Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[OH-].[Na+].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>O>[O:16]1[CH2:15][CH:14]1[CH2:12][O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9]
Reactant: ClCC1CO1
Reactant: Cc1occc(=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1occc(=O)c1OCC1CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A mixture of 3-hydroxy-2-methyl-4-oxopyrane (12.6 g), sodium hydroxide (4 g), epichlorohydrin (9.25 g) and water (50 ml) is stirred at room temperature, under nitrogen atmosphere, for 3 hours; then it is extracted four times with chloroform (120 ml) and the organic extracts are combined, washed with water, dried and evaporated to dryness yielding 8.3 g of 3-(2,3-epoxypropoxy)-2-methyl-4-oxopyrane. A mixture of said product and 2-aminotetralin (7.3 g) in absolute ethanol (100 ml) is charged into a sealed vessel, heated to 80° C. for 5 hours, then cooled and evaporated under reduced pressure. The obtained residue is dissolved into ethyl acetate and a solution of fumaric acid in ethyl acetate is then added thereto. The precipitate which forms is recovered by filtration and crystallized from ethanol affording N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methyl-4-oxopyran-3-yloxy)propanamine hydrogenfumarate ((i): R=H, Ar=radical 10 wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](OB(O)O)[CH3:8].Br[C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:21]=[C:22]([CH2:23][N:24]([CH:32]3[CH2:34][CH2:33]3)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=12.O>O1CCOCC1.Cl[Pd]Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:32]1([N:24]([CH2:23][C:22]2[C:15]3[C:16](=[N:17][CH:18]=[CH:19][C:14]=3[CH2:7][CH3:8])[N:20]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[CH:21]=2)[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:33][CH2:34]1
Reactant: CCOB(O)O
Reactant: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(Br)ccnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccnc2c1c(CN(C(=O)OC(C)(C)C)C1CC1)cn2CCCOC
Temperature: 110 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
Potassium carbonate (207 mg), ethyl boric acid (92.4 mg) and bis(diphenylphosphino)ferrocene dichloropalladium(II) (36.6 mg) were added to a solution of tert-butyl {[4-bromo-1-(3-methoxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methyl}cyclopropylcarbamate (219 mg) in 1,4-dioxane (14.5 ml) and the mixture was stirred under argon atmosphere at 110° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added therein and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=4/1 to 1/3) to give tert-butyl cyclopropyl{[4-ethyl-1-(3-methoxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methyl}carbamate (119 mg) as a pale yellow oil.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH3:15].C(=O)(O)[O-].[Na+].ClCCl>O.CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([CH3:15])=[O:1]
Reactant: CSc1ccccc1Br
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CS(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 113.2 %

Procedure:
Oxone (9.7 g) in water (40 ml) was added slowly to a stirred, cooled cooled (0° C.) solution of 2-bromothioanisole (5 g, 24.6 mmol) and sodium bicarbonate (16 g) in acetone (20 ml). The mixture was stirred for at room temperature 16 h., then water and dichloromethane was added. The layers were separated and the organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane/EtOAc (80:20 increasing to 40:60) to give the title compound (6.1 g). m/z (ES+) 219 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.Cl[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2ccc3ccccc3c2)c1

Procedure:
2-Naphthylboronic acid (3.50 g) and ethyl 2-chloroisonicotinate (3.77 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [N:1]([C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][CH2:5]1)=[C:2]=[O:3].Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[NH2:35][C:21]1[N:22]=[C:23]([C:25]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][N:31]([C:2]([NH:1][C:4]4([C:7]([F:10])([F:9])[F:8])[CH2:6][CH2:5]4)=[O:3])[CH2:32]3)=[CH:27][CH:26]=2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=NC1(C(F)(F)F)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3(C(F)(F)F)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 1-isocyanato-1-(trifluoromethyl)cyclopropane, and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=476.2.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:12]=[O:13])=[CH:5][N:6]2[CH3:11].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([CH:12]=[O:13])=[CH:5][N:6]3[CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cc(C=O)c2c(Br)cccc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C=O)c2c(-c3ccccc3)cccc21
Temperature: 100 °C
Reaction time: 18.5 h

