Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:9]([CH3:10])[C:20](=[O:22])[CH2:19][NH:18][C:16](=[O:17])[O:15][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: CNCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: CN(Cc1cccc(Br)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 1-(3-bromophenyl)-N-methylmethanamine (12.0 g) and N-(tert-butoxycarbonyl)glycine (11.5 g) in dichloroethane (80 ml) were added HOBt (9.7 g) and WSC hydrochloride (13.7 g), followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl3. The mixture was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (21.3 g).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:23]([O:24][CH3:25])[CH3:22])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Ten grams (10 g 65 mmol) of 2-fluoro-3-(trifluoromethyl)benzoic acid and oxalyl chloride in 10 mL of anhydrous CH2Cl2 were treated with a few drops of DMF, and stirred at ambient temperature for 1 hour (gas evolution ceased). N,O-Dimethyhydroxylamine hydrochloride (16.8 g, 174 mmol) was added followed by 16 ml of pyridine. The reaction mixture was stirred overnight, then washed successively with H2O, 2 N HCl, and brine. The resulting solution was dried over sodium sulfate. Evaporation of solvents in vacuo gave 13.3 g of product as an oil, which was pure enough to be used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24]>>[Br:1][C:2]1[C:7]([F:8])=[C:6]([CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[CH:23]=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(F)c1Br
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C=O)c(F)c1Br
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-3-fluoroanisol (5.00 g, 24.4 mmol) in trifluoroacetic acid (25 mL) was heated to 80° C. and then a solution of hexamethylenetetramine (6.83 g, 48.8 mmol) in trifluoroacetic acid (25 mL) was added dropwise over 1.5 h. Upon completion of the addition, the reaction was stirred at 80° C. for 1 h under nitrogen. The excess trifluoroacetic acid was removed under vacuum, and the pH was adjusted to 7.5-8.0 by addition of saturated aqueous potassium carbonate (˜100 mL). The white solid that formed was filtered to give I-30 which was used without additional purification.
Reaction SMILES: COC1C=CC(C([NH:18][C:19]2[N:27]=[C:26]([Cl:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34]3[CH:38]=[C:37]([CH3:39])[CH:36]=[N:35]3)[C@@H:31]([OH:40])[C@H:30]2[OH:41])C2C=CC(OC)=CC=2)=CC=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[NH2:18][C:19]1[N:27]=[C:26]([Cl:28])[N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2[C@@H:29]1[CH2:33][C@H:32]([N:34]2[CH:38]=[C:37]([CH3:39])[CH:36]=[N:35]2)[C@@H:31]([OH:40])[C@H:30]1[OH:41]
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](n3cc(C)cn3)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn([C@H]2C[C@@H](n3cnc4c(N)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,2S,3R,5S)-3-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BB1) (0.020 g, 35 μmol) is dissolved in TFA (200 μL). The reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). 1H nmr (MeOD, 400 MHz); 8.50 (s, 1H), 7.85 (s, 1H), 7.55 (s, 1H), 4.95 (m, 1H), 4.70 (m, 1H), 4.65 (m, 1H), 4.30 (m, 1H), 2.95 (m, 1H), 2.65 (m, 1H), 2.15 (s, 3H), MS (ES+) m/e 350 (MH+).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C.C(OC(C1C(NC(OCC2C=CC=CC=2)=O)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C>>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([N:9]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:8]2[C:6]([OH:7])=[O:5])(=[O:28])=[O:27])=[CH:34][CH:33]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)CCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)CCc3ccccc3)C2C(=O)O)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-(3-phenylpropionyl amino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (22 mg, 0.04 mmol) is reacted in the same manner as 3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester and purified by flash-chromatography, Dichloromethane/Methanol (9:1) to afford the acid: Cal. 457.5 found (M−H)+ 456.6; 1H NMR (DMSO, 400 MHz), ppm: 7.78 (d, 2H), 7.28 (m, 2H), 7.20 (m, 3H), 7.01 (d, 2H), 5.6 (m, 1H), 5.5 (m, 1H), 4.3 (m, 3H), 4.0 (m, 1H), 3.82 (s, 3H), 2.8 (t, 2H), 2.35 (m, 2H), 2.05 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15].O>CN(C)C=O>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:15]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of methyl 4-bromomethylbenzoate (22.8 g) in N,N-dimethylformamide (450 ml) is added dropwise 50% aqueous dimethylamine solution (27 mL) and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into water with ice and extracted with ethyl acetate. The extract is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant crude product is purified by flash column chromatography on silica gel (Solvent; chloroform:methanol=10:1) to give methyl 4-[(dimethylamino) methyl]benzoate (27.5 g, yield; 99%) as brown oil. MS (APCI) m/z: 194 [M+H]+
