Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.C[O-].[Na+].[N:19](OCCCC)=[O:20]>>[OH:20][N:19]=[C:10]([C:7]1[C:6]2[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH:8]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)Cc1csc2ccc(Cl)cc12
Reactant: CCCCON=O
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C(=NO)c1csc2ccc(Cl)cc12

Procedure:
Reaction of chloroacetone with 4-chlorothiophenol gave (4-chlorophenyl)thiomethyl methyl ketone, which was cyclized by reaction with polyphosphoric acid to 5-chloro-3-methylbenzothiophene. Bromination of the latter compound by photochemical reaction with N-bromosuccinimide provided 5-chloro-3-bromomethylbenzothiophene, which was reacted with sodium cyanide to give 5-chloro-3-cyanomethylbenzothiophene. The latter compound was hydrolyzed and esterified to give methyl α-(5-chloro-3-benzothienyl)acetate. Reaction of the ester with sodium methoxide and n-butyl nitrite afforded methyl α-hydroxyimino-α-(5-chloro-3-benzothienyl)acetate. Reduction of the oxime by reaction with zinc and formic acid and subsequent reaction with di-tert.-butyl carbonate gave N-tert.-butoxycarbonyl-(5-chloro-3-benzothienyl)glycine. NMR (CDCl3): δ 1.1-1.5 (broad s, 9H); δ 5.4-5.7 (broad s, 1H); δ 7.2-8.0 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].CC1CCCCC1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:8][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCO)cc1
Reactant: O=C(O)CCl
Solvent: CC1CCCCC1
Product: Cc1ccc(CCOCC(=O)O)cc1
Yield: 83.5 %

Procedure:
6.8 g of 4-methylphenethyl alcohol were reacted with 4.73 g of chloroacetic acid in a manner analogous to that described in Example 1(a) to give 8.1 g (84%) of 2-(4-methylphenyl)ethoxyacetic acid of melting point 65°-67° C. (from methylcyclohexane).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:28])[NH:22][CH2:21][C:20](=[O:23])[N:19]1[CH2:24][C:25]([NH2:27])=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:13])[C:14]([N:22]1[CH2:21][C:20](=[O:23])[N:19]([CH2:24][C:25]([NH2:27])=[O:26])[C:18]1([CH3:28])[CH3:17])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(NC(=O)OCc1ccccc1)C(=O)N1CC(=O)N(CC(N)=O)C1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, ice cold solution of N-(benzyloxycarbonyl)alanine (6.7 g) and 2,2-dimethyl-5-oxo-1-imidazolidineacetamide (5.2 g) in 100 ml of dimethylformamide (DMF), a solution of dicyclohexylcarbodiimide (DCC) (6.2 g) in 50 ml of DMF was added dropwise during 15'. The suspension was stirred at 0° C. for 2 hours and at room temperature for additional 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, affording crude 3-[2-(benzyloxycarbonylamino)propionyl]-2,2-dimethyl-5-oxo-1-imidazolidineacetamide m.p. 206°-210° C. Into a solution of this compound (3 g) in methanol (100 ml) containing 5% palladium on charcoal (0.6 g) hydrogen was bubbled at 20° C. for 1.5 hours. Removal of catalyst and evaporation of the solvent gave a residue which was triturated with ethanol to afford the title compound, m.p. 196°-197° C.
Reaction SMILES: C(OC(=O)C(N)[C@@H](C(OC(C)(C)C)=O)C(N[C@@H](CC1C=CC=CC=1)COC)=O)C1C=CC=CC=1.[C:35]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]([CH2:46][C:47]([OH:49])=O)=[CH:44][CH:45]=2)=[CH:37][CH:36]=1.FC(F)(F)C(O)=O.[CH3:63][NH:64][C:65](=[O:72])[C@H:66]([C:68]([CH3:71])([CH3:70])[CH3:69])[NH2:67].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CO.C(Cl)Cl>[CH3:69][C:68]([CH3:71])([CH3:70])[C@H:66]([NH:67][C:47](=[O:49])[CH2:46][C:43]1[O:42][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:40][CH:39]=2)=[CH:45][CH:44]=1)[C:65](=[O:72])[NH:64][CH3:63]
Reactant: O=C(O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COC[C@H](Cc1ccccc1)NC(=O)[C@H](C(=O)OC(C)(C)C)C(N)C(=O)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Yield: 58 %

