Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:16][CH2:17][C:18](Cl)=[O:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:16][CH2:17][C:18]([NH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1(C)CNC(=O)CCl

Procedure:
A solution of tert-butyl 2-(aminomethyl)-2-methylpyrrolidine-1-carboxylate (1.2 g), excess 2-chloroacetyl chloride (2 mL) and diisopropyl ethyl amine (2 mL) in DCM was stirred at room temperature for about 2 h. The reaction was monitored by LC-MS. After the solution was concentrated in vacuo, 0.7 g of the desired product was obtained by column chromatography purification. MS (ESI): 291, 293 (MH+).
Reaction SMILES: [Mg].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.C(Cl)(=O)C(Cl)=O.[F:17][C:18]1[C:26]([CH3:27])=[C:25]([N+:28]([O-:30])=[O:29])[C:24]([F:31])=[CH:23][C:19]=1C(O)=O>O1CCCC1.CN(C)C=O.C(Cl)Cl.C(O)C.C(Cl)(Cl)(Cl)Cl>[F:17][C:18]1[C:26]([CH3:27])=[C:25]([N+:28]([O-:30])=[O:29])[C:24]([F:31])=[CH:23][C:19]=1[C:4]([CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[O:6]
Reactant: Cc1c(F)c(C(=O)O)cc(F)c1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Mg]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Magnesium (733 mg), ethanol (3 mg) and carbon tetrachloride (0.1 ml) were stirred at room temperature in a three necked flask to activate them. A solution of ethyl malonate (4.5 ml) in tetrahydrofuran (20 ml) was slowly added dropwise to the activated mixture, followed by stirring at 80° C. for 4 hours. After the reaction mixture was cooled back to room temperature, it was chilled to -40° C. Oxalyl chloride (2.5 ml) and N,N-dimethylformamide (3 drops) were added to a solution of 2,5-difluoro-3-methyl-4-nitrobenzoic acid (6.1 g) in methylene chloride (10 ml). After the mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure. Toluene was added to the residue to conduct azeotropic distillation. The residue wets dissolved in tetrahydrofuran (15 ml), and the solution was slowly added dropwise at -40° C. to the reaction mixture obtained previously. After completion of the addition, the temperature of the reaction mixture was given back to room temperature to conduct stirring overnight. After the solvent was distilled off under reduced pressure, concentrated hydrochloric acid (5 ml) was added to the residue to keep its pH at about 2. The residue was then extracted with chloroform, and the solvent was distilled off under reduced pressure. Water (20 ml) and p-toluenesulfonic acid monohydrate (250 mg) were added to the resultant residue, and the mixture was heated under reflux for 5.5 hours. After the reaction mixture was cooled back to room temperature, water was added to the reaction mixture to conduct extraction with chloroform. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent; ethyl acetate:hexane=1:7) to obtain the title compound (6.0 g) as a red oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[Br:30].[C:31](=[O:33])=[O:32].Cl>C1COCC1.C(OCC)C>[Br:30][C:23]1[C:22]([F:21])=[C:27]([C:26]([F:28])=[C:25]([F:29])[CH:24]=1)[C:31]([OH:33])=[O:32]
Reactant: O=C=O
Reactant: Fc1cc(F)c(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(F)cc(Br)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
Step (i) n-Butyllithium (2.5M in hexane, 10.5 mL, 1.1 eq.) was added dropwise over 15 min to a solution of diisopropylamine (4.0 mL, 1.2 eq.) in THF (25 mL) at 0° C. After stirring for 15 min, the LDA solution was added dropwise over 40 min to a solution of 2,4,5-trifluorobromobenzene (5.0 g, 24 mmol) in THF (50 mL) at −78° C. The solution was stirred for 10 min and then transferred to a slurry of dry ice (50 g) in diethylether (65 mL). The reaction was allowed to warm to rt and treated with 1M HCl. The phases were separated and the organic layer extracted with 0.5M NaOH. The basic extracts were acidified to pH 1 with 6M HCl and extracted with diethylether. The combined organic phases were dried over sodium sulfate and evaporated to yield 3-bromo-2,5,6-trifluorobenzoic acid as a white solid (3.2 g, 52%). Step (ii)
