Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:25]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:26]=1)=[O:20]>CC(=O)CC>[OH:20][CH:19]([C:21]1[CH:22]=[CH:23][C:24]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[C:25]([S:27]([NH2:30])(=[O:28])=[O:29])[CH:26]=1)[CH2:18][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1N1CCCCC1
Agent: Br
Solvent: CCC(C)=O
Product: NS(=O)(=O)c1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1N1CCCCC1
Reaction time: 1 h

Procedure:
A solution of dibenzylamine (3.34 g) in butanone (10 ml) was added to a vigorously sitrred suspension of 5-(2-bromoacetyl)-2-(1-piperidinyl)benzenesulphonamide, hydrobromide (2.5 g) in butanone (100 ml). After 3 hours the mixture was filtered and the filtrate concentrated to a yellow oil. This oil was dissolved in ethanol (100 ml) and treated with sodium broohydride (0.42 g) at room temperature. After 1 hour, excess borohydride was destroyed with 2N hydrochloric acid. Ethanol was removed, the residue basified with 8% sodium bicarbonate solution and extracted with ethyl acetate (3 × 100 ml). The extracts were washed with water (100 ml), dried, and concentrated to a pale yellow oil (2.7 g). This was chromatographed on Merck Kieselgel 60 (50 g) to give the product as a white solid, 2 g, m.p. 133°-142°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:19][C:18]1[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.4 %

Procedure:
To a suspension of methyl 2-[(tert-butoxycarbonyl)amino]-3-nitrobenzoate (103 g, 348 mmol) in methanol (800 mL) was added 10% palladium on carbon (50% wet; 10 g), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 5 hr. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residual solid was suspended in diisopropyl ether (300 mL), and the suspension was stirred at room temperature for 3 hr. The resulting solid was collected by filtration and washed with diisopropyl ether to give the title compound (42.0 g, 158 mmol, 45%). The mixture of the removed catalyst described above and a colorless solid (the title compound) was suspended in tetrahydrofuran (200 mL), and the suspension was stirred at room temperature for 30 minutes. The insoluble material (the catalyst) was removed by filtration, and the filtrate was concentrated in vacuo. The residual solid was suspended in diisopropyl ether (300 mL), and the suspension was refluxed for 30 min. The resulting solid was collected by filtration and washed with diisopropyl ether to give the title compound (33.9 g, 127 mmol, 36%) as a colorless solid. Total amount: 75.9 g, 285 mmol, 82%.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH2:17]([O:21][C:22]1[CH:27]=[C:26](/[CH:28]=[C:29](\[CH3:35])/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:25]=[CH:24][C:23]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH:43][CH3:44])[CH:37]=1)[CH2:18][CH2:19][CH3:20].C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([CH2:44][NH:43][CH2:42][C:38]1[CH:37]=[C:36]([C:23]2[CH:24]=[CH:25][C:26](/[CH:28]=[C:29](\[CH3:35])/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][C:22]=2[O:21][CH2:17][CH2:18][CH2:19][CH3:20])[CH:41]=[CH:40][CH:39]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1cc(/C=C(\C)C(=O)OCC)ccc1-c1cccc(CNC)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCCOc1cc(/C=C(\C)C(=O)OCC)ccc1-c1cccc(CNCC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
142 μL of benzoyl chloride (1.2 mmol) are added to a solution of 0.36 g (0.6 mmol) of ethyl (E)-3-(2-butoxy-3′-methylaminomethylbiphenyl-4-yl)-2-methylacrylate trifluoroacetate, 6.5 mL of dichloromethane, 257 μL (1.84 mmol) of triethylamine and 7 mg (10 mol %) of 4-dimethylaminopyridine. The reaction medium is stirred at room temperature for 18 hours and then treated with 1 N hydrochloric acid solution and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The crude residue obtained is purified by chromatography on a column of silica eluted with an 85/15 and then 70/30 heptane/ethyl acetate mixture. 270 mg (91%) of ethyl (E)-3-{3′-[(benzoylmethylamino)methyl]-2-butoxybiphenyl-4-yl}-2-methylacrylate are obtained in the form of a yellow oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[H][H]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: CC(C)(C)c1cc(C[C@H](NC(=O)OCc2ccccc2)C(N)=O)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O

