Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=2)[O:4][CH:3]=1.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:16][C:13]1[O:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([C:22]4[CH:23]=[CH:24][C:19]([S:18][CH3:17])=[CH:20][CH:21]=4)=[CH:3][O:4][C:5]3=[CH:6][N:7]=2)=[N:15][N:14]=1
Reactant: Cc1nnc(-c2cc3c(Br)coc3cn2)o1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2coc3cnc(-c4nnc(C)o4)cc23)cc1
Yield: 52 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole and using [4-(methylthio)phenyl]boronic acid instead of (4-fluorophenyl)boronic acid, the title compound (yield 52%) was obtained as colorless crystals.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(CO[Si](C)(C)C(C)(C)C)cc3ccoc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(CO)cc3ccoc23)CC1
Yield: 89.6 %

Procedure:
A mixture of 0.42 gm 1-(5-(tert-butyldimethylsilyloxymethyl)benzofur-7-yl)-4-tert-butoxycarbonylpiperazine and excess tetrabutylammonium fluoride was stirred in tetrahydrofuran for 30 minutes. The reaction mixture was then diluted with ethyl acetate and washed three times with dilute aqueous sodium bicarbonate. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5:2 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.28 gm (89%) 1-(5-(hydroxymethyl)benzofur-7-yl)-4-tert-butoxycarbonylpiperazine. This material was dissolved in trifluoroacetic acid and the resulting solution stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with dichloromethane containing 10% methanol and a trace of ammonia. Fractions containing product were combined and concentrated under reduced pressure to provide 1-(5-hydroxymethyl)benzofur-7-yl)piperazine. This compound was treated with hydrogen chloride to provide the title compound as a white solid.
Reaction SMILES: C(S([NH:7][C@@:8]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)([CH3:18])[CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])=O)(C)(C)C.Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>CO>[F:26][C:21]1[CH:20]=[C:19]([C@@:8]2([CH3:18])[NH:7][C:12](=[O:13])[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: COC(=O)C(C)(C)CC[C@](C)(NS(=O)C(C)(C)C)c1cc(F)cc(F)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(C)CC[C@@](C)(c2cc(F)cc(F)c2)NC1=O
Temperature: 110 °C

