Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](/[NH:14][CH:15]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:16])=[C:8](\[C:12]#[N:13])/[C:9]([OH:11])=O.[CH:22]([NH2:25])([CH3:24])[CH3:23].OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:14][CH:15]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:16])=[C:8]([C:12]#[N:13])[C:9]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:11]
Reactant: CC(N/C(=C(/C#N)C(=O)O)c1sccc1Br)c1nccs1
Reactant: CC(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)C(C#N)=C(NC(C)c1nccs1)c1sccc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of (2Z)-3-(3-bromo-2-thienyl)-2-cyano-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylic acid (0.18 g, 0.468 mmol, 1 eq.) in 5 ml of DCM (CH2Cl2) were added isopropylamine (0.083 g, 1.40 mmol, 3 eq.), hydroxybenzotriazole (HOBT) (0.066 g, 0.49 mmol, 1.05 eq.) and diisopropylethylamine (DIPEA) (0.090 g, 0.70 mmol, 1.5 eq.). The reaction was cooled to 0° C. and dicyclohexylcarbodiimide (DCC) (0.101 g, 0.49 mmol, 1.05 eq.) was added. Stirring was allowed overnight and the solid formed removed by filtration. The solvent was removed under reduced pressure and the residual oil submitted to chromatography on silica gel to give 2Z)-3-(3-bromo-2-thienyl)-2-cyano-N-isopropyl-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylamide (0.090 g, 43% yield) as a white solid and a mixture of atropoisomers.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[N:24]=[C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)[CH:22]=[CH:21][CH:20]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CCO.CCOC(C)=O>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[C:23]1[N:24]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][CH:10]=[C:9]3[OH:8])[CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(COc2ccnc3ccc(-c4cccc(-c5nccs5)n4)cc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccnc2ccc(-c3cccc(-c4nccs4)n3)cc12
Reaction time: 72 h
Yield: 88 %

Procedure:
To a solution of 2-(6-(4-(benzyloxy)quinolin-6-yl)pyridin-2-yl)thiazole (1.0 equiv.) in 1:1 EtOH/EtOAc, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 72 hours. At this time the mixture was filtered through a pad of celite eluting with EtOAc. The volatiles were removed in vacuo yielding 6-(6-(thiazol-2-yl)pyridin-2-yl)quinolin-4-ol (88%). LCMS (m/z): 305.9 (MH+); LC Rt=2.57 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([NH:15]C(=O)OC(C)(C)C)=[CH:10][C:9]=2[CH3:23])=[CH:5][C:4]=1[CH:26]([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH:26]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH2:7][C:8]1[C:9]([CH3:23])=[CH:10][C:11]([NH2:15])=[CH:12][C:13]=1[CH3:14])([CH3:28])[CH3:27]
Reactant: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cc2c(C)cc(N)cc2C)cc1C(C)C
Reaction time: 4 h

