Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[N+:31]([O-])=O)[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CCOC(C)=O.O=[Pt]=O>[NH2:31][C:21]1[CH:22]=[CH:23][C:24]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:20]=1[CH2:19][N:15]1[C@@H:14]([CH3:34])[C@@H:13]([C:5]2[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:4]=2)[O:17][C:16]1=[O:18]
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one (1.07 g, 2.01 mmol) in EtOAc (30 mL) was added PtO2 (100 mg, 0.44 mmol). The reaction was placed under a H2 atmosphere (balloon) and stirred vigorously. After 1 hour, the catalyst was removed by filtration, and the filtrate was concentrated. Purification of the residue by flash chromatography (5 to 40% EtOAc/hexanes) afforded (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.45 (40% EtOAc/hexanes). LCMS=503.2 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.89 (s, 1H), 7.75 (s, 2H), 7.03 (dd, J=8.7, 2.0 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.67 (d, J=8.7 Hz, 1H), 5.67 (d, J=8.5 Hz, 1H), 4.73 (d, J=15.4 Hz, 1H), 4.35 (bs, 2H), 4.09 (d, J=15.4 Hz, 1H), 4.04 (m, 1H), 0.78 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][O:8][CH:9](OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[CH2:4][O:5][C@@H:7]([O:8][CH3:9])[O:6]1
Reactant: COC(OC)OC
Reactant: OCC(O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CO[C@@H]1OC[C@@H](CBr)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
To a solution of 3-bromo-1,2-propanediol (6.0 g, 38.7 mmol) in benzene (90 mL) was added trimethylorthoformate (4.23 mL, 38.7 mmol, 1 eq.) and p-toluenesulfonic acid (pTSA, few crystals). The mixture was stirred for 20 hr at 85°-90° C., then cooled to room temperature and benzene was removed under reduced pressure. The crude material was obtained in 96% yield (7.26 g) as a mixture of cis and trans isomers in a 1:1 ratio. 1H NMR (300 MHz, CDCl3) δ: 3.34 and 3.35 (2s, 3H, OCH3), 3.35 (m, 1H, CHAHBBr), 3.44 and 3.58 (dd, 0.5H, J=5.0 Hz, 15.0 Hz, and dd, 0.5H, J=5.0 Hz, 9.9 Hz, CHAHB Br), 3.92 (dd, 0.5H, J=8.3 Hz, 10.7 Hz, and d, 0.5H, J=8.2 Hz, H-5a), 4.21 (dd, 0.5H, J=6.9 Hz, 15.0 Hz, and d, 0.5H, J=8.3 Hz, H-5b), 4.45 and 4.55 (2m, 1H, H-4), 5.80 and 5.82 (2s, 1H, H-2).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.I[C:23]1[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][N:24]=1>CN(C=O)C.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:29][C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1cccnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.34 g (12 mmol) sample of the compound from step 1c above was dissolved in 15 mL of DMF, and (Ph3P)2PdCl2 (0.6 mmol), CuI (0.74 mmol) and triethylamine (14.25 mmol) were added. The mixture was stirred at room temperature for 1 hour, then 3.14 g (14.4 mmol) of 2-iodo-3-hydroxypyridine (Lancaster Chem. Co.) was added. The reaction mixture was stirred at 60° C. for 16 hours. The solution was cooled, diluted with toluene, and the volatiles were removed under reduced pressure. The residue was dissolved in 1 N HCl, and this solution was extracted with ether. The acidic aqueous layer was adjusted to pH 10 with K2CO3, and this solution was extracted with CH2Cl2. The CH2Cl2 extract was washed with 20% Na,OH, dried over MgSO4, and evaporated. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :MeOH to give 980 mg of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 9H), 1.90-2.20 (m, 4H), 2.95-3.15 (m, 2H), 5.05 (m, 1H), 6.68 (s, 1H), 7.15 (br s, 1H), 7.67 (d, 1H, J=8 Hz), 8.48 (d, 1H, J=3 Hz); MS m/z: 289 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](C1C=CC=CC=1)(=[O:17])C.C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]1([C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:15]=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC=C(c1ccccc1)c1ccccc1

Procedure:
First, a Grignard's reagent prepared from methyl chloride and magnesium is reacted with p-amino substituted benzophenone (2), followed by dehydration, to obtain 1,1-diphenylethylene derivative (3). Alternatively, the 1,1-diphenylethylene derivative (3) can be synthesized by reacting a Grignard's reagent, prepared from p-amino substituted bromobenzene, with an acetophenone compound (5), followed by dehydration. Next, a Vilsmeier reagent prepared from phosphorus oxychloride and N,N-dimethylformamide is reacted with the 1,1-diphenylethylene derivative (3) to obtain a 3,3-diphenylacrolein derivative (6). This 3,3-diphenylacrolein derivative (6) which is a mixture of a cis-isomer and a trans-isomer is subjected to a treatment using column chromatography or recrystallization treatment or a combination of these treatments to obtain a 3,3-diphenylacrolein derivative (7) embracing excess trans-isomers. The compound (7) and a diethyl 1,1-diphenylmethyl phosphonate derivative (9) are condensed by a Wittig-Horner reaction to synthesize 1-(p-aminophenyl)-1,4,4-triphenylbutadiene derivative (1) embracing excess tans-isomers (the ratio of trans-isomer≥0.6).
