Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH2:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:32][CH3:33])[CH:17]=2)[N:12]=1)(=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[OH:9][CH2:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:32][CH3:33])[CH:17]=2)[N:12]=1
Reactant: COc1ccc2nc(COC(=O)c3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2nc(CO)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 89.5 %

Procedure:
1.5 g of 10% palladium/carbon powder was added to a solution of 1.26 g (2.93 mmol) of 2-benzoyloxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline in an ethyl acetate/ethanol (20 ml-20 ml) mixture. The obtained mixture was stirred at room temperature in a stream of hydrogen for 24 hours and filtered through Celite. The filter cake was washed with hot ethyl acetate/ethanol. The filtrate and the washings were distilled under a reduced pressure to remove the solvent. Thus 0.89 g of the title compound was obtained as a pale-yellow crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:23])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1N(C)C)(C)(C)C.O>[Cl:23][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:38]1[C:33]([F:32])=[N:34][CH:35]=[CH:36][CH:37]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC2(CCOC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: CN(C)c1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 90 °C

Procedure:
To a vial was added (E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine (80 mg, 0.203 mmol), potassium phosphate (129 mg, 0.608 mmol), 2-fluoropyridin-3-ylboronic acid (30.0 mg, 0.213 mmol), 1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(ii) chloride (7.18 mg, 10.14 μmol), dioxane (1014 μL), water (338 μL). The resulting mixture was purged with N2 gas and heated at 90° C. in microwave reactor for 25 mins. It was diluted with water and extracted into EtOAc. The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude material as a orange solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a gold Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 50% to 80% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane, to provide (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].CN([C:20]([O:24][N:25]1N=NC2C=CC=C[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.CNOC>O.CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]([N:25]([O:24][CH3:20])[CH3:26])=[O:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(C(=O)O)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(C#C[Si](C)(C)C)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.9 %

Procedure:
2-amino-5-[2-(trimethylsilyl)ethynyl]benzoic acid (630 mg, 2.7 mmol, 1 eq.), HBTU (1.54 g, 4.0 mmol, 1.5 eq.), and 4-methylmorpholine (0.74 mL, 6.7 mmol, 2.5 eq.) were added, in order, to DMF (10 mL) and stirred at room temperature for 10 minutes. N,O-dimethylhydroxylamine hydrochloride (290 mg, 3.0 mmol, 1.1 eq.) was then added to the reaction, and the reaction was stirred at room temperature for 16 hours. Water was then added (20 mL), and the reaction was extracted three times with ethyl acetate (50 mL each). To remove residual water, saturated sodium chloride (20 mL) was added to the organic layer, and the organic layer was separated and dried over sodium sulfate. The solvent was evaporated by rotary evaporation, and the residue was purified on silica column (hexanes/ethyl acetate, 3:1) to result in 320 mg (43%) of the title compound as an orange solid. 1H NMR (500 MHz, CDCl3) δ 8.38 (d, J=1.5, 1H, Ar—H), 7.82 (dd, J=1.5, 7.5, 1H, AR—H), 7.10 (d, J=7.3, 1H, Ar—H), 5.61 (s, 2H, NH2), 4.09 (s, 3H, OCH3), 3.66 (s, 3H, NCH3), 0.22 (s, 9H, Si(CH3)3). 13C NMR (126 MHz, CDCl3) δ 169.20 (CON), 147.35 (C—Ar), 135.24 (C—Ar), 133.50 (C—Ar), 116.65 (C—Ar), 116.55 (C—Ar), 111.21 (C—Ar), 105.40 (CSi(CH3)3), 91.90 (CCSi(CH3)3), 61.44 (NOCH3), 34.53 (NCH3), 0.29 (Si(CH3)3). Exact Mass, 276.13. 277.1046 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.Cl[CH:12]([F:14])[F:13]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:12]([F:14])[F:13])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(O)cc(Cl)n1
Reactant: FC(F)Cl
Product: CSc1nc(Cl)cc(OC(F)F)n1