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:7]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH2:6][O:5]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:21][C@H:16]([C@@H:7]1[CH2:6][O:5][C:4]([CH3:22])([CH3:3])[N:8]1[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:17]([F:18])([F:20])[F:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@H](C(O)C(F)(F)F)COC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](OCc2ccccc2)C(F)(F)F)COC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 300.0 mg, 7.50 mmol) in DMF (20 mL) was added (S)-tert-butyl 2,2-dimethyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazolidine-3-carboxylate (1.09 g, 3.64 mmol) in DMF (20 mL) and the mixture was stirred at room temperature for 1 h. Then, benzyl bromide (0.86 mL, 7.23 mmol) was added and the mixture was stirred at room temperature overnight then quenched with ice-water, extracted with EtOAc. The organic extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by silica gel chromatography to give (S)-tert-butyl 4-((R)-1-(benzyloxy)-2,2,2-trifluoroethyl)-2,2-dimethyloxazolidine-3-carboxylate (1.21 g, 85%), which showed a complicated NMR spectrum because of the different rotamers. 1H NMR (400 MHz, CDCl3, δ in ppm) 7.28˜7.33 (m, 5H), 4.60˜4.85 (m, 3H), 3.93˜4.23 (m, 3H), 1.42˜1.65 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].BrBr.BrC(C1C=CC(S(C)(=O)=O)=C(F)C=1)C(=O)C.[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39]([NH:42][C:43]([NH2:45])=[S:44])=[CH:38][CH:37]=1>O1CCOCC1.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:44][C:43]([NH:42][C:39]3[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)=[N:45][C:9]=2[CH3:10])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COc1ccc(NC(N)=S)cn1
Reactant: CC(=O)Cc1ccc(Cl)c(S(C)(=O)=O)c1
Agent: BrBr
Agent: CC(=O)C(Br)c1ccc(S(C)(=O)=O)c(F)c1
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(C)c(-c3ccc(Cl)c(S(C)(=O)=O)c3)s2)cn1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
1-(4-chloro-3-methanesulfonyl-phenyl)-propan-2-one (32b) (0.23 g, 1 mmol) is dissolved in dioxan (10 ml) and the solution is cooled to 10° C. at which point the mixture is semi-frozen. Bromine (0.045 ml, 0.8 mmol, 0.8 eq.) is added slowly and the mixture is stirred for an additional 15 minutes in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a brown oil containing starting material and 1-bromo-1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one. This material is dissolved in ethanol (10 ml). (6-Methoxy-pyridine-3-yl)-thiourea (0.183 g, 1 mmol) is added in one portion. The mixture is stirred at 60° C. for 30 minutes then allowed to cool whereupon the product crystallised. Filtration affords the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12](=[O:16])[CH:13](Br)[CH3:14].C([O-])([O-])=O.[K+].[K+]>COCCOC>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:13]([CH3:14])[C:12]([O:11][CH3:10])=[O:16]
Reactant: COC(=O)C(C)Br
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)C(C)Oc1ccc(Cl)cc1Br

Procedure:
A mixture of 2-bromo-4-chlorophenol (250 mg; 1.21 mmol) and methyl-2-bromopropionate (VWR; 135 μL, 1.21 mmol) in DME (5 mL) was treated with K2CO3 (250 mg, 1.81 mmol) and refluxed for 18 hours. The reaction mixture was filtered, the filtrate was concentrated and purified by flash column chromatography (silica), eluting with heptane containing increasing amounts of EtOAc. The title compound was obtained as a yellow liquid (306 mg; 87%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH:14]1[S:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]1=[O:29].[CH3:30][C:31]([C:34]1[CH:38]=[CH:37][NH:36][N:35]=1)([CH3:33])[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:30][C:31]([C:34]1[CH:38]=[CH:37][N:36]([CH:14]2[S:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:15]2=[O:29])[N:35]=1)([CH3:33])[CH3:32]
