Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C:5]1[C:6](=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8].[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[CH3:2][O:3][C:4](=[O:18])[C:5]1[C:6](=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)OC
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: COC(=O)c1cccc(N)c1C(=O)OC
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 3:1 ethanol-conc. HCl (200 mL) was cooled to 0° C. and then 3-nitrophthalic acid dimethyl ester (15.0 g, 62.8 mmol) was added. Maintaining the cooling, tin chloride (70.8 g, 314 mmol) was added portionwise, over a period of 15 minutes. Following completion of the addition, the cooling bath was removed, and stirring proceeded at room temperature. After 2 hours, the mixture was neutralized by the addition of solid sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (3×150 mL) and the combined extracts were washed with water (5×250 mL), were dried (MgSO4) and evaporated, providing 11.3 g of the product as a yellow oil in 86% yield: 1H NMR (CDCl3) δ 3.84 (s, 3H), 3.86 (s, 3H), 5.20 (br, 2H), 6.78 (dd, J=8.5 Hz, J=1.0 Hz, 1H), 6.90 (dd, 1H, J=7.3 Hz, J=1.0 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H).
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=O)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>ClCCl>[Cl:18][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: ClCCl
Product: ClC1=Nc2cccnc2Nc2ccccc21

Procedure:
A solution of 5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (18 g, 85.3 mmol) and PCl5 (20.5 g) in dichloromethane (650 mL) was stirred at reflux until the starting material was all consumed (use LC/MS to follow the reaction). The reaction mixture was concentrated in vacuo to half volume and the resulting solid was collected by filtration and washed with dichloromethane. The filtrate was further concentrated and a second crop was similarly obtained and combined. The 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine was obtained as a yellow solid (total 14 g, 71%). LCMS [M+H]: 230.
Reaction SMILES: C(C1C=CC(C[S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1>>[F:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[F:33])[CH2:26][S:8][C:9]1[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: Fc1ccc(CCl)cc1F
Product: COCOc1cc(SCc2ccc(F)c(F)c2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 1-(chloromethyl)-3,4-difluorobenzene instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[N:19][OH:20]
Reactant: NO
Reactant: Cc1cccc(Nc2ccccc2C=O)c1C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(Nc2ccccc2C=NO)c1C

Procedure:
A solution of 2-[(2,3-dimethylphenyl)amino]benzaldehyde (11 g, 0.049 mol) and hydroxylamine hydrochloride (17 g, 0.25 mol) in pyridine (250 ml) is stirred at room temperature overnight. The solvent is evaporated and the residue is partitioned between ethyl acetate (200 ml) and 10% aqueous HCl (200 ml). The organic layer is washed with 10% aqueous HCl (200 ml) and water (2×100 ml). The organic layer is dried (MgSO4) and the solvent is evaporated to give 2-[(2,3-dimethylphenyl) amino]benzaldehyde oxime which is recrystallized from hexane. Yield 7.3 g (62%); mp 107°-108° C.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14]1>O1CCCC1>[CH:13]1([CH:17]([OH:18])[C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=CC1CCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)C2CCC2)cc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 51.6 %