Procedure:
On the other hand, in the latter process, 4-chloro-6-hydroxy-2-methylthiopyrimidine as the starting material is first reacted with monochlorodifluoromethane to obtain 4-chloro-6-difluoromethoxy-2-methylthiopyrimidine, then this product was reacted with sodium nitrite in dimethylformamide t obtain 4-hydroxy-6-difluoromethoxy-2-methylthiopyrimidine, which is further reacted with monochlorodifluoromethane in dioxane in the presence of potassium hydroxide to obtain desired 4,6-bis(difluoromethoxy)-2-methylthiopyrimidine at a yield of 50%. However, this process also involves long process steps and is very cumbersome, and as such, it is not suitable as an industrial process.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>CN(C)C=O>[CH:1]1([CH2:6][O:7][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: COc1ccc(CCl)cc1
Reactant: OCC1CC=CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCC2CC=CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of cyclopent-3-en-1-ylmethanol (3.50 g, 35.66 mmol) in anhydrous dimethylformamide (100 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.71 g, 42.79 mmol) portionwise under nitrogen. The mixture was stirred at 0° C. for 1 hour and then stirred at ambient temperature for 1 hour. para-Methoxybenzyl chloride (5.80 mL, 42.79 mmol) was added to the reaction mixture and the resulting mixture was stirred for 2 hours. The reaction mixture was quenched with methanol (10 mL) and then water (200 mL). The mixture was extracted with ethyl acetate and the organic layer was washed with saturated ammonium chloride (2×200 mL) and brine (200 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (3:1 hexanes:ethyl acetate) to provide the title compound (6.15 g, 79%): 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.67-5.60 (m, 2H), 4.44 (s, 2H), 3.79 (s, 3H), 3.34 (d, J=7.2 Hz, 2H), 2.66-2.40 (m, 3H), 2.16-2.03 (m, 2H); MS (ES+) m/z 241.2 (M+23).
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.N(OCCC(C)C)=O.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:11]1([C:9]2[O:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc2nc(-c3ccccc3)oc2n1
Reactant: c1ccccc1
Agent: CC(C)CCON=O
Product: c1ccc(-c2ccc3nc(-c4ccccc4)oc3n2)cc1

