Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[NH2:1][C:2]1[N:11]=[C:10]([Cl:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2ccccc2c(=O)[nH]1
Product: Nc1nc(Cl)c2ccccc2n1
Yield: 18.9 %

Procedure:
2-Amino-4-(3H)-quinazolone (2.0 g, 0.0124 mol) was heated under reflux in phosphoryl chloride (19.02 g, 0.0124 mol) for 2.5 hours. The reaction mixture was partitioned between chloroform, ice and NaOH solution (pH 9) and the organic phase dried, filtered, excess solvent removed and the residue triturated with chloroform to give 2-amino-4-chloroquinazoline (0.42 g, 19%) m.p. 275°-278°.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.[I:24]I.Cl>C1COCC1>[Cl:13][C:14]1[N:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([I:24])=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: II
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: FC(F)(F)c1nc(Cl)ccc1I
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7.1 ml of n-BuLi (1.6M in hexane, 11.3 mmol) in 7 ml THF under argon at −73° C. were added 1.6 ml of diisopropylamine (11.3 mmol) in 3 ml THF within 8 min. After 10 min stirring at the same temperature a solution of 1 g of 2-chloro-6-(trifluoromethyl)-pyridine (5.51 mmol) in 5 ml THF was added within 15 min (temperature between −76 and −75° C.). The dark brown solution was stirred at −75° C. for 1 h 15 min. Finally a solution of 1.4 g of iodine (5.51 mmol) in 10 ml THF was added at −75° C. over 25 min. After additional 45 min stirring at the same temperature 12 ml 2M aqueous HCl were added within 2 min (temperature raised from −78 to −50° C. The cooling device was then removed, the reaction mixture diluted with diethylether. After separation of the organic phase, the aqueous phase was reextracted with diethylether. The combined organic phases were successively washed with 10 ml 1M sodium thiosulfate, saturated NaHCO3 and brine, dried over magnesium sulfate, filtered off and concentrated in vacuo to yield 1.54 (69%) of 6-chloro-3-iodo-2-trifluoromethyl-pyridine as a brown semisolid residue. MS: 307.0
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:16]1([CH2:22][SH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH2:22]([S:23][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)/C=C/c1cc(Br)cnc1Cl
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)cnc1Cl
Temperature: 80 °C
Yield: 104.1 %

Procedure:
A vial was charged with (E)-ethyl 3-(5-bromo-2-chloropyridin-3-yl)acrylate (660 mg, 2.272 mmol), phenylmethanethiol (296 mg, 2.385 mmol), Xantphos (131 mg, 0.227 mmol), Pd2(dba)3 (104 mg, 0.114 mmol), 1,4-dioxane (9086 μl), and Hunig's base (793 μl, 4.54 mmol). The vial was purged with argon and the mixture was heated at 80° C. for 1 h. Water and EtOAc were added, and the layers were separated. The organic portion was dried, filtered and concentrated. The crude material was purified by silica gel chromatography, 0-50% EtOAc/heptane to provide (E)-ethyl 3-(5-(benzylthio)-2-chloropyridin-3-yl)acrylate (790 mg, 2.366 mmol, 104% yield) as a yellow oil. m/z (ESI) 334.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=O.[CH3:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].Cl>CCCCCC.O1CCCC1>[CH3:18][O:17][C:13]1[CH:12]=[C:7]([C:8](=[O:10])[CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:6]=[C:5]([O:4][CH3:3])[C:14]=1[O:15][CH3:16]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C(=O)CC(=O)C(C)(C)C)cc(OC)c1OC
Reaction time: 5 h
