Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:17])[C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:26])[C:22]([CH3:24])([O:17][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[C:2]([CH3:1])[NH:3]2)[CH3:23])[CH3:19]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1[nH]c2cccc(O)c2c1-c1ccccc1
Product: CCOC(=O)C(C)(C)Oc1cccc2[nH]c(C)c(-c3ccccc3)c12

Procedure:
The above compound was prepared from 2-methyl-3-phenyl-1H-indole-4-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:7]=1[O:14][CH3:15])(=[O:4])=[O:3].S(=O)(=O)([OH:18])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:15][O:14][C:7]1[CH:8]=[CH:9][C:10]([C:12]([OH:18])=[O:13])=[CH:11][C:6]=1[O:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COc1ccc(C=O)cc1OS(C)(=O)=O
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)O)cc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 268.1 %

Procedure:
5-formyl-2-methoxyphenyl methanesulfonate (3.3 g, 14 mmol) was dissolved in acetic acid (50 ml) and sulfamic acid (500 mg, 5.15 mmol) was added. Sodium chlorite (3 g, 33.2 mmol) was dissolved in H2O (20 ml) and added dropwise. The reaction was stirred at RT overnight, then the precipitate was filtered and washed with HCl 1 M, MeOH and dried in the vacuum oven, to give 3.4 g of the desired product (Yield: 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH3:11])[C:8]([OH:10])=O)=[O:4].[C:12]([O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)([CH3:15])([CH3:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:12]([O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:8](=[O:10])[CH:7]([CH3:11])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CCC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)CCC(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
4-Methoxycarbonyl-2-methylbutanoic acid (3.1 g.) and L-proline tert.-butyl ester (3.78 g.) are dissolved in dichloromethane (40 ml.). The solution is chilled with stirring in an ice bath and dicyclohexylcarbodiimide (4.12 g.) is added. After stirring 15 minutes in the ice bath and 18 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is chromatographed on a column of silica gel with chloroform to obtain 1-(4-methyoxycarbonyl-2-methylbutanoyl)-L-proline tert.-butyl ester, yield 3.5 g.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH2:15].C1C=CC=CC=1>C(OCC)C.CCCCC>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCNCC=O
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: CCOCC
Solvent: CCCCC
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 0.25 h

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (8.7 grams), the diethyl acetate of 2-allylaminoacetaldehyde (8.0 grams) and benzene (30 ml) was charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture was heated with stirring for a period of about 15 minutes. After this time the reaction mixture was stripped of benzene to yield an oil. The oil was dissolved in a diethyl ether-pentane mixture and was filtered through diatomaceous earth. The filtrate was stripped of solvent to yield the desired product the diethyl acetal of 2-[1-allyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde as a dark oil.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[C:10]([CH:15]=[O:16])[C:11]=1[C:12]([NH2:14])=[O:13])=[O:5].O1CCCC1CO>[Cl-].[NH4+]>[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[C:10]([CH2:15][OH:16])[C:11]=1[C:12]([NH2:14])=[O:13])=[O:5]
Reactant: NC(=O)Nc1[nH]c(-c2cccc(Cl)c2)c(C=O)c1C(N)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: OCC1CCCO1
Product: NC(=O)Nc1[nH]c(-c2cccc(Cl)c2)c(CO)c1C(N)=O
Yield: 37 %

Procedure:
Sodium borohydride (18 mg, 0.48 mmol) was added to a solution of 2-aminocarbonylamino-5-(3-chlorophenyl)-4-formylpyrrole-3-carboxamide (Compound No. 17-1, 50 mg, 0.16 mmol) in the mixed solvent (tetrahydrofuran methanol=2:1, 1.5 mL) and the mixture was stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained solid was washed with chloroform (15 mL) and dried under reduced pressure to give the target compound (19 mg) as an orange solid (Yield 37%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:15])[CH:10]=[CH:11][C:12]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C\C(=O)Nc1cccc(I)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1C=CC(=O)N1c1cccc(I)c1
Temperature: 120 °C
Yield: 79.6 %