Procedure:
A mixture of 180 mg. of 5-amino-2-phenyloxazolo[5,4-b]pyridine, 10 ml. of benzene and 0.2 ml. of isoamyl nitrite was refluxed for 11/2 hours. The hot solution was filtered and concentrated to dryness. The residue was extracted with ether and the extract was filtered through aluminum oxide and concentrated to dryness. The crystalline residue was recrystallized from ethyl acetate to give 2,5-diphenyloxazolo[5,4-b]pyridine, m.p. 151°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].O.[Sn](Cl)(Cl)(Cl)[Cl:16]>Cl.O>[ClH:16].[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: Nc1ccc(Br)cc1Br
Reactant: O=N[O-]
Reactant: Cl[Sn](Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Br)cc1Br
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a stirred, cooled (-5° C.) solution of 2,4-dibromoaniline (50.0 g,0.2 mol.) in concentrated HCl solution (110 mL) was added sodium nitrite (13.8 g, 0.2 mol.) in water (110 mL) dropwise at such a rate as to maintain temperature below 5° C. After complete addition, the mixture was further stirred at 5° C. for 30 minutes. A solution of tin chloride monohydrate (135.4 g, 0.6 mol.) in concentrated HCl (total volume 170 mL) was added dropwise again maintaining temperature below 50° C. After complete addition and 30 minutes of further stirring, the mixture was placed in the freezer overnight. The light brown solid which precipitated was isolated by filtration and washed with cold brine followed by a solution of petroleum ether/ diethyl ether (2/1 by volume). This solid was slowly added to an ice cooled mixture of 50% sodium hydroxide solution/ ethyl acetate. The mixture was extracted with ethyl acetate and the organic phase dried over magnesium sulfate. After filtration, the solution was concentrated to 400 mL total volume, diluted with diethyl ether (1.5 L) and treated with dry HCl. The product, 2,4-dibromophenyl-hydrazine hydrochloride (45.9 g) was isolated as a white solid and used without further purification. ##STR24##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20]N(CN(C)C)C.C(OC(=O)C)(=O)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[CH2:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CN(C)C
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
2-[[(4-chlorophenyl)sulfonyl]methyl]-1,4-difluorobenzene (Example 2) (100 g, 0.33 mol) and N,N,N′,N′-tetramethyldiaminomethane (34.2 g, 0.50 mol) were dissolved in dimethyl formamide (1000 mL) at 60° C. Acetic anhydride (68.3 g, 1.00 mol) was added slowly and the reaction mixture was aged for 5 hours. Water (1000 mL) was added dropwise and the resulting slurry was cooled to 5° C. The solids were filtered, and the cake washed sequentially with dimethyl formamide:water (40:60, 200 mL) and water (500 mL). Drying overnight in vacuo at 40° C. under a nitrogen stream furnished 2-[1-[(4-chlorophenyl)sulfonyl]ethenyl]-1,4-difluorobenzene (98 g, 95%). 1H NMR (CDCl3) 7.64-7.59 (2H, m), 7.43-7.39 (2H, m), 7.27-7.22 (1H, m), 7.08-6.88 (2H, m), 6.88 (1H, s) and 6.09 (1H, s).
Reaction SMILES: BrC1C(=O)[O:4][C:5]2[C:10](C=1C)=[CH:9]C=[C:7]([OH:13])[CH:6]=2.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O:21](C(C(F)(F)F)=O)C(C(F)(F)F)=O>C(Cl)Cl>[OH:4][C:5]1[CH:10]=[CH:9][C:20]2[NH:15][C:16](=[O:21])[CH:17]=[CH:18][C:19]=2[C:6]=1[CH:7]=[O:13]
Reactant: c1ccncc1
Reactant: Cc1c(Br)c(=O)oc2cc(O)ccc12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1c(O)ccc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
Compound 1 (38 g, 249.6 mmol) and pyridine (21.7 g, 275.0 mmol) were dissolved in DCM (750 mL). (CF3CO)2O (57.7 g, 275.0 mmol) was added dropwise at 0° C. After that the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with DCM (500 mL), washed with 1N HCl, concentrated. The residue was purified by silica gel column (PE:EA=10:1), afforded compound 2 (45 g, 72%) as white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:4]=[N:3]1.[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cn1cc(-c2nc(C(=O)O)cs2)cn1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cnn(C)c2)n1
Yield: 76 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxylic acid (0.254 g, 1.215 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.457 mmol). The product was triturated using diethyl ether. Yield 76%. 1H-NMR (400 MHz; DMSO-d6): δ 1.17 (d, 3H), 3.90 (s, 3H), 4.35 (dd, 1H), 4.42 (dd, 1H), 4.50 (m, 1H), 6.96 (d, 1H), 7.85 (d, 1H), 7.86 (d, 1H), 7.93 (d, 1H), 7.93 (dd, 1H), 8.05 (d, 1H), 8.07 (s, 1H), 8.34 (d, 1H), 8.34 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:17]1C3.C(Cl)(Cl)[Cl:27]>>[ClH:27].[NH2:17][CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: ClC(Cl)Cl
Reactant: O=C(O)COc1ccc(C(=O)CBr)cc1
Product: Cl
Product: NCC(=O)c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(bromoacetyl)phenoxyacetic acid (26g.) in chloroform (150ml.) was stirred as hexamine (14g.) was added. The mixture was stirred at room temperature for 3 days and then filtered. The solid was suspended in ethanol (250ml.), concentrated hydrochloric acid (50ml.) was added and the mixture stirred at room temperature for 18 hours. The mixture was then filtered and the filtrate diluted with diethyl ether (1,500ml.). The solid so produced was filtered off, washed with a mixture of ethanol and diethyl ether to give 4-(aminoacetyl)phenoxyacetic acid hydrochloride, m.p. > 250° C. N.m.r. δ 7.0-7.14, 7.92-8.06 each 2H (aromatic protons), 4.5 (2H, N⊕H3CH2CO) and 4.81 (2H, --OCH2.COOH).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].C(N)C1C=CC=CC=1.C(O)(=O)C>CC(O)C>[N+:8]([CH:11]=[CH:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccsc1
Reactant: C[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: NCc1ccccc1
Product: O=[N+]([O-])C=Cc1ccsc1
Yield: 56 %

