Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH2:26])=[C:9]2[CH2:28][N:29]([S:33]([C:36]3[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=3)(=[O:35])=[O:34])[C:30]([CH3:32])([CH3:31])[C:8]2=[N:7]1)=O)C.[CH:44]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45]1>ClCCl.C(N(CC)C(C)C)(C)C>[CH:44]1([C:48]([NH:26][C:14]2[CH:15]=[C:16]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[CH:17]=[CH:18][C:13]=2[C:12]([NH:11][C:10]2[C:9]3[CH2:28][N:29]([S:33]([C:36]4[CH:37]=[C:38]([F:43])[CH:39]=[C:40]([F:42])[CH:41]=4)(=[O:34])=[O:35])[C:30]([CH3:32])([CH3:31])[C:8]=3[NH:7][N:6]=2)=[O:27])=[O:49])[CH2:47][CH2:46][CH2:45]1
Reactant: O=C(Cl)C1CCC1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)C4(C)C)c(NC(=O)C3CCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
To a solution of 3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (105 mg, 0.17 mmol) in dichloromethane (5 mL) and N,N-diisopropylethylamine (1 mL), cyclobutanecarbonyl chloride (28.5 microL, 0.25 mmol) was added and the reaction mixture stirred at room temperature for 2 hours. The mixture was then diluted with dichloromethane (30 mL), washed with water (30 mL), dried over sodium sulphate and evaporated to dryness. The crude oil was then treated with MeOH (5 mL) and triethylamine (3 mL) and stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue purified by flash chromatography on silica gel, using a mixture dichloromethane-MeOH-30% NH4OH 100:10:1 as the eluant, affording the title compound as white solid (21 mg).
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:21]S(C)=O>>[O:4]1[CH2:21][CH:3]1[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CS(C)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CCC(C2CO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of NaH (10.4 g, 60% dispersion in mineral oil) in DMSO was added (CH3)3SOI (57 g). The reaction mixture was stirred for 30 min at room temperature followed by the dropwise addition at 0° C. of phenylmethyl 4-formyl-1-piperidinecarboxylate (43 g, which can be purchased from AstaTech, Inc., Bristol, Pa.). The mixture was allowed to stir at room temperature for 1 hour and then quenched with water and extracted with Et2O. The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated to yield a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[N:16](COCCOC)[C:15]3[CH:23]=[C:24]([Cl:37])[C:25]([S:27](=[O:36])(=[O:35])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:26][C:14]=3[N:13]=2)[CH:11]=1)=[O:6])[CH3:3]>O1CCOCC1.C(O)C>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[NH:16][C:15]3[CH:23]=[C:24]([Cl:37])[C:25]([S:27](=[O:36])(=[O:35])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:26][C:14]=3[N:13]=2)[CH:11]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)Nc4ccccc4)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)Nc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
Hydrochloric acid in dioxane (4M, 0.241 mL) was added to 1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-phenylsulfamoyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (35.0 mg, 65.5 μmol) in ethanol (0.50 mL) and allowed to stir at 23° C. for 2.5 h. The solvent was evaporated and the residue was purified via FCC (5-100% EtOAc/hexanes) to yield the titled compound (28.7 mg, 98% yield). MS (ESI/CI): mass calcd. for C19H16ClN5O4S, 445.1; m/z found, 446.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:18]1[S:19][CH:20]=[CH:21][N:22]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C@@H:14]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)[OH:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[Si](C)(C)c1nccs1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1nccs1
Reaction time: 48 h
Yield: 4.6 %