Procedure:
To a solution of ethyl 4-iodobenzoate (1.45 mL, 8.69 mmol) in anhydrous tetrahydrofuran (14.5 mL) at −40° C. was added isopropyl magnesium chloride lithium chloride complex (8.0 mL, 10.4 mmol) dropwise. The resulting brown solution was stirred for 40 min at −40° C. The crude cyclobutanecarbaldehyde (1.8 g, approximately 10.5 mmol pure) was added and the reaction was warmed to room temperature and stirred for 18 h. The reaction is then quenched with 1 N hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 2.0 g of crude material. Purification by silica gel flash chromatography (0-20% ethyl acetate in heptane) afforded ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (1.05 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 4.64 (d, J=7.6 Hz, 1H), 4.47-4.25 (m, 2H), 2.73-2.47 (m, 1H), 2.13-1.94 (m, 2H), 1.95-1.70 (m, 4H), 1.55 (br. s., 1H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][C:20]=2[CH3:27])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CC#N.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[CH:24]=[C:23]([CH:22]=[CH:21][C:20]=2[CH3:27])[CH:25]=[O:26])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(C=O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one (1.5 g, 3.33 mmol) was dissolved in 75% CH3CN/CH2Cl2 (20 ml) and cooled to 0° C. Dess-Martin Periodinane (2.8 g, 6.66 mmol) was added and the reaction stirred for four hours. At this time, the reaction was quenched with 5% sodium bisulfite (aq.). The product was extracted with ethyl acetate. The combined organic extracts were then washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The resulting residue was taken up in diethyl ether and the precipitate was collected on a filter pad and washed with more diethyl ether to yield a white solid (1.35 g, 91%). 1H NMR (300 MHz, CDCl3) δ 10.00 (s, 1H), 7.91 (dd, J=7.65, 1.61 Hz, 1H), 7.65 (m, 2H), 7.57 (d, J=7.85 Hz, 1H), 7.03 (m, 1H), 6.95 (ddd, J=12.69, 8.86, 2.62 Hz, 1H), 6.19 (s, 1H), 5.31 (s, 2H), 2.20 (s, 3H), 1.96 (s, 3H); ES-MS m/z 448 (M+H). ES-HRMS m/z 448.0347 (M+H calcd for C21H17BrF2NO3 requires 448.0354).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:20]([NH2:23])[C:21]#[CH:22].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([NH:23][CH2:20][C:21]#[CH:22])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: C#CCN
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared in Step II (200 mg; 0.59 mmol; 1 eq) is dissolved in anhydrous DCM (10 ml). The reaction is put under nitrogen. Prop-2-ynylamine (0.08 ml; 1.19 mmol; 2 eq), diisopropylethylamine (0.61 ml; 3.56 mmol; 6 eq) are added successively and the reaction mixture is stirred for 3 hours at room temperature. Solvents are evaporated and the resulting crude product is purified by preparative HPLC. Compound (1) is isolated as a beige powder (25 mg; 12%).
Reaction SMILES: [C:1]1([CH:9]=O)[C:2]([CH:7]=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][C@@H:12]([CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14]>C(#N)C>[CH:17]1([CH2:16][C@H:12]([N:11]2[CH2:9][C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:7]2=[O:8])[C:13]([OH:15])=[O:14])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: N[C@@H](CC1CCCC1)C(=O)O
Reactant: O=Cc1ccccc1C=O
Solvent: CC#N
Product: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Temperature: 4 °C
Yield: 84.4 %

Procedure:
A solution of benzene-1,2-dicarbaldehyde (1.9 g, 14 mmol) and (S)-2-amino-3-cyclopentyl-propionic acid (2.0 g, 13 mmol) in acetonitrile was heated to reflux for 17 h. The solution was cooled to 4° C. for 3 h during which time a precipitate formed. The mixture was filtered and the solid washed with cold acetonitrile and dried under vacuum to give (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (3.0 g, 86%) as a white solid: LR-ES(+) m/e calcd for C16H19NO3 [M+H]+ 274.15, observed 274.1; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89-2.29 (m, 11H), 4.23-5.12 (m, 3H), 7.20-7.99 (m, 4H), 13.00 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[NH:12]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccccc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
A mixture of methyl 3-bromobenzoate (5.87 g, 27.3 mmol), aniline (3.73 mL, 41.0 mmol), cesium carbonate (12.5 g, 38.2 mmol), tris(dibenzylidenacetone)dipalladium (0) (1.0 g, 1.09 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.02 g, 1.64 mmol) and toluene (60 mL) was stirred under a nitrogen atmosphere at 80° C. for 16 hrs. The reaction mixture was cooled, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (2.13 g, yield 34%) as pale-yellow crystalsitle compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10](NCCNC(=O)OC(C)(C)C)=[O:11])[CH:3]=1.C(OCC)(=[O:25])C.CCCCCC>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]([OH:11])=[O:25])[CH:3]=1
Reactant: COc1cnc(C(=O)NCCNC(=O)OC(C)(C)C)cc1Cl
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cnc(C(=O)O)cc1Cl