Procedure:
When R2Was H the thiophene-3-carboxaldehyde (1 eq) was dissolved in 2-propanol and treated with nitromethane (1 eq), benzylamine (0.065 eq) and glacial acetic acid (0.1 3 eq). After a 60 min reflux period, the mixture was cooled and the solid was collected and washed with ice-cold ether to afford the product (56%); mp 94.5°-96.5° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1.[N:26]1[N:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]2=[C:28]([C:35]([OH:37])=O)[CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:12]([O:13][CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[C:11]([NH:10][C:35]([C:28]2[CH:27]=[N:26][N:30]3[CH:29]=[CH:34][CH:33]=[N:32][C:31]=23)=[O:37])[CH:24]=1
Reactant: Nc1cc(Cl)ccc1OC1CCC(O)CC1
Reactant: O=C(O)c1cnn2cnccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Cl)ccc1OC1CCC(O)CC1)c1cnn2cccnc12
Temperature: 80 °C
Yield: 37.2 %

Procedure:
Diisopropylethylamine (0.35 mL, 2.01 mmol) was added at room temperature to a suspension of 4-(2-amino-4-chloro-phenoxy)-cyclohexanol (127 mg, 0.525 mmol), pyrazolo[1,5-c]pyrimidine-3-carboxylic acid (85 mg, 0.521 mmol) and HBTU (0.21 g, 0.55 mmol) in anhydrous acetonitrile (15 mL) and the resulting solution was heated at 80° C. overnight. The resulting mixture was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%). The aqueous layer was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The brown oily residue was purified on a silica gel plug and by flash chromatography (DCM/MeOH/NH4OH) to give a pale yellow solid which was washed with dichloromethane and methanol to give 75 mg (38% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide as a white powder. MS=387 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].C([O:8][C:9](=[O:12])[CH2:10]Br)(C)(C)C.NN.N(C(O[CH2:36][C:37]1[CH:42]=CC=C[CH:38]=1)=O)[C@H](C(N[C@H](C(ON1C(=O)CCC1=O)=O)C)=O)C>>[C:37]([CH:10]([NH:2][NH2:3])[C:9]([OH:8])=[O:12])([CH3:42])([CH3:38])[CH3:36]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NN
Solvent: O
Product: CC(C)(C)C(NN)C(=O)O

Procedure:
The inhibitors 18, 22 and 24 were prepared as described in Scheme 2. The compound tert.-Butyl 2-(hydrazino)acetic acid was prepared from 80% hydrazine hydrate and t-butylbromoacetate according to the procedure of Niedrich, 1969. The hydrazine was coupled with Z-Ala-Ala-OSu 1 (prepared as described in Experimentals, Starting Material) to obtain the compound 14. Treatment of the t-butyl ester with TFA in dichloromethane provided the compound 15, which was converted into the compound 16 via coupling reaction with HATU, HOAt and triphenylmethylamine. Acylation with chloroacetyl chloride or bromoacetyl bromide gave the corresponding chloroacetyl and bromoacetyl derivative 17 and 21. The trityl protecting group was removed by TFA in the presence of triisopropylsilane to give the inhibitor 2-[2-(Cbz-L-Ala-L-Ala)-1-chloroacetyl)hydrazino]acetamide 18 and 22 (Method D). Treatment of 21 with benzoic acid in the presence of potassium fluoride was followed by treatment with trifluoroacetic acid (Method D) generated the benzoyloxymethylketone 24. The asparagine analogues were recognised by the protease resulting in potent inhibition. The second-order rate constant for the inactivation of legumain by the chloromethylketone (18), 139088 M−1s−1 is approximately 200 fold higher than that of the Michael acceptor inhibitors (Table 3). Whereas the bromomethylketone (22) is another potent inhibitor, the benzoyloxymethylketone (24) displays only moderate inhibition. Neither papain nor cathepsin B is inhibited by these inhibitors.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)#[N:4].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15](F)[N:14]=1>CN(C)C=O>[N:14]1[C:15]([O:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]#[N:4])=[CH:16][CH:17]=[CH:18][C:13]=1[O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]#[N:4]
Reactant: Fc1cccc(F)n1
Reactant: N#Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2cccc(Oc3cccc(C#N)c3)n2)c1
Temperature: 100 °C