Procedure:
To a cold solution (0° C.) of 4-bromo-indole-3-carboxaldehyde (0.767 g, 3.4 mmol) in dry DMF (2 mL) was added NaH (60% dispersion in mineral oil, 173 mg, 4.37 mmol). The resulting mixture was stirred at 0° C. for 20 min. Iodomethane (0.8 mL, excess) was added to the reaction mixture in a drop wise fashion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was quenched with water and was extracted repeatedly from EtOAc. The combined organic extracts were washed with water (twice) and brine. After drying over magnesium sulfate, solvent was removed. The resulting solid was taken in hexane and sonicated for 30 min, filtered to provide the product, 4-bromo-1-methyl-indole-3-carboxaldehyde (0.687 g, 85% yield). A mixture of 4-bromo-1-methyl-indole-3-carboxaldehyde (109 mg, 0.45 mmol), phenyl boronic acid (85 mg, 0.69 mmol) in DMF (4 mL) was degassed (argon). To the mixture was added bis(triphenylphosphine)-palladium II chloride (25 mg, 0.035 mmol) followed by addition of 2M Na2CO3 solution (2 mL, 4 mmol) and the mixture was stirred under argon at 100° C. for 18.5 h and then at reflux for 3 h. The mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted repeatedly with ethyl acetate. The combined extract was washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, solvent was removed in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc 1:1). The desired product was isolated as syrup (79% yield). MS: 236, 238.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](OC(C)(C)C)[CH2:13][C@H:12]1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC([C@@H]1C[C@H](N)C[N:31]1CC1CCCCC1)=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:31])[CH2:13][C@H:12]1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Product: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1

Procedure:
(2S,4S)-4-Amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4R)-4-tert-butoxy-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C15H18N3O3 [(M+H)+] 288, obsd. 288.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:29])=[C:5]([CH3:28])[C:6]2[O:11][C:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:17][CH2:16]3)([CH3:12])[CH2:9][CH2:8][C:7]=2[C:26]=1[CH3:27]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:29])=[C:5]([CH3:28])[C:6]2[O:11][C:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:17][CH2:16]3)([CH3:12])[CH2:9][CH2:8][C:7]=2[C:26]=1[CH3:27]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCN(CC=C(C)C)CC1)O2
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCN(CCC(C)C)CC1)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
A solution composed of 2.0 g of the 3,4-dihydro-6-methoxy-2-[2-[4-(3-methyl-2-butenyl)piperazin-1-yl]ethyl]-2,5,7,8-tetramethyl-2H-benzopyran obtained by the process of Example 13, 0.1 g of 5% palladium on carbon and 50 ml of ethanol was stirred at room temperature for 48 hours. The reaction mixture was filtered to remove the palladium on carbon and low-boiling substances were distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 1.24 g of 1-[2-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)ethyl]-4-isopentylpiperazine [Compound (34)] having the following physical characteristics.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([CH3:21])[C:9](=[N:16][NH:17][C:18]([NH2:20])=[S:19])[CH:10]1SCCCS1)([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[Ca+2].IC>C(#N)C.O>[CH3:23][S:19][C:18]1[N:17]=[N:16][C:9]([CH:8]([NH:7][C:6](=[O:22])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:21])=[CH:10][N:20]=1
Reactant: O=C([O-])[O-]
Reactant: CC(NC(=O)OC(C)(C)C)C(=NNC(N)=S)C1SCCCS1
Agent: [Ca+2]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: CSc1ncc(C(C)NC(=O)OC(C)(C)C)nn1
Temperature: 40 °C
Yield: 17.1 %

