Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([P:29]([O:34]CC)([O:31]CC)=[O:30])([F:28])[F:27])=[CH:16][C:15]=3[CH3:37])=[CH:7][C:6]=2[C:5]2[CH:38]=[CH:39][C:40]([CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[CH:41][C:4]=2[N:3]=1.C[Si](Br)(C)C.[OH-].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([F:27])([F:28])[P:29]([OH:34])([OH:31])=[O:30])=[CH:16][C:15]=3[CH3:37])=[CH:7][C:6]=2[C:5]2[CH:38]=[CH:39][C:40]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[CH:41][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc3C)cc12
Agent: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(OCCOCCC(F)(F)P(=O)(O)O)ccc1CCc1cnc2c(N)nc3cc(CCC(=O)O)ccc3c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-15) (1.0 equiv.) in DCM (0.16 M) at 0° C. was added slowly TMSBr (10 equiv.). The reaction was stirred at room temperature overnight. Additional TMSBr (5.0 equiv.) was added at 0° C., and the reaction was again stirred at room temperature overnight. The solvent was removed by evaporation and the crude orange solids dried on hi-vac briefly. The solids were suspended in EtOH (0.5 M) and added 2.5 N NaOH (10.0 equiv.). The reaction was stirred at 80° C. for 3 hours. After cooling to room temperature, the mixture was adjusted to pH 9 to 10 and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo. The resulting white gel was dissolved in refluxing 1:1 EtOH/water (0.04 M) with the addition of a few drops of ammonium hydroxide. While hot, the mixture was slowly poured into a stirring hot solution of acetone (0.009 M) preheated at 50° C. The acetone suspension was slowly cooled to room temperature for 15 minutes with continued stirring, and then sat in an ice bath for 10 minutes. The solids were filtered and washed successively with acetone (2×) and ether (2×). The solids were dried on hi-vac overnight to give the 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid (19) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 9.02 (s, 1H), 8.82 (s, 1H), 8.55 (d, 1H, J=8.4 Hz), 7.58 (s, 1H), 7.48 (d, 1H, J=8.4 Hz), 7.07 (d, 1H, J=8.4 Hz), 6.75 (s, 1 H), 6.68 (d, 1H, J=8.4 Hz), 4.03-4.00 (m, 2H), 3.72-3.68 (m, 4H), 3.16-3.12 (m, 2H), 3.03-2.96 (m, 4H), 2.67-2.64 (m, 2H), 2.33-2.32 (m, 2H), 2.26 (s, 3H). LRMS [M+H]=604.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:38]#[C:39][CH2:40][OH:41])=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[H][H]>C(O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH2:40][OH:41])=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1C#CCO
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1CCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a Parr bottle charged with methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-hydroxyprop-1-ynyl)benzoate (140 mg, 0.23 mmol) in degassed ethanol (10 mL) was added PtO2 (100 mg). The reaction vessel was pressurized to 60 psi with hydrogen gas and agitated at room temperature for 16 h. After LCMS analysis showed complete conversion, the reaction mixture was filtered through Celite™ and concentrated in vacuo to give the title compound (120 mg, 85%). MS (EI) m/z 619 (MH+).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)[O:13][C@@H:12]([C@H:14]2[CH2:16][N:15]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][O:10]1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH:1]1([CH2:16][C@H:14]([NH:15][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:12]([OH:13])[CH2:11][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]1[C@H]1COC(C)(C)O1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)[C@H](O)CO
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Cyclopentyl magnesium bromide (8 mL of 2M ethereal solution) was added to cuprous bromide/dimethylsulfide complex (0.33 g, 1.6 mmol) in 10 mL of dry THF cooled to −25° C. under nitrogen. After 20 min, a solution of tert-butyl (2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]aziridine-1-carboxylate (1.95 g, 8 mmol) in 4 mL of dry THF was introduced. The mixture was allowed to warm to ambient temperature overnight. It was quenched with saturated aqueous NH4Cl and extracted with ethyl ether. The organic phase was washed with aqueous saturated NH4Cl, 1 N NaHCO3, and brine. It was dried over anhydrous Na2SO4 and concentrated to 2.38 g of a solid. This material was dissolved in 70 mL of methanol, 12 g of Dowex 50WX2-400 was added, and the mixture was refluxed for 2 h. The mixture was filtered, washing with methanol and dichloromethane. A clean receiver was attached, and the resin was washed with 100 mL of 1:1 concentrated NH4OH:ethanol. The filtrate was concentrated to 1.16 g of tan crystals. The crystals were dissolved in 30 mL of dry THF, and 1.5 g (6.9 mmol) of di-t-butyldicarbonate was introduced. The mixture was stirred under nitrogen overnight. It was concentrated, extracted with ether and the ether was washed with several portions of water and brine. Drying over Na2SO4 and concentration afforded 1.8 g (6.7 mmol, 84% from tert-butyl (2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]aziridine-1-carboxylate) of tert-butyl (1S,2S)-1-[cyclopentylmethy]-2,3-dihydroxypropylcarbamate: 1H NMR (CDCl3) δ 4.5 (d, 1H, NH), 3.7 (m, 1H), 3.6-3.49 (m, 2H), 3.36 (m, 1 H), 3.26 (t, 1H, OH), 2.76 (d, 1H, OH), 1.45 (s, 9H), 1.88-1.36 (m, 9H), 1.17-1.08 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:31][CH2:32][CH2:33][OH:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH2:33][OH:34])[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCCNCc1ccccc1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Product: COc1ccc(N(CC(=O)N(CCO)Cc2ccccc2)S(=O)(=O)c2ccccc2C)cn1