Procedure:
578 mg (1.36 mmol) of tert-butyl 4-(4-methoxy-3-isopropylbenzyl)-3,5-dimethylphenylcarbamate (Example VI) are dissolved in 10 ml of 5% trifluoroacetic acid in dichloromethane at 0° C. and stirred for 4 hours. The mixture is neutralized with sodium bicarbonate solution and dried over sodium sulphate. The product after removal of the solvent is reacted further without further purification.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:17]2[S:16][C:15]=1[NH2:35])(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:13][C:14]2[CH:19]([C:20]([OH:22])=[O:21])[N:18]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:17]3[S:16][C:15]=2[NH2:35])=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: CC(=O)OCC1=C(N)S[C@@H]2[C@H](C(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(CC2=C(N)S[C@@H]3[C@H](C(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1.5 ml of thioanisol in 10 ml of trifluoroacetic acid is treated with 1.17 g of 3-acetyloxymethyl-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid and the mixture is left to stand for 30 minutes at room temperature. After diluting the mixture with an equal volume of toluene, the volatile fractions are evaporated under reduced pressure. The residue is partitioned between ethyl acetate and a 10% aqueous dipotassium hydrogen phosphate solution (pH = 7.5). The layers are separated; the aqueous phase is washed several times with ethyl acetate, adjusted to pH 2.5 with 20% aqueous phosphoric acid and extracted with ethyl acetate. The resulting organic extracts are washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure, to yield the 3-(4-methylthio-benzyl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid, which is further processed without purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=1[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=2[C:21]([F:22])([F:24])[F:23])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methylpiperazine (600 mg, 1.5 mmol), ethyl 4-(bromomethyl)-3-(trifluoromethyl)benzoate (310 mg, 1.0 mmol), and potassium carbonate (276 mg, 2.0 mmol) in N,N-dimethylformamide (8 mL) were stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated to give the product without further purification (600 mg, 72%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][N:14]([CH2:28][CH3:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH2:28]([N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)[CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH3:29]
Reactant: CCN(C[C@H]1CCCN1C(=O)OC(C)(C)C)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C[C@H]1CCCN1)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-2-{[ethyl-(3-phenoxy-phenyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.162 g, 0.41 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (1 ml) and the mixture was stirred for 3 h at room temperature. Aqueous sodium hydroxide solution (4N) was added until basic pH and the mixture was extracted with ethyl acetate (2 times 30 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate) to yield a colourless oil, (0.043 g, 36%); MS (ISP): 297.5 ((M+H)+.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.C[Si](Cl)(C)C.[Br:25]N1C(=O)CCC1=O>C1COCC1>[Br:25][CH:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Br)C1CCOCC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a dry 250 mL round-bottomed flask was added 2.20 g of methyl 2-(tetrahydro-2H-pyran-4-yl)acetate (0.014 mol) and 100 mL of dry THF. This solution was cooled to −78° C. and LDA (2.0 M in THF/heptane/ethyl benzene, 10.4 mL, 0.021 mol) was added. The resulting brown solution was stirred at −78° C. for 45 min. TMSCl (3.22 g, 3.5 mL, 0.028 mol) was then added at −78° C., and the reaction mixture was then warmed to room temperature. After being re-cooled to −78° C., N-bromosuccinimide (4.94 g, 0.028 mol) was added to the reaction mixture, and the resulting suspension was allowed to slowly warm to room temperature where it continued to stir for an additional 1.5 h. The suspension was then filtered thru a pad of SiO2 using diethyl ether as the eluant. Purification of the filtrate by column chromatography (SiO2 gel, 10:1 to 4:1 hexanes/ethyl acetate) delivered the desired α-bromo ester, which was used in subsequent steps without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]1([C:20]2[CH2:24][C:23]3([CH2:28][CH2:27][NH:26][CH2:25]3)[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:26]2[CH2:27][CH2:28][C:23]3([O:22][N:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:24]3)[CH2:25]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: c1ccc(C2=NOC3(CCNC3)C2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC(c4ccccc4)=NO3)C2)cc1
Reaction time: 2 h

Procedure:
4-Tert-butylphenyl isocyanate (350 mg, 2 mmol) was added to a solution of compound R (420 mg crude product, approx. 2 mmol) in abs. THF (20 ml) under argon at RT within 10 min. After 1 h the cloudy solution was mixed with triethylamine (0.3 ml, 2.22 mmol). The reaction mixture was stirred for a further 2 h and then mixed with 2 N HCl solution (10 ml). The acidic reaction mixture was stirred for 10 min and then extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. Na2HCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. The residue was recrystallised from toluene (15 ml). The desired product N-(4-tert-butylphenyl)-3-phenyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxamide was thus obtained in a yield of 415 mg (55%) having a melting point of 207-208° C. (from EtOH, crystal transformation between 183 and 188° C.).
Reaction SMILES: C[O:2][C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]([CH3:20])[C:18]#N.C(O)(=[O:23])C>I>[CH3:18][CH:17]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:3]=2[O:2][C:20]1=[O:23]
Reactant: CC(=O)O
Reactant: COc1c(Sc2ccccc2F)cccc1C(C)C#N
Agent: I
Product: CC1C(=O)Oc2c(Sc3ccccc3F)cccc21

Procedure:
A solution of 2-[2-methoxy-3-(2-fluorophenylthio)phenyl]propionitrile (3.2 g) in hydriodic acid (58%, 20 ml) and acetic acid (40 ml) was refluxed under heating for 20 hours, and acetic acid was distilled off under reduced pressure. To the residue were added water and aqueous sodium bicarbonate, and the mixture was extracted with diethyl ether. The extract was washed with dil. aqueous sodium hydrogen sulfite and water in turn, dried and evaporated under reduced pressure. The oily residue (2 g) was purified by column chromatography (silica gel 40 g, toluene) to give oily 3-methyl-7-(2-fluorophenylthio)-2,3-dihydrobenzofuran-2-one (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.O>C(O)(=O)C.[Fe]>[NH2:9][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cnc(Cl)c(Cl)c1