Reaction SMILES: I[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH:14]=[O:15].O>CN(C=O)C>[CH2:2]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH:14]=[O:15])[CH3:3]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 18 h

Procedure:
At 20° C. iodoethane (3.78 g) was added to a suspension of K2CO3 (1.09 g) and 3-hydroxy-4-nitro-benzaldehyde (1.0 g) in DMF (5 ml). The reaction mixture was stirred at 70° C. for 18 h, poured into water and then extracted with ethyl acetate. The organic phases were combined, dried (MgSO4) and concentrated in vacuo. The title product was obtained as a yellow solid. Yield: 1.17 g. MS-ESI: [M+H]+=196.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH3:14]O>>[Br:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([O:10][CH3:14])=[O:9])=[CH:5][CH:4]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (3 mL, 18 mmol) was added to an ambient temperature solution of 4-bromomandelic acid (5 g, 21.6 mmol) in methanol (50 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo to afford methyl (4-bromophenyl)(hydroxy)acetate which was used in the subsequent step without further purification.
Reaction SMILES: [Si](O[CH:9]([C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]([NH:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(C(C)(C)C)(C)C.N12CCCC1=NCCC2.[Cl-].[NH4+]>CN(C)C=O>[CH3:17][N:16]1[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:9]=[C:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(NC)C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Agent: C1CN=C2CCCN2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccnc2n1C
Yield: 27.6 %

Procedure:
A solution of 994 mg of ethyl 3-t-butyldimethylsilyloxy-3-(2-chloropyridin-3-yl)-2-methylaminopropionate (prepared as described in Preparation 79) and 393 mg of 1,5-diazabicyclo[4.3.0]non-5-ene in 5 ml of dimethylformamide was stirred at 150° C. for 5 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 9:1 to 5:1 by volume as the eluent, to give 150 mg of the title compound having Rf=0.40 (on silica gel thin layer chromatography using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:22]([CH2:29][CH2:30][CH3:31])[CH2:23][C:24]([O:26]CC)=[O:25].[O-]CC.[Na+].O>C(O)C>[N:13]1([CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:1]3[C:22]([CH2:29][CH2:30][CH3:31])=[C:23]([C:24]([OH:26])=[O:25])[N:3]=[N:2]3)=[CH:20][CH:19]=2)=[O:9])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCCCC2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
4-Azido-N-(2-piperidin-1-ylethyl)benzamide obtained in Example 62a) and ethyl 3-oxohexanoate (1.08 ml, 6.44 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (487 mg, 6.44 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 13 hr. Water (40 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was washed twice with ethyl acetate-hexane (2:1, 50 ml). The aqueous layer was neutralized (pH 6-7) with 6N hydrochloric acid and concentrated. The residue was dissolved in isobutanol, THF and ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate and THF were added to the residue. The precipitate was collected by filtration, washed with ethyl acetate and dried to give the title compound as a pale-brown powder (purity 90%, 2.05 g, 4.78 mmol, 92.9%).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH2:16]([OH:19])[CH2:17][OH:18].[C:20]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([NH:30][C@H:31]([C:35]([O:18][CH2:17][CH2:16][OH:19])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: OCCO
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a mixture of DCC (11.4 g, 55 mmol), DMAP (0.611 g, 5 mmol) and ethyleneglycol (55.8 mL, 1 mol) in CH2Cl2 (300 mL) at 0° C., was added dropwise a solution of N-CBz-L-valine (12.6 g, 50 mmol) in CH2Cl2 (100 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 5→10% MeOH in CH2Cl2), to give 12.0 g 2-(N-CBz-L-valyloxy)-ethanol.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>[Cu](Cl)Cl>[C:16]([O:20][C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl[Cu]Cl
Product: CC(C)(C)OC(=NC1CCCCC1)NC1CCCCC1
Yield: 91.9 %

Procedure:
A suspension of dicyclohexyl carbodiimide (2.00 g, 9.70 mmol), tert-butanol (1.00 ml, 10.6 mmol) and a catalytic amount of copper chloride (9.0 mg, 90 μmol) was stirred at room temperature for 24 h. The reaction mixture was filtered through a pad of celite, washed with CHCl3 (5 ml) and the solvent was evaporated under vacuum to afford 2.5 g (74%) of compound 2-tert-butyl-1,3-dicyclohexylisourea as a pale green thick liquid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)=[C:5]([CH3:18])[CH:4]=1.B(Br)(Br)Br>ClCCl>[CH3:18][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][C:6]=1[N:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]1