Procedure:
To a solution of 9.89 g (26.7 mmol) of Z-Tyr(3-tBu)-NH2 in 350 ml of methanol, 3.5 g of 10% palladium carbon was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 hours. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; methylene chloride:methanol=20:1) to yield Tyr(3-tBu)-NH2 in the amount of 5.11 g (81%). NMR(method g,CDCl3): δ 1.40(9H,s), 2.64(1H,dd,J=9.6,13.9 Hz), 3.18(1H,dd,J=4.0,13.9 Hz), 3.49(1H,s), 3.58(1H,dd,J=4.0,9.6 Hz), 5.45(1H,brs), 6.65(1H,d,J=7.9 Hz), 6.92(1H,dd,J=2.0,12.0 Hz), 7.10(1H,d,J=2.0 Hz), 6.94(1H,d,6.6 Hz), 7.2-7.4(8H,m), 7.7-7.9(2H,m), 8.46(1H,d,7.6 Hz), 9.06(1H,d).
Reaction SMILES: C12BC(CCC1)CCC2.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[N:30]([S:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)(=[O:35])=[O:34])[CH:31]=[CH:32][C:25]=34)=[CH:22][N:21]([CH2:42][CH:43]=[CH2:44])[N:20]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].[O:45]1CCCC1>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[N:30]([S:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)(=[O:35])=[O:34])[CH:31]=[CH:32][C:25]=34)=[CH:22][N:21]([CH2:42][CH2:43][CH2:44][OH:45])[N:20]=2)=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: C=CCn1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: O=[N+]([O-])c1ccc(-c2nn(CCCO)cc2-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 84 %

Procedure:
To a solution of 0.5M 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (6.16 mL) cooled to 0° C. was added a solution of 4-[3-(4-nitrophenyl)-1-(2-propen-1-yl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.06 mmol) in tetrahydrofuran (14 mL). The reaction mixture was stirred at room temperature under an inert atmosphere for 4.5 h and then re-cooled to 0° C. followed by quenching with water (1.7 mL). After 15 minutes of stirring at 0° C., 6N aqueous sodium hydroxide (1.24 mL) was added dropwise followed by 30% aqueous hydrogen peroxide (0.865 mL). The reaction mixture was stirred for 1.5 h at 0° C., neutralized with 6N aqueous hydrochloric acid and concentrated in vacuo. Water (10 mL) was added to the residue and the solution extracted with ethyl acetate (3×15 mL), the combined organic layers dried over magnesium sulfate and concentrated in vacuo to afford the title compound (84%). ESMS [M+H]+: 504.2
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.C(O)(=O)C.[N-:18]=[C:19]=[O:20].[K+]>O>[NH:1]([CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:19]([NH2:18])=[O:20]
Reactant: [N-]=C=O
Reactant: NCCNc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NCCNc1ccc([N+](=O)[O-])cc1
Yield: 73.6 %

Procedure:
37 g (0.2 mole) of para-[N-(β-amino-ethyl)]amino nitrobenzene is dissolved in 200 cm3 of water at 30° C, to which 15 cm3 (0.26 mole) of acetic acid had been added. 17 g (0.21 mole) of potassium isocyanate is then rapidly added. The desired product precipitates immediately in a form which is very difficult to dry. 150 cm3 of acetic acid is added to the reaction mixture and it is heated until the urein is completely dissolved. After slow cooling, drying yields 33 g of para-[N-(β-ureidoethyl)]amino nitrobenzene in a well crystallized form, which is practically prue and melts at 187° C.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:12]2[CH:23]=[CH:24][N:25]=[C:11]2[NH:10][C:9]=1[CH3:26])(=O)[NH2:6].C(Cl)(Cl)Cl>CN(C)C=O>[C:5]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:12]2[CH:23]=[CH:24][N:25]=[C:11]2[NH:10][C:9]=1[CH3:26])#[N:6]
Reactant: CC1=C(C(N)=O)C(c2cccc([N+](=O)[O-])c2)n2ccnc2N1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)n2ccnc2N1
Yield: 39 %

Procedure:
1.5 ml of thionyl chloride is added dropwise to a solution of 3 g of 6-carbamoyl-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine in 30 ml of dimethylformamide. After stirring for an hour, the mixture is poured into chloroform and washed with sodium bicarbonate solution followed by passing the mixture through a column containing 50 g of silica gel with a mixture of dichloromethane and ethanol as an eluent. Upon allowing the eluates to stand, crystals are precipitated and collected by filtration to give 1.1 g of 6-cyano-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 278°-280° C. with decomposition.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=O)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:22][C:21](=[O:23])[CH3:24])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(CCC=O)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(CCC=CC(C)=O)ccc1OCc1ccccc1
Yield: 56.4 %

