Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH2:18][OH:19])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH2:34]>C(Cl)(Cl)(Cl)Cl.CC#N>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:34])=[O:19])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cccc2ccccc12)N1CC(CO)C(CN2CCC(c3ccc(F)cc3)CC2)C1
Reactant: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A mixture of 0.126 g (0.28 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethyl pyrrolidine, 0.18 g (0.85 mmol) of NaIO4, and 0.0029 g (0.014 mmol) of RuCl3.3 H2O in 2 mL of CCl4, 3 mL of H2O and 2 mL of CH3CN was stirred at rt for 1 h. The reaction mixture was partitioned between CH2Cl2 and H2O. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give the title compound. 1H NMR (key peaks) (CDCl3) δ7.81-7.88 (m, 3H), 7.43-7.74 (m, 4H), 7.11-7.14 tm, 2H), 6.97 (t, 2H, J=8.0 Hz), Mass Spectrum (ESI) m/e=461 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][NH2:35])[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].O.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][O:24][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:36])[CH:32]=[CH:31][CH:30]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCN)c3)c2)Cc2ccccc2C1
Solvent: O
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(CCNC(C)=O)c1

Procedure:
The compound of Step 2 of example 246 (85 mg, 0.174 mmol) was dissolved in acetic anhydride and stirred under reflux for 30 min. Water was added in excess and the mixture was refluxed for 10 min. After cooling, the mixture was extracted with EA, the combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the methyl ester of the title compound. Hydrolysis of this ester in analogy to example 2 yielded 17 mg of the title compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]([C:13]1[CH:17]=[C:16]([Br:18])[N:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=1)=[O:12].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1>[CH3:9][O:10][C:11]([C:13]1[CH:17]=[C:16]([Br:18])[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[CH:27]([C:26]1[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=1)[OH:28])=[O:12]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
LDA (6.20 mmol) was added dropwise to a solution of 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step D4) (2.066 mmol) in THF (15 mL) at −78° C. and the mixture was stirred for 2 h. A solution of 4-chlorobenzaldehyde [104-88-1] (6.20 mmol) in THF (5 mL) was added and the mixture was stirred for 1 h. The mixture was warmed to −20° C., quenched with HOAc and stirred at rt overnight. The reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as an off-white solid. tR: 5.57 min (HPLC 1); ESI-MS: tR=1.36 min, [M+H]+ 368/370/372 (LC-MS 1); TLC: Rf=0.23 (1:6 EtOAc/heptanes).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(C(C)(C)C)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-bromo-4-tert-butylbenzene in analogy to Example 1a): MS (ISP): 436.1 and 438.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N+:10]([O-])([OH:12])=[O:11].C(=O)(O)[O-].[Na+]>O>[N+:10]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)([O-:12])=[O:11]
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncccc12
Temperature: 0 °C

Procedure:
3-nitro-7-azaindole 504 is prepared by adding 7-azaindole 1 to fuming nitric acid while cooling (e.g. 0° C.). After stirring for one to several hours, water is carefully added and the mixture neutralized with saturated sodium bicarbonate. The solids are collected by filtration and dried to provide 3-nitro-7-azaindole 504.
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](O)=[O:32]>>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([NH:6][C@H:5]([C:4]([OH:3])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)=[O:32]
Reactant: O=C(O)c1ccccn1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O)c1ccccn1

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 2-picolinic acid. δH (DMSO-d6) 8.8-8.6 (2H, m), 8.0 (2H, m), 7.7-7.4 (4H, m), 7.14 (2H, d, J 8.7 Hz), 6.92 (2H, d, J 8.7 Hz), 5.15 (2H, s), 4.72 (1H, m), 3.17 (2H, m); m/z (ESI, 60V) 445 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:10]1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O.[OH-].[Na+]>[N+](C)([O-])=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:18]([O-:20])=[O:19])=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:10]1
Reactant: CCC(=O)N1CCC(c2ccccc2OC)C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(=O)N1CCC(c2cc([N+](=O)[O-])ccc2OC)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
1-[3-(2-Methoxy-phenyl)-pyrrolidin-1-yl]-propan-1-one (0.7 g; 3 mmol) were dissolved in 10 ml of nitromethane. At −5° C. to −10° C., a mixture of 0.290 g nitric acid, 0.5 g water and 5.52 g sulphuric acid were added within 25 minutes, and the reaction mixture was stirred for another 1 h at low temperature and 16 h at room temperature. Ice was added, the reaction mixture was adjusted to alkaline pH with 50% aqueous NaOH, and the aqueous phase was extracted twice with diethylether. The organic layers were combined, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 0.85 g of the desired product as a mixture of isomers and small amounts of the dinitro derivative which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[Cl:11])[CH:2]=[CH2:3].[C:13](Cl)([Cl:15])=[S:14]>[OH-].[Na+].O.C(Cl)(Cl)Cl>[Cl:15][C:13]([O:12][C:7]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=1)=[S:14]
Reactant: S=C(Cl)Cl
Reactant: C=CCOc1cc(O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCOc1cc(OC(=S)Cl)ccc1Cl