Procedure:
To a solution of 10.8 g of t-butoxycarbonyl-L-leucinal in 40 of dichloromethane was added 9.4 g of 2-trimethylsilyl thiazole in 10 ml of dichloromethane. The reaction was allowed to stand for 48 hours, then was cooled in an ice bath and treated cautiously with 30 ml of 1M tetra-n-butylammonium fluoride in tetrahydrofuran. This mixture was refluxed for 1.5 hours and then concentrated to an oil. The oil was dissolved in 100 ml of ethyl acetate, washed with 50 ml each of 2N citric acid, 1M sodium bicarbonate and brine and dried. The solution was treated with activated carbon, filtered through a pad of hydrous magnesium silicate and concentrated to an oil. This oil was dissolved in 50 ml of 10% ethyl acetate in dichloromethane and chromatographed on two columns in the same solvent. Refractive index was monitored at S 20, 250 ml/minute. The main peak in hold-back volumes 6-10 was cut into 1 liter portions which were separately evaporated. The first three of these all crystallized and the solids were recrystallized form isopropyl ether and hexane, giving 0.7 g of (S)2-(t-butoxycarbonyl)amino-4-methyl-(S)1-(2-thiazolyl)pentan-1-ol as crystals, mp 121°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[NH2:12][NH2:13]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:13][N:12]=[C:8]2[CH3:9]
Reactant: NN
Reactant: CC(=O)c1cc(Br)ccc1F
Product: Cc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To 1-(5-Bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol) was added anhydrous hydrazine (240 mL, 7.65 mol). The reaction mixture was heated under reflux for 10 hours. The reaction mixture was allowed to cool to room temperature and was stirred for 16 hours. The reaction mixture was added to ice (1.4 L). The reaction mixture was stirred for 30 minutes. The reaction mixture was filtered and the white solid product was washed with water. The white solid was dried in a vacuum oven to afford the desired 5-bromo-3-methyl-1H-indazole 104 (86.1 g, 0.408 mol) which was used without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]1([CH3:29])[CH:15]([CH2:16][CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1>O.C(O)C>[N:1]([CH2:17][CH2:16][CH:15]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][C:6]1([CH3:5])[CH3:29])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3OC2(C)C)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)Oc2ccccc2CC1CCN=[N+]=[N-]

Procedure:
A solution of 3.9 g (60 mmol) of sodium azide in 10 ml of water is added to a solution of 14.4 g (40 mmol) of 2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman (prepared as described in Example 38) in 200 ml of ethanol. The mixture is boiled under reflux for 18 hours. After cooling, the ethanol is evaporated off in vacuo, water is added to the residue and extraction is carried out with dichloromethane. The dichloromethane phase is washed with water, dried over sodium sulfate and concentrated by evaporation, yielding 8.7 g (94% of the theoretical yield) of 3-(2-azidoethyl)-2,2-dimethyl-chroman in the form of a yellow oil.
Reaction SMILES: [C:1]1([CH3:37])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:36])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]([CH3:35])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:12][CH:11]=1.[OH-].[Na+].CO>O1CCCC1>[C:1]1([CH3:37])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:36])[NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]([CH3:35])[CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCc3cc(C(C)CC(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of ethyl (R/S) 3-(1-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyrate [0.55 g, Reference Example 4(b)], aqueous sodium hydroxide solution (5.5 ml, 1M), methanol (5.5 ml) and tetrahydrofuran (11 ml) was stirred at room temperature overnight then evaporated to low bulk. The residue was diluted with water and the mixture was acidified by the addition of hydrochloric acid. The precipitate was collected by filtration, washed with water and then dried to give the title compound (0.41 g) as a white powder. LC-MS: RT=3.77 minutes (100% total area by ELS); MS (ES+) 472 (MH+), 494 (MNa+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27](O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cccc(CCc2ccccc2OC2CCCN(C(=O)OC(C)(C)C)C2)c1
Yield: 62.1 %

Procedure:
Following a procedure similar to that described in Example 36(a), 1.50 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 2.64 g of 1-t-butoxycarbonyl-3-hydroxypiperidine, 3.44 g of triphenylphosphine and 2.29 g of diethyl azodicarboxylate were reacted. The mixture was then worked up as described in Example 36(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 7:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.68 g (yield 62%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[F:10].C(N(CC)CC)C.[C]=O.C[CH2:21][O:22][C:23](C)=[O:24]>CO>[CH3:9][C:5]1[CH:4]=[C:3]([F:10])[C:2]([C:23]([O:22][CH3:21])=[O:24])=[CH:7][C:6]=1[Cl:8]
Reactant: CCOC(C)=O
Reactant: Cc1cc(F)c(Br)cc1Cl
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(Cl)c(C)cc1F
Temperature: 80 °C
Yield: 93 %