Procedure:
In analogous manner, from 3.3 g of 4-chloro-5-methoxy-2-pyridinecarboxylic acid there was obtained t-butyl [2-(4-chloro-5-methoxypyridine-2-carboxamido)ethyl]carbamate as pale yellow crystals (ethyl acetate/n-hexane), m.p. 132°-133°, which, in turn, was converted into N-(2-aminoethyl)-4-chloro-5-methoxypyridine-2-carboxamide hydrochloride, white crystals (methanol/ether), m.p. 256°-257°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:18][C:12]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a solution of 3-nitrophenol (7.5 g, 53.9 mmol) and ethyl 2-bromo-2-methylpropanoate (12.62 g, 64.7 mmol) in DMF (25 ml) was added K2CO3 (14.90 g, 108 mmol). After stirring at rt for 16 hr, the reaction mixture was concentrated under vacuum. The residue was diluted with water and extracted with ethyl acetate (3×30 ml), the combined organic layer was washed with NaOH solution (10%, 75 mL), water (75 mL) and brine, dried over sodium sulphate and concentrated under vacuum to give the title product (6.7 g).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=2[C:15]#[N:16])[CH2:7][CH2:6]1.C(=O)(O)O.[NH2:31][C:32]([NH2:34])=[NH:33]>CC(N(C)C)=O>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:14]=2[C:15]([NH2:16])=[N:31][C:32]([NH2:34])=[N:33]3)[CH2:7][CH2:6]1
Reactant: N#Cc1c(F)cccc1OCC1CCC(Oc2c(F)cccc2F)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCC3CCC(Oc4c(F)cccc4F)CC3)cccc2n1
Yield: 9 %

Procedure:
Cyclization of 2-[4-(2,6-difluorophenoxy)cyclohexylmethoxy]-6-fluorobenzonitrile was carried out using Method F (95 mg; 0.26 mmol) and guanidine carbonate (43 mg; 0.26 mmol) in 1.5 mL of dimethylacetamide. Material was purified using C18 reverse phase silica and 0-100% acetonitrile in water gradient to give 9 mg of title compound. (9% yield. 1HNMR (400 MHz, DMSO-d6) δ 7.37 (m, 1H), 7.14 (m, 5H), 6.77 (m, 1H), 6.51 (m, 1H), 5.96 (br s, 2H), 5.7 (s, 1H), 4.02 (m, 3H), 2.02 (m, 4H), 1.62 (m, 4H). MS m/z (ESI) 401 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([OH:22])=O)=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[F:49][C@H:50]([CH3:53])[CH2:51][NH2:52]>ClCCl>[F:49][C@@H:50]([CH3:53])[CH2:51][NH:52][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:22]
Reactant: C[C@@H](F)CN
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncnc(Cn2cc(C(=O)NC[C@H](C)F)c3ncc(C)cc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
See FIG. 19(d). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.32 mmol) was taken in dichloromethane (10 mL) to get a suspension. Added triethyl amine (0.133 mL, 0.96 mmol) followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.381 mL, 0.64 mmol). The reaction mass was stirred at RT for 5 minutes. (R)-2-fluoropropan-1-amine (49.4 mg, 0.64 mmol) was added and stirred at RT for overnight. After the completion of the reaction, diluted the reaction mass with DCM, washed ith water, and brine solution. The organic layer was dried over sodium sulphate, evaporated and the crude compound was purified by silica gel chromatography. Yield-75%. ES+MS m/z: 373.2 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25-1.42 (m, 4 H ) 2.24 (s, 3H) 2.40 (s, 3 H ) 3.42-3.81 (m, 2 H ) 3.94 (s, 3 H ) 4.65-4.85 (m, 1 H ) 4.93 (td, J=6.50, 3.39 Hz, 1 H ) 5.64 (s, 2 H ) 7.76 (s, 1 H ) 8.16 (s, 1 H ) 8.29-8.47 (m, 2 H ) 8.91 (t, J=6.03 Hz, 1 H ).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:30]=[C:29]([C:31](=[O:42])[NH:32][C:33]5([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[CH2:35][CH2:34]5)[CH:28]=[CH:27][C:26]=4[CH3:43])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15]CC)=[O:14])=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:30]=[C:29]([C:31](=[O:42])[NH:32][C:33]5([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)[CH2:34][CH2:35]5)[CH:28]=[CH:27][C:26]=4[CH3:43])=[CH:18][C:11]=3[C:12]=2[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12
Solvent: CO
Product: Cc1ccc(C(=O)NC2(c3ccccc3)CC2)cc1-c1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]