Procedure:
N-(m-iodophenyl)maleamic acid (1 g, 3.15 mmol) was placed in acetic anhydride (10 mL). Sodium acetate (1 g) was added and the solution stirred at 120° C. The dark brown filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in diethyl ether. The ether mixture was filtered and the filtrate was again evaporated to dryness. The residue obtained was applied to a flash chromatography column (30×200 mm) of Kieselgel 60, 230-400 mesh). Elution with ethyl acetate/hexane (1:3) (400 mL) yielded forty fractions. Fractions 25-35 were combined to provide pure pale yellow N-(m-iodophenyl)maleimide (0.75 g, 80%): TLC (EtOAc/hexane, 1:3) Rf 0.42; mp 154°-155° C.; 1H NMR (CDCl3, δ); 7.1-7.7 (multiplets, 4H, 4 aryl CH); 6.8 (singlet, 2H, 2 CHC=O ).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[CH:15][C:16]([C:17]3[CH:22]=[C:21]([C:23]([C:25]4[NH:57][C:28]5=[N:29][C:30]([N:33]6[CH2:38][CH2:37][CH:36]([O:39][Si](C(C)(C)C)(C7C=CC=CC=7)C7C=CC=CC=7)[CH2:35][CH2:34]6)=[CH:31][CH:32]=[C:27]5[N:26]=4)=[O:24])[CH:20]=[CH:19][C:18]=3[C:58]#[N:59])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[CH:15][C:16]([C:17]3[CH:22]=[C:21]([C:23]([C:25]4[NH:57][C:28]5=[N:29][C:30]([N:33]6[CH2:34][CH2:35][CH:36]([OH:39])[CH2:37][CH2:38]6)=[CH:31][CH:32]=[C:27]5[N:26]=4)=[O:24])[CH:20]=[CH:19][C:18]=3[C:58]#[N:59])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C(=O)c4nc5ccc(N6CCC(O[Si](c7ccccc7)(c7ccccc7)C(C)(C)C)CC6)nc5[nH]4)ccc3C#N)cncc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C(=O)c4nc5ccc(N6CCC(O)CC6)nc5[nH]4)ccc3C#N)cncc21
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of 4-(5-{5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine-2-carbonyl}-2-cyano-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester in THF (0.2M) was added a 1M TBAF in THF solution at 23° C. After 24 hr, the reaction was quenched with sat'd NaHCO3 and extracted with EtOAc (3×), the combined organics washed with brine, dried over Na2SO4, filtered, and concentrated to a red solid. The crude was purified using chromatography eluting with MeOH/DCM mixtures giving 4-{2-Cyano-5-[5-(4-hydroxy-piperidin-1-yl)-3H-imidazo[4,5-b]pyridine-2-carbonyl]-phenyl}-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester as a red-orange solid (420 mg, 0.738 mmol, 66%). MS ESI m/z 564.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:17][C:18]4[C:23]([N:24]=3)=[CH:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:17][C:18]4[C:23]([N:24]=3)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=4)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(OC)cc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C2CCN(c3nc4cc(C(=O)O)ccc4nc3-c3ccccc3)CC2)cc1

Procedure:
To a solution of methyl 3-(4-(4-methoxyphenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (179.6 mg, 0.36 mmol, 1.00 equiv, 90%) in methanol (17 mL) was added a solution of sodium hydroxide (80 mg, 2.00 mmol, 5.00 equiv) in water (2 mL) dropwise with stirring. The resulting solution was stirred for 7 h at 50° C. in an oil bath, then the pH of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum, followed by washing with methanol yielding 81.9 mg (50%) of 3-(4-(4-methoxyphenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[CH3:22][S:23]([OH:26])(=[O:25])=[O:24]>CO>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:23]([O-:26])(=[O:25])(=[O:24])[CH3:22]
Reactant: CS(=O)(=O)O
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: CO
Product: CS(=O)(=O)[O-]

Procedure:
Clopidogrel base was dissolved in methanol to obtain a clear solution. Methanesulfonic acid was added to the solution at 20° C. The reaction mixture was heated to reflux temperature for 2 to 10 hrs. The solvent was evaporated to dryness under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[CH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]>N1C=CC=CC=1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Solvent: c1ccncc1
Product: CCCCc1nc(=O)c2cc(CC)ccc2[nH]1
Reaction time: 48 h
Yield: 63.3 %