Procedure:
To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (Comm, 10 g, 44.7 mmol) in methanol (200 mL) was added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)-dichloropalladium (1:1) (358 mg, 0.447 mmol) and N,N-diethylethanamine (8.11 mL, 58.2 mmol). The resulting mixture was placed in a bomb and pressurized with carbon monoxide to 80 psi and heated at 80° C. for 18 hours. The reaction mixture was then concentrated in vacuo to yield a semi-solid, which was dissolved in EtOAc (300 mL) and washed with water (200 mL). The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to yield an orange oil, which solidified on standing (9.87 g). The solid was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to afford the title compound as a crystalline white solid (8.47 g, 93%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]=[O:29]>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]([OH:29])[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Nc1c(F)cccc1F
Reactant: O=Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(c1ccccc1)N(O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), 1,3-difluoro-2-nitrosobenzene (143 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C:23]2[O:24][C:25]3[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([Br:34])[C:26]=3[CH:27]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Br:34][C:28]1[C:26]2[CH:27]=[C:23]([CH2:22][O:21][CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[O:24][C:25]=2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=1
Reactant: COc1ccc(Br)c2cc(COC3CCN(C(=O)OC(C)(C)C)CC3)oc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Br)c2cc(COC3CCNCC3)oc12
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a stirred solution of 4-(4-bromo-7-methoxybenzofuran-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.3 g) in dichloromethane (50 ml). After stirring at room temperate overnight the reaction was diluted with dichloromethane (150 ml) washed with 1M sodium hydroxide (100 ml) and dried over magnesium sulfate. The organic phase was concentrated in vacuo to afford the title compound as a pale yellow gum (0.98 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH:20]([CH3:22])[CH3:21])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOCC>[C:1]([O:5][C:6](=[O:23])[CH:7]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH3:27])[CH:20]([CH3:21])[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(C)C(C(=O)OC(C)(C)C)C(C)C)cc1
Reaction time: 15 h
Yield: 95.3 %

Procedure:
To a solution of 1.00 g (2.915 mmol) of N-[(4-methoxyphenyl)sulfonyl]-D-valine tert-butyl ester (J. Med. Chem. 1997, 40, 2525) in 10 mL of DMF was added 0.128 g (3.207 mmol) of 60% sodium hydride. After 30 minutes at room temperature 0.45 mL (7.289 mmol) of iodomethane was added and the reaction was stirred for 15 h. The reaction mixture was then diluted with ether and washed with water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.993 g (95%) of the N-methyl sulfonamide as a colorless oil. Electrospray Mass Spec: 357.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[C:14]([C:13]([O:20][CH3:21])=[O:19])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OC)cc1OC)C(=O)OC
Temperature: 25 °C
Yield: 105.8 %

Procedure:
2,4-Dimethoxybenzaldehyde (10.0 g, 0.060 mol), dimethyl malonate (9.5 g, 0.072 mol), piperidine (1.5 g, 0.017 mol), benzoic acid (1.8 g, 0.015 mol) and 100 mL of toluene are stirred at reflux for 5.5 hours under a Dean Stark trap to remove water. After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with 10% hydrochloric acid, water and brine. The resulting solution is dried over anhydrous magnesium sulfate and then concentrated to yield 17.8 g of an orange syrup which is purified by chromatography on silica gel (2:1, heptane:ethyl acetate) to provide 12.8 g of the title compound as a pale yellow solid melting at 71–73° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:7])[CH3:3].[C:18]([NH:25][C:26]([CH3:31])([C:28](O)=[O:29])[CH3:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:17])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:7][C:28](=[O:29])[C:26]([NH:25][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:31])[CH3:27])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CSCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of S-benzyl-L-cysteine ethyl ester hydrochloride (7.98 g, 29 mmol), BOC-α-methylalanine (5.89 g, 29 mmol), triethylamine (2.93 g, 29 mmol), 1-hydroxybenzotriazole (HOBT, 3.92 g, 29 mmol) and EDCI (5.57 g, 29 mmol) in methylene chloride (200 mL) is stirred under an argon atmosphere at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with water (50 mL), 1 N HCl (50 mL), water (50 mL), 5% sodium bicarbonate (50 mL), water (50 mL) and finally brine (25 mL). The solution is then dried over sodium sulfate, filtered and evaporated to dryness to give N-[2-(BOC-amino)-2-methylpropionyl]-S-benzyl-L-cysteine ethyl ester.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([S:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Sc1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC#CCOc1cc(Sc2ccccc2Cl)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 64.1 %