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[F:23][C:24]([F:31])([F:30])[C:25]([F:29])=[C:26](F)[F:27].Cl>CCOCC.CCCCCC.O>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Si:14]([CH3:17])([CH3:15])[CH3:16])=[CH:12][C:13]=1[C:26]([F:27])=[C:25]([F:29])[C:24]([F:31])([F:30])[F:23])(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1ccc([Si](C)(C)C)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1sc([Si](C)(C)C)cc1C(F)=C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.3 %

Procedure:
Two grams of the N-tert-butyl-5-trimethylsilyl-2-thiophenesulfonamide prepared in (1) above was dissolved in 100 ml of dry ether under nitrogen stream. To the solution, 15 ml of a 1.6M solution of n-butyllithium in n-hexane was added dropwise at 10° to 15° C., followed by stirring at room temperature for 4 hours. Subsequently, a dry ice condenser was attached to the reactor, and then 10 g of hexafluoropropene was charged at 0° to 10° C. under nitrogen stream. Reaction was performed under stirring for 3 hours. After completion of the reaction, the resulting product was poured into water, acidified with hydrochloric acid and extracted with ether. The ether layer was washed with water and dried. After distilling off ether under vacuum, the residue was purified by column chromatography on silica gel (eluent: methylene chloride) to provide 1.6 g of N-tert-butyl-3-(1,2,3,3,3-pentafluoropropen-1-yl)-5-trimethylsilyl-2-thiophenesulfonamide having a melting point of 92° to 94° C.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([O-])=O.C(O)C.O>C(O)(=O)C>[NH2:1][C:4]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1ccccc1Oc1ccc(Br)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Br)ccc1Oc1ccccc1C(=O)O
Temperature: 75 °C

Procedure:
A mixture of 2-(2-nitro-4-bromophenoxy)benzoic acid (0.6 g, 0.0018 mol) iron powder (0.69 g 0.012 mol), ethanol (46 mL), water (41 mL), and acetic acid (4.6 mL) was heated to 75° C. for 30 minutes. The mixture was filtered and the solvents evaporated to give the crude product which was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid) to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ8.09 (dd, 1H), 7.45-7.50 (m, 1H), 7.16-7.26 (m, 1H), 6.99 (d, 1H), 6.84-6.89 (m, 2H), 6.78 (d, 1H), 5.35 (br s, 3H).
Reaction SMILES: CC([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])(C)C.[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl.O>O1CCCC1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)CCSc1ccc(O)c(C(C)(C)C)c1
Temperature: 12.5 °C
Reaction time: 3 h

Procedure:
2.0 g of the aldehyde of Example 4 was dissolved in 20 ml of dry tetrahydrofuran under argon and added to 8.5 ml of 2 M isopropylmagnesium chloride in tetrahydrofuran that had previously been added under argon gas to a flask that had been dried in vacuo overnight. Reaction temperature was maintained at 10-15° C. with an ice bath. When addition was complete, the reaction mixture was allowed warm to room temperature and stirred for 3 hours. 2 N hydrochloric acid (2 ml) was added followed by 50 ml of water and the mixture extracted with ethyl acetate three times. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed in vacuo after filtration and the crude product chromatographed on silica to give the title compound.