Procedure:
A solution of 2.3 g of 3-(p-benzyloxy-m-methoxyphenyl)propionaldehyde and 2.97 g of acetylmethylenetriphenylphosphorane in 22 ml of toluene was heated under reflux for 2 hours, toluene and then evaporated and the residue was purified by a chromatography using 30 g of silica gel and recrystallization from a mixture of ethyl ether and n-hexane (1:5) afforded 1.49 g of the desired compound melting at 59.5°-60.5° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH2:20]=O.[OH-].[Na+]>>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH2:20][O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1OC)C1C(CO)COCN1CC2
Yield: 89 %

Procedure:
6 mmoles (1.6 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are stirred with 10 ml of aqueous (30-35%) formaldehyde for half an hour. The reaction mixture is alkalized with 10 ml of a 30% aqueous sodium hydroxide solution and extracted with ethyl acetate. Drying and evaporation of the extract yields the aimed compound in a yield of 89%.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:39]12([C:45]3[C:46]([O:50][C:51]4[N:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=4)=[CH:47][CH:48]=[CH:49][C:44]=3[O:43][CH2:42]1)[CH2:41][CH2:40]2>CN(C)C=O>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[C:11](=[O:13])[NH:57][C:54]1[CH:55]=[N:56][C:51]([O:50][C:46]2[C:45]3[C:39]4([CH2:42][O:43][C:44]=3[CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:40]4)=[CH:52][CH:53]=1
Reactant: Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (80 mg, 0.393 mmol) in dry N,N-dimethylformamide (1.5 mL) DIPEA (0.096 mL, 0.551 mmol) and then HATU (150 mg, 0.393 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature. This solution was added to a solution of 6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinamine (Reference Intermediate 218, 40 mg) in dry N,N-dimethylformamide (0.5 ml) and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with water (2 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sium sulphqte, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound as a white solid (52 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:15])[CH:9]([Cl:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[Cl:14][C@@H:9]([C@H:8]([OH:15])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(Cl)C(=O)Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H](Cl)[C@H](O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 125069.9 %

Procedure:
In a 500 ml Schlenk tube was put 0.36 g (0.4 mmol) of Ru2Cl4 ((R)-tol--BINAP)2 (NEt3). After purging with nitrogen, 56.7 g (0.2 mmol) of methyl 4-phenyl-2-chloro-3-oxobutyrate (compound (III)) and 280 ml of methanol were dissolved therein. The solution was charged in a 500 ml autoclave and stirred at room temperature under a hydrogen pressure of 80 atm for 20 hours. The reaction mixture was concentrated to give 57.2 g (95%) of the title compound (IV).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[C:8]([F:10])[CH:9]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]2[C:36]1[N:37]=[N:38][N:39]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([O:49]C)=[O:48])=[CH:43][CH:42]=2)[CH:40]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.[OH-].[Na+].CS(C)=O>[F:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[C:36]3[N:37]=[N:38][N:39]([C:41]4[CH:46]=[CH:45][C:44]([C:47]([OH:49])=[O:48])=[CH:43][CH:42]=4)[CH:40]=3)[N:16]=2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=c1ccc(-c2cc(F)cc(F)c2)n[nH]1
Reactant: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(CBr)cc34)nn2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5nc(-c6cc(F)cc(F)c6)ccc5=O)cc34)nn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.2 %

Procedure:
Sodium hydride (34. mg; 0.78 mmol; 2.0 eq.) was added in one portion to a solution of 6-(3,5-Difluoro-phenyl)-2H-pyridazin-3-one (106 mg; 0.51 mmol; 1.3 eq.) in DMF (3 mL). After 10 min a solution of tert-butyl 5-(bromomethyl)-3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole-1-carboxylate (392 mg; 0.38 mmol; 1.0 eq.) in DMF (3 mL) was added dropwise over 2 min and the reaction solution stirred for 4 h at RT. The reaction mixture was then poured into saturated solution of NaHCO3 and extracted with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentrated to give a yellow solid. This solid was redissolved in NaOH (5N, 0.5 mL) and DMSO (2 mL) and heated in MW for 10 min at 80° C. Reaction mixture was poured in a saturated solution of NaHCO3 and washed with EtOAc. The basic aqueous phase was acidified to pH 1 with 1N HCl and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow solid (218 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 13.43 (s, 1H), 9.44 (s, 1H), 8.47 (s, 1H), 8.29-8.09 (m, 6H), 7.68 (d, J=7.2 Hz, 2H), 7.63-7.47 (m, 2H), 7.40-7.30 (m, 1H), 7.14 (d, J=9.8 Hz, 1H), 5.52 (s, 2H). HPLC (Condition A): Rt 3.87 min (purity 52.8%). MS (ESI+): 526.2, MS (ESI−): 524.2.
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:4][N:3]=1.[CH3:18][C:19]([C:26]1[C:27](=[O:33])[CH:28]=[CH:29][C:30](=[O:32])[CH:31]=1)([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CO>[CH2:13]([C:5]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([S:1][C:29]2[CH:28]=[C:27]([OH:33])[C:26]([C:19]([CH3:25])([CH3:18])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:31][C:30]=2[OH:32])=[N:3][N:4]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)CC(C)(C)C1=CC(=O)C=CC1=O
Reactant: CCCCCc1nnc(S)n1-c1ccccc1
Solvent: CO
Product: CCCCCc1nnc(Sc2cc(O)c(C(C)(C)CC(C)(C)C)cc2O)n1-c1ccccc1
Yield: 20.3 %