Procedure:
To 5 ml of chloroform were added 0.95 ml of diisopropylethylamine, 0.5 g of 4-(2-butynyloxy)-6-chloropyrimidine, and 0.42 g of 2-chlorothiophenol, followed by stirring at room temperature for 7 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.51 g of 4-(2-butynyloxy)-6-(2-chlorothiophenoxy)pyrimidine (the present compound (142)).
Reaction SMILES: [NH:1]([CH2:3][C:4]([NH:6][C@H:7]([C:19]([N:21]([CH2:23][C:24]([NH:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:25])[CH3:22])=[O:20])[CH:8](CC1C=CC=CC=1)[C:9](=[O:11])[OH:10])=[O:5])[CH3:2].C1(C[O:46][C:47]([C@@:49](C(Cl)=O)([CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:57])[NH2:56])[NH2:50])=O)C=CC=CC=1>C(O)(=O)C.O.[Pd]>[NH2:50][C@H:49]([C:47]([N:1]([CH2:3][C:4]([NH:6][C@H:7]([C:19]([N:21]([CH2:23][C:24]([NH:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)=[O:25])[CH3:22])=[O:20])[CH2:8][C:9](=[O:11])[OH:10])=[O:5])[CH3:2])=[O:46])[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:56])[NH2:57]
Reactant: N=C(N)NCCC[C@](N)(C(=O)Cl)C(=O)OCc1ccccc1
Reactant: CNCC(=O)N[C@H](C(=O)N(C)CC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)C(Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CN(CC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)C(=O)[C@H](CC(=O)O)NC(=O)CN(C)C(=O)[C@@H](N)CCCNC(=N)N
Reaction time: 15 h
Yield: 50.4 %

Procedure:
Alpha-Phenylmethoxycarbonyl-L-Arginyl(HCL)-Sarcosyl-beta-benzyl-L-Aspartyl-Sarcosyl-L-Tyrosine amide (1.0 g) was dissolved in 100 ml of 75% aqueous acetic acid and reduced with 0.5 g of 10% Pd/C at 50 p.s.i. for 15 hours. The catalyst was removed by filtration and the solution lyophilized to give 0.8 g. The material was dissolved in 7 ml water, filtered through a 3μ multipore filter, adjusted to pH 5 with NH4OH(conc.) and chromatographed in an SP-C-25 column (2.5×100 cm) with 0.20 M NH4OAc, pH 5.0, 100 ml/hr, 20 ml/tube. Tubes 71 to 78 were pooled and lyophilized to give 0.35 g of Arg-Sar-Asp-Sar-Tyr-NH2.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[N:6][CH:7]=1.[C:11](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:11][O:9][C:8]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[CH:5][N:4]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncncc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ncncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
5-Bromopyrimidine-4-carboxylic acid (prepared according to the procedure described in U.S. Pat. No. 4,110,450) (1.0 eq, 6.14 g, 30.2 mmol) was suspended in CH2Cl2 (100 ml). Oxalylchloride (1.1 eq, 2.9 ml, 33.0 mmol) was added followed by 2 drops of DMF. The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The residue was taken in MeOH (50 ml) and heated. After evaporation of MeOH in vacuo the compound was dissolved in CH2Cl2 and poured on a prepacked silica gel column. The material was eluted using 20% Ethyl acetate in hexanes. Evaporation of the solvent provided methyl-5-bromopyrimidine-4-carboxylate as a light orange crystalline solid (2.54 g, 39% yield). LCMS (ES): 95% pure, m/z 217 [M]+; 219 [M+2]+; 1H NMR (CDCl3, 400 MHz) δ 4.04 (s, 3H), 9.02 (s, 1H), 9.21 (s, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.Cl>CS(C)=O.O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(O)ccc2o1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4oc(C(=O)O)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-hydroxybenzofuran-2-carboxylic acid (Step a, 2.00 g, 11.23 mmol) in DMSO (23 mL) at RT was added cesium carbonate (11.0 g, 33.7 mmol). The reaction was stirred for 10 min followed by the addition of 4-chloro-6,7-dimethoxyquinoline (prepared by the method described in WO 03/33472) (1.75 g, 7.86 mmol). The reaction was stirred at 100° C. for 16 h. After cooling to RT, water was added. The aqueous layer was acidified with a 6M aqueous hydrochloric acid solution until pH=5, filtered and the solid was suspended in EtOAc. The organic phase was extracted with a 3M sodium hydroxide aqueous solution. After acidification of the aqueous layer, the title compound was isolated by filtration and dried under high vacuum.