Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](O)[N:11]=1)[CH:7]=[CH:6][S:5]2.P(Cl)(Cl)([Cl:19])=O>>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1)[CH:7]=[CH:6][S:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc(-c2c(Cl)nc3sccn23)n1
Product: Clc1nccc(-c2c(Cl)nc3sccn23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of EXAMPLE 80D (9.97 g, 39.5 mmol) and phosphoryl trichloride (110 ml, 1184 mmol) was stirred at 80° C. for 5 hours. The mixture was cooled to room temperature, then concentrated to dryness. Water (150 mL) was added cautiously. The mixture was cooled with an ice bath and adjusted to pH˜11 with concentrated aqueous NaOH, then stirred for 30 minutes. The solid was collected by filtration, washed with water (3×50 mL), and dried in a vacuum oven overnight at ˜50° C. to provide the title compound. (ESI(+)) m/e 271.1 (M+H)+.
Reaction SMILES: COC1C=C2C(=CC=1)C=C(C1C=CC=CC=1N)C(C)(C)C2.Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N1(CCOC2C=C[C:55]([CH2:56][NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[C:64]3[C:73]([CH3:75])([CH3:74])[CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:76][CH3:77])[CH:70]=4)[CH:65]=3)=CC=2)CCCCCC1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([CH2:37][N:57]([CH2:56][CH3:55])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[C:64]3[C:73]([CH3:74])([CH3:75])[CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:76][CH3:77])[CH:70]=4)[CH:65]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1NCc1ccc(OCCN3CCCCCC3)cc1)=C2
Agent: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1N)=C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1=Cc2ccc(OC)cc2CC1(C)C

Procedure:
Synthesized from 2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenyl]amine (451 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenyl]amine (423 mg). This compound (421 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (355 mg).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][C:11](=[O:23])[CH:12](C(OC(C)(C)C)=O)[C:13](=[O:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)=O>C(OCC)C>[CH2:1]([S:8][CH2:9][CH2:10][C:11](=[O:23])[CH2:12][C:13](=[O:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(C(=O)CCSCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C=O
Solvent: CCOCC
Product: CC(=O)CC(=O)CCSCc1ccccc1

Procedure:
101 g (0.3 mol) of 1-benzylthio-4-tert-butoxycarbonyl-3,5-hexanedione (see Example 1) and 1.0 g of p-toluenesulfonic acid are heated at 70°-75° C. for 225 minutes in a 250 ml flask equipped with a stirrer, a thermometer, a reflux condenser and a bubble counter until the evolution of gas (CO2) is complete. 100 ml of diethyl ether are added and the mixture is washed first with 50 ml of bicarbonate and then with 100 ml of water and is subsequently concentrated and fractionated.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)=[C:11]([CH3:39])[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH3:39])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(COc2ccc(CCC(=O)OC(C)(C)C)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(CCC(=O)OC(C)(C)C)cc2)c1
Yield: 89.8 %

Procedure:
To a solution of tert-butyl 3-{4-[(4′-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (2.38 g, 4.35 mmol) in tetrahydrofuran (24 mL) was added tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 4.79 mmol, 4.79 mL) at room temperature with stirring and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) to give the title compound (1.69 g, yield 90%) as a colorless oil.
Reaction SMILES: C(NCCCN[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(C)(C)C.[Cl:32]C1C2C(=CC(Cl)=CC=2)N=CC=1I>ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd+2]>[Cl:32][C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1
Reactant: CC(C)(C)NCCCNc1c(-c2ccc(OC(F)(F)F)cc2)cnc2cc(Cl)ccc12
Reactant: Clc1ccc2c(Cl)c(I)cnc2c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Product: FC(F)(F)Oc1ccc(-c2cnc3cc(Cl)ccc3c2Cl)cc1