Reactant: COc1ccc(-n2cc(C(F)(F)F)cn2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)ccc1-n1cc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a 0° C. solution of 1-(4-methoxy-2-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (400 mg, 2 mmol) in dichloromethane (5 mL) was added boron tribromide (1 g, 6 mmol). The mixture was allowed to warm to room temperature and stir overnight. The reaction was quenched with methanol (2 mL), diluted with water (10 mL), and extracted with dichloromethane (3×10 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give 3-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (390 mg, 99%) as a brown solid. 1H NMR (400 MHz, CDCl3, δ): 7.83 (s, 1H), 7.74 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.65 (s, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.57 (s, 1H), 2.05 (s, 3H).
Reaction SMILES: ClCCl.[Si:4]([O:11][CH2:12][C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)#[N:21]>N1C=CC=CC=1>[Si:4]([O:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19][S:34]([C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)(=[O:36])=[O:35])[CH:16]=[CH:15][CH:14]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Reactant: N#Cc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(NS(=O)(=O)c2ccc(-c3ccc(C#N)cc3)cc2)n1
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of dichloromethane (3 mL) was added 6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (0.15 g, 0.63 mmol), 4′-cyanobiphenyl4-sulfonyl chloride (0.18 g, 0.63 mmol) and pyridine (1.0 mL). The mixture was stirred for 3 hours then was washed with saturated sodium bicarbonate (2×30 mL) and aqueous hydrochloric acid (2×30 mL, 0.1 N). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification was done using silica gel chromatography eluting with hexane: ethyl acetate (1:1) and combined fractions were concentrated to afford the above-titled intermediate as a white solid (0.21 g, 76%). HPLC: Rt4.236 min. (81% area). 1H NMR (400 MHz, CDCl3), δ: 7.89 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.52-7.49 (m, 4H), 7.43 (t, J=7.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.59 (d, J=7.3Hz, 1H), 6.22 (d, J=8.0 Hz, 1H), 4.55 (s, 2H), 0.82 (s, 9H), 0.05 (s, 6H); LRMS (ESI): m/z: 480.1.
Reaction SMILES: [OH:1][CH:2]([CH:9]([NH:14][C:15](=[O:58])[CH:16]([NH:32][C:33](=[O:57])[CH:34]([CH2:46][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1)[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(OCC1C=CC=CC=1)=O)[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].C.[H][H]>C(O)C>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([NH:32][C:33](=[O:57])[CH:34]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[CH2:46][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1)[C:15]([NH:14][CH:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:2]([OH:1])[C:3]([O:5][CH:6]([CH3:7])[CH3:8])=[O:4])=[O:58]
Reactant: CC(C)CC(NC(=O)C(CCCCNC(=O)OCc1ccccc1)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Reactant: [H][H]
Solvent: CCO
Product: CC(C)CC(NC(=O)C(CCCCN)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C

Procedure:
[2R-[2R*,3S*(S*)]-2-hydroxy-5-methyl-3-[[2-[[3-(1-naphthalenyl)-2-(1-naphthalenylmethyl)-1-oxopropyl]amino]-1-oxo-6-[[(phenylmethoxy)carbonyl]amino]hexyl]amino]hexanoic acid, 1-methylethyl ester, 3.97 g (5.0 mmol), is dissolved in 250 ml of absolute ethanol, 0.5 g of 20% palladiun charcoal is added, and the mixture exposed to hydrogen gas for 18 hours. After complete uptake of hydrogen the mixture is filtered and concentrated to afford 3.44 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][CH:7]1[CH2:9][CH2:8]1)[CH3:2].[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][N:6]([CH:7]1[CH2:9][CH2:8]1)[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:15][CH:16]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)CNC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a vigorously stirred solution of 4.9 g (34 mmol) of cyclopropylamino-acetic acid ethyl ester in 50 ml of CH2Cl2 and 25 ml of saturated sodium hydrogen carbonate was added a solution of 8.4 g (37 mmol) of 4-(trifluoromethoxy)benzoyl chloride in 10 ml of CH2Cl2 and the reaction stirred for 1 h. The organic phase was then separated, dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:9 to 3:7] afforded 8.9 g (80%) of the title compound as a colorless oil. MS: 332.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:12][CH2:13][CH2:14][CH2:15][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: BrCCCBr