Yield: 73.6 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 3.0 gm (75 mmol) of 60% sodium hydride, 10 gm (44.3 mmol) of methyl 3,4,5-trimethoxybenzoate, and 80 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and refluxed with heating while 5.3 gm (53.2 mmol) of pinacolone was added dropwise. Refluxing under heat was continued for 5 hours. After cooling the reaction mixture, 45 ml of 2N hydrochloric acid was added, the mixture was extracted twice with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Hexane was added to the crude product and insoluble substances were filtered off. The filtrate was concentrated by evaporation, and recrystallization afforded 9.6 gm of the target compound as colorless needles (yield: 74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][CH2:18][NH2:19])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N:21]#[C:22]Br.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pd].CCOCC>[C:1]([O:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:22]#[N:21])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)OC(C)(C)C
Reactant: N#CBr
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC#N)C(=O)OC(C)(C)C
Temperature: 22 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
To a solution of 6.1 g (14.44 mmol) N5-((Benzyloxy)carbonyl-N2-(tert-butoxycarbonyl-L-ornithine tert-butyl ester in 100 mL ethyl acetate was added 1.0 g 10% palladium on carbon. The suspension was shaken at 22° C. under 50 psi H2 for 45 minutes in a 500 mL Parr bottle. The catalyst was removed by filtration through celite. The resulting solution was concentrated to yield a crude oil. The oil was disolved into 50 mL of diethyl ether and added dropwise to a 0° C. stirred solution of 1.52 g (14.3 mmol) of cyanogen bromide in 30 mL ether. The solution was stirred for 2 h, poured into aqueous sodium bicarbonate, and extraced with ether. The ether solution was dried (magnesium sulfate), concentrated, and purified by silica gel chromatography (100 g, 230-400 mesh silica gel). Elution with a gradient of ethyl acetate in hexanes (30%-60%) gave 3.0 g (67% yield) N2-(tert-butoxycarbonyl)-N5-cyano-L-ornithine tert-butyl ester as an oil.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][C@H:12]1[CH2:22][OH:23])=O)C1C=CC=CC=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:25].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>CN(C)C=O>[CH:16]1([CH:14]2[CH2:15][NH:11][C@H:12]([C:22]([OH:23])=[O:25])[CH2:13]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(OCc1ccccc1)N1C[C@H](C2CCCCC2)C[C@H]1CO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CC(C2CCCCC2)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S-trans)-1-[(benzyloxy)-carbonyl]-4-cyclohexyl-2-pyrrolidinemethanol (0.65 g) in dimethylformamide (10 ml) was added pyridinium dichromate (2.1 g). The mixture was stirred at room temperature for 16 hours and poured onto crushed ice and hydrochloric acid (25 ml). Extraction with ethyl acetate followed by solvent evaporation yielded 0.4 g of (trans)-1-[benzyloxy)carbonyl]-4-cyclohexyl-L-proline as a thick oil. The compound can be deprotected using catalytic hydrogenation as described in Method V.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][CH3:17])[CH:9]=[CH:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.O.Cl>C1COCC1>[CH2:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:6]([CH2:4][OH:3])=[CH:7][CH:8]=[CH:9]2)[CH3:17]
Reactant: CCOC(=O)c1cccc2cccc(CC)c12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc2cccc(CO)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A solution of 8-ethyl-naphthalene-1-carboxylic acid ethyl ester (1.04 g) in THF (30 ml) was cooled to 0° C. and treated with diisobutyl aluminium hydride solution (11.4 ml; 1.2 M in toluene). The reaction mixture was stirred for 2 hrs at r.t., then again cooled to 0° C. and treated with H2O (50 ml) and 0.1N HCl (50 ml). The mixture was extracted with EtOAc. The organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient cyclohexane→cyclohexane/EtOAc 4:1) to give (8-ethyl-naphthalen-1-yl)-methanol (769 mg) as white solid. MS (ISP): 187.3 ((M+H)+.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:13]1[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=2)[CH:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]2