Procedure:
Alternatively, compound 1 can be synthesized according to Scheme 2 by performing the Suzuki coupling directly on the 4-chloro 3-iodo quinoline (C) using dichloro [1,1′ bis(diphenylphosphino)ferrocene)]palladium (II) [PdCl2(dppf)] (Hayashi, T. J. Am. Chem. Soc. 1984, 106, 158-163, incorporated by reference herein) as a catalyst to give 4,7-dichloro-3-(4-(trifluoromethoxy)phenyl)quinoline (P) in 79% yield a white solid after flash chromatography. Finally, the desired product compound 1 is obtained using the same procedure as described in Scheme 2 in approximately 90% yield. In some embodiments, this new and more efficient method (Scheme 2) may give an overall yield of approximately 42%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Br)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].[BH4-].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CO>[CH2:1]([O:8][C:9]1[C:10]([CH2:24][OH:25])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1cnc(Br)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1ncc(Br)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 61.7 %

Procedure:
A solution of 3-benzyloxy-2,5-dibromopyridine (210 mg, 0.612 mmol) in toluene was cooled to −78° C. under N2 and n-butyllithium (1.60M, 0.46 mL, 0.735 mmol) was added dropwise. The mixture was stirred at −78° C. for 2.5 hours followed by the addition of dry N,N-dimethylformamide (0.095 mL, 1.22 mmol). After gradually warming to room temperature, methanol (5 mL) and sodium borohydride (23 mg, 0.612 mmol) was added to the mixture. The resulting mixture was stirred for 30 minutes, to which was added saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound as a yellow crystal (111 mg, yield 62%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH2:9][C:10](=[O:20])[N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2I)[N:12]=1.[CH3:21][N:22]1CCCC1=O>C(=O)(O)[O-].[Na+].[C-]#N.[Zn+2].[C-]#N.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH2:9][C:10](=[O:20])[N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:21]#[N:22])[N:12]=1
Reactant: O=C1COC(c2ccccn2)=NN1c1ccccc1I
Reactant: CN1CCCC1=O
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C([O-])O
Product: N#Cc1ccccc1N1N=C(c2ccccn2)OCC1=O
Reaction time: 1 h
Yield: 54 %