Procedure:
To a mechanically stirred solution of tert-butyl-2-[(aminocarbonothioyl)hydrazono]-2-(1,3-dithian-2-yl)-1-methylethylcarbamate (Intermediate 2) (600 g, 1.6 mol) in acetonitrile (11 L) and water (1.3 L) was added calcium carbonate (490 g, 4.9 mol) followed by slow addition of iodomethane (2.3 kg, 16 mol) using an addition funnel. After the addition was complete, the solution was heated to 40° C. for 24 hours. The solution was allowed to cool to room temperature and concentrated under reduced pressure until about 1.5 L remained. Water (1.0 L) was added to the solution and the product was extracted with ethyl acetate (6×1 L). The combined extracts were washed with water (4×1 L) and brine (1 L). The solution was dried with magnesium sulfate, filtered and concentrated until a red oil remained (190 g). The oil was dissolve in dichloromethane (250 mL) and 25 mL of this solution was loaded into a RediSep silica gel cartridge (330 g; ISCO) and subjected to a gradient elution using dichlormethane to dichloromethane:ethyl acetate (70:30). The separation was repeated in 25 mL portions until all of the solution was consumed. The appropriate (higher Rf) fractions were combined and concentrated under reduced pressure to give tert-butyl 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethylcarbamate (74 g) as a yellow solid. 1H NMR (CDCl3): δ8.41 (s, 1H), 5.35 (br, 1H), 4.99 (br, 1H), 2.67 (s, 3H), 1.57 (d, J=6.9 Hz, 3H), 1.42 (s, 9H).). MS m/z 271 (M+1). Additionally, the appropriate (lower Rf) fractions were combined and concentrated under reduced pressure to give the isomer tert-butyl 1-[3-(methylthio)-1,2,4-triazin-5-yl]ethylcarbamate (11 g) as a gold oil. 1H NMR (CDCl3): δ8.94 (s, 1H), 5.23 (br, 1H), 4.80 (br, 1H), 2.67 (s, 3H), 1.47 (d, J=7.2 Hz, 3H), 1.43 (s, 9H). MS m/z 271 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[N:13]([CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27])[C:12]2=[O:28])(C)(C)C.[ClH:30]>CO.C(Cl)Cl.CCOCC>[ClH:30].[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[N:13]([CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27])[C:12]2=[O:28]
Reactant: Cc1nc2ccc(CNC(=O)OC(C)(C)C)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 8 h

Procedure:
To a stirred brown solution of [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-carbamic acid tert-butyl ester (3.5 g, 8.7 mmol) in methanol (36 mL) and methylene chloride (36 mL), was added 2 M HCl in ether (102 mL), and the mixture was stirred overnight. The solvent was evaporated, and the residue was stirred in ether (100 mL) for 2 hours. The suspension was filtered to give 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride as a light yellow solid (3.2 g, 109% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](O)=O.N>>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)cc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-chloro-4-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.54 (t, J=8.8 Hz, 1 H), 7.64 (ddd, J=8.1, 5.0, 0.8 Hz, 1 H), 8.24 (ddd, J=8.6, 4.6, 2.0 Hz, 1 H), 8.39 (dd, J=7.0, 2.2 Hz, 1 H), 8.55 (dt, J=8.1, 1.9 Hz, 1 H), 8.74 (dd, J=4.9, 1.5 Hz, 1 H), 9.29 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: O[N:2]=[C:3]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[H][H]>C(O)(=O)C.[Pd]>[NH2:2][CH:3]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[OH:5]
Reactant: COc1ccc(C(=O)C(CC(C)C)=NO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(C(O)C(N)CC(C)C)cc1
Yield: 82.1 %

Procedure:
2-Hydroxyimino-1-(4-methoxyphenyl)-4-methylpentan-1-one (8.72 g, 37.1 mmol) was dissolved in acetic acid (88 ml). To the solution was added 5% palladium-charcoal (0.87 g) and the reactant was catalytically hydrogenated at normal pressure at 80° C. until hydrogen was absorbed in a molar amount of three times that of the reactant. After removal of the catalyst by filtration, the acetic acid was removed under reduced pressure. The residue was dissolved in lN-HCl (80 ml). The solution was washed twice with ether (30 ml) and the aqueous layer was basified with a 20% aqueous solution of sodium hydroxide. The aqueous layer thus treated was extracted three times with chloroform and the extracts were combined together and then washed once with brine. The resulting extract was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure to give light-yellowish crystals (6.80 g). The crystals were recrystallized from benzene and hexane to obtain 5.24 g of the title compound as white crystals (yield : 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-:17])[CH:8]=[CH:9][CH:10]=1
Reactant: Clc1ccccc1Oc1cccnc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: [O-][n+]1cccc(Oc2ccccc2Cl)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 74.3 g of 3-(o-chlorophenoxy)pyridine [Agr. Biol. Chem. 34, 68 (1970)] in 75 ml of glacial acetic acid at 35° C. is treated with 76 g of 40% peractic acid in acetic acid in three equal portions. The mixture is held at 35° C. for 16 hours, refluxed 1 hour, cooled to 60° C. and 75 ml of isopropanol is added. The mixture is refluxed for 1 hour, cooled and concentrated at reduced pressure. The oil is dissolved in 700 ml of dichloromethane, washed with excess 25% sodium hydroxide solution, concentrated at reduced pressure and distilled to yield 3-(o-chlorophenoxy)pyridine N-oxide, bp 150°-155° C. at 0.15 mm.
Reaction SMILES: [C:1]1([C@@H:7]2[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH2:9][N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]1([Mg]Br)[CH2:29][CH2:28]1>[Cu](I)I.C1COCC1>[CH:27]1([C:10]2[CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)=C[C@H]1c1ccccc1
Reactant: Br[Mg]C1CC1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C2CC2)=C[C@H]1c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Tert-butyl (2S)-2-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydro-1H-pyrrole-1-carboxylate (5-4, 100 mg, 0.254 mmol, 1 equiv) was added to a solution of dry THF (5 ml) containing copper iodide (5 mg, 0.025 mmol, 0.2 equiv) at −10° C. Cyclopropyl magnesium bromide (0.508 mL, 0.508 mmol, 2 equiv) was added drop wise and the resulting solution was stirred at −10° C. for 15 minutes. The reaction mixture was partitioned between aqueous ammonium chloride solution (15 mL) and ethyl acetate (3×10 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated to give tert-butyl (2S)-4-cyclopropyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (32-1), which is converted to (2S)-4-cyclopropyl-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (32-2) in the experimental mentioned above. 1H NMR (300 MHz, CDCl3) δ 7.22 (m, 5H), 5.82 (m, 1H), 5.35 (m, 1H), 4.43 (dd, J=14.5, 5.5 Hz, 1H), 4.00 (d, J=14.5 Hz, 1H), 2.82 (s, 6H), 1.40 (m, 1H), 0.76 (m, 2H), 0.54 (m, 2H). LRMS m/z (M+H) 257.2 found, 257.3 required.
Reaction SMILES: [C:1]([C:6]1[CH:16]=[C:15]([C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10](O)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:24])=O>>[C:1]([C:6]1[CH:16]=[C:15]([C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([Cl:24])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(OCC(=O)O)c(C(C)(C)CC)c1
Reactant: O=S(Cl)Cl
Product: CCC(C)(C)c1ccc(OCC(=O)Cl)c(C(C)(C)CC)c1