Procedure:
To a solution of methyl (5S)-5-[(tert-butylsulfinyl)amino]-5-(3,5-difluorophenyl)-2,2-dimethylhexanoate (1.14 g, 2.93 mmol) in MeOH (60 mL), cooled to 0° C., was added anhydrous HCl gas for 1 minute. The reaction was sealed and allowed to sit at 0° C. for fifteen minutes at which point the reaction was complete by LCMS analysis. Nitrogen was bubbled through the reaction for twenty minutes. The reaction was concentrated in vacuo. Additional MeOH (50 mL) was added and it was again concentrated in vacuo. This was repeated with another addition of MeOH and triethylamine (1.18 g, 11.7 mmol). To the resulting residue was added toluene (50 mL) and triethylamine (1.18 g, 11.7 mmol). A reflux condenser was attached and the mixture stirred at 110° C. After five days of stirring at reflux, the reaction was judged to be complete by LCMS. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with diethyl ether (75 mL) and washed individually with 30 mL of each of the following aqueous solutions: 1 M HCl (twice), water, saturated brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2-1:99 to 5.5:94.5, to give the title compound. MS: m/z=254 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH2:12][C@@H:13]([O:16][CH2:17][P:18]([O:23]CC)([O:20]CC)=[O:19])[CH2:14][OH:15])=[C:4]([O:26]C)[N:3]=1.C[Si](Br)(C)C>CN(C)C=O>[OH:15][CH2:14][C@H:13]([O:16][CH2:17][P:18]([OH:20])([OH:23])=[O:19])[CH2:12][O:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:26])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: CCOP(=O)(CO[C@@H](CO)COn1cnc2c(OC)nc(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2OC[C@H](CO)OCP(=O)(O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a solution of (S)-2-amino-9-[2-(diethoxyphosphorylmethoxy)-3-hydroxypropoxy]-6-methoxypurine (0.56 g, 1.38 mmol) in dry dimethylformamide (5 ml) was added trimethylsilyl bromide (1.82 ml, 13.8 mmol) and the solution stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure and the residue co-evaporated with acetone/water 1:1 (x2). The white solid obtained was crystallised from hot water to give the title compound as a white solid (0.305 g, 66%). IR:νmax (KBr) 3380, 3320, 3160, 1715, 1645, 1600, 1385, 1185, 1160, 1100, 1060, 1045, 925, 770 cm-1. 1H NMR: δH (D2O+NH3) 3.61 (1H, dd, J=12.1 Hz J=9.9 Hz, CHBP), 3.65-3.75 (2H, m, CHAP, CHBOH), 3.82-3.89 (1H, m, CH), 3.93 (1H, dd, J=12.3 Hz, J=3.6 Hz, CHAOH), 4.46-4.53 (2H, m, NOCH2), 8.03 (1H, s, H-8). Found: C, 32.24; H, 4.16; N, 20.59%. C9H14N5O7P requires: C, 32.24; H, 4.21; N, 20.89%. m/z: (FAB, thioglycerol matrix) 336 (MH+). [α]D25 (0.1M NaOH)+12.8° (c=0.43).
Reaction SMILES: [CH3:1][N:2]([C:4]([O:12][Si](C)(C)C)=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:3].[F:17]OC(F)(F)F>ClC(F)(F)F>[F:17][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]([N:2]([CH3:3])[CH3:1])=[O:12]
Reactant: CN(C)C(=Cc1ccccc1)O[Si](C)(C)C
Reactant: FOC(F)(F)F
Agent: FC(F)(F)Cl
Product: CN(C)C(=O)C(F)c1ccccc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A solution of 3.0 g (0.0127 mol) of β-(N,N-dimethylamino)-β-(trimethylsiloxy)styrene (from above) in 100 ml of chlorotrifluoromethane was cooled to -70° C. and 1.6 g (0.013 mol) of trifluoromethyl hypofluorite were passed into the solution over a period of 3 hours. The reaction mixture was warmed to room temperature and then distilled to give 1.49 g (65% yield) of α-fluoro-N,N-dimethylbenzeneacetamide as a colorless oil: bp 98°-100° C. (0.45 mm); 19F NMR (CCl3F) δ-175.9 ppm (d,J=50 Hz); 1H NMR (CCl3F) δ 2.86 ppm (s, 6H), 5.54 ppm (d,J=50 Hz, 1H) and 7.10-7.8 ppm (m, 5H). Anal. Calcd for C10H12FNO: C, 66.27; H, 6.68; F, 10.49; N, 7.73; Found: C, 66.41; H, 6.75; F, 10.30; N, 7.70.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:36][CH3:37])=[C:33]([NH2:35])[CH:34]=1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:35][C:33]3[CH:34]=[C:29]([F:28])[CH:30]=[CH:31][C:32]=3[O:36][CH3:37])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: COc1ccc(F)cc1N
Product: COc1ccc(F)cc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 5-fluoro-2-methoxyphenylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=403.4 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[N-:14]=[N+:15]=[N-:16].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[OH-].[Na+]>C(#N)C>[CH3:1][N:2]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=2)=[N:16][N:15]=[N:14]1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1nnnc1-c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 53.9 %