Procedure:
2-(2-Pyridyl)-4-(2-iodophenyl)-4H-1,3,4-oxadiazine-5(6H)-one (100 mg) obtained in Example 105 was dissolved in N-methyl pyrrolidone (2 ml). Zinc cyanide (80 mg), copper iodide (5 mg) and tetrakis(triphenyl phosphine) palladium (10 mg) were added thereto, followed by stirring for 1 hour. The reaction solution was diluted with an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the reaction solution was evaporated and purified by silica gel chromatography (hexane/ethyl acetate system), to give the title compound (40 mg, 54%).
Reaction SMILES: C([O:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)CC.[OH-].[Na+]>O>[F:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][CH2:6][C:5]([OH:17])=[O:4])[CH:10]=[C:11]([F:16])[CH:12]=1
Reactant: CCCOC(=O)CCCc1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCc1cc(F)cc(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
A mixture of crude 4-(3,5-difluoro-phenyl)-butyric acid propyl ester (3.3 kg), water (4.4 kg), and 50% sodium hydroxide (3.35 kg) were stirred at 50° C. for 1 hour. The hydrolysis was monitored by HPLC. The resulting solution was washed with hexane (4.2 kg) to remove organic impurities. The aqueous layer was acidified with conc. HCl (4.73 kg), and extracted with MTBE (4.23 kg). The solution was concentrated, and residual MTBE was removed by solvent exchange with n-heptane (4.0 liters) to give crude 4-(3,5-difluoro-phenyl)-butyric acid (2.8 kg) as an oil: H1 NMR (300 MHz): δ(CDCl3): 1.94 (2H, p, J=7.54 Hz), 2.38 (2H, t, J=7.54 Hz), 2.65 (2H, t, J=7.54 Hz), 6.63 (1H, tt, J=2.26, 9.04 Hz), 6.7 (2H, m, J=2.26, 6.4 Hz), 11.70 (1H, bs, COOH)
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:24]2[CH2:28][C:27]([O:29][C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])=[CH:26][C:25]2=[O:38])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]3[CH2:21][O:20]C(C)(C)[O:18]3)[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:6][C@H:7]([N:24]2[CH2:28][C:27]([O:29][C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])=[CH:26][C:25]2=[O:38])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([OH:18])[CH2:21][OH:20])[N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](CC3CCCC3)N3CC(Oc4c(F)cccc4F)=CC3=O)n2)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](CC1CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
A solution of (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-propionamide (prepared as in Example 87, 120 mg, 0.22 mmol) in tetrahydrofuran (20 mL) was treated with 2N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 4 h at 25° C. The reaction mixture was adjusted to neutral and diluted with ethyl acetate, washed with water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated to afford (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (70 mg, 63%) as an off-white solid: HR-ES-MS m/z calculated for C24H28F2N4O5 [M+H]+ 491.2101, observed 491.2102; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08 (br. s., 1H) 1.28 (br. s., 1H) 1.36-1.95 (m, 9H) 3.19-3.30 (m, 2H) 3.64-3.80 (m, 1H) 3.80-3.91 (m, 1H) 4.07 (dd, J=13.6, 3.9 Hz, 1H) 4.28 (d, J=18.7 Hz, 1H) 4.61 (d, J=18.7 Hz, 1H) 4.69 (t, J=5.6 Hz, 1H) 4.79 (dd, J=10.3, 4.8 Hz, 1H) 4.92 (d, J=5.4 Hz, 1H) 5.01 (s, 1H) 6.39 (d, J=2.1 Hz, 1H) 7.22-7.48 (m, 3H) 7.51 (d, J=2.1 Hz, 1H) 10.78 (s, 1H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5].[CH2:20]([O:27][C:28]([CH2:30][CH2:31][CH2:32][C@H:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:34](O)=[O:35])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:20]([O:27][C:28]([CH2:30][CH2:31][CH2:32][C@H:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:34]([O:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5])=[O:35])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCC[C@H](O)CC(N)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a suspended solution of (S)-3-hydroxyhexadecanamide (3.45 g) and (S)-5-benzyloxycarbonyl-2-(tertiarybutoxycarbonylamino)pentanoic acid (4.50 g) in dichloromethane (150 ml) were added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (5.66 g) and 4-dimethylaminopyridine (3.13 g). The mixture was stirred overnight. The precipitates were filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml) and washed with 1N hydrochloric acid (100 ml×3), water (100 ml), saturated sodium bicarbonate (100 ml×2), and brine (100 ml). Then, the solution was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give (3S)-3-[(2S)-5-benzyloxycarbonyl-2-(tertiarybutoxycarbonylamino)-pentanoyl]oxyhexadecanamide (3.85 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:39])([F:38])[C:13]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:33][C:13]([OH:32])([CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]([F:38])([F:11])[F:39])=[O:6]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: Cc1ccccc1C(=O)O
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 11 from 2-methylbenzoic acid and 1,1,1-trifluoro-3-[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [Cl:1][CH:2]([C:7]1([C:16]([F:19])([F:18])[F:17])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([CH:2]([Cl:1])[C:3]([F:6])([F:5])[F:4])([C:16]([F:19])([F:18])[F:17])[O:11][C:10]=2[CH:12]=1
Reactant: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccc(Br)cc2O1
Reaction time: 3 h

Procedure:
51 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 2 or 17 were dissolved in 300 ml of carbon tetrachloride, and 0.5 g of anhydrous FeCl3 was added. 32 g of bromine were then added and the mixture was stirred for 3 hours under reflux. After cooling, it was washed with 10% NaHSO3 solution, dried over MgSO4 and distilled. The yield was 49 g (63% of theory) and the boiling point was 94°-98° C. at 8 mbar.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:16])[O:4][N:3]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1C
Yield: 44.4 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (212 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.141 ml, 0.812 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 126 mg (44.3%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:43])[CH2:22][C@H:23]([NH:35]C(=O)OC(C)(C)C)[CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:16]1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl.CO.CC#N.O>[NH2:35][C@H:23]([CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH2:22][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C:7]2[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH2:16]1)=[O:43].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2ccccc21