Procedure:
3-Allyloxy-4-chlorophenol (35.0 g) was dissolved in a solution of 7.7 g of sodium hydroxide in 30 ml of water. To the solution, there was added with stirring a solution of 14.6 ml of thiophosgene in 55.0 ml of chloroform. The reaction mixture was allowed to stand for phase separation. The chloroform layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Reduced pressure distillation of the residue gave 33.0 g of O-(3-allyloxy-4-chlorophenyl) chlorothioformate as a fraction boiling at 128°-129° C./0.4 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:6]=1)[CH3:2]>CCOC(C)=O.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[C:7]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(-c2nnnn2C)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N)cc(-c2nnnn2C)c1
Yield: 72.5 %

Procedure:
A solution of 3-(1-Methyl-1H-tetrazol-5-yl)-5-nitro-benzoic acid ethyl ester (6.5 g) in EtOAc:ethanol (1:1, 320 ml) was hydrogenated at 20° C. and 50 psi with 10% Pd/C (750 mg). After reaction completion, the mixture was filtered and the filtrate concentrated in vacuum to give the title compound (4.2 g). Rt=1.21 min (method D).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O

Procedure:
To a stirred solution of methyl 2-methoxy-4-(1-tert-butyloxycarbonyl-4-piperidinylmethoxy)benzoate from Step 2 above (750 mg, 1.98 mmol) in methanol (10 mL) was added 2N NaOH (4.95 mL, 9.90 mmol). The reaction mixture was refluxed for 30 minutes then cooled in a ice water bath. The solution was acidified with 5% citric acid and the solvent evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (2×25 mL). The organic layer was dried (MgSO4), filtered, then the solvent was evaporated to give 2-methoxy-4-(1 -tert-butyloxycarbonyl-4-piperidinylmethoxy)benzoic acid as a white solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.[Cl:13][CH2:14][C:15](=O)[CH2:16][C:17](OCC)=[O:18]>>[Cl:13][CH2:14][C:15]1[N:1]=[C:2]2[S:3][C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][N:6]2[C:17](=[O:18])[CH:16]=1
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: CCOC(=O)CC(=O)CCl
Product: O=c1cc(CCl)nc2sc(-c3ccccc3)nn12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-amino-5-phenyl-1,3,4-thiadiazole (10 g) was reacted with ethyl 4-chloro-acetoacetate (18.6 g) in polyphosphoric acid (100 g) under stirring at 100° C. for 1 hour. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water until neutral: crystallization from methanol gave 7-chloromethyl-2-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 201°-202° C. (11.6 g), which was reacted with triphenylphosphine (12.4 g) in acetonitrile (500 ml) under stirring at reflux temperature for 48 hours. After cooling the precipitate was filtered and washed with isopropyl ether to give (5-oxo-2-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-7-yl)-methyl-triphenylphosphonium chloride, m.p. 295°-300° C. (20 g), which was suspended in dimethylsulphoxide (100 ml) and treated dropwise with potassium terbutoxide (5 g) dissolved in dimethylsulphoxide (100 ml) at a temperature of about 20° C. The solution of the ylide so obtained was then reacted with benzaldehyde (4.55 g) at room temperature for 90 minutes. After dilution with ice water the precipitate was filtered and washed with water: crystallization from methanol gave 5.1 g of 2-phenyl-7-trans-(2-phenyl-ethenyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 217°-219° C., N.M.R. (CDCl3) δp.p.m.: 6.34 (s) (1H, C-6-proton), 6.82 (d) (1H, β-ethenyl proton), 7.58 (d) (1H,α-ethenyl proton), 7.12-7.98 (m) (10H, phenyl protons); JHαHβ =16 Hz.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:35])[CH2:6][O:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:10][C:9]=1[CH3:34])[CH3:3].[H-].[Na+].[Br:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O>C1COCC1>[Br:38][C:39]1[CH:40]=[C:41]([CH:42]=[CH:12][C:11]2[CH:32]=[CH:33][C:8]([O:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:35])=[C:9]([CH3:34])[CH:10]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCOC(=O)COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C=Cc2cccc(Br)c2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
A suspension of [4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphonium chloride (500 mg, 0.99 mmol) in dry THF (10 mL) was cooled to 0° C. (ice/water bath) and treated with NaH (44 mg of a 60% dispersion in mineral oil, 1.10 mmol) portion-wise over 5 minutes. The resulting yellow suspension was stirred for 15 minutes and was then treated with 3-bromobenzaldehyde (184 mg, 0.99 mmol) in dry THF (5 mL). The resulting white suspension was allowed to warm to rt over 3.5 hours and was then heated at reflux for 1 hour. The reaction mixture was then allowed to cool to rt, stirred overnight and was then reduced under vacuum. The residue was then partitioned between CHCl3 (20 mL) and water (20 mL) and the layers separated. The cloudy organic layer was dried through a hydrophobic frit and then concentrated to a cream coloured gum (700 mg). Purification by SPE (silica) eluting with cyclohexane:EtOAc (9:1) afforded the title compound (mixture of E:Z isomers) (258 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:4].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2([C:36]([F:39])([F:38])[F:37])[O:23][N:22]=[C:21]([C:24]3[S:35][C:27]4=[N:28][CH:29]=[C:30]([C:32](O)=[O:33])[CH:31]=[C:26]4[CH:25]=3)[CH2:20]2)[CH:15]=[C:16]([Cl:18])[CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:18][C:16]1[CH:15]=[C:14]([C:19]2([C:36]([F:38])([F:37])[F:39])[O:23][N:22]=[C:21]([C:24]3[S:35][C:27]4=[N:28][CH:29]=[C:30]([C:32]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:33])[CH:31]=[C:26]4[CH:25]=3)[CH2:20]2)[CH:13]=[C:12]([Cl:11])[CH:17]=1
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1)NCC(F)(F)F
Yield: 34.8 %