Procedure:
77.2 g (0.4 mol) of 2,3-dichloro-5-nitropyridine were dissolved in 135 ml of glacial acetic acid, and 800 ml of water were added with stirring. 111.7 g (2 mol) of iron powder were introduced in portions into the mixture (temperature≤50° C.). After completion of the reaction, the mixture is filtered under suction and the product extracted using ethyl acetate. The organic phase was washed with water until neutral, dried using MgSO4 and concentrated by evaporation. The product was recrystallized from toluene.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([F:25])[CH:12]=1)[C:2]1C=CC=C[CH:3]=1.C([Li])CCC.CCCCCC.[O:38]1CCCC1>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[CH:2]([CH3:3])[C@H:1]([OH:38])[O:8][C:9]2=[O:26])=[CH:12][C:13]=1[F:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC1[C@H](O)OC(=O)N1c1ccc(OCc2ccccc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 17.5 g (4-benzyloxy-3-fluoro-phenyl)-carbamic acid benzyl ester (MW: 351.38, 50 mmol) in 30 ml of dry tetrahydrofuran was cooled to −78° C. with a dry ice/acetone bath. 22.8 ml of a 2.3M n-butyl-lithium solution in n-hexane (52.5 mmol) was added drop wise and the reaction mixture stirred at −78° C. for 15 min. 7.92 g R(−)-glycidyl butyrate (MW: 144.17, 60 mmol) were added and the reaction was allowed to warm up to room temperature. The reaction was monitored by HPLC, quenched with a saturated ammonium chloride solution and diluted with 100 ml of ethyl acetate. The organic layer was washed with 200 ml water and 200 ml brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue was crystallized from 200 ml of a 1/1-ethyl acetate/hexane mixture. The solid was collected and recrystallized from 150 ml of a 9/1 ethyl acetate/dichloro-methane mixture. The colorless crystals were collected and dried. Yield: 10.4-g, 65.5%. MS: 318.1 (M+H)+. Method ESI+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([N+:18]([O-])=O)[C:5]=1[CH:21]=[CH:22][C:23]([O:25]C)=O)(=[O:3])[CH3:2]>[Ni].C(O)C>[C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]2[C:5]=1[CH2:21][CH2:22][C:23](=[O:25])[NH:18]2)(=[O:3])[CH3:2]
Reactant: COC(=O)C=Cc1c(C(C)=O)cc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1CCC(=O)N2

Procedure:
5.0 g (14.07 mmol) methyl 3-(2-acetyl-4-benzyloxy-6-nitro-phenyl)-acrylate are combined with 100 mL ethanol and hydrogenated with Raney nickel as catalyst at 4 bar. The catalyst is separated off and the filtrate is acidified with 15 mL 2 N hydrochloric acid. The product that crystallises out is suction filtered and dried.
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.Cl[CH:18]([C:22](=[O:24])[CH3:23])[C:19](=[O:21])[CH3:20]>O>[C:3]([O:11][CH:18]([C:22](=[O:24])[CH3:23])[C:19](=[O:21])[CH3:20])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: O=C(O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Temperature: 50 °C
Yield: 96.1 %

Procedure:
A flask was charged with powdered potassium hydroxide (21.89 g, 390.2 mmol), benzoic acid (47.65 g, 390.2 mmol), and DMF (500 mL) was added. The mixture was heated at 50° C. for 1 hour. 3-Chloropentane-2,4-dione (52.5 g, 390.2 mmol) and the reaction was stirred at 50° C. overnight. The reaction was cooled to ambient temperature, diluted in water (1.5 L) and extracted with ether (3×500 mL). The combined organic layers were washed with water, saturated NH4Cl and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2,4-dioxopentan-3-yl benzoate (82.59 g, 96.12% yield) as yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:35]>>[NH2:35][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCO
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCO

Procedure:
The methods described in Parts B and C of Example 1 can be used to treat 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol with mCPBA and ammonium hydroxide to provide 4-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][CH2:19][C@H:9]1[C:10]([S:12][CH2:13][CH:14]([CH3:18])[C:15](O)=[O:16])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH3:18][CH:14]1[CH2:13][S:12][C:10](=[O:11])[C@@H:9]2[CH2:19][CH2:20][CH2:21][N:8]2[C:15]1=[O:16]
Reactant: CC(CSC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1CSC(=O)[C@@H]2CCCN2C1=O
Reaction time: 72 h