Procedure:
tert-Butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (7E) (0.257 mmol, 0.150 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen and dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (2 mL) was then added and the solution was stirred at room temperature for 2 hr. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative CH3CN in H2O (25-95%). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford (R)-3-amino-1((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-(naphthalen-2-yl)butan-1-one (74) as its trifluoroacetic acid salt and as a white flocculent solid (0.152 mmol, 0.091 g, yield 59%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.56 (m, 1H) 1.75-2.00 (m, 3H) 2.03-2.18 (m, 2H) 2.62-2.75 (m, 3H) 2.90-3.00 (m, 1H) 3.03-3.29 (m, 8H) 3.34-3.45 (m, 2H) 3.77-3.87 (m, 2H) 4.09-4.68 (m, 3H) 7.42-7.55 (m, 5H) 7.72-8.02 (m, 6H) ESI-MS: 485.5 m/z (M+H)+.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C@H:7]2[O:12][C:10](=[O:11])[C:9]([OH:13])=[C:8]2[OH:14])[CH2:4][O:3]1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C[O:29][P:30](=O)([O:33]C)[O:31]C.[OH-].[Ca+2].[OH-].P(Cl)(Cl)(Cl)=O>O.N1C=CC=CC=1.CC(C)=O.CN(C)C=O>[P:30]([O:13][C:9]1[C:10]([O:12][C@H:7]([C@H:5]([CH2:4][OH:3])[OH:6])[C:8]=1[OH:14])=[O:11])([OH:33])([OH:31])=[O:29]
Reactant: COP(=O)(OC)OC
Reactant: CC1(C)OC[C@@H]([C@H]2OC(=O)C(O)=C2O)O1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1OP(=O)(O)O
Reaction time: 1.5 h

Procedure:
The above-described method is to react 5,6-isopropylidene-L-ascorbic acid or L-ascorbic acid with a phosphoric halide in a specific solvent (such as water, or a mixed solvent composed of water and acetone, dimethylformamide or trimethylphosphoric acid) in the presence of a base at temperature not higher than room temperature. More particularly, L-ascorbic derivative of which the hydroxyl groups at the 5- and 6-positions have been protected with acetone under acidic conditions (i.e., 5,6-isopropylidene-L-ascorbic acid) or L-ascorbic acid is dissolved in a mixed solvent composed of water and pyridine or a mixture of water and calcium hydroxide, and phosphorus oxychloride is added dropwise to the resulting solution or mixture at a temperature not higher than 0° C., and the reaction is continued at the same temperature for 90 minutes (reaction ratios: 94.5% and 70.6%, respectively). Then, the reaction mixture is treated with Amberlite Resin IR-120 (H+ -form) at room temperature to desalt the product, followed by neutralization with magnesium oxide, removal of the solvent by distillation, dropwise addition of ethanol to the residue to obtain white powder of magnesium salt of L-ascorbic acid 2-phosphate, which is recrylstallized from water-ethanol (yields: 75.1% and 55.3%, respectively).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CCN1CCC(c2ccc(F)cc2)CC1
Yield: 111.2 %

Procedure:
A mixture of 4-(4-fluorophenyl)-piperidine (15 g), ethyl 3-bromopropionate (20 g), and potassium carbonate (14 g) in methyl isobutyl ketone was refluxed for 16 h. Filtration and removal of solvent in vacuo gave 26 g of crude ethyl 3-(4-(4-fluorophenyl)-1-piperidyl)propionate as an oil which was used directly in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1.Cl[C:16]1[C:17]2[C:24]([CH3:25])=[C:23]([C:26]([O:28][CH3:29])=[O:27])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+].O>O1CCOCC1>[CH3:25][C:24]1[C:17]2[C:16]([NH:14][C:13]3[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:9][CH:10]=[CH:11][CH:12]=3)=[N:21][CH:20]=[N:19][C:18]=2[S:22][C:23]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: Nc1cccnc1OC1CCOCC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Temperature: 25 °C
Yield: 47.2 %

Procedure:
2-(Tetrahydro-2H-pyran-4-yloxy)pyridin-3-amine (0.99 g, 5.10 mmol), methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (1.237 g, 5.10 mmol) and para-toluene sulfonic acid (0.097 g, 0.51 mmol) were heated at reflux in anhydrous 1,4-dioxane (20 mL) for 16 hours. The solution was cooled to ambient temperature and poured into a stirred solution of ammonium hydroxide/water (1:4). The precipitate was filtered off, washed with water, diethyl ether and dried. The product was purified by reverse phase preparative HPLC to yield grey solid (0.963 g, 47%).