Procedure:
According to the procedure described in Example 1(f) for the preparation of N-(1(S)-benzyl-2-methoxy-ethyl)-3(R)-t-butoxycarbonyl-amino-succinamic acid benzyl ester, 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid was coupled to L-t-leucine N-methylamide trifluoroacetic acid salt with BOP. Flash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant provided in 58% yield N-[2,2-dimethyl-1(S)-(N-methyl-carbamoyl)-propyl]-2-(2-biphenyl-4-yl-furan-5-yl)-acetamide as an orange foam, which decomposed >75° C. and was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15]I)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[O-:17][CH2:18][CH3:19].[Na+].[CH2:21](O)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][O:17][CH2:18][CH3:19])[C:11]=1[CH3:12])[C:5]([O:7][CH2:8][CH3:21])=[O:6]
Reactant: CC[O-]
Reactant: COC(=O)c1cc(Br)c(C)c(CCCI)c1
Reactant: CCO
Agent: [Na+]
Product: CCOCCCc1cc(C(=O)OCC)cc(Br)c1C
Temperature: 25 °C

Procedure:
To an ethanol (0.1 M) solution of methyl 3-bromo-5-(3-iodopropyl)-4-methylbenzoate (1 eq.) from the previous step was added freshly prepared sodium ethoxide (3 eq.). The resulting solution was heated at reflux for 18 h. After cooling to RT, the volatiles were removed in vacuo. The resulting residue was then taken up in ether and washed further with 10% aq. HCl, 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:13]([CH3:26])[CH:12]=1>ClCCl>[CH3:8][O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:13]([CH3:26])[CH:12]=1
Reactant: COC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (20 ml) was added to a solution of 4-tert-butoxycarbonylmethoxy-3-methyl-benzoic acid methyl ester from Example E41.1 (3.8 g, 13.6 mmol) in di-chloromethane (40 ml) and the mixture was stirred for 1 h at room temperature. Volatiles were removed in vacuo and azeotroped with dichloromethane to yield the title compound (3.04 g, 100%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:41].FC(F)(F)C([O-])=O>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:41]
Reactant: Cc1ccc2[nH]c(=O)n(CCC(C)(C)N)c2c1
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc2[nH]c(=O)n(CCC(C)(C)NCC(O)c3cc(O)cc4c3OCC(=O)N4)c2c1

Procedure:
The compound is prepared according to General Method 1 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 233 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-6-methyl-1,3-dihydro-benzimidazol-2-one. Yield: 170 mg (31%, trifluoroacetate); mass spectroscopy: [M+H]+=441.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:49][C:50]1[CH:62]=[CH:61][C:53]2[NH:54][C:55]([C@@H:57]([NH2:60])[CH2:58][OH:59])=[N:56][C:52]=2[CH:51]=1.BrBr.[Cl:65]Cl>O1CCCC1>[Cl:65][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:60][C@H:57]([C:55]1[NH:54][C:53]2[CH:61]=[CH:62][C:50]([Br:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][OH:59])=[O:7]
Reactant: ClCl
Reactant: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Br)c1
Agent: BrBr
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Yield: 57 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxyethylamine in tetrahydrofuran. Yield: 57%; melting point: 124° C.-126° C.; C21H18BrClN4O3 (489.76); mass spectrum: (M+H)+=489/491/493 (bromine/chlorine isotope).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15](CC)[CH2:14][CH2:13]2)[C:7]=1[F:20])(=[O:4])=[O:3].ClC(OC(Cl)=O)C>ClCCCl>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:7]=1[F:20])(=[O:3])=[O:4]
Reactant: CCN1CCC(c2cccc(OS(C)(=O)=O)c2F)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CS(=O)(=O)Oc1cccc(C2CCNCC2)c1F

