Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31]C)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:34]([CH2:36][NH2:37])[OH:35]>CS(C)=O>[OH:35][CH2:34][CH2:36][NH:37][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[OH:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4OC)c3)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccccc1O
Temperature: 135 °C

Procedure:
A suspension of 3-[3-(2-methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (28.0 mg, 0.061 mmol) (from Example 14 supra) in methyl sulfoxide (1 mL) and ethanolamine (3 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. The solvent was removed in vacuum and the residue was treated with MeOH (2 mL). The resulting white precipitate was filtered, washed with cold MeOH and dried to give 3-[3-(2-hydroxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 7 mg, 25%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][O:22][C:23]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:24]=1[NH2:25]>>[NH2:25][C:24]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:29][C:23]=1[O:22][CH3:21]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)c(OC)c3)ccn2c1=O
Yield: 41.7 %

Procedure:
Methyl 8-(4-amino-3-methoxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (76 mg, 0.26 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (78 mg, 0.31 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (41 mg, 40%).
Reaction SMILES: [H][H].[CH2:3]([O:10][CH2:11][C@@H:12]1[C@@H:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C@@H:13]1[OH:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Pt]=O.C(OCC)C>[CH2:3]([O:10][CH2:11][C@@H:12]1[C@H:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][C@H:13]1[OH:22])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)C[C@H]1C=C[C@H](O)[C@@H]1COCc1ccccc1
Agent: O=[Pt]
Solvent: CCOCC
Product: COC(=O)C[C@@H]1CC[C@@H](O)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
In an atmosphere of hydrogen, a mixture of 10.0 g of (1S,2S,3S)-2-benzyloxymethyl-3-methoxycarbonylmethyl-4-cyclopenten-1-ol (prepared in Reference Example 1), 60.0 mg of platinum oxide and 50 ml of diethyl ether was stirred for 2.5 hrs at room temperature. The mixture was filtered for removing platinum oxide. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 8.55 of the title compound having the following physical characteristics, in a 85% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][F:18].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:16][CH2:17][F:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(CCF)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A mixture of 1-tert-butoxycarbonylhomopiperazine (800 mg, 3.99 mmol), 1-bromo-2-fluoroethane (0.46 mL, 11.98 mmol) and potassium carbonate (1.10 g, 7.98 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred overnight at 70° C. and was cooled to room temperature. The reaction mixture was filtered through a Celite pad, and the filtrate was evaporated to dryness under vacuum to afford yellowish oil. The crude product was purified by MPLC on silica gel (3% MeOH in CHCl3) to afford the titled compound (653 mg, 67%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2](C(O)=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:16]OC1C=C(C=CC=1)C=O.S(=O)(=O)(O)O>C(#N)C>[CH:16]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH:3]=[CH:2][N:1]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: COc1cccc(C=O)c1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: c1ccc2c(c1)[nH]c1cnccc12