Reactant: c1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1cc(CCl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cn2cc3ccccc3n2)ccc1O
Temperature: 23 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
In a 100 mL round-bottomed flask was added 4-(chloromethyl)-2-nitrophenol (1.0 g, 5.33 mmol), 1H-indazole (0.630 g, 5.33 mmol), and potassium carbonate (0.884 g, 6.40 mmol) in DMF (26.7 mL). The mixture was stirred at 23° C. for 18 h. The reaction was diluted with water (100 mL) and the resulting solid was isolated by filtration, washed with water, and dried in vacuo. The crude solid was purified via ISCO flash chromatography (0-75% EtOAc in hexanes; 40 g column) to give the title compound as a yellow solid (341 mg, 24% yield): 1H NMR (DMSO-d6, 400 MHz): δ=8.50 (d, J=1.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.68-7.72 (m, 1H), 7.56-7.61 (m, 1H), 7.48 (dd, J=8.6, 2.3 Hz, 1H), 7.10 (dd, J=8.5, 7.2 Hz, 2H), 7.00-7.06 (m, 1H), 5.62 ppm (s, 2H). ESI-MS: m/z 270.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Br:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[Br:13][C:12]1[C:11]([F:14])=[CH:10][CH:9]=[C:3]2[C:2]=1[NH:1][C:16](=[O:18])[N:6]([CH2:7][CH3:8])[C:4]2=[O:5]
Reactant: CCNC(=O)c1ccc(F)c(Br)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1c(=O)[nH]c2c(Br)c(F)ccc2c1=O
Temperature: 25 °C
Yield: 291 %

Procedure:
A solution of 2-amino-3-bromo-N-ethyl-4-fluorobenzamide (512a, 2.00 g, 7.66 mmol) and triphosgene (Aldrich; 0.796 g, 2.68 mmol) in toluene (80 mL) was heated at 110° C. for 18 h (water-cooled reflux condenser attached to flask). The reaction mixture was then cooled to RT and concentrated in vacuo to give 8-bromo-3-ethyl-7-fluoroquinazoline-2,4(1H,3H)-dione (2.238 g, 7.80 mmol) as a light-yellow solid: m/z (ESI, +ve) 286.9/288.8 (M+H)+. This material was used directly in the subsequent transformation.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:16][C:17]([F:27])([F:26])[C@H:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[NH2:19]>>[F:27][C:17]([F:16])([F:26])[C@@H:18]([NH:19][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Product: O=C(N[C@@H](c1cccnc1)C(F)(F)F)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (αS)-α-(trifluoromethyl)-3-pyridinemethanamine (CAN 749839-26-7) as starting materials and isolated (21 mg, 54%) as colorless oil; LC-MS (m/z), 386.0870 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH:23]([CH3:28])[C:24]2=[O:27])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH:23]([CH3:28])[C:24]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:27])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC1CCC2CN(Cc3ccccc3)CC2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)C(C)CCC2CN(Cc3ccccc3)CC21
Yield: 98.9 %

Procedure:
To a suspension of 2.13 g of 2-methoxyphenylmagnesium bromide in 15 cm3 of tetrahydrofuran is added dropwise, at room temperature and with stirring, a solution of 0.7 g of (3aRS,5RS,7aSR)-2-benzyl-5-methyl-4-perhydroisoindolone in 15 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 48 hours, treated with 50 cm3 of saturated aqueous ammonium chloride solution, taken up in ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 15 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 25 cm3 fractions. Fractions 10 to 20 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 1 g of (3aRS,4RS,5RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-5methyl-4-perhydroisoindolol is obtained in the form of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:10]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26]I)[CH2:21]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH2:10]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH2:26][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[O:1])[CH2:21]1)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccccn1