Procedure:
3-[1-(tert-butyloxycarbonyl)-L-prolylthio]-2-methylpropanoic acid (2.3 g) is dissolved in a mixture of trifluoroacetic acid (15 ml) and anisole (1.1 g). After fifteen minutes at room temperature the mixture is concentrated to dryness in vacuo and the residue triturated with ether-hexane (1:1). The insoluble material is dried in vacuo, dissolved in dichloromethane (100 ml) and added dropwise to a stirred solution of 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate (20 g) in 900 ml of dichloromethane under argon. The reaction mixture is stored at room temperature for three days and the dichloromethane is then removed in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with 10% potassium biculfate, water, saturated sodium bicarbonate and water. The organic layer is dried and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[CH:9]=[C:10]1[CH3:14]
Reactant: COC(=O)c1ccc2cc(C)[nH]c2c1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(C)n(Cc3ccccc3Cl)c2c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 44.7 %

Procedure:
A mixture of 6-methoxycarbonyl-2-methylindole (0.89 g), 2-chlorobenzyl bromide (1.45 g), potassium carbonate (0.780 g) and N,N-dimethylformamide (2 ml) is stirred at 80° C. for 18 hours. The solvent is evaporated away under reduced pressure, and the resulting residue is purified through silica gel column chromatography (eluent: hexane/chloroform=3/1) to obtain 1-(2-chlorobenzyl)-6-methoxycarbonyl-2-methylindole (30) (0.660 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccc(C)cc1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: Cc1ccc(C#Cc2cnc3cc(C(C)(C)C)nn3c2)cc1

Procedure:
The title compound, light yellow solid, MS: m/e=290.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-4-methylbenzene.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([O:7][Si](C)(C)C)[CH2:3][CH2:2]1.C[Si](C)(C)[O:14][C:15]([CH3:17])=[CH2:16].C(=O)(O)[O-].[Na+].O>C(#N)C>[O:14]=[C:15]([CH3:17])[CH2:16][CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1
Reactant: C[Si](C)(C)OC1=CCOCC1
Reactant: C=C(C)O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)CC1COCCC1=O
Yield: 46.4 %

Procedure:
(3,6-dihydro-2H-pyran-4-yloxy)trimethylsilane (1.0 g, 5.80 mmol) and trimethyl(prop-1-en-2-yloxy)silane (7.56 g, 58.0 mmol) were added dropwise to a vigorously stirred suspension of ceric ammonium nitrate (6.36 g, 11.61 mmol) and sodium bicarbonate (1.950 g, 23.22 mmol) in dry acetonitrile (40 ml). The resulting mixture was stirred until the orange color disappeared and a thick white precipitate formed. The reaction mixture was then poured into water and extracted with EtOAc. The combined extracts were washed by brine, and dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel, using EtOAc/Hex 10-50% to give the product (0.42 g, 46.3% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 4.30-4.25 (m, 1H), 4.21-4.16 (m, 1H), 3.68-3.62 (m, 1H), 3.37-3.31 (m, 1H), 3.19-3.15 (m, 1H), 2.91-2.85 (m, 1H), 2.75-2.66 (m, 1H), 2.39-2.34 (m, 1H), 2.21-2.15 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[O:29]=[S:25]1(=[O:30])[CH2:26][CH2:27][CH2:28][N:24]1[CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:32])[CH:38]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCCS2(=O)=O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCN4CCCS4(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.984, m/z=520.1; 1H NMR (CDCl3) 1.52 (d, 3H), 2.11-2.29 (m, 5H), 2.32 (m, 2H), 2.81 (s, 3H), 2.83-2.96 (m, 2H), 2.98-3.08 (m, 3H), 3.11-3.22 (m, 2H), 5.67 (m, 1H), 7.06 (d, 2H), 7.24-7.36 (m, 5H), 7.38 (d, 2H), 7.61 (s, 1H), 7.69 (m, 1H), 8.73 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[OH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:38]5[CH2:39][CH2:40][C@@H:36]([OH:35])[CH2:37]5)=[O:27])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: O[C@@H]1CCNC1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CC[C@@H](O)C4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50B, Step 1) and (R)-3-hydroxypyrrolidine (Aldrich, Cat. No. 382981). LCMS (M+H)+: m/z=529.3.