Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:7]([N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)CCNCCC(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a stirred solution of diisopentylamine (5.0 ML, 24.7 mmol) and triethylamine (9.4 mL, 67.4 mmol) in dichloromethane (23 mL) at 0° C. was added slowly isonicotinoyl chloride hydrochloride (4 g, 22.5 mmol). The mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The mixture was diluted with saturated sodium bicarbonate and the separated aqueous layer was extracted with methylene chloride (3×25 mL). The combined organics were washed with water (10 mL), brine, dried (anh. sodium sulfate), filtered and evaporated. The residue solidified upon standing to afford 4.7 g of an orange solid. LCMS m/z 263.2 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.[CH2:16]([N:18]1[CH:22]=[C:21](I)[C:20]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[N:19]1)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:16]([N:18]1[CH:22]=[C:21]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:20]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[N:19]1)[CH3:17]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CCn1cc(I)c(-c2cccs2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cc(-c2ccncc2)c(-c2cccs2)n1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.60 mmol) and bis(tricyclohexylphosphine)palladium(II) chloride (0.05 mmol) were weighed into a microwave vial (reaction volume 2-5 mL). A solution of 1-ethyl-4-iodo-3-(2-thienyl)-1H-pyrazole (0.50 mmol) in 3.3 mL degassed dioxane and 1.1 mL of a degassed 2 M aqueous sodium carbonate solution were added. The reaction mixture was purged with argon, the microwave vial was capped with a septum and transferred to a laboratory microwave oven. The reaction mixture was irradiated to a reaction temperature of 120° C. for 15 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 95:5 to 0:100) to afford 105 mg 4-[1-ethyl-3-(2-thienyl)-1H-pyrazol-4-yl]pyridine (82% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH:6]=1.CCN(CC)CC.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])[O:4][CH2:3][CH2:2][NH:1][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCOc1ccc(C=O)c(OCc2ccccc2Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(OCCNC(=O)c2ccccc2)cc1OCc1ccccc1Br

Procedure:
4-(2-Aminoethoxy)-2-(2-bromobenzyloxy)benzaldehyde (200 mg, 0.43 mmol) was dissolved in CH2Cl2 (20 ml) and Et3N (87.02 mg, 0.12 ml, 0.86 mmol) was added to the solution, followed by stirring for 2˜3 min. Benzoyl chloride (60.45 mg, 50 μl, 0.43 mmol) was also added before additionally stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was extracted with brine and CH2Cl2 (×3). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in a vacuum. The residue was purified using column chromatography (ethyl acetate/n-hexane=1/5→1/3) to afford the object compound (white solid, 78 mg, 40%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccccc1Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccccc2Cl)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-chlorophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-chlorophenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH:28]([CH3:30])[CH3:29])[C:13]([N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[O:14]>>[CH2:21]([N:15]([CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])[C:13](=[O:14])[C@@H:12]([NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10])[CH:28]([CH3:29])[CH3:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)C(N)C(=O)N(CCN(C)C)Cc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Product: CC(C)[C@H](NC(=O)Nc1ccc(F)cc1)C(=O)N(CCN(C)C)Cc1ccccc1

Procedure:
Compound 14b was prepared from 4-fluorophenyl isocyanate and compound 13, using the method described in Example 22. MS (EI)=414 (M+).
Reaction SMILES: [C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH2:24](I)[CH2:25][CH3:26]>>[C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:24][CH2:25][CH3:26])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2)c1N=Cc1ccccc1
Reactant: CCCI
Product: CCCn1c(C)c(C(C)=O)c(N=Cc2ccccc2)c1-c1ccccc1

Procedure:
Starting from the compound of Example 46 and propyl iodide, and using procedure (a) of Example 49, 4-acetyl-3-benzylideneamino-5-methyl-2-phenyl-1-propylpyrrole is obtained as an oily substance. This compound is hydrolyzed as in procedure (b) of Example 49. Yield of the title compound: 50%, m.p. 113°-115° C. (from ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]3[N:23](O)[C:24]([CH3:27])=[N:25][CH:26]=3)[CH:19]=[C:18]([O:29][CH2:30][CH3:31])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([O-])(O)=O.[Na+]>O.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]3[NH:23][C:24]([CH3:27])=[N:25][CH:26]=3)[CH:19]=[C:18]([O:29][CH2:30][CH3:31])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2cnc(C)n2O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2cnc(C)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.6 %

Procedure:
A 20% solution of TiCl3 in H2O was added dropwise at 0° C. to a solution of the ethyl (RS)-(4-cyano-phenylamino)-[3-ethoxy-5-(3-hydroxy-2-methyl-3H-imidazol-4-yl)-phenyl]-acetate (355 mg, 0.844 mmol) obtained in Example 247.1 in MeOH (4.2 ml). The mixture was stirred for 3 h. at room temperature, subsequently poured into NaHCO3 solution/ice-water and extracted with CH2Cl2. The organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2, CH2Cl2->CH2Cl2/MeOH 95:5). There were obtained 50 mg (15%) of ethyl (RS)-(4-cyano-phenylamino)-[3-ethoxy-5-(2-methyl-3H-imidazol-4-yl)-phenyl]-acetate as a yellowish solid; MS: 405 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=O.[CH3:17][C:18](=O)[CH2:19][C:20](=[O:22])[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:17][C:18]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]2=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:19]=1[C:20](=[O:22])[CH3:21]
Reactant: Nc1sc2c(c1C(=O)c1cccs1)CCC2
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1cccs1)CCC3
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 39.2 %

Procedure:
To a stirred solution of 55 mg (0.22 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-thiophen-2-yl-methanone in 2 ml acetic acid was added 0.016 ml (0.24 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 80° C. for 15 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 27 mg (39%) 1-(2-methyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 314 (M+H+, 100).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([NH:17][C:18]1[C:19](=[O:36])[N:20]([C:24]2[CH:25]=[C:26]([CH:31]=[C:32]([F:35])[C:33]=2[CH3:34])[C:27]([O:29]C)=[O:28])[CH:21]=[CH:22][N:23]=1)([CH3:16])[CH3:15].Cl>O.C1COCC1>[Cl:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([NH:17][C:18]1[C:19](=[O:36])[N:20]([C:24]2[CH:25]=[C:26]([CH:31]=[C:32]([F:35])[C:33]=2[CH3:34])[C:27]([OH:29])=[O:28])[CH:21]=[CH:22][N:23]=1)([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc(F)c(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCCl)c2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)O)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
Lithium hydroxide monohydrate (0.177 g) in water (5.00 mL) was added to methyl 3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate (Example 316b, 1.17 g) in THF (10 mL) and the reaction mixture was stirred for 4 h at room temperature. Water was added and the solution acidified with 2M HCl. This was extracted into ethyl acetate (2×). The combined organics were dried (MgSO4), filtered and evaporated to afford the subtitle compound as a solid (1 g).
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[P:