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccccc1OCCCBr
Yield: 83.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 4.0 grams (0.025 mole) of 2-trifluoromethylphenol, 17.8 mL (0.178 mole) of 1,3-dibromopropane, and 9.0 grams (0.065 mole) of potassium carbonate in 120 mL of acetone was heated at reflux for about 18 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using petroleum ether. The product containing fractions were combined and concentrated under reduced pressure, yielding 5.9 grams of 2-trifluoromethylphenyl 3-bromopropyl ether. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][CH2:2][C@@:3]([OH:8])([CH3:7])[C:4](O)=[O:5].O=S(Cl)Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.O>[Br:1][CH2:2][C@@:3]([OH:8])([CH3:7])[C:4]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:5]
Reactant: COc1ccc(N)cc1
Reactant: C[C@](O)(CBr)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)[C@@](C)(O)CBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
(R)-3-Bromo-2-hydroxy-2-methylpropanic acid (8.54 g, 46.7 mmol) was placed in a 250 mL three-necked round-bottomed flask fitted with a stirring bar and an addition funnel, and dissolved in 100 mL anhydrous THF at room temperature. The solution was cooled to 0° C. Then, SOCl2 (7.78 g, 65.4 mmol) was added dropwise with stirring in 3 hours. p-Anisidine (5.00 g, 40.6 mmol) and triethylamine (6.62 g, 65.4 mmol) were added to the mixture at 0° C. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give a yellow residue which was dissolved in ethyl acetate and water. The organic layer was separated, washed with saturated NaHCO3 solution and dried over anhydrous MgSO4. The solvent was removed and residue was subjected to flash column chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give a white solid product, 8.50 g, 63.2% yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[BH4-].[Na+].N.O>C(O)C>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:12]2[CH2:13][CH2:14][N:15]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][CH2:17]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: O=C1CCCCC1
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(C3CCCCC3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of compound 6 (100 mg, 0.29 mmol), cyclohexanone (36 ul, 0.35 mmol) and Ti(OPr-i)4 (0.17 ml, 0.58 mmol) was ultrasonicated for 1 hr and then stirred at rt overnight under a nitrogen atmosphere. The mixture was diluted with ethanol (5 ml) and followed by addition of NaBH4 (33 mg, 0.87 mmol). The resulting mixture was stirred for 12 hr at rt. 2N NH3.H2O was added to quench the reaction and the mixture filtered through celite. The filtrate was extracted with ethyl acetate several times and the combined organic phases washed with water and brine, and dried over Na2SO4. Concentration in vacuo and MPLC purification (0:100 to 100:0 EtOAc:Heptane eluting on silcal gel 60) gave the title compound (24 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].O.O.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
Methyl 6-chloro-5-fluoropicolinate (1.35 g, 7.095 mmol) was dissolved in THF:H2O=6:1 (42 ml), followed by addition of lithium hydroxide monohydrate (596 mg, 14.19 mmol), and then the resulting mixture was stirred at room temperature for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, dissolved by addition of distilled water (20 ml), acidified by slow addition of 1N aqueous HCl solution, and then extracted with 5% MeOH/MC (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 1.04 g of white solid (80%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](Cl)([O-])(=O)=O.C(OCC)C>ClCCl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: OCc1ccc(Cl)nc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc(Cl)nc1Cl
Reaction time: 2 h
Yield: 66.4 %

Procedure:
Dissolve (2,6-dichloropyridin-3-yl)-methanol (876 mg, 4.92 mmol) in dichloromethane (20 mL). Add pyridium chlorochromate (2.12 g, 9.84 mmol). Stir for 2 hours. Add diethyl ether and stir for 20 minutes. Filter the mixture through a pad of Celite® and silica gel and concentrate to give 2,6-dichloropyridine-3-carbaldehyde (575 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.18 (d, 1H, J=8.0 Hz), 7.43 (d, 1H, J=8.0 Hz).