Procedure:
N-Methyl-3-nitro-benzamide (30.0 g, 167 mmol) was dissolved in acetonitrile (835 mL). Upon dissolution, sodium azide (10.9 g, 167 mmol) was added. The mixture was cooled in an ice bath, and trifluoromethanesulfonic anhydride (29 mL, 172 mmol) was added dropwise at a rate to maintain the reaction temperature below 3° C. The reaction mixture was stirred for 3.5 hours at 0° C. and then poured into 1N aqueous sodium hydroxide (100 mL). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum to 50 mL. The solution was diluted with dichloromethane and water was added. The resuling precipitate was isolated by filtration to give a yellow solid (18.46 g, 54%). The filtrate was concentrated in vacuo and added to boiling ethyl acetate to give a second crop of crystals. Upon cooling to 0° C., additional material (6.07 g, 18%) was isolated by filtration. 1H NMR (300 MHz, CDCl3), δ8.67 (m, 1H), 8.49 (dd, J=8, 2 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 7.94 (dd, J=8, 8 Hz, 1H), 4.22 (s, 3H).
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.C[NH:25]OC.C1C=NC2N(O)N=NC=2C=1.CCN(CC)CC.C(Cl)CCl>C(Cl)Cl>[C:1]([NH2:25])(=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC=CCC=CCCCCCCCCCC(=O)O
Reactant: CNOC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC=CCC=CCCCCCCCCCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
11,14-Eicosadienoic acid, (11Z,14Z)-(50 g, 162 mmol), N,O-Dimethylhydroxylamine hydrochloride (31.6 g, 324 mmol), HOAt (44.1 g, 324 mmol), Et3N (45.2 mL, 324 mmol), and EDC (62.1 g, 324 mmol) were mixed in DCM (810 mL) and stirred overnight at ambient temperature. Reaction was then washed 5×700 mL water, then washed 1×600 mL 1 M NaOH, dried with sodium sulfate, filtered through celite and evaporated to obtain 53.06 g (93%) 11,14-eicosadienamide, N-methoxy-N-methyl-, (11Z,14Z) as a clear golden oil. 1H NMR (400 MHz, CDCl3) δ 5.35 (m, 4H), 3.68 (s, 3H), 3.18 (s, 3H), 2.77 (m, 2H), 2.41 (t, J=7 Hz, 2H), 2.05 (m, 4H), 1.63 (m, 2H), 1.40-1.26 (m, 18H), 0.89 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([C:6](OCCO[Si](C(C)C)(C(C)C)C(C)C)=[O:7])=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:29]([CH3:31])[CH3:30])[CH:32]([CH3:34])[CH3:33]
Reactant: Cc1ccc(C(=O)OCCO[Si](C(C)C)(C(C)C)C(C)C)cc1OCCO[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1OCCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
The solution of 2.0 g of 2-triisopropylsilanyloxyethyl 4-methyl-3-(2-triisopropylsilanyloxyethoxy)benzoate in 6 ml of tetrahydrofuran is added dropwise at 20-40° C. to the stirred mixture of 0.149 g of lithium aluminium hydride in 6 ml of tetrahydrofuran. The reaction mixture is stirred at 40° C. over 4 hours and subsequently cooled to room temperature. 0.6 ml of water, 0.6 ml of 2N NaOH and once again 0.6 ml of water are added dropwise successively and the suspension is stirred at room temperature over 1 hour. The reaction mixture is poured onto 100 ml of 2N HCl (cold) and extracted with ethyl acetate (2×100 ml). The organic phases are washed successively with 2N HCl (100 ml), water (100 ml) and brine (1×100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.71 (1:1 EtOAc-heptane); Rt=6.30.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH:10](Br)[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)Br)=[CH:5][CH:4]=1)#[N:2].[CH3:23][O:24][Na].O>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[O:24][CH3:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)C(Br)C(Br)c2ccc(C#N)cc2)cc1
Reactant: CO[Na]
Solvent: CO
Solvent: O
Product: COC(=CC(=O)c1ccc(C#N)cc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 15 g (35.9 mmol) dibromochalcone ii in 150 mL dry MeOH (distilled from Mg metal) was heated to reflux. Freshly prepared 3N MeONa (2.49 g Na in 36 mL MeOH) was added dropwise, and stirring was continued for 30 min. The clear orange solution was cooled to room temperature, and poured into 100 mL water. The aqueous suspension was extracted with CH2Cl2 and the solvent was removed under reduced pressure. The oily orange residue crystallized in part, and was used for the next reaction without further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([CH:31]([OH:44])[CH2:32][NH:33][C:34]4([C:37]5[N:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=5)[CH2:36][CH2:35]4)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:48])[CH3:47])(=[O:3])[CH3:2].[O:49](C(OC(C)(C)C)=O)[C:50](OC(C)(C)C)=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([CH:31]4[O:44][C:50](=[O:49])[N:33]([C:34]5([C:37]6[N:38]=[CH:39][C:40]([Cl:43])=[CH:41][N:42]=6)[CH2:36][CH2:35]5)[CH2:32]4)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:48])[CH3:47])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)CNC5(c6ncc(Cl)cn6)CC5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C5CN(C6(c7ncc(Cl)cn7)CC6)C(=O)O5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((1-(5-chloropyrimidin-2-yl)cyclopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (106) (400 mg, 0.588 mmol) in dichloromethane (15 ml) stirred at rt was added BOC2O (1.365 ml, 5.88 mmol). The reaction mixture was stirred at rt overnight then evaporated under reduced pressure and the residue was subjected to a silica gel chromatography with petroleum ether/EtOAc (6:1 to 3:1) to give (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (107) (350 mg, 0.496 mmol, 84% yield) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][C:14]([O:21][CH2:22][CH2:23][CH3:24])=[C:13]([CH3:25])[C:12]=1[C:26]([CH3:29])([CH3:28])[CH3:27])(=O)C.[Cl-].[NH4+]>O1CCCC1>[C:26]([C:12]1[C:13]([CH3:25])=[C:14]([O:21][CH2:22][CH2:23][CH3:24])[CH:15]=[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:10])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCCOc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCOc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1C