Procedure:
3-(1-ethylpiperidin-4-yl)-2-fluorophenyl methanesulfonate (0.020 g, 0.033 mmol) was dissolved in dry 1,2-dichloroethane (5 ml) and a-chloroethylchloroformat (0.014 ml, 0.033 mmol) was added. The resulting mixture was refluxed for 1 h, and the solvent was evaporated. MS m/z (rel. intensity, 70 eV) 273 (M+, 2), 195 (11), 194 (bp), 178 (5), 56 (60).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]#[N:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][NH2:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: N#CC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: NCC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-3-phenylpropanenitrile (1.6 g, 4.12 mmol), prepared as described in Procedure 4, in CH3OH (40 mL) was added CoCl2.6H2O (1.07 g, 8.25 mmol). The resulting solution turned purple in color. NaBH4 (1.57 g, 41.2 mmol) was then added in portions over 10 min. The resulting black solution was stirred at rt for 1 h. After this time, the reaction mixture was concentrated under reduced pressure, quenched with 6N HCl (4 mL), and diluted with sat. ammonium chloride (40 mL). The aqueous phase was extracted with CH2Cl2 (4×50 mL). The combined organic portions were washed successively with sat. NaHCO3 (50 mL) and sat. NaCl (50 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (40 g) with elution at 35 mL/min gradient 0 to 5% CH3OH in CH2Cl2 over 22 min (RT=17-19 min). 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-3-phenylpropan-1-amine (1.0 g, 60% yield) was isolated as a pale yellow oil. LCMS: RT=1.68 min [M+H] 393.04 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.31 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 3.29-3.37 (m, 2 H), 3.59 (t, J=13.2 Hz, 2 H), 6.62 (d, J=7.0 Hz, 2H), 6.97 (d, J=10.1 Hz, 1 H), 7.06-7.14 (m, 5 H), 7.20 (d, J=8.35 Hz, 1 H), 7.34 (td, J=8.57, 3.08 Hz, 1 H), 8.45 (d, J=3.08 Hz, 1 H). The racemate (1.0 g) was dissolved in CH3OH and resolved by chiral prep HPLC (Chiralpak AD 20μ column, 5×50 cm isocratic elution with 100% EtOH/CH3OH(50/50)/0.1% DEA, 50 mL/min, monitoring at 254 nm). Enantiomer 1 (470 mg) was isolated as a yellow oil: analytical chiral HPLC (Diacel Chiralpak AD 10μ column, 4.6×250 mm isocratic elution with 100% EtOH/CH3OH(50/50)/0.1% DEA, 1 mL/min, monitoring at 254 nm), RT=3.70 min. Enantiomer 2 (470 mg) was isolated as a yellow oil: analytical chiral HPLC (Diacel Chiralpak AD 10μ column, 4.6×250 mm isocratic elution with 100% EtOH/CH3OH(50/50)/0.1% DEA, 1 mL/min, monitoring at 254 nm), RT=4.05 min.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:23][CH:22]([CH3:24])[C:21]([N:16]1[CH:17]=[CH:18][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[N:15]1)=[O:25]
Reactant: c1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Reactant: CC(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)n1ccc(-c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1H-pyrazole (123 mg, 0.52 mmol) and NaH (28 mg, 0.70 mmol) in 5 mL of DMF was stirred at room temperature for 30 minutes. Neat isobutyryl chloride (80 μL, 0.75 mmol) was added and the reaction was stirred at room temperature. The reaction was then partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the pooled organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Column chromatography (5% EtOAc/hexane) gave 127 mg (80%) of the title compound as a white solid, mp 49-51° C. 1H NMR (CDCl3): δ8.30 (d, J=3.0 Hz, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.39 (t, J=8.0 Hz, 2H), 7.17 (t, J=7.2 Hz, 2H), 7.12-7.08 (m, 4H), 6.75 (d, J=3.0 Hz, 1H), 4.03 (m, 1H), 1.78 (d, J=6.9 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[S:25][CH:26]=[C:27]([CH3:29])[N:28]=3)[N:3]=[CH:4][C:5]=2[C:17]2[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=2)[N:10]=1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Reactant: Cn1cncc1Br
Product: Cc1csc(Nc2ncc(-c3cncn3C)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=337.3 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 5-bromo-1-methyl-1H-imidazole and 2-amino-4-methylthiazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH:11]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][CH:20]=1)[CH:12]([CH3:14])[CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+].O>ClCCl.C(O)C>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH:11]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:19][CH:20]=1)[CH:12]([CH3:13])[CH3:14])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(NC(=O)OC(C)(C)C)nc1)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C(=O)O)C(c1ccc(NC(=O)OC(C)(C)C)nc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propyl]-malonic acid diethyl ester (1.569 g, 3.84 mmol) in a mixture of dichloromethane (6 mL) and ethanol (12 mL, 95%) at 0° C. a solution of potassium hydroxide (0.272 g, 85%, 4.2 mmol) in ethanol (6 mL, 95%) was added dropwise over 40 min. After additional 1 h stirring the mixture was allowed to warm up to room temperature and stirring was continued for 18 h. Then water (30 mL) and dichloromethane (30 mL) were added, and after 3 min stirring the layers were separated. The organic was extracted once with water and the combined aqueous were washed once with ether. Then an aqueous solution of citric acid (10%) was added to adjust the pH to 4, and the solution was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulphate. After evaporation of the solvent crude 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propyl]-malonic acid monoethyl ester (0.94 g, 64%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([CH:9]([O:12]C)OC)[CH:3]=1.CC[O:16]CC.[B:19]([O:24]C)(OC)[O:20]C>Cl>[CH:9]([C:4]1[CH:3]=[C:2]([B:19]([OH:24])[O:20][OH:16])[CH:7]=[CH:6][CH:5]=1)=[O:12]
Reactant: CCOCC
Reactant: COB(OC)OC
Reactant: COC(OC)c1cc(Br)ccc1O
Agent: Cl
Product: O=Cc1cccc(B(O)OO)c1
Temperature: -95 °C