Reactant: O=C1C(O)SCN1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc[nH]n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccn(C2SCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tetrahydrofuran (15 mL) at about −10° C. stirred under a nitrogen atmosphere were added diethyl azodicarboxylate (0.66 mL, 4.18 mmol), 5-hydroxy-3-[3-(trifluoromethyl)phenyl]-4-thiazolidinone (1 g, 3.8mmol), 3-(1,1-dimethylethyl)-1H-pyrazole (0.48 g, 3.8 mmol) and triphenylphosphine (1.2 g, 4.41 mmol). After the addition, the reaction mixture was allowed to warm up to room temperature, and stirred overnight under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue taken into a small amount of methylene chloride and then filtered. The filtrate was loaded on silica gel in a medium pressure liquid chromatography column and eluted with a solution of 20% ethyl acetate and 80% hexanes followed by a solution of 33% ethyl acetate and 67% hexanes to give 0.26 g of a crude product. The crude product was further purified by medium pressure liquid chromatography (silica gel, 9% ethyl acetate/91% hexanes) to afford the title compound, a compound of this invention, as a viscous oil (130 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:12]=[C:11]([CH2:13]Br)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([NH:19][CH:20]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])=[O:18]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:20]([NH:19][CH:17]=[O:18])([CH:24]([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(NC=O)C(=O)O
Reactant: Fc1ccc(Oc2cccc(CBr)n2)cc1
Product: CC(C)C(Cc1cccc(Oc2ccc(F)cc2)n1)(NC=O)C(=O)O

Procedure:
Following the procedure of Example 1, [6-(4-fluorophenoxy)-2-pyridyl]methyl bromide can be reacted with 2-(N-formylamino)-3-methyl-butanoic acid to give [6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(N-formylamino)-3-methyl-butanoic acid, which is further reacted with methanol, yielding [6-4-fluorophenoxy)-2-pyridyl]methyl 2-amino-3-methylbutanoate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]2[CH:13]=[C:12]([NH:14]C(=O)C(F)(F)F)[CH:11]=[CH:10][C:9]=2[S:21](Cl)(=[O:23])=[O:22])[O:5][CH:6]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1.N1C=CC=CC=1>C(#N)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([S:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:33][O:32][B:31]([OH:34])[C:30]=3[CH:35]=2)(=[O:22])=[O:23])=[C:8]([CH2:7][C:4]2[O:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:13]=1
Reactant: Cc1coc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)n1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1coc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-((4-methyloxazol-2-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (180 mg, 0.47 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (106 mg, 0.71 mmol) in 10 mL of ACN was added pyridine (114 uL, 1.41 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow residue (236 mg, yield 94%). A small portion of the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid. 2,2,2-Trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-((4-methyloxazol-2-yl)methyl)phenyl)acetamide MS calcd for (C20H17BN3O6F3S): 495.2. MS found (ESI negative): (M−H)−=494.1. 1H NMR (DMSO-d6) δ (ppm): 11.51 (s, 1H), 10.43 (s, 1H), 9.20 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.77 (s, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 4.86 (s, 2H), 4.47 (s, 2H), 2.01 (s, 3H).
Reaction SMILES: Br.[CH3:2][C:3]([NH:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:22]=1)=[O:20])([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+].CO.[Cl-].[Na+]>CC(O)C>[CH2:36]([O:35][C:23]1[CH:22]=[C:21]([CH:19]([OH:20])[CH2:18][NH:17][C:3]([CH3:2])([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(CNC(=O)COc1ccccc1)NCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Br
Agent: [BH4-]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(CNC(=O)COc1ccccc1)NCC(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2[1,1-dimethyl-2-(2-phenoxyacetamido)ethyl]amino-3',4'-bis(benzyloxy)acetophenone hydrobromide (1.26 g.) in 2-propanol (10 ml.) was cooled to -10° C. and sodium borohydride (0.22 g.) was added in two portions interspersed by a a portion of methanol (10 ml.). The reaction mixture was allowed to warm to 10° C. After 30 minutes at this temperature, a saturated aqueous solution (100 ml.) of sodium chloride was added and the mixture was extracted with ether (3×100 ml.). The combined ether extracts were washed with water (100 ml.) and then brine (100 ml.), dried (MgSO4) and evaporated to give 1-[3,4-bis(benzyloxy)phenyl]-2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]ethanol as a sticky residue (1.2 g.). This residue was dissolved in ethanol (30 ml.) and benzyl bromide (0.24 ml.) was then added. The mixture was hydrogenated at atmospheric pressure and temperature in the presence of 10% w/w palladium-on-carbon (0.4 g.) for 3 hours. The catalyst was separated by filtration, washed with ethanol (10 ml.) and the combined filtrate and washings evaporated to give 1-(3,4-dihydroxyphenyl)-2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]ethanol hydrobromide as a foam (0.8 g.) having a satisfactory NRM spectrum and sufficiently pure for direct use in the above procedure.