Procedure:
Tryptophan A (1.0 g, 5.0 mmol) and 3-methoxybenzaldehyde (670 μL, 5.5 mmol) are suspended/dissolved in acetonitrile (100 mL) and concentrated sulfuric acid (100 μL) is added. The reaction is heated to reflux until all the aldehyde was consumed (overnight). The solvent was removed in vacuo and the residue was dissolved in 5 mL of ethanol. The product was precipitated out with ether, filtered, and washed with 10 mL of ether. The desired β-carboline product/intermediate B (1-(3-Methoxy-phenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid) is isolated as a beige solid (1.2 g, 76%). LC/MS RT=2.33 min. M/Z+323, 100%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21]=1>C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[S:22](=[O:29])(=[O:30])[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: ClC(Cl)Cl
Product: O=S1(=O)N=C(NCCCOc2cccc(CN3CCCCC3)c2)c2ccccc21
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a gently refluxing solution of 3-[3-[(1-piperidinyl)-methyl]phenoxy]propylamine (992 mg, 4 mmol) in 90 ml of chloroform is added dropwise a solution of 880 mg (4.4 mmol) of 3-chlorobenzisothiazole 1, 1-dioxide in 30 ml of chloroform. Following the addition, the reaction mixture is refluxed for an additional 15 min., cooled to room temperature and solvent removed in vacuo. Column chromatography of the resultant residue (foam) on silica gel utilizing methylene chloride:methanol:ammonium hydroxide (90:10:1) as eluting solvent affords after evaporation a white solid. The crude product is suspended in ethyl acetate, filtered and dried to give 620 mg (37.5%) of the title compound, m.p., 138°-140° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:10][CH:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:20]=[CH:19]3)[C:12]([F:15])([F:14])[F:13])[CH:3]=[CH:2]1.[OH-].[K+].I[CH2:35][C:36]([NH2:38])=[O:37]>CN(C=O)C>[F:14][C:12]([F:15])([F:13])[CH:11]([NH:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:1]([CH2:35][C:36]([NH2:38])=[O:37])[CH:2]=[CH:3]2)[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[N:20]=[CH:19]2
Reactant: Fc1ccc(-n2ncc3cc(C(Nc4cccc5cc[nH]c45)C(F)(F)F)ccc32)cc1
Reactant: NC(=O)CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)Cn1ccc2cccc(NC(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a chilled (0° C.) solution of 78 mg (0.18 mmol) of (1H-Indol-7-yl)-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethyl}amine in 5 mL of DMF was added 15 mg (1.09 mmol) of powder KOH followed by 37 mg (1.09 mmol) of iodoacetamide. The mixture stirred overnight at room temperature. The mixture was then poured onto ice water and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were washed with brine, saturated aqueous ammonium chloride, brine, and dried over sodium sulfate. The crude material was loaded onto a silica cartridge and purified by Combiflash chromatography using a 0-60% EtOAc-hexanes (0-60% gradient) to afford 30 mg (38%) of the title compound as a colorless foam, m.p. 105° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]#[N:9].[ClH:10].CC[OH:13]>>[ClH:10].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8](=[NH:9])[OH:13]
Reactant: CCO
Reactant: N#CC=Cc1ccco1
Agent: Cl
Product: N=C(O)C=Cc1ccco1
Reaction time: 18 h
Yield: 63 %

Procedure:
A solution of 2-furanacrylonitrile (10.9 g; 91 mmol) in EtOH (75 mL) was cooled in an ice bath. The cold mixture was then saturated with hydrogen chloride. The reaction solution was refrigerated for 18 hours. The reaction mixture was concentrated to 20 mL and diethyl ether was added. The brown solid gave 10.5 g (63% yield) of 2-Furanacryloimidate hydrochloride which was used in the next reaction.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]2[C:27]([CH2:28][NH:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[Cl:42])[CH:33]=[N:32][N:31]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[N:18]1([C:22]2[C:27]([CH2:28][NH:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[Cl:42])[CH:33]=[N:32][N:31]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:19][CH2:20][CH2:21][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ncccc2CNc2nncn2-c2cccc(Cl)c2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(-n2cnnc2NCc2cccnc2N2CCCNCC2)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (15 mL) was added to a solution of Example 112C (2.0 g, 3.86 mmol) in dichloromethane (75 mL) at 0° C. 5 minuted later, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane. The organic was washed with saturated sodium bicarbonate and the pH was adjusted to 9. The layers were separated and the aqueous layer was extracted with dichloromathane. The combined organic layer was washed with brine, dried over magnium sulfate, filtered and concentrated to yield the title compound that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](C(O)=O)=[CH:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(C(=O)O)n(-c2ccc(OC)cc2)n1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccn(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
A solution of 1-[(4-methoxy)phenyl]-3-(ethoxycarbonyl)pyrazole-5-carboxylic acid (3.2 g, 11.1 mmol) in 20 mL of thionyl chloride was stirred at 80° C. for 1 h. The volatiles were then removed and the residue was azeotroped with 20 mL of toluene and dried in vacuo. The residue was dissolved in 50 mL of methylene chloride and then there was added triethylamine (4.6 mL, 33.3 mmol) and 4-(N-pyrrolidinocarbonyl)aniline (3.2 mL, 54.3 mmol). The reaction mixture was allowed to stir at ambient temperature for 4 h. The volatiles were removed and the residue was dissolved in ethyl acetate, washed sequentially with 10% aq HCl and brine, dried (MgSO4), filtered through a short pad of silica gel and concentrated to afford 2.5 g (50%) of the title compound. A small portion was further purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford the title compound as a white powder. LRMS (ES+): 463.1 (M+H)+.
Reaction SMILES: [C:1]([N:11]1[CH2:18][C:17](=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H][H]>C(O)C.[Pt](=O)=O>[C:1]([N:11]1[CH2:18][C@@H:17]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: [H][H]
Reactant: O=C(O)[C@@H]1CC(=Cc2ccc(Cl)cc2)CN1C(=O)OCc1ccccc1
Agent: O=[Pt]=O
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@H](Cc2ccc(Cl)cc2)CN1C(=O)OCc1ccccc1
Reaction time: 0.13 h
Yield: 87.9 %