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([CH:13]([O:16][CH3:17])[O:14][CH3:15])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>ClCCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:11]([CH3:10])[CH:13]([O:16][CH3:17])[O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(OC)C(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: COC(OC)C(C)NCc1ccc(F)cc1
Reaction time: 14 h
Yield: 98.1 %

Procedure:
4-Fluorobenzylamine (3.00 mL, 26.2 mmol), pyruvic aldehyde dimethyl acetal (3.11 mL, 26.2 mmol), DCE (87 mL), and sodium triacetoxyborohydride (7.79 g, 36.7 mmol) were stirred at ambient temperature. After 14 hours, the reaction was complete as indicated by LCMS. To the reaction mixture was added 30% aqueous K3PO4 (pH=14; 60 mL). The layers were partitioned and the aqueous layer was, extracted with EtOAc (2×50 mL), and washed with brine (60 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (5.83 g, 25.7 mmol, 98% yield). MS (DCI/NH3) m/z 228 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:15][CH3:16])[CH:10]([N+:12]([O-])=O)[CH3:11].Cl>[Zn].CC(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:15][CH3:16])[CH:10]([NH2:12])[CH3:11]
Reactant: COC(c1ccc(Cl)cc1Cl)C(C)[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CC(C)O
Product: COC(c1ccc(Cl)cc1Cl)C(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
2,4-dichloro-1-(1-methoxy-2-nitro-propyl)-benzene (0.35 g, 1.32 mmol), was dissolved with i-PrOH (27 ml) and treated with 1N HCl (13.2 ml, 13.2 mmol). Zinc dust (1.73 g, 26.4 mmol) was then added in small portions over 15 minutes and the solution allowed to stir for two hours at ambient temperature. The suspension was quenched by addition of saturated NaHCO3 (45 ml), stirred for 15 minutes and filtered through a small plug of Celite, washing with ethylacetate (40 ml). The organic extract was dried over anhydrous MgSO4, filtered and the solvent was removed under reduced pressure. 240 mg (77.6% of theory) of 2-(2,4-dichlorophenyl)-2-methoxy-1-methyl-ethylamine (compound Z1.14) was obtained in the form of a colourless oil as a mixture of diastereomeres.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17]C)=[C:10]([O:15]C)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]>Br>[CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:17])=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCNC1CCc2cc(OC)c(OC)cc2C1
Agent: Br
Product: CCCNC1CCc2cc(O)c(O)cc2C1

Procedure:
2-(N-propyl)amino-6,7 dimethoxy tetraline (prepared as described in Example 2 of the Italian patent 48779 A/86-23/12/1986) (6.6 g; 0.026 moles) were dissolved in 33 ml of 47% HBr and the resulting solution was kept at the reflux temperature overnight. Subsequently the solution was concentrated under vacuum and the residue was repeatedly washed with acetone to eliminate the excess amount of bromide acid. 8 g of a solid residue was obtained that was used as such in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[C:8]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:32]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH:9]([OH:12])[C:8]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:32]=1
Reactant: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(Cl)ccc2OCC1=O
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(Cl)ccc2OCC1O