Procedure:
To a suspension of 0.278 g of 2-butyl-6-ethynyl-4(1H)quinazolinone in 8 ml of pyridine is added 0.080 g of 5% palladium-on-barium sulfate. The reaction is stirred under a hydrogen atmosphere for 48 hours, filtered, concentrated in vacuo and the residue purified by flash chromatography on silica gel eluting with ethyl acetate-hexanes to give 0.179 g of the desired product. CI MASS SPEC 231(MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1.C(OC1C=C(C=CC=1)N)C1C=CC=CC=1.COCCC(Cl)=O.C(OC1C=CC(N)=CC=1)C1C=CC=CC=1.C(OCC(Cl)=O)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:99][S:100][CH2:101][CH2:102][CH2:103]O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:103][CH2:102][CH2:101][S:100][CH3:99])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1
Reactant: CCCn1c(CCOC)nc2cnc3cc(O)ccc3c21
Reactant: CSCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCOCC(=O)Cl
Agent: COCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCn1c(CCOC)nc2cnc3cc(OCCCSC)ccc3c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A modification on the methods described in Parts A-H of Example 2 were used to prepare 2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol, with 3-benzyloxyaniline and 3-methoxypropanoyl chloride used in lieu of 4-benzyloxyaniline and ethoxyacetyl chloride, respectively. Diisopropyl azodicarboxylate (2.07 mL, 10.5 mmol) was added dropwise to a slurry of 2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (2.00 g, 7.01 mmol), triphenylphosphine (2.75 g, 10.5 mmol), and 3-(methylthio)propan-1-ol (1.08 mL, 10.5 mmol) in tetrahydrofuran (70 mL) at 0° C. The solution was stirred for 30 minutes at 0° C., then at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, treated with 1 M hydrochloric acid (40 mL), and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The aqueous layer was adjusted to approximately pH 14 with 50% aqueous sodium hydroxide and then was extracted with dichloromethane (3×50 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 1-4% methanol in dichloromethane) to provide 2.0 g of 2-(2-methoxyethyl)-7-[3-(methylthio)propoxy]-1-propyl-1H-imidazo[4,5-c]quinoline as an opaque solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([C:18]([CH:20]2[CH2:22][CH2:21]2)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH:20]1([CH:18]([NH:26][CH2:23][CH2:24][CH3:25])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH2:21]1
Reactant: CCCN
Reactant: O=C(c1ccccc1)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCNC(c1ccccc1)C1CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
4 Å molecular sieves and 100 mg of paratoluenesulphonic acid are added to 10 g of cyclopropyl phenyl ketone in 60 ml of anhydrous toluene, followed by 6 g of propylamine. Imine formation is monitored by gas chromatographic assay. After heating for 6 hours at 55° C., the reaction mixture is cooled, the molecular sieves are filtered off and the solution is evaporated to dryness under vacuum. The residue is taken up in 100 ml of anhydrous ethanol. The solution is cooled to 0° C. and 2.65 g of sodium borohydride are added portionwise. After stirring overnight at room temperature, the mixture is evaporated to dryness under vacuum and the residue is taken up in water, hydrolysed with 1N hydrochloric acid in order to bring the pH to 2, and washed with ethyl acetate. The pH is brought to 9 by addition of 2N sodium hydroxide and the mixture is then extracted several times with methylene chloride.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl.O1CCOCC1>C(Cl)Cl.O>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:7]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (2.00 g, 9.99 mmol) in DCM (200 ml) was added DIPEA (3.66 ml, 20.97 mmol) and then 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (1.69 ml, 9.99 mmol) and the resulting mixture stirred at room temperature for 90 min. The reaction mixture was then concentrated under vacuum and re-dissolved in 1,4-dioxane (100 ml). A 4M solution of HCl in 1,4-dioxane (100 ml, 400 mmol) and a few drops of distilled water were added and the mixture stirred for 3 h. The reaction mixture was concentrated under vacuum, re-dissolved in DCM (200 ml) and washed with 2M aqueous NaOH (2×50 ml). The organic layer was dried (MgSO4), filtered and concentrated under vacuum. The residue was dissolved in ether and concentrated under vacuum. The oil was dissolved in MeOH (150 ml), applied to an SCX cartridge (50 g), which was washed with MeOH, DCM and MeOH again. The product was eluted from the column with 2M ammonia in methanol, DCM and then 2M ammonia in methanol; concentration under vacuum gave the title compound as a yellow transparent oil (2.92 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]=1[CH3:19].C([Li])CCC.[C:25](=[O:27])=[O:26].[OH-].[Na+]>C1COCC1.CCOCC>[C:8]([C:6]1[C:5]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]([CH3:19])=[C:2]([CH:7]=1)[C:25]([OH:27])=[O:26])([CH3:11])([CH3:10])[CH3:9]
Reactant: COCCOCOc1cc(C)c(Br)cc1C(C)(C)C