Reaction SMILES: CN(C=O)C.[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:35])[C:18]([NH:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:19][N:20]3[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:15][C:14]=2[F:36])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:37]([N:28]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:18]1[C:17](=[O:35])[C:16]2[C:21](=[CH:22][C:13]([NH:12][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)=[C:14]([F:36])[CH:15]=2)[N:20]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:19]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CNc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(Cc1ccccc1)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 3.2 ml DMF solution of 160 mg of ethyl {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}acetate were added 0.05 ml of benzyl bromide and 75 mg of potassium carbonate, followed by overnight stirring at room temperature. By adding water to the reaction mixture and collecting the insoluble materials by filtration, 200 mg of ethyl {benzyl[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}acetate was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]=[CH:15][CH2:16][CH2:17][OH:18])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O.[NH4+].[Cl-]>C(Cl)Cl.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]=[CH:15][CH2:16][CH:17]=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C=CCCO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1C=CCC=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-(2-tert-Butyl-5-nitro-phenyl)-but-3-en-1-ol (1.024 g) was dissolved in 10 ml of CH2Cl2 and added dropwise over 5 min to a −78° C. mix of oxalyl chloride (0.645 ml), DMSO (0.583 ml), and 10 ml CH2Cl2. The reaction was stirred at −78° C. for 1 h, then treated with a solution of TEA (1.52 ml) in 7 ml CH2Cl2 and stirred at −78° C. for an additional 25 min, then warmed to −30° C. for 35 min. The reaction was treated with 50 ml of saturated aqueous NH4Cl, diluted with H2O and extracted with EtOAc. The organic layer was brine-washed, dried over Na2SO4, filtered, and concentrated in vacuo to yield a yellow oil which was used as is in Preparation LXXXVIII.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:13][N:12]=3)=[N:9][N:8](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:5]2=[N:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:13][N:12]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[C@@H](CC(=O)O)Nc1ccnc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1ccnc(-c2n[nH]c3ncc(F)cc23)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of crude (R)-3-((2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid, 138a, (0.11 g, 0.21 mmol) in CH2Cl2 was added triethylsilane (0.15 mL, 0.94 mmol) followed by trifluoroacetic acid (0.15 mL, 1.95 mmol). After stirring the resulting solution at room temperature for 1 hour, the reaction mixture was kept below 5° C. overnight (refrigerator). The mixture was then allowed to warm to room temperature and kept at that temperature for an additional 5 hours. The solution was diluted with toluene and concentrated in vacuo. Trituration with Et2O followed by preparative HPLC purification provided 15 mg of the desired product as the TFA salt. 1H NMR indicated a 3 to 1 mixture of atropisomers: 1H NMR (400 MHz, MeOD, major isomer) δ 8.63-8.45 (m, 2H), 7.96 (d, J=7.3 Hz, 2H), 6.66 (d, J=7.3 Hz, 2H), 4.95 (d, J=10.6 Hz, 2H), 2.84 (dd, J=15.4, 2.4 Hz, 2H), 2.44 (dd, J=15.9, 10.7 Hz, 2H), 0.98 (s, 9H); LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, Retention Time=2.12 minutes (M+H) 359.02.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.[CH2:9](I)[CH3:10].[Li+].CC([N-]C(C)C)C.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][CH3:10]
Reactant: CCI
Reactant: Brc1cccc(I)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(Br)cccc1I
Temperature: -78 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
A three necked round-bottom flask was purged with argon and then filled with dry THF (250 mL), 1-bromo-3-iodo-benzene (50 g, 176.74 mmol) and ethyl iodide (50 g, 320.57 mmol). The mixture was cooled to −78° C. and LDA (made with 50 mL of iPr2NH and 122.5 mL of BuLi (2.5 M in hexane) in 250 mL of THF) was added slowly at −50° C. The reaction was stirred for 4 hr and poured into sat. aq. NH4Cl solution (1000 mL) and stirred vigorously for 20 min, extracted with DCM. The organic layers were separated, dried over Na2SO4 and evaporated to give the crude product, which was purified by column chromatography to afford 1-bromo-2-ethyl-3-iodo-benzene (D126) (50 g,). δH (CDCl3-d6, 400 MHz): 1.14 (3H, t), 3.06 (2H, q), 6.68 (1H, t), 7.52 (1H, d), 7.70 (1H, d)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:20]=[CH:19][N:18]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:17][CH:16]2[OH:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:44]([CH:51]([CH3:53])[CH3:52])([CH:48]([CH3:50])[CH3:49])[CH:45]([CH3:47])[CH3:46])(=O)=O.O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:20]=[CH:19][N:18]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:17][CH:16]2[O:29][Si:44]([CH:51]([CH3:53])[CH3:52])([CH:48]([CH3:50])[CH3:49])[CH:45]([CH3:47])[CH3:46])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(c1ccccc1)N1C=CC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: CC(c1ccccc1)N1C=CC(c2ccc(OCc3ccccc3)cc2)C(O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 14.70 g of 4-(4-benzyloxyphenyl)-1-(1-phenylethyl)-1,2,3,4-tetrahydro-pyridin-3-ol [257928-45-3] in 250 ml of dichloromethane is mixed with 6.80 ml of 2,6-lutidine and cooled to 0° C. 12.60 ml of triisopropysilyl trifluoromethanesulphonate are added dropwise, and the reaction mixture is stirred at 0° C. for 1 hour. The reaction solution is poured into 400 ml of water, and the phases are separated. The aqueous phase is back-extracted with 200 ml of dichloromethane, and the combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained as a yellow-brown oil from the residue by flash chromatography (SiO2 F60). Rf (EtOAc/heptane 1:2)=0.66; Rt=5.83.