Procedure:
In the same manner as in Reference Example 12, methyl 7-chloro-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate was reduced with sodium borohydride to give cis-isomer and trans-isomer of methyl 7-chloro-3-hydroxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate. Trans-isomer
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]2[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=2[F:44])=[O:35])=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[O:17])[CH:12]=2)[CH:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:30]=[C:31]([C:34]([NH:36][C:37]4[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:35])[CH:32]=[CH:33][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of tert-butyl {3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}carbamate (100 mg, 0.165 mmol) in 10 ml of methylene chloride was added 1 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 60 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8-9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide as grey solid.
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1([CH3:32])[CH2:11][C:10]2[C:12]([CH3:31])=[C:13]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:14]([CH3:17])=[C:15]([OH:16])[C:9]=2[O:8]1.Br[CH2:34][CH2:35][O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:37][O:36][CH2:35][CH2:34][O:16][C:15]1[C:9]2[O:8][C:7]([CH3:32])([CH3:6])[CH2:11][C:10]=2[C:12]([CH3:31])=[C:13]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)[C:14]=1[CH3:17]
Reactant: Cc1ccc(N2CCN(c3c(C)c(O)c4c(c3C)CC(C)(C)O4)CC2)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 100 °C
Reaction time: 24 h
Yield: 14.5 %

Procedure:
To a solution of DMF (5 mL) containing 2,2,4,6-tetramethyl-5-[4-(4-methylphenyl)piperazin-1-yl]-2,3-dihydro-1-benzofuran-7-ol (200 mg, 0.546 mmol) synthesized in Example 72, 1-bromo-2-methoxyethane (382 mg, 2.75 mmol) and potassium carbonate (380 mg, 2.75 mmol) were added, and the mixture was stirred at 100° C. for 24 hours. After cooled to room temperature, water was added to the mixture, and extraction was performed using ethyl acetate. The extract was dried using anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0-90:10) to obtain 33.5 mg of the title compound (yield 14%). Melting point was 118 to 120° C. (hexane).
Reaction SMILES: Br[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([C:14]1[CH:18]=[C:17]([NH2:19])[N:16]([CH3:20])[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:10]([C:14]1[CH:18]=[C:17]([NH:19][C:2]2[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:16]([CH3:20])[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: N#Cc1ncccc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1nc(C(C)(C)C)cc1Nc1cccnc1C#N
Temperature: 80 °C
Yield: 58 %

Procedure:
A mixture of 3-bromopyridine-2-carbonitrile (150 mg, 0.98 mmol), 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (179 mg, 0.98 mmol), cesium carbonate (638 mg, 1.96 mmol), BINAP (98 mg, 0.16 mmol) and Pd2(dba)3 (90 mg, 0.10 mmol) was taken in anhydrous toluene (2 mL) and heated to 80° C. for 24 h under nitrogen atmosphere. The reaction mixture was cooled to rt, diluted with ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/Hex (1:9 to 1:4, v/v) as the eluent. The product was obtained as a yellow oil (145 mg, 58%). ES-MS m/z 256.1 (MH+); HPLC RT (min) 2.37.
Reaction SMILES: [C:1]([O:4][O:5][CH:6]1[CH2:10][CH:9]([OH:11])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])(=O)=O>C(Cl)Cl>[C:1]([O:4][O:5][CH:6]1[CH2:10][CH:9]([O:11][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:8]=[CH:7]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)OOC1C=CC(O)C1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(=O)OOC1C=CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a stirred solution of 4-hydroxy-cyclopent-2-enyloxy acetate (4.1 g, 29 mmol) in CH2Cl2 (35 mL) and 2,6-lutidine (8.2 mL, 67 mmol) was added t-butyldimethylsilyl trifluoromethanesulfonate (10 mL, 44 mmol) at 0-5° C. The reaction mixture was stirred at r.t. for 1 hour. It was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated Column chromatography (silica gel, 5:1 hexanes:diethylether) gave desired product (5.1 g, 69%). 1H NMR (CDCl3, 400 MHz) δ; 5.88 (m, 1H); 5.84 (m, 1H); 5.42 (t, 1H); 4.64 (t, 1H); 2.80 (m, 1H); 2.02 (s, 3H); 1.59 (m, 1H); 0.83 (s, 9H); 0.04 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1.[CH3:12]I>C1COCC1>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([CH2:8][O:9][CH3:12])=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1nc(CO)ccc1Br
Solvent: C1CCOC1
Product: COCc1ccc(Br)c(OC)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
step 1—A NaH dispersion (226 mg, 5.64 mmol, 60% mineral oil dispersion) was triturated with hexanes (3×10 mL) and dried under a stream of N2 then suspended in THF (23.5 mL) and cooled to 0° C. A solution of 3-bromo-2-methoxy-6-(hydroxymethyl)pyridine (0.88 g, 3.79 mmol) in THF (10 mL) was added drop-wise and the mixture was stirred for 30 min. To the solution was added MeI (1.00 g, 441 μl, 7.05 mmol) and the mixture was warmed to RT. After 1 h the crude reaction mixture was concentrated in vacuo and the mixture was poured into H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed sequentially with H2O, brine, dried, filtered and concentrated to afford 3-bromo-2-methoxy-6-methoxymethyl-pyridine (136) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:41]1[CH2:46][CH2:45][O:44][CH2:43][CH:42]1[C:47]1[C:55]2[S:54][C:53]([NH2:56])=[N:52][C:51]=2[C:50]([O:57][CH3:58])=[CH:49][CH:48]=1>C1COCC1.C(Cl)(Cl)Cl>[O:41]1[CH2:46][CH2:45][O:44][CH2:43][CH:42]1[C:47]1[C:55]2[S:54][C:53]([NH:56][C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])=[N:52][C:51]=2[C:50]([O:57][CH3:58])=[CH:49][CH:48]=1
Reactant: COCCC(=O)O
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1