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOCOc1cc(C)c(C(=O)O)cc1C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-bromo-5-tert-butyl-4-(2-methoxy-ethoxymethoxy)-2-methyl-benzene from Example ZZ (44.7 g, 135 mmol) in dry THF was cooled to -78° C. under nitrogen and treated with 1.6M n-butyllithium (93 mL, 149 mmol). The solution was stirred at -78° C. for 45 minutes and then poured over crushed dry ice. The mixture was allowed to warm to room temperature. Et2O (100 mL) and 2N NaOH (200 mL) were added; the organic layer was separated and re-extracted with 2N NaOH. The aqueous layers were combined, acidified to pH 2 with 6N HCl, and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.35 (s, 9 H), 2.57 (s, 3 H), 3.37 (s, 3 H), 3.57 (m, 2 H), 3.81 (m, 2 H), 5.35 (s, 2 H), 6.98 (s, 1 H), 8.01 (s, 1 H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[O:11]=[C:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]1)[CH2:13][C:14]([OH:16])=O.CCN=C=NCCCN(C)C.Cl.[C:47]1([C:53]2[CH:54]=[CH:55][C:56]([NH2:59])=[N:57][CH:58]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[O:11]=[C:12]([N:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22]1)[CH2:13][C:14]([NH:59][C:56]1[CH:55]=[CH:54][C:53]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:58][N:57]=1)=[O:16]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)cn1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
HOBt (57 mg, 0.42 mmol) and DMAP (46 mg, 0.38 mmol) were added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (60 mg, 0.35 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (81 mg, 0.42 mmol) followed by 5-phenyl-pyridin-2-ylamine (120 mg, 0.35 mmol) were added. The reaction mixture was stirred at the room temperature overnight, then diluted with water and the product extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated. The residue was purified by column chromatography using silica gel 60-120 mesh and 80% ethyl acetate in hexane as the eluant to afford 65 mg (38% 0 of 3-oxo-N-(5-phenyl-pyridin-2-yl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 497.18 (M+1)+, 90.4%, 1H NMR: (CDCl3): δ 9.6 (d, 1H), 8.5 (s, 1H), 8.2 (m, 1H), 7.9 (m, 1H), 7.75 (d, 1H), 7.6 (m, 4H), 7.45 (t, 2H), 7.35 (m, 2H), 4.0 (m, 2H), 3.7 (m, 3H), 3.55 (m, 4H), 3.26 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[CH2:17])[CH2:9][CH:10](O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:41][C:42]([NH2:44])=[S:43]>C(#N)C>[NH2:44][C:42]1[S:43][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)([CH3:17])[N:41]=1
Reactant: C=C(CC(O)C(=O)OCC)c1cccc(Br)c1
Reactant: NC(N)=S
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C1CC(C)(c2cccc(Br)c2)N=C(N)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 4-(3-bromophenyl)-2-hydroxypent-4-enoate (5.1 g, 17 mmoles) in acetonitrile (68 mL) is added 2,6-lutidine (2.19 g, 20.4 mmol, 1.2 equiv). The reaction is cooled to 0° C. and trifluoromethanesulfonic anhydride (3.30 mL, 19.6 mmol, 1.15 equiv) is added dropwise over approximately 5 minutes. The mixture is stirred at 0° C. for 20 minutes. Thiourea (2.59 g, 34.0 mmol, 2 equiv) is added and the reaction is warmed to room temperature. After 45 minutes, the mixture is concentrated under reduced pressure. The resulting viscous orange oil is then added via large pipette to stirring sulfuric acid (17.8 M, 8 mL) at room temperature. After 20 minutes, the mixture is added dropwise to a vigorously stirring, 0° C. solution of K2CO3 (ca. 50 g) in 50 mL H2O). Additional water is added to enable stirring upon solid formation during the quench. The tan/orange solid is collected by filtration. The solid is allowed to dry on the filter paper by a stream of air for 1 h to give the title compound as a mixture of diastereomers which is used without further purification: MS (m/z): 357, 359 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2ccc(C)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ccc2c(c1)C(C)NCC2

Procedure:
In close analogy to the procedure described above, 1,7-dimethyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.C(C(C(C(OCC)=O)O)O)(OCC)=[O:27].C(N(C(C)C)CC)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH2:14][S@:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:27])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(OCC(F)(F)F)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Temperature: 52.5 °C
Reaction time: 0.5 h

Procedure:
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole (30.0 g, 0.085 mol, containing 31 mg of water), toluene (150 mL), water (59 mg, 0.0033 mol, total amount of water 0.0050 mol) and diethyl (+)-tartrate (3.19 mL, 0.019 mol) were mixed and heated to 50 to 55° C. Titanium(IV) isopropoxide (2.49 mL, 0.0085 mol) was added to the mixture under a nitrogen atmosphere, and the mixture was stirred at 50 to 55° C. for 30 min. Under a nitrogen atmosphere and under cooling, diisopropylethylamine (4.88 mL, 0.028 mol) was added to the obtained mixture and cumene hydroperoxide (46.0 mL, 0.26 mol) was added at −5 to 5° C. The mixture was stirred at −5 to 5° C. for 5.5 hr to allow reaction.