Reactant: O=C(OCc1ccccc1)N1CCCC(CI)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCC(Cn2ccccc2=O)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a stirred solution of 2-hydroxypyridine (200 mg, 2 mmol) in DMF (5 mL) was added NaH (60% mixture in mineral oil, 100 mg, 2.5 mmol). The mixture was stirred at 80° C. under N2 for 2 h, and then 3-iodomethylpiperidine-1-carboxylic acid benzyl ester (720 mg, 2 mmol) was added. The mixture was stirred at 80° C. for 10 h, cooled to room temperature, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by chromatography with CH2Cl2-EtOAc-MeOH (10:10:1) to give a viscous oil (475 mg, 73%). 1H NMR (CDCl3) δ 7.30 (m, 7H), 6.55 (d, 1H, J=9.0 Hz), 6.12 (m, 1H), 5.11 (s, 2H), 4.10-3.50 (m, 4H), 3.09 (t, 1H, J=10.2 Hz), 2.92 (dd, 1H, J=13.2, 9.0 Hz), 2.10 (m, 1H), 1.85-1.20 (m, 4H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[OH:9][CH2:10][C:11]1[CH:16]=[C:15]([N:17]([CH3:21])[CH2:18][CH2:19][OH:20])[CH:14]=[CH:13][N:12]=1>C(O)(=O)C>[Cl:1][C:16]1[C:11]([CH2:10][OH:9])=[N:12][CH:13]=[CH:14][C:15]=1[N:17]([CH3:21])[CH2:18][CH2:19][OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(CCO)c1ccnc(CO)c1
Solvent: CC(=O)O
Product: CN(CCO)c1ccnc(CO)c1Cl

Procedure:
N-Chlorosuccinimide (25 g, 187 mmol) is added in 5 portions to a solution of 2-[(2-hydroxymethyl-pyridin-4-yl)-methyl-amino]-ethanol (30 g of the crude product isolated in step a), 140 mmol) in acetic acid (170 ml) over a period of 3 h. Stirring is continued for I h and the solvent is evaporated in vacuo. The residue is treated with 6N sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed (silica, toluene/dioxane 2:1) to give the title compound as a brown solid. M.p. 49-53° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[CH2:24][OH:25])=[O:18])=[CH:10][C:9]=1[O:26][CH3:27].[H][H].CCOC(C)=O>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[CH2:24][OH:25])=[O:18])=[CH:10][C:9]=1[O:26][CH3:27]
Reactant: [H][H]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(=O)N2CCCC2CO)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CCCOc1cc(N)c(C(=O)N2CCCC2CO)cc1OC

Procedure:
The nitro ester 14 (38.4 g, 97 mmol) was dissolved in ethanol (2 batches of 19.2 g in 200 mL ethanol per 500 mL hydrogenation flask). 10% Pd/C was added as a slurry in ethanol (1 g per batch) and the mixture was hydrogenated in a Parr hydrogenation apparatus at 40 psi until no further hydrogen uptake was observed. Reaction completion was confirmed by TLC analysis (EtOAc) and the mixture was filtered through celite. The solvent was removed in vacuo and the amine 15 was used directly in the next step. (35.4 g, quantitative yield).
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].N[CH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:27]=CC=1>>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:31]([NH:30][C:26]2[CH:27]=[C:2]([CH:23]=[CH:24][CH:25]=2)[CH2:3][NH:4][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][CH:20]=[CH:21][C:14]=23)=[O:6])=[O:39])=[CH:37][CH:36]=1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: NCc1cccc(NC(=O)c2ccc(F)cc2)c1
Product: O=C(Nc1cccc(CNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1)c1ccc(F)cc1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using N[3-(aminomethyl)phenyl]-4-fluorobenzamide instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 486 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, s) 10.39 (1H, s) 10.26 (1H, s) 8.66-8.78 (1H, m) 8.02 (4H, dt, J=5.48, 2.70 Hz) 7.81 (1H, d, J=5.42 Hz) 7.68 (2H, d, J=8.20 Hz) 7.51 (1H, d, J=5.47 Hz) 7.24-7.40 (5H, m) 7.06 (1H, d, J=7.42 Hz) 6.86 (1H, d, J=5.52 Hz) 6.43 (1H, dd, J=3.54, 1.93 Hz) 4.47 (2H, d, J=5.86 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1)[CH3:2].Cl.O1CCOCC1>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(CN)c1
Reaction time: 20 h

Procedure:
