Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][OH:26])=[CH:19][C:18]=1[CH3:27]>ClCCl.CN(C1C=CC=CN=1)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][O:26][Si:12]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:15])[CH3:14])=[CH:19][C:18]=1[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(NCCO)ccc1Br
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NCCO[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
Triethylamine (0.39 ml, 2.80 mmol), dimethylaminopyridine (13 mg, 0.11 mmol) and tert-butyl-dimethyl-chloro-silane (319 mg, 2.11 mmol) were added to a solution of 2-(4-bromo-3-methyl-phenylamino)-ethanol (430 mg, 1.87 mmol) in dichloromethane (3.8 ml) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (4-bromo-3-methyl-phenyl)-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amine (629 mg, 98%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16](/[C:29](/[CH3:39])=[CH:30]\[CH:31]=[CH:32]\[C:33](\[CH3:38])=[CH:34]\[C:35]([OH:37])=[O:36])=[CH:17][C:18]2[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=2[CH:24]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>C1COCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16](/[C:29](/[CH3:39])=[CH:30]\[CH:31]=[CH:32]\[C:33](\[CH3:38])=[CH:34]\[C:35]([OH:37])=[O:36])=[CH:17][C:18]2[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=2[CH:24]=1
Reactant: C/C(=C/C=C/C(C)=C/C(=O)O)c1cc2c(cc1OCCCCCO[Si](C)(C)C(C)(C)C)C(C)(C)CCC2(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C/C(=C/C=C/C(C)=C/C(=O)O)c1cc2c(cc1OCCCCCO)C(C)(C)CCC2(C)C

Procedure:
A mixture of (E,E,Z)-7-{3-[5-(tert-butyldimethylsilyloxy)pentyloxy]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl}-3-methyl-2,4,6-octatrienoic acid (850 mg, 1.5 mmol) and a 1M solution in THF of tetrabutylammonium fluoride (TBAF) (3.1 ml) in THF (10 ml) was stirred at room temperature for 1 h and then treated with ethyl acetate and with water. After settling, the organic phase was separated and washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=O)[N:6]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:10]([C:7]1[N:6]=[C:5]([CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: CCOC(=O)c1noc(Cc2cccc(F)c2F)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cccc(F)c2F)n1
Yield: 25.3 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2,3-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.081 g; 0.303 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL) and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.070 g; 0.303 mmol), HATU (0.131 g; 0.346 mmol), N,N diisopropylethylamine (0.149 mL; 0.865 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and preparative HPLC method 2 to yield 0.032 g (25%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,3-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@H:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]2[C@H:15]([O:23]C(=O)C)[CH2:14][N:13]1[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@H:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]2[C@H:15]([OH:23])[CH2:14][N:13]1[S:27]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)(=[O:29])=[O:28])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H](OC(C)=O)[C@H]3OC(C)(C)O[C@@H]3[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2C[C@@H](O)[C@H]3OC(C)(C)O[C@@H]3[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
The above compound (2-2) (100 mg) was dissolved in methanol (2 mL) and 28% sodium methoxide (18 mg) was added, and then the mixture was stirred at room temperature for 2 hours. After neutralizing with a cation exchange resin, the insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2→1:1→2:1) to obtain the titled compound (69 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[O:22])=[CH:24][CH:25]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1ccc(C(N)=O)cc1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide (83.4 mg) in acetonitrile (10 mL) were added sodium iodide (74.3 mg) and chloro(trimethyl)silane (0.251 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and the obtained solid was washed with ethyl acetate to give the title compound (75.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.CCCCCC.O>[Cl:1][C:2]1[CH:14]=[C:13]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)COc1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)COc1ccc(C(=O)CCC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
To a stirred solution of ethyl 2-chlorophenoxyacetate (32.0 g, 149 mmol) in dichloromethane (75 mL) at ambient temperature under nitrogen was added succinic anhydride (22.4 g, 224 mmol). The reaction mixture was cooled in ice-water and to this was added portion wise aluminum trichloride (59.6 g, 447 mmol), whilst maintaining the temperature below 20° C. The reaction mixture was then allowed to stir at ambient temperature for 20 minutes and was then heated to reflux and stirred at this temperature for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then poured into a mixture of ice, water (200 ml) and HCl (10 N, 100 ml). The two phase system was separated and the aqueous layer was extracted with ethyl acetate (5×100 mL). All organic layers were then combined and washed with water (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure to give an orange oily solid. Hexane (300 mL) was added, and after standing at ambient temperature for 1 hour, the precipitate was filtered off and re-crystallized from ethyl acetate/hexane to give 9 as a light yellow powder (21.5 g, 46% yield, 98% pure by LCMS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.79 (m, 1H); 7.66 (m, 1H); 6.79 (m, 1H); 4.90 (s, 2H); 4.12 (q, 2H); 2.82 (m, 2H); 2.42 (m, 2H); 1.30 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.C(Cl)Cl>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CNC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.6 %