Procedure:
Prepared by the hydrolysis of ethyl 2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxylate. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=551.34, HPLC Rt=1.895 min.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[N:4][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[CH:7]=1)=[O:9]
Reactant: COC(=O)c1cnn(CCl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnn(CC(C#N)(C#N)CCC(F)(F)F)c1
Yield: 34.9 %

Procedure:
0.80 g of 1-(chloromethyl)-4-methoxycarbonyl-1H-pyrazole and 0.75 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.27 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from hexane-chloroform to obtain 0.48 g of [{4-(methoxycarbonyl)-1H-pyrazole-1-yl}methyl](3,3,3-trifluoropropyl) malononitrile (referred to as the compound of the present invention (23), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][C@:2]1([C:19]([O-])=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[Li+].Cl.[NH2:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26]>>[CH3:1][C@:2]1([C:19]([NH:24][C@H:25]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH3:26])=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: C[C@]1(C(=O)[O-])CCCCN1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@@]2(C)CCCCN2Cc2ccc(C(F)(F)F)cc2)cc1
Yield: 33.2 %

Procedure:
The title compound (D158) (10 mg) was prepared according to the general procedure for amides preparation (Method B) starting from lithium (R)-2-methyl-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxylate (D112) (20 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (16.32 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: COc1cccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)c1
Yield: 17.6 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-methoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (12.3 mg, 17.6%) as light yellow oil. MS m/e=521.4 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][S:6]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=2Cl)(=[O:8])=[O:7])[CH2:3][CH2:2]1.[H-].[Na+].[OH2:22]>>[Cl:15][C:14]1[C:9]([S:6]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)(=[O:8])=[O:7])=[C:10]([OH:22])[C:11]([N+:16]([O-:18])=[O:17])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Yield: 72.7 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-cyclopropylmethyl-2,6 dichloro-3-nitrobenzenesulfonamide (0.85 g, 2.6 mmol), 80% NaH (0.23 g, 9.88 mmol) and water (56 μL, 3.1 mmol) were reacted to form the desired product (0.58 g, 72%). LC-MS m/z 307 M+).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:29]([NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30][CH3:31])=[N:16]2)=[O:11].[CH3:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1>C(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:29]([N:32]([CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:49](=[O:50])[C:48]1[CH:52]=[CH:53][C:45]([CH3:44])=[CH:46][CH:47]=1)[CH2:30][CH3:31])=[N:16]2)=[O:11]
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
Triethylamine (0.011 mL, 0.079 mmol) was added to a solution of 3-benzyl-2-[1-(3-tert-butoxycarbonylamino-propylamino)-propyl]-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.013 g, 0.026 mmol) and 4-methyl-benzoyl chloride (0.01 mL, 0.079 mmol) in CH2Cl2 (0.50 mL) at 0 C. The reaction mixture was stirred at 0° C. for 4 h, quenched with saturated NaHCO3 (3 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 8/1 to 1/1 hexane/EtOAc to afford the title compound (0.015 g, 94%) as a solid: 1H NMR (CDCl3) δ 7.02–7.32 (m, 11H), 5.95 (m, 3H), 4.85 (m, 1H), 3.86 (s, 3H), 3.25 (m, 2H), 2.65 (m, 2H), 2.32 (s, 3H), 2.00 (m, 1H), 1.80 (m, 1H), 1.60 (m, 1H), 1.32 (s, 9H), 0.85 (m, 1H), 0.65 (m, 3H); MS (ESI+) 616 (M++H); HRMS (ESI+) calculated: 616.3135 (M++H). found: 616.3110 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]>C(O)C.[H][H].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[NH2:8]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCOc1ccc(N)cc1F
Yield: 92.9 %

Procedure:
To a stirred solution of 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (2.5 g, 11.62 mmol, 1.0 eq.) in ethanol (20 mL) was added 10% Pd/C (500 mg) and stirred in hydrogen gas atmosphere for 16 h at RT. The catalyst was filtered over a celite pad and the filtrate was concentrated to get 3-fluoro-4-(2-methoxyethoxy)aniline (2.0 g, 93.9%; TLC system: EtOAc/PE (3:7), Rf: 0.3).