Procedure:
A solution of 5.3 g (0.014 mole) of N-carbobenzyloxy-4-[(4-chlorophenyl)methylene]-L-proline in 150 ml of ethanol is treated with 0.45 g of platinum dioxide and shaken on a Parr hydrogenator at a starting pressure of 15 lbs. (bottle gauge). The uptake of hydrogen is carefully monitored and whenever the pressure falls to 5 lbs the bottle is replenished with hydrogen to 15 lbs. A noticeable slowing down of the rate of hydrogen uptake is observed after eight minutes and the hydrogenation is interrupted after a total of ten minutes (21.5 lbs of hydrogen). The catalyst is filtered off (celite bed under nitrogen atmosphere), washed well with ethanol, and the combined filtrates are evaporated, finally at 0.2 mm, to yield 4.6 g of N-carbobenzyloxy-cis-4-[(4-chlorophenyl)methyl]-L-proline as a colorless brittle foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1.[CH:14]1([Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[OH:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: Cc1c(C=O)oc2ccc(Cl)cc12
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution (10 mL) of 5-chloro-3-methyl-1-benzofuran-2-carbaldehyde (600 mg) synthesized above in tetrahydrofuran was added a 1.0M solution (4.62 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane) to give the title object compound (518 mg, 60%) as a pale-yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:14])[C@H:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[NH2:8])C1OC1.N1CC[O:18]CC1>>[OH:18][O:5][C:6](=[O:14])[C@H:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[NH2:8]
Reactant: N[C@@H](CCC(=O)O)C(=O)OCC1CO1
Reactant: C1COCCN1
Product: N[C@@H](CCC(=O)O)C(=O)OO
Reaction time: 8 h
Yield: 220.5 %

Procedure:
To a solution of 712 mg (1.81 mmol) of glycidyl ester 28 and 0.316 mL (3.62 mmol, 2.0 equiv) of morpholine was added 1 g of neutral alumina. The reaction mixture was stirred overnight and then filtered and concentrated. Purification by flash chromatography (30×150 mm silica gel, 200 mL of 1.5% and 200 mL of 2.5% methanol/dichloromethane) provided 651 mg (75%) of the title compound: 1H NMR (300 MHz, CD3OD) δ7.38-7.29 (m, 5H), 5.09 (s, 2H), 4.19-3.97 (m, 3H), 3.69-3.60 (m, 5H), 2.56-2.41 (m, 8H), 2.22-2.08 (m, 1H), 1.97-1.84 (m, 1H), 1.45 (s, 9H); MS(FAB) 481 (M+1), 425.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:25]C(=O)OC(C)(C)C)[CH2:10][N:11]([CH3:24])[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:33]>C(Cl)Cl>[ClH:33].[NH2:25][C@@H:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13]
Reactant: CN(C[C@@H](NC(=O)OC(C)(C)C)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CN(C[C@@H](N)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 67.7 %