Procedure:
Stir a mixture of 2-Amino-N-(2,2,2-trifluoro-ethyl)-acetamide (156 mg, 1 mmol), 2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine-5-carboxylic acid (160 mg, 0.24 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (0.2 mL) at room temperature for 10 hours. After removal of solvent, purify the mixture by preparative-HPLC to afford 2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide as a white solid (50 mg, 34.78%). MS (m/z): 599 (M+1). 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.51 (s, 1H), 7.52 (s, 2H), 7.44-7.41 (m, 2H), 7.22 (s, 1H), 6.64 (s, 1H), 4.27 (d, J=5.2, 2H), 4.17 (d, J=16.8, 1H), 4.04-3.95 (m, 2H), 3.80 (d, J=16.08, 1H).
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17]C(=O)C)[O:13][CH2:12][CH:11]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C(=O)C)=[CH:23][CH:22]=1)[C:10]2=[O:31]>C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[OH:17])[O:13][CH2:12][CH:11]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:10]2=[O:31]
Reactant: CC(=O)Oc1ccc(C2COc3cc(OC(C)=O)c(Cl)cc3C2=O)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: O=C1c2cc(Cl)c(O)cc2OCC1c1ccc(O)cc1
Reaction time: 8 h
Yield: 802.7 %

Procedure:
Imidazole (0.60 g) was added to a suspension of 6-chloro-4′,7-diacetoxyisoflavan-4-one (0.24 g, 0.06 mmol) in absolute ethanol (5.0 ml) and the mixture was refluxed for 45 min under argon. The solution was concentrated under reduced pressure and distilled water (10 ml) was added to the residue. The mixture was left overnight in the fridge and the resulting precipitate was filtered, washed with water and dried to yield 6-chloro-4′,7-dihydroxyisoflavan-4-one (0.14 g, 75%) as a white powder. 1H NMR (d6-acetone): δ 3.87 (t, 1H, J 7.2 Hz, H3), 4.64 (d, 2H, J 6.2 Hz, H2), 6.59 (s, 1H, H8), 6.78 (d, 2H, J 8.7 Hz, ArH), 7.10 (d, 2H, J 8.7 Hz, ArH), 7.70 (bs, 1H, OH), 7.77 (s, 1H, H5).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:17][C@H:18]1[CH2:22][C@@H:21]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][C:26]([N:47]2[CH2:51][CH2:50][C@@H:49]([NH:52][C:53]([NH:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:54])[CH2:48]2)=[N:27][C:28]=3[NH:32][CH2:33][CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:20]([OH:62])[C@@H:19]1[OH:63])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:17][C@H:18]1[CH2:22][C@@H:21]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][C:26]([N:47]2[CH2:51][CH2:50][C@@H:49]([NH:52][C:53]([NH:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:54])[CH2:48]2)=[N:27][C:28]=3[NH:32][CH2:33][CH:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:20]([OH:62])[C@@H:19]1[OH:63]
Reactant: O=C(Nc1cccnc1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)OCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
To a solution of ((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-carbamic acid benzyl ester trifluoroacetate (step 1) (35 mg, 46 μmol) in ethanol (1 ml) under an inert atmosphere of argon is added 10% palladium on carbon (10 mg). The reaction mixture is purged with argon and placed under a positive atmosphere of hydrogen overnight after which time, the mixture is filtered through celite and the catalyst washed with ethanol. The organic portions are combined and concentrated in vacuo to yield the title compound. MS (ES+) m/e 635 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)=[O:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:35][O-:36].[Na+].C1(C)C=CC=CC=1>ClCCl>[N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12]([O:36][CH3:35])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)=[O:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[O-]