Procedure:
A methylene chloride solution (5.0 ml) of N-acetylglycine ethyl ester (72.5 mg, 0.50 mmol) and N-methylimidazole (50.4 mg, 0.61 mmol) was cooled to −45° C., and a methylene chloride solution (0.5 ml) of palmitoyl chloride (142.6 mg, 0.50 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 20 minutes at the same temperature, a methylene chloride solution (0.5 ml) of titanium tetrachloride (340.4 mg, 1.78 mmol) and a methylene chloride solution (0.5 ml) of tributylamine (372.4 mg, 2.01 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −45° C. Water was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. Further, the water layer was extracted twice with methylene chloride, and the organic layers were combined and dried with magnesium sulfate. After the solvent was removed in reduced pressure, the obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, hexane:ethyl acetate=3:2) to obtain the title compound (148.8 mg, yield: 88%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl:13]N1C(=O)CCC1=O>CN1C(=O)CCC1.C(=O)(O)[O-].[Na+]>[Cl:13][C:11]1[C:5]2[S:4][C:3]([S:2][CH3:1])=[N:7][C:6]=2[CH:8]=[CH:9][C:10]=1[OH:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1nc2ccc(O)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1nc2ccc(O)c(Cl)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To the solution of 2-(methylthio)benzo[d]thiazol-6-ol (500 mg, 2.53 mmol, 1.0 eq) in 10 mL of NMP was added N-chlorosuccinimide (507 mg, 3.80 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at room temperature for 1 hour thereafter the mixture was diluted with saturated sodium bicarbonate solution (ca. 100 mL) and aqueous layer extracted with DCM (ca. 150 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure. Purification on ISCO using gradient 0%-100% ethyl acetate-hexane gave 283.39 mg of product in 48% yields structure of which was confirmed by H+NMR. LC/MS (m/z) [232.0] (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](\[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])/[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccccc1Cl
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2-chlorobenzene (277 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. Yield: 50 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.38 (d, 1H), 7.25 (m, 2H), 7.16-7.0 (m, 4H), 6.85 (s, 1H), 4.40 (m, 1H), 4.30 (m, 1H), 3.70 (m, 1H), 3.50 (m, 1H), 3.10 (m, 2H), 3.0 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [Br:1][CH:2]([P:9](=[O:14])([O:12]C)[O:10]C)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si](Br)(C)C>C(Cl)Cl>[Br:1][CH:2]([P:9](=[O:10])([OH:14])[OH:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COP(=O)(OC)C(Br)c1ccccc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.5 %