Procedure:
To sodium hydride (0.38 g, 9.5 mmol) in N,N-dimethylformamide (3 mL) was added 3-cyanophenol (1.1 g, 8.9 mmol) and 2,6-difluoropyridine (0.4 mL, 4.4 mmol). After heating in an oil bath at 100° C. for 15 hours the reaction was partitioned with ethyl acetate and water. The organic layer was separated, washed with water, dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica gel (50 g) with methylene chloride/hexane (3/1) to give 3,3'-[2,6-pyridinediylbis(oxy)]bis(benzonitrile). Recrystallization from ethyl acetate/hexane gave pure 3,3'-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl3) 7.79 (t,1), 7.45 (m,4), 7.32 (m,4), 6.72 (d,2) ppm.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C[O:21][C:22]([CH2:24]P(OC)(OC)=O)=O.[C:31](OC(=O)C)(=O)C>N1C=CC=CC=1>[C:22]([O:18][C:10]1([CH3:17])[CH:9]([CH3:31])[CH2:8][C:7]2[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]=2[CH3:19])[O:11]1)(=[O:21])[CH3:24]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CP(=O)(OC)OC
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)C(C)(OC(C)=O)O2

Procedure:
By the procedure of Example 6, 26.43 g. (0.10 mol.) of (±)-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman was reacted with trimethyl phosphonoacetate and then with 80 ml. of pyridine and 120 ml. of acetic anhydride by stirring under N 2 overnight. The solution was poured into ice-H 2 O and worked up and dried in the manner of Example 2. The crude product was filtered throgh 750 g. of 0.05-0.2 mm silica gel with 95:5 parts by volume benzene ether and then distilled to give (±)-methyl-(6-acetoxy-2, 5,7,8-tetramethylchroman-2-yl) acetate as a colorless resin: b.p. 147°-149°C./10 mmHg.
Reaction SMILES: COC1C=CC(CN[C@H](CC(C)C)C(N)=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:41]([NH2:43])=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>CO.[Pd]>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]([C@H:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:41]([NH2:43])=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: CC(C)CC(C(N)=O)N(Cc1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: COc1ccc(CN[C@H](CC(C)C)C(N)=O)cc1
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 88.7 %

Procedure:
(2R)-(2-[N-(4-Chlorobenzenesulfonyl)-N-(4-nitrobenzyl)amino]-4-methylpentanoic acid amide (Compound of Example 24; prepared as described in Reaction Scheme 1; 2.8 g, 6.6 mmol) was suspended with 10% Pd/C (1 g) and conc. HCl (1 mL) in MeOH (100 mL) and placed under a hydrogen atmosphere at 40 psi for 1 h. The suspension was filtered through Celite and then concentrated to give the title compound as a tan solid (2.4 g, 88% yield). MS (ESI), (M+H)+410.1; 1H NMR (CDCl3) δ7.80 (d, 2H, J=8.5), 7.63 (d, 2H, J=8.5), 7.52 (br s, 1H), 7.46 (d, 1H, J=8.0), 7.26 (d, 1H, J=8.0), 7.02 (br s, 1H), 4.70 (dd, 2H, J=50, 18), 4.30-4.41 (m, 1H),: 3.67 (br s, 2H), 1.28-1.33 (m, 3H), 0.86 (d, 3H, J=7.0), 0.57 (d, 3H, J=7.0).