]([O:10][C@@H:9]1[C@@H:8]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@H:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:5][C@:4]21[C:43]1[C:44](=[CH:45][C:46]([Cl:58])=[C:47]([CH2:49][C:50]3[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=3)[CH:48]=1)[O:59][CH:2]([CH2:3][OH:65])[CH2:1]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(CO)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a solution of 34 (70 mg, 86 μmol) in anhydrous DCM (1 mL) was added 3-chlorobenzoperoxoic acid (23 mg, 104 μmol, 1.2 equiv). The reaction was stirred overnight, directly loaded onto a preparatory TLC plate, and eluted with 15% EtOAc in petroleum ether to give 39 (17 mg, 24% yield), a single diastereomer. 1H NMR (300 MHz, CDCl3) δ 7.14-7.32 (m, 18H), 6.98 (d, J=8.1 Hz, 2H), 6.96 (s, 1H), 6.90 (d, J=8.1 Hz, 2H), 6.79-6.83 (m, 2H), 4.85 (d, J=10.8 Hz, 1H), 4.80 (s, 2H), 4.58 (d, J=10.8 Hz, 1H), 4.57 (d, J=12.0 Hz, 1H), 4.45 (d, J=12.0 Hz, 1H), 4.37 (d, J=10.8 Hz, 1H), 4.07-4.15 (m, 1H), 4.05 (d, J=15.6 Hz, 1H), 3.61-3.91 (m, 10H), 2.49 (q, J=7.5 Hz), 2.08-2.35 (m, 3H), 1.12 (t, J=7.5 Hz, 3H). LCMS m/z 826 (M+H), 848 (M+Na).