Procedure:
To a solution of (S)-tert-butyl (1-(3-bromo-5-fluorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)carbamate (40 g, 75 mmol) in DCM (420 ml) at room temperature was added HCl (4M in dioxane, 150 ml, 601 mmol). The resultant solution was stirred at room temperature for 4 hours during which time a white solid precipitated out. The reaction mixture was filtered, the white solid was washed with DCM (50 ml×2), and vacuum dried to afford 23.8 grams of the desired product as a white solid. (HCl salt). (S)—N-(2-amino-2-(3-bromo-5-fluorophenyl)ethyl)-N-methyl-2-nitrobenzenesulfonamide (23.8 g, 68% yield over four steps). LC-MS: (M+1): 433.9 m/z at 0.66 min. 1H NMR (400 MHz, <dmso>) ppm 2.86 (s, 3H) 3.56-3.82 (m, 2H) 4.61 (t, J=7.24 Hz, 1H) 7.42-7.61 (m, 2H) 7.68 (d, J=1.57 Hz, 1H) 7.75-8.05 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=1>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[C:25]([F:33])[CH:26]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:28]=2)[CH:12]=[C:13]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([F:35])=[CH:37][C:38]=2[C:43]([F:46])([F:44])[F:45])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2ccc(F)cc2C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield from 2-(5′-fluoro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 40, step (a)) and 4-fluoro-2-(trifluoromethyl)aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:25]([CH3:27])=[CH2:26].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([CH:25]([CH3:27])[CH3:26])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(C)OC
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNc2ccccc2)COC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)N(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 40 °C
Yield: 89 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester (650 mg) at r.t. in 1,2-dichloroethane (15 ml) under an argon atmosphere were added 2-methoxypropene (0.30 ml), trifluoroacetic acid (0.16 ml) and sodium triacetoxyborohydride (674 mg). The mixture was heated to 40° C. overnight. The mixture was cooled to r.t., directly adsorbed on silica gel and purified by chromatography (SiO2; gradient:cyclohexane->cyclohexane/EtOAc 7:3) to give (S)-4-[(isopropyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (659 mg, 89%) as light yellow viscous oil. MS (ISP): 349.5 ([M+H]+)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([F:30])([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].[Cl-].[NH4+]>[Zn].C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:20]([OH:21])[C:23]([F:30])([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a mixture of the objective compound of step (10) (42.8 g, 0.151 mol), zinc dust (15.9 g, 0.243 mol) and THF (105 ml) was added ethyl bromodifluoroacetate (31.6 mL, 0.246 mol) with dropwise over 2 hours at 26˜49° C. The resulting mixture was stirred at room temperature for 2 hours. To this reaction mixture was added saturated ammonium chloride aqueous solution (110 mL), and the mixture was stirred for a few minutes. The obtained mixture was added to saturated ammonium chloride aqueous solution (650 mL) and extracted with ethyl acetate (500 mL, 2×300 mL). The extract was washed with saturated brine (400 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2:1 hexane-ethyl acetate) to give 56.15 g of ethyl 4-benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-5-phenylpentanoate as a light-yellow oil (a mixture of diastereomers, 75%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1.[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.O>CN(C)C=O>[CH2:42]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3ccccc3)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Sodium hydride (60%, oily, 28.0 mg) was added to a solution of ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (378 mg) in N,N-dimethylformamide (5 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. Benzyl bromide (0.10 ml) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[3-benzyloxy-5-[2-(2-pyrazinyl)-4-thiazolyl methoxy]benzyl]-4-pheny-3-pyrrolyl]propionate (419 mg, yield: 95%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 126–127° C.
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5]([CH:7]=O)[N:6]=1.[Br-].[CH2:29]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:30]=[CH2:31].[OH-].[Na+]>C(Cl)Cl>[CH:7]([C:5]1[N:6]=[C:2]([F:1])[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:31][CH:30]=[CH2:29]
Reactant: C=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
2-Fluoro-4-formyl-1-triphenylmethylimidazole was reacted with allyl triphenyl phosphonium bromide in CH2Cl2 in the presence of aqueous NaOH to give 4-(buta-1,3-dienyl)-2-fluoro-1-triphenylmethylimidazole having the following n.m.r. spectrum in CDCl3 : 5.06-5.39 (m, 2H); 5.87 (d, 1H); 6.06 (dd, 1H); 6.49 (s, 1H); 7.51 and 7.7 (d of t, 3H); 7.08-7.44 (br, 15H).