Procedure:
5 (0.3 g, 1.08 mmol, 1 eq) was dissolved in dry DCM (5 mL). TMSBr (1.2 mL, 8.64 mmol, 8 eq) was added under an inert atmosphere. The reaction was stirred for 20 h at room temperature. The solvent was then evaporated, and MeOH (5 mL) was added to the reaction mixture and stirred for 1 h. The solvent was evaporated and the crude product was dissolved in water (5 mL), filtered and freeze dried yielding 7 as a white powder (229 mg, 85%). 1H NMR (400 MHz, D2O) δ 7.61-7.52 (m, 2H), 7.44-7.33 (m, 3H), 5.10-5.02 (m, 1H). 13C NMR (101 MHz, D2O) δ 136.49 (d, JC-P=3.3 Hz), 129.35 (d, JC-P=6.0 Hz), 129.09 (s), 43.54 (s). 31P NMR (162 MHz, D2O) δ 15.44 (s). ESIMS calculated for C7H7BrO3P [M-H]− 248.93, found: 248.93 mp 158-60° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]([CH3:32])[CH3:31])[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([NH:40][CH3:41])=[O:39])=[CH:36][C:35]=1[O:44][CH3:45].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:30]([O:29][C:4]1[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=[C:2]([NH:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([NH:40][CH3:41])=[O:39])=[CH:36][C:35]=2[O:44][CH3:45])[N:3]=1)([CH3:32])[CH3:31]
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC(C)C)c34)cc2o1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(Nc2nc(OC(C)C)c3c(-c4ccc5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c(OC)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
6-(2-Chloro-4-isopropoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-methoxy-N-methylbenzamide (1.2 equiv), palladium acetate (0.1 equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.2 equiv), cesium carbonate (5 equiv), and 1,4-dioxane (0.14 M) were combined and allowed to stir at 110° C. for 4 h and then cool to ambient temperature overnight. The reaction mixture was diluted with ethyl acetate and filtered through a pre-wetted (with ethyl acetate) bed of Celite. The filtrate was concentrated to an oil under reduced pressure that was purified by silica gel chromatography (0-70% ethyl acetate with 10% MeOH/hexane) to afford the title compound (82% yield). MS (ESI) m/z 617.5 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([CH3:11])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[S:24][C:23]([S:25]([NH:1][C@H:2]([CH2:3][OH:4])[C@H:5]([CH3:11])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: C[C@H](CC(F)(F)F)[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
To a stirred solution of (2S,3R)-2-amino-5,5,5-trifluoro-3-methylpentan-1-ol (2.6 g, 15.18 mmol), triethylamine (4.2 mL, 30.38 mmol) and methylene chloride (50 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (4.8 g, 18.22 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15 min, the ice bath was removed and the reaction allowed to attain 25° C. overnight. The reaction was quenched by pouring it into saturated sodium bicarbonate solution (25 mL) and additional methylene chloride (150 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil (6.1 g) that was purified by flash chromatography using ethyl acetate-hexane, 1-6 as eluent. This produced the title compound 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white amorphous solid (5.15 g, 96.4%). The product contained impurities. The white amorphous solid was further purified by recrystallization from 1:4 EtOAc-heptane. The mixture of solvents was added to 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide, heated to obtain a solution, allowed to cool to 25° C. for 3 h and then stored at 0° C. for 19 hours. A crystalline white solid precipitated, was filtered and washed with ice-cold heptane to obtain a white crystalline solid (2.7 g, 40.9%). The recrystallized material still contained impurities. The white solid (2.7 g) was further purified by prep-chiral HPLC [SFC; AD, 25×0.46 cm; mobile phase, 8:2 hexane-I-PrOH (1 mL/min)] to obtain 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white crystalline solid, mp 132-133° C. (0.93 g, 14.1%, chiral purity 100%, analytical purity 100%). Mass Spectrum (−ESI): 350 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1>CO.ClCCl.[Pd]>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@]1(O)CO
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@]1(O)CO
Reaction time: 12 h
Yield: 84.4 %

Procedure:
The compound from Step B (120 mg, 0.2 mmol) was dissolved in 1:1 methanol/dichloromethane, 10% Pd—C was added, and the suspension stirred under an H2 atmosphere for 12 h. The catalyst was removed by filtration through a celite pad and washed with copious amounts of methanol. The combined filtrate was evaporated in vacuo and the residue was purified by flash chromatography (SiO2, 10% methanol in EtOAc containing 0.1% triethylamine) to give the title compound (50 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH2:5][CH2:6][C:7]2=[O:15].FC1C=CC([N+]([O-])=O)=C2C=1C(N1C(=O)C3C(=CC=CC=3)C1=O)CCC2=O>>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]2[C:8]=1[C:7](=[O:15])[CH2:6][CH2:5][CH:4]2[N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: Cc1ccc([N+](=O)[O-])c2c1C(N1C(=O)c3ccccc3C1=O)CCC2=O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)c2c(F)ccc([N+](=O)[O-])c21
Product: Cc1ccc(N)c2c1C(N1C(=O)c3ccccc3C1=O)CCC2=O

Procedure:
The reaction was carried out in the same manner as in Example 13-(10), except that 145 mg of the compound prepared in (2) above was used instead of 5-fluoro-8-nitro-4-(1,3-dioxoisoindoline-2-yl)-1-tetralone of Example 13-(10). The reaction product was post-treated to produce 75 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37]O)[CH3:33].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)[CH3:33]
Reactant: CCN(CC)CCCO
Reactant: COc1cc(C=O)c(F)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCCOc1cc(F)c(C=O)cc1OC
Temperature: 0 °C

Procedure:
To 2-fluoro-4-hydroxy-5-methoxy-benzaldehyde (39, 1.20 g, 7.05 mmol, prepared as described in Scheme 12 of Example 15) in tetrahydrofuran (60.0 mL) were added triphenylphosphine (1.93 g, 7.35 mmol) and 3-(diethylamino)-propan-1-ol, (0.96 g, 7.30 mmol). The reaction was cooled to 0° C., followed by slow addition of diethyl azodicarboxylate (1.28 g, 7.35 mmol). The reaction was allowed to warm to room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give a colorless oil (102, 0.90 g, 45.0%).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(O)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
After a mixture of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (650 mg), 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (10 ml) was stirred at room temperature for three hours, 1 N hydrochloric acid (5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (560 mg, yield: 91%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 197–198° C.