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.[Br:49][C:50]1[CH:51]=[N:52][C:53](Cl)=[N:54][CH:55]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[Br:49][C:50]1[CH:51]=[N:52][C:53]([N:33]2[CH2:34][CH2:35][CH:30]([C:10]3[C:9]([CH:36]([F:47])[C:37]4[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[C:8]([CH:5]4[CH2:6][CH2:7][C:2]([F:1])([F:48])[CH2:3][CH2:4]4)[C:17]4[CH:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=4[N:11]=3)[CH2:31][CH2:32]2)=[N:54][CH:55]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a solution of 1.0 g (1.5 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, in 5 ml of N,N-dimethylformamide, 0.58 g (3.0 mmol) of 5-bromo-2-chloropyrimidine and 0.27 ml (1.8 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene were added, and the reaction solution was stirred at 100° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. 5% Ethyl acetate/n-hexane solution was added to the obtained residue and the precipitate was obtained by filtration to provide 0.78 g of 2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline as a white solid (yield: 64%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21].C1C(=O)N([I:29])C(=O)C1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.CS(O)(=O)=O.S1(CCCC1)(=O)=O>CN(C)C(=O)C.CN(C)C=O.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C.CS(C)=O.CCOCC.C(O)(=O)C.C(O)=O>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:29])=[CH:17][C:16]=1[F:21]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1F
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid can be reacted with halogenations reagent (such as NIS) in the presence of acid (such as trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, acetic acid) at ambient temperature in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid is obtained after conventional workup.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([N:23]2[CH2:28][C:27]3([CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][O:37][C:38]4[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=4)[CH:41]=O)[CH2:30][CH2:29]3)[O:26][CH2:25][CH2:24]2)=[O:22])[N:20]=1.[NH2:46][CH2:47][C@@H:48]([C:57]1[CH:66]=[CH:65][C:64]([OH:67])=[C:63]2[C:58]=1[CH:59]=[CH:60][C:61](=[O:68])[NH:62]2)[O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51].C(O)(=O)C>CO>[Si:50]([O:49][C@H:48]([C:57]1[CH:66]=[CH:65][C:64]([OH:67])=[C:63]2[C:58]=1[CH:59]=[CH:60][C:61](=[O:68])[NH:62]2)[CH2:47][NH:46][CH2:41][C:40]1[CH:43]=[CH:44][CH:45]=[C:38]([O:37][CH2:36][CH2:35][CH2:34][N:31]2[CH2:32][CH2:33][C:27]3([O:26][CH2:25][CH2:24][N:23]([C:21]([C:19]4[N:20]=[C:16]([CH3:15])[S:17][CH:18]=4)=[O:22])[CH2:28]3)[CH2:29][CH2:30]2)[CH:39]=1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4cccc(C=O)c4)CC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4cccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (0.113 g) was added in one portion to a stirred solution at 0° C. of 3-(3-(4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)propoxy)benzaldehyde (example 95, step b) (0.157 g), (R)-5-(2-amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one (WO2004106333) (0.118 g) and acetic acid (0.020 mL) in methanol (7 mL). The resulting mixture was stirred at 20° C. for 2 hours. Most of the methanol was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous phosphate buffer (pH=7.2), the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 8% methanol and 1% ‘880’ aqueous ammonia in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.160 g.
Reaction SMILES: [C:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>O.C(OCC)(=O)C.CC(O)=O.C1(C)C=CC=CC=1.CCO>[C:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NS(=O)(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 88.3 %

Procedure:
A mixture of Example 9A (3.10 g, 9.22 mmol), 4-trifluoromethoxyphenylboronic acid (2.13 g, 10.14 mmol), absolute EtOH (15 mL), 2 M aqueous Na2CO3 (9.22 mL, 18.44 mmol), and toluene (65 mL) was sparged with N2, treated with tetrakis(triphenylphosphine)paladium (0) (538 mg, 0.461 mmol), and heated at reflux for 1.25 hours. The reaction mixture was cooled, diluted with H2O (50 mL) and ethyl acetate (100 mL), and acidified to pH 3 with HOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. Purification on silica gel with a gradient of CH2Cl2 to 2% MeOH/Cf 2CH2 provided 3.40 g (88%) of the desired compound as a white solid.