A solution of (3-cyano-phenyl)-acetic acid ethyl ester (6.3 g, 33.29 mmol) in EtOH (50 mL) was added to a mixture of 10% Pd/C (1.26 g) in EtOH (50 mL) under Nitrogen. Additional EtOH (150 mL) was added followed by a solution of HCl in dioxane (4 M, 11.4 mL, 45.6 mmol). The mixture was hydrogenated on a Parr shaker at 45 psi for 20 h and the catalyst was removed by filtration through celite. The solution was concentrated to afford (3-aminomethyl-phenyl)-acetic acid ethyl ester as the hydrochloride salt (7.31 g). 1H NMR (400 MHz, CD3OD) δ 7.42–7.32 (m, 4H), 4.12 (q, 2H), 4.09 (s, 2H), 3.68 (s, 2H), 1.23 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>[Cu].C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cu]
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
In a reaction flask with a thermometer and a stirrer, 25 g of p-nitrobenzenesulfonamide, 18 g of benzoylchloride, 1 g of copper powder, and 100 g of toluene were charged and refluxed until evolution of hydrogen chloride gas was completely ended. The reaction mixture was then cooled to room temperature to precipitate a crystal, which was filtered. The crystal was dissolved in an aqueous sodium carbonate solution and filtered. The filtrate was neutralized with hydrochloric acid to precipitate a crystal. The crystal was filtered to obtain 30.6 g of N-(4-nitrobenzenesulfonyl)benzamide.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]([NH:51][C:52]2[C:53]([S:61][CH3:62])=[N:54][C:55]([CH3:60])=[CH:56][C:57]=2[S:58][CH3:59])=[O:50])[CH2:44][CH2:43]1)(=O)=O>CN(C=O)C.O>[NH:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:2]1[S:1][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]([NH:51][C:52]2[C:53]([S:61][CH3:62])=[N:54][C:55]([CH3:60])=[CH:56][C:57]=2[S:58][CH3:59])=[O:50])[CH2:44][CH2:43]1
Reactant: Sc1nc2ncccc2[nH]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCOS(C)(=O)=O)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ncccc3[nH]2)CC1
Yield: 40 %

Procedure:
To a solution of 2-mercaptoimidazolo[4,5-b]pyridine (38.1 mg, 0.252 mmol) in DMF (0.5 ml) were added 18-crown-6 (6.6 mg, 0.025 mmol) and potassium carbonate (63 mg, 0.454 mmol) and the mixture was stirred. Then to the mixture was dropped a solution of crude 2-[4-(2-methanesulfonyloxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide in DMF (1 ml) and stirred at 80° C. for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:methanol=10:1) to provide 51 mg (yield 40%) of the desired compound as colorless powdery crystals. IR (KBr) cm−1: 3140, 1688, 1600, 1564, 1485. 1H-NMR (CDCl3) δ: 2.38 (3H, s), 2.46 (3H, s), 2.49 (3H, s), 2.72-3.00 (10H, m), 3.29 (2H, s), 3.37 (2H, t, J=5.8 Hz), 6.63 (1H, s), 7.12 (1H, dd. J=7.8, 4.9 Hz), 7.82 (1H, d. J=7.8 Hz), 8.25 (1H, d. J=4.9 Hz), 8.49 (1H, br s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH:18]3[CH2:20][CH2:19]3)=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:24][CH:23]=1>>[CH:18]1([C:13]2=[N:14][NH:15][C:16](=[O:17])/[C:12]/2=[C:4]2\[NH:5][C:6]3[C:11]([C:2]([S:21][C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:29]([CH:31]5[CH2:32][CH2:33]5)=[O:30])=[CH:26][CH:27]=4)=[CH:3]\2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:20][CH2:19]1
Reactant: O=C1NN=C(C2CC2)/C1=C1\C=C(Cl)c2ccccc2N1
Reactant: O=C(Nc1ccc(S)cc1)C1CC1
Product: O=C1NN=C(C2CC2)/C1=C1\C=C(Sc2ccc(NC(=O)C3CC3)cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one and N-(4-mercaptophenyl)cyclopropanecarboxamide under conditions similar to those described in Example 6. The final compound was purified by precipitating it from methanol. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.17-0.29 (m, 2H) 0.47-0.59 (m, 2H) 0.77-0.87 (m, 4H) 1.05-1.17 (m, 1H) 1.74-1.84 (m, 1H) 6.96 (s, 1H) 7.49-7.60 (m, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.77-7.81 (m, 4H) 8.06 (d, J=7.07 Hz, 1H) 10.52 (s, 1H) 11.03 (s, 1H) 11.82 (s, 1H); ESI-MS: m/z calc'd for C25H22N4O2S 442.15. found 443.3 (M+H)+.