Procedure:
Lithium aluminum hydride (100 mg) was suspended in tetrahydrofuran (5 ml) under a nitrogen atmosphere. A solution of the 1-acetoxy-2,6-di-tert-butyl-3-methyl-4-propyloxybenzen in tetrahydrofuran (5 ml) was added to the suspension and the mixture was refluxed for 3 h. A saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice cooling and the precipitate was filtered off together with the anhydrous sodium sulfate. The filtrate was concentrated and purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 2,6-di-tert-butyl-3-methyl-4-propyloxyphenol (150 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:15](O)=[O:16])[CH:8]=2)[O:3]1.B.C1COCC1>C1COCC1>[CH3:1][C:2]1([CH3:23])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][OH:16])[CH:8]=2)[O:3]1
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: B
Solvent: C1CCOC1
Product: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
0.8 g of (RS)-2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptanoic acid were dissolved in 15 ml THF and treated dropwise, at 0° C., with 12.3 ml of 1M BH3.THF in THF. The mixture was stirred at 0° C. for two hours and then was quenched at 0° C. with careful addition of one portion of 15 ml of 3N HCl. The mixture was stirred at room temperature for 30 min. then was extracted with three portion of 75 ml of ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated in vacuo, giving a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes), yielding 0.5 g of a pale yellow oil. 1H NMR (CDCl3): 7.06 (d, J=2.2 Hz, 1H), 6.90 (dd, J=8.3, 2.2 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 3.72 (dd, J=10.7, 5.7 Hz, 1H), 3.64 (dd, J=10.7, 8.0 Hz, 1H), 2.75-2.65 (m, 1H), 1.82 (s, 2H), 1.70-1.45 (m, 2H), 1.35 (s, 6H), 1.34 (s, 6H), 1.30-1.15 (m, 6H), 0.83 (t, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[C:26]([CH2:33]Br)=[N:27][C:28]([Cl:32])=[CH:29][C:30]=1[CH3:31]>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:33][C:26]3[C:25]([Br:24])=[C:30]([CH3:31])[CH:29]=[C:28]([Cl:32])[N:27]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc(Cl)nc(CBr)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1Br

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (30.6 g, 98 mmol) in THF (800 mL) was added NaH (60% dispersion in mineral oil) (3.35 g, 84 mmol). After stirring the reaction at room temperature for 10 minutes, 3-bromo-2-(bromomethyl)-6-chloro-4-methylpyridine (16.7 g, 55.8 mmol) was added as a solution in THF (300 mL). The reaction was stirred at room temperature for 16 hours and then quenched with saturated NH4Cl (200 mL). The mixture was diluted with EtOAc (1 L). The organic layer was separated, washed with water (500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 50% EtOAc/heptanes afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloro-4-methylpyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=530.8, 532.8 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.81 (s, 2H), 7.18 (s, 1H), 5.87 (d, J=8.3 Hz, 1H), 5.04 (d, J=17.2 Hz, 1H), 4.42 (m, 1H), 4.32 (d, J=17.3 Hz, 1H), 2.43 (s, 3H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[C:45]([NH:47]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:46]=2)[C:15]([NH:17][C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:47][C:45]1[CH:44]=[C:14]([CH:13]=[C:12]([O:11][CH2:10][C:7]2[S:8][CH:9]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[N:6]=2)[CH:46]=1)[C:15]([NH:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)(=[O:35])=[O:36])[CH:28]=[CH:27][C:19]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:16]
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cc(NC(=O)OCc2ccc([N+](=O)[O-])cc2)cc(OCc2nc(C(C)(C)C)cs2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cc(N)cc(OCc2nc(C(C)(C)C)cs2)c1
Yield: 42.1 %

Procedure:
Ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]-5-(4-nitrobenzyloxycarbonylamino)benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (0.50 g, 0.57 mmol) was dissolved in a mixed solution of ethanol (10 ml) and tetrahydrofuran (10 ml), 10% palladium-carbon (0.10 g) was added to the solution, and the mixture was stirred at room temperature for 3 hours in an atmosphere of hydrogen. The reaction solution was filtered and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent=acetone:chloroform=3:100) and crystallized from acetonitrile to give ethyl 2-[3-amino-5-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4- chlorophenylsulfonyl)propyl]phenoxyacetate (0.17 g, 0.24 mmol, 43%) as light yellow crystals. Its structure is shown in Table 30.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:23]#[N:24])[C:10]([CH3:22])=[C:11]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:23]#[N:24])[C:10]([CH3:22])=[C:11]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=4)[C:12]=3[N:36]3[CH2:37][CH2:38][C@H:34]([N:33]([CH3:39])[CH3:32])[CH2:35]3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(-c2cc(F)cc(F)c2)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2cc(F)cc(F)c2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 90 °C
Reaction time: 15 h
Yield: 16 %

Procedure:
2-Cyclopropyl-6-(3,5-difluorophenyl)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-176) (including impurities, estimated as 0.68 mmol) was dissolved in dimethyl sulfoxide (5 ml), then at room temperature, triethylamine (142 μl, 1.02 mmol) and (3S)-3-(dimethylamino)pyrrolidine (112 μl, 0.88 mmol) were added, the solution was stirred under nitrogen atmosphere at 90° C. for 15 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=96:4) to obtain a roughly-purified product (211 mg, 74% for 2 steps) as a white solid. This was recrystallized from ethyl acetate and diisopropyl ether to obtain the entitled compound (46 mg) as a white solid.