Reactant: N#Cc1ccc(C(=O)c2ccc3nc(Cl)c(Cc4ccc(-n5cncn5)cc4)c(Cl)c3c2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(C(=O)c3ccc(C#N)cc3)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
A heterogeneous mixture containing 4-(3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-2,4-dichloroquinoline-6-carbonyl)benzonitrile (583 mg, 1.20 mmol, Intermediate 16: step d), sodium methoxide (780 mg, 14.4 mmol), and toluene (17 mL) was heated to 110° C. After 45 minutes, the flask was allowed to cool to 23° C. Dichloromethane (100 mL) was added to the flask and then the mixture was filtered through Celite®, rinsing with dichloromethane. Silica gel (5 g) was added to the filtrate and the solvent was removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a column of silica gel for flash chromatography purification. Elution with hexanes initially, grading to 80% ethyl acetate-hexanes afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:3]([NH:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)(=[O:22])=[O:21])[CH:14]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4].[Sn](Cl)Cl>>[NH2:29][C:25]1[CH:24]=[C:23]([S:20]([NH:19][C:15]2[CH:14]=[C:13]([CH:6]([NH:5][C:3](=[O:4])[CH:2]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[Cl:1])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CC(NC(=O)C(Cl)c1ccc(Cl)cc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Product: CCOC(=O)CC(NC(=O)C(Cl)c1ccc(Cl)cc1)c1cccc(NS(=O)(=O)c2cccc(N)c2)c1
Yield: 73.3 %

Procedure:
Corresponding to Example 3d, 1.18 g of (5c) were treated with tin-(II) chloride. 820 mg of a yellowish solid were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH:13]=O)[CH2:9][CH2:8][N:7]1[C@@H:15]([CH3:22])/[C:16](/[CH3:21])=[CH:17]/[CH:18]=[CH:19]\[CH3:20])=[O:5])[CH3:2].[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>CCO.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH2:13][NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][CH2:8][N:7]1[C@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:22])=[O:5])[CH3:2]
Reactant: NCCc1ccccc1
Reactant: C/C=C\C=C(/C)[C@H](C)N1CC[C@@H](CCC=O)[C@H]1C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1[C@H](CCCNCCc2ccccc2)CCN1[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of (2S,3R)-1-((2E,4Z)—(S)-1,2-Dimethyl-hexa-2,4-dienyl)-3-(3-oxo-propyl)pyrrolidine-2-carboxylic acid ethyl ester (1.g, crude) in EtOH (10 mL) is added phenethylamine (0.44 g, 3.65 mmol) at r.t. After stirring at r.t. for 30 min, NaBH3CN (0.3 g, 4.87 mmol) is added in one portion, After stirring at r.t. for 1.5 Hrs, the reaction solution is diluted with 50 mL of ether and washed with 20 mL of brine. The ether layer is concentrated and the crude product is purified by chromatography (CH2Cl2/MeOH: 97/3) to give a pale liquid (405 mg, 30.0%). (NMR and MS data confirmed, U-4117-52-20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[O:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17]>>[O:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH:17][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCC(=O)c1ccccc1
Product: O=C(CNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1ccccc1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-oxo-2-phenylethylamine. The product was purified by mass directed purification to give the title compound as an orange solid. m/z (ES+)=314 [M+H]+; RT=3.30 min.