Procedure:
13 g of 3-mercapto-5-n-pentyl-4-phenyl-1,2,4-triazole was dissolved in 200 ml of methanol, and the solution was stirred under ice cooling. To the solution was added 12 g of 2-(1,1,3,3-tetramethylbutyl)benzoquinone in small portions. After the addition, the solution was stirred under ice cooling for 2 hours, and then allowed to stand at room temperature (25°±5° C.) overnight. The methanol was removed under reduced pressure, and 20 ml of diethyl ether was added to the residue. The crystals obtained were collected by filtration, and recrystallized from ethyl acetate to obtain 5 g of 2-(5-n-pentyl-4-phenyl-1,2,4-triazol-3-ylthio)-5-(1,1,3,3-tetramethylbutyl)hydroquinone having a melting point of 198° C.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.Cl.[CH2:28]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH2:41][C@@H:40]([NH:44][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[C:50]([C:55]([F:58])([F:57])[F:56])[CH:49]=2)=[O:47])[CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18](=[O:20])[N:44]([C@@H:40]2[CH2:41][CH2:42][CH2:43][N:38]([C:36]([O:35][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH2:39]2)[CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[C:50]([C:55]([F:56])([F:57])[F:58])[CH:49]=2)=[O:47])[CH2:16][CH2:17]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(CN[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(CC(=O)c2ccc(F)c(C(F)(F)F)c2)[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Reaction time: 1.5 h
Yield: 63 %

Procedure:
Add thionyl chloride (1.2 equiv; 10.5 mmol; 765 μL) dropwise over 3 min at 20° C. to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.00 equiv; 8.75 mmol; 2.03 g) and pyridine (5 equiv; 43.74 mmol; 3.54 mL) in DCM (60 mL). Stir 90 min. Add (R)-3-[2-(4-fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylamino]-piperidine-1-carboxylic acid benzyl ester hydrochloride (0.80 equiv; 7.00 mmol; 3.32 g) followed by TEA (3.5 equiv; 30.62 mmol; 4.3 mL) dropwise over 3 min and stir 18 h. Wash the organic phase 3× with 1N HCl, water, brine, dry over MgSO4, filter and evaporate. Purify the residue on 150 g silica gel with 20-50% EA/DCM to provide the title compound (2.86 g; 4.41 mmol; 50%). MS (ES+): m/z=672 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C@@H:5]([OH:9])[C:6]([OH:8])=[O:7].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:13][O:7][C:6](=[O:8])[C@@H:5]([C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=1)[OH:9]
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@H](O)c1cccc(Cl)c1

Procedure:
Into methanol (20 ml) were added (R)-3-chloromandelic acid (5.0 g) and p-toluenesulfonic acid (0.1 g), and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled, then neutralized and concentrated. Ethyl acetate and water were added to the resulting residue and the organic layer was collected by layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (5.27 g, 98.3%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-:22])=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 40 mL of a chloroform solution containing 2.0 g of 6-isopropylquinoline, 2.9 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature overnight. Thereto was added an aqueous saturated sodium hydrogen carbonate solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 2.1 g of a brown oily substance, 6-isopropylquinoline N-oxide.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11](Br)[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.CS(C)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(Br)C1
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NCc2ccc(OC)cc2)C1
Temperature: 85 °C
Reaction time: 15 h
Yield: 61.9 %

Procedure:
To a suspension of 8.20 g (20.80 mmol) of 9-bromo-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester in 208 mL of toluene was added 8.56 g (62.40 mmol) of 4-methoxybenzylamine and 14.77 mL (208.00 mmol) of dimethylsulfoxide. The reaction mixture was stirred at 85° C. for 15 hours. The cooled solution was evaporated to remove solvent. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with dichloromethane, washed with saturated solution of sodium chloride. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane methanol/ammonia 98/2/0.2 to 97/3/0.3) to afford 5.80 g (62%) of product.