Procedure:
From 3-methoxypropionic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.4° (c=1.02, CHCl3), ES-MS m/e (%): 353 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1C=CC=C[CH:3]=1.CNC(=O)[C@H](C(C)(C)C)N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[CH:2]=[CH2:3]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](N)C(C)(C)C
Agent: F[B-](F)(F)F
Product: C=CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Yield: 84 %

Procedure:
According to Example 1(b) for 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, P-allyl-N-t-butoxycarbonyl-D-aspartate (Belshaw, P.; Mzengeza, S.; Lajoie, G. Syn Commun 1990, 20, 3157-3160; 2.00 g, 7.32 mmol) and L-t-leucine N-methylamide (Malon, P.; Pancoska, P.; Budesinsky, M.; Hlavacek, J.; Pospisek, J.; Blaha, K. Coll. Czech. Chem Commun. 1983, 48, 2844-2861; 1.05 g, 7.32 mmol) were coupled with TBTU. The resultant yellow oil was routinely used without further purification. Flash column chromatography with 2% MeOH/CH2Cl2 provided 2.44 g (84%) of 3(R)-(t-butoxycarbonylamino)-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester as a pale yellow oil. 1H NMR (CDCl3): δ 7.05 (d, 1H, J=9.0 Hz), 5.98 (d, 1H, J=4.4 Hz), 5.77 (ddt, 1H, J=5.6, 10.3, 16.2 Hz), 5.29 (ddd, 1H, J=1.5, 2.8, 15.6 Hz), 5.23 (dd, 1H, J=1.3, 10.5 Hz), 4.57 (dddd, 2H, J=1.6, 3.1, 5.6, 12.1 Hz),4.11 (d, 1H, J=9.4 Hz), 2.77(d, 3H, J=5.0 Hz), 1.46(s, 9H), 0.99 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:8][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:6]1.[Li+].[OH-].Cl>O1CCOCC1.O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]([OH:24])=[O:2])[N:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
30.8 g of (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid methyl ester was dissolved in 250 mL dioxane and a solution of 2.4 g LiOH in 250 mL of water was added. The mixture was stirred for 24 h at RT. Then, HCl-solution was added and the precipitate was filtered to give 29 g of the desired product. Rt: 1.28 min (method B), (M+H)+: 316
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH2:22][CH3:23])=[N:10][CH:9]2[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)([Cl:39])=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([C:37]([Cl:39])=[O:38])[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH2:22][CH3:23])=[N:10][CH:9]2[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (160 mg, 0.387 mmol) in methylene chloride (15 mL) cooled to 0° C. were sequentially added triethylamine (108 μL, 0.774 mmol) and phosgene (589 μL, 1.161 mmol, 1.97 M in toluene). The reaction mixture was stirred at 0° C. under Argon for 30 min. The solvent and excess reagents were removed by rotovap, and the residue was purified by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 20–25% ethyl acetate in hexanes to give 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (132.6 mg, 72%) as white solids.