Procedure:
To a solution of 4-bromo-2-dimethoxymethylphenol (10.0 g, 0.36 mol) in abs. ether (200 ml) n-BuLi (68 ml of 1.6 M hexane solution, 0.109 mol) was added dropwise under argon keeping the reaction mixture temperature below 25° C. Than the reaction mixture was refluxed for 3 h, then cooled to −95° C., trimethyl borate (14.3 ml, 0.128 mol) was added dropwise keeping the temperature below −95° C. After the addition was completed the temperature was increased to the RT overnight. Aqueous 1 M HCl (200 ml) was added to the stirring reaction mixture to reach pH 1.0. Organic phase was separated; aqueous phase was extracted with ether (4×50 ml). Combined organic phases were evaporated; the residue was triturated with benzene (25 ml) using an ultrasonic bath. Tan precipitate formed was collected by filtration, washed with hexane (2×10 ml) dried. Yield 2.63 g (15.8 mmol, 43%).
Reaction SMILES: [CH:1]1([C:6]2[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:11])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[N:37]1([S:42]([C:45]2[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=2[CH:47]=O)(=[O:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.[Au]>[CH:1]1([C:6]2[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:11])=[C:9]([CH2:47][C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[S:42]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)(=[O:43])=[O:44])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccccc1S(=O)(=O)N1CCCC1
Reactant: CCOC(=O)Cn1c(C)ccc1C1CCCC1
Agent: [Au]
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C2CCCC2)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Yield: 37.4 %

Procedure:
The general procedure was followed using ethyl 2-(2-cyclopentyl-5-methyl-1H-pyrrol-1-yl)acetate (3.49 g, 14.8 mmol), triethylsilane (7.11 mL, 44.5 mmol), trimethylsilyl trifluoromethanesulfonate (5.36 mL, 29.7 mmol), and 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde (3.55 g, 14.8 mmol) in dichloromethane of (total volume: 170 ml). Purification on silica gel (Luknova 330 g, 20 mL/min) using 1 to 7% of a 7:1 acetonitrile/methanol solution in dichloromethane over 70 minutes afforded ethyl 2-(5-cyclopentyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (2.54 g, 5.54 mmol, 37% yield) as a viscous gold residue that was approximately 90% pure by 1H-NMR analysis, with the impurity being ethyl 2-(2-cyclopentyl-5-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.96 (dd, 1H), 7.40 (ddd, 1H), 7.22-7.28 (m, 2H, composite of two shifts), 4.56 (s, 2H), 4.23 (s, 2H), 4.18 (q, 2H), 3.28-3.31 (m, 4H), 2.83 (m, 1H), 2.03 (s, 3H), 1.89-1.99 (m, 3H), 1.84-1.88 (m, 4H), 1.49-1.74 (m, 5H, composite of multiple shifts), 1.29 (t, 3H).
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:55][NH2:56]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:56][N:55]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=1
Reactant: NN
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: CCOc1ccc(C(CCCCCl)C(=O)O)cc1
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(C(CCCCCl)c2nc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)n[nH]2)cc1

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (0.500 g, 1.18 mmol), from preparation A) and 6-chloro-2-(4-ethoxyphenyl)hexanoic acid (0.351 g, 1.30 mmol, from preparation AAN) were coupled [N-methylmorpholine (0.647 mL, 5.89 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.148 mL, 4.71 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-ethoxyphenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown residue. The crude product was used in the next step without purification. LC-MS (M+H)+ 515.1.
Reaction SMILES: [NH2:1]N1C2C=NC=CC=2C2C1=CC(Cl)=CC=2.N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C1COCC1>[C:23](=[O:24])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:1]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nn1c2cnccc2c2ccc(Cl)cc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 224 %

Procedure:
A cold (3° C. to 5° C.) solution of the product of example 15 (30 mg, 0.14 mmol) and pyridine (0.014 ml, 0.17 mmol) in THF (0.7 ml) was treated with phenyl chloroformate (0.018 ml, 0.145 mmol). After stirring at RT for 2 h, the reaction was partitioned in ethyl acetate and buffer (pH 7.2). The organic layer was dried (brine, Na2SO4) and concentrated to give 43 mg of phenyl carbamate.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5].Cl.[C:11](=O)([O-])O.[Na+]>CO>[O:1]([CH3:11])[C@H:2]1[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[CH2:3]1
Reactant: O=C([O-])O
Reactant: O=CC[C@H](O)[C@H](O)CO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CO[C@@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 1.1 liters of methanol, 52 g of 2-deoxy-D-erythro-pentose was dissolved, and 3.8 ml of 1M hydrochloric acid solution in methanol was added at room temperature, followed by stirring the resulting solution at room temperature for 1 hour. To the reaction mixture, 1 g of sodium hydrogen carbonate was added and the resultant was concentrated after confirming that the solution was weakly basic. To the residue, 100 ml of toluene and 100 ml of pyridine were added to dissolve the residue and the resultant was concentrated. This operation was repeated totally twice to completely remove methanol. The thus obtained crude methyl 2-deoxy-α-D-erythro-pentofuranoside was used in the subsequent step without purification.