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C@H:10]([OH:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[C:25]([C:27]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:22]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[C@@H:10]([O:18][C:22]1[CH:23]=[CH:24][C:25]([C:27]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)([C:28]([F:31])([F:30])[F:29])[C:32]([F:33])([F:34])[F:35])=[CH:26][C:21]=1[CH3:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(c2ccc(O)c(C)c2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COC(c2ccc(O[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)c(C)c2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To 1.27 g (4.9 mmol) of (R)-2-hydroxy-3-phenyl-propionic acid benzyl ester in 10 mL of THF were added 1.5 g (3.8 mmol) of 2-methyl-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenol (example 2) and 1.3 g (4.9 mmol) of triphenylphosphine. The mixture was cooled to 0° C., treated with 0.77 mL (4.9 mmol) of DEAD and stirred at room temperature overnight. The solvent was evaporated and the crude mixture was purified by column chromatography on silica gel with EtOAc/n-heptane 1:4 to yield 1.7 g (71%) of (S)-2-{2-methyl-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propionic acid benzyl ester as a light yellow oil, MS: 632 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1.[CH:24](=O)[CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH3:26])[CH2:10][CH:9]=2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1
Reactant: Cc1ccc(C2=CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN1CC=C(c2ccc(C)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a solution of 4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine (70 mg, 0.23 mmol) produced in Example (104f) in tetrahydrofuran (2 mL) were added propionaldehyde (15.7 mg, 0.27 mmol), sodium triacetoxyborohydride (72 mg, 0.34 mmol) and acetic acid (27 mg, 0.45 mmol), followed by stirring for 12 hours at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 63 mg of 4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine as a light yellow oil.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6]1)[CH2:2][C:3]#[CH:4].CN1C(=O)N(C)CCC1.[Li][CH2:22][CH2:23][CH2:24][CH3:25].CCCCCC>C1COCC1>[CH:24]1([CH2:25][C:4]#[C:3][CH2:2][CH2:1][CH:5]2[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6]2)[CH2:22][CH2:23]1
Reactant: [Li]CCCC
Reactant: C#CCCC1COC(C)(C)O1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN1CCCN(C)C1=O
Product: CC1(C)OCC(CCC#CCC2CC2)O1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-But-3-ynyl-2,2-dimethyl-[1,3]dioxolane (6 mmol, 1.0 g) in 40 ml anhydrous THF and anhydrous DMPU (26 mmol, 3 g) was added a solution of 2.5M BuLi in hexane (9.01 mmol, 3.6 mL) at −78° C. It was stirred at −78 ° C. for 15 minutes and slowly warmed up to room temperature. The reaction mixture was quenched with sat. NH4Cl and extracted by EtOAc. The combined organic layer was washed with H2O and brine, dried by MgSO4 and concentrated. Silica gel chromatography (2˜10% EtOAc/Hexane) 4(5-Cyclopropyl-pent-3-ynyl)-2,2-dimethyl-[1,3]dioxolane as a clear oil; 1H NMR (400 MHz, CDCl3): δ 4.22–5.15 (m, 1H), 4.07 (dd, 1H, J3=8.0 Hz, J2=6.0 Hz), 3.57 (dd, 1H, J1=7.9 Hz, J2=7.1 Hz), 2.29–2.23 (m, 2H), 2.20–2.16 (m, 2H), 1.83–1.77 (m, 1H), 1.72–1.65 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H), 0.91–0.86 (m, 1H), 0.46–0.41(m, 2H), 0.21–0.17 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4](/[N:6]=[C:7](/[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)\SC)=O.[F:16][C:17]([F:22])([F:21])[CH2:18][NH:19][NH2:20]>C(OCC)(=O)C>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[N:19]([CH2:18][C:17]([F:22])([F:21])[F:16])[N:20]=[C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:6]=1
Reactant: NNCC(F)(F)F
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Solvent: CCOC(C)=O
Product: CC(C)=Cc1nc(N2CCCC2)nn1CC(F)(F)F
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A mixture of (Z)-methyl N-3-methylbut-2-enoylpyrrolidine-1-carbimidothioate (2.515 g, 11.1 mmol, Eq: 1.00) and (2,2,2-trifluoroethyl)hydrazine (5 g, 30.7 mmol, Eq: 2.76) was stirred for 1 hour at 100° C. The mixture was dissolved in ethyl acetate and washed with water 3 times and once with brine. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 5-(2-methyl-prop enyl)-3-pyrrolidin-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,4]triazole (1.599 g/52.5%) as an off-white waxy solid. MS: m/e=275.4 (M+H+)