Procedure:
2-(2,4-Di-t-pentylphenoxy)ethanoic acid (CAS Registry Number 13402-96-5) (11.05 g, 0.038 mol) and thionyl chloride (50 ml) were heated under reflux on a steam-bath for 1.5 h. The resulting yellow solution was allowed to cool before being distilled under reduced pressure. The residue was dissolved in 60-80 petroleum-ether (200 ml) and the solution was distilled under reduced pressure to remove volatiles, leaving 2-(2,4-di-t-pentylphenoxy)ethanoyl chloride as a red oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:25])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:26]([O:28]C)=[O:27])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:25])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:26]([OH:28])=[O:27])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N3CCCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccc(F)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of methyl 2-(6-fluoro-1-benzofuran-2-yl)-3-[(2S)-2-methylpiperidin-1-yl]quinoxaline-6-carboxylate (50 mg, 0.12 mmol) in methanol (25 mL) and water (5 mL) was added sodium hydroxide (14.4 mg, 0.36 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted pH to 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(6-fluoro-1-benzofuran-2-yl)-3-[(2S)-2-methylpiperidin-1-yl]quinoxaline-6-carboxylic acid (36.6 mg, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1coc2ccc(C=O)cc12
Reactant: O=C1CSC(=O)N1
Product: CCOC(=O)C=Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-(5-Formyl-benzofuran-3-yl)-acrylic acid ethyl ester (intermediate 60) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27](=[O:30])[NH:28][CH3:29])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][C:37](OC)=[O:38].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.CCCCCC.CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:28][CH3:29])=[O:30])=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][CH2:37][OH:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(CC(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(CCO)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 65 %

Procedure:
To a solution of methyl 2-(2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)acetate (500 mg, 0.884 mmol) in THF (6 mL) at 0° C. was added 3.5M lithium aluminum hydride/THF (0.20 mL, 0.71 mmol). After stirring for 45 minutes at 0° C. aqueous work-up followed by flash chromatography (silica gel, hexane/EtOAc) afforded the title compound in 65% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.89 (dd, J=7.82, 5.47 Hz, 1H) 7.70 (s, 0H) 7.40 (s, 1H) 7.15-7.25 (m, 2H) 6.61-6.73 (m, 1H) 5.78 (br. s., 0H) 3.89 (t, J=5.96 Hz, 1H) 3.18 (s, 2H) 3.10-3.24 (m, 3H) 3.00 (d, J=4.89 Hz, 1H) 2.76 (t, J=5.86 Hz, 1H) 2.29 (br. s., 0H) 0.99 (br. s., 2H). LCMS (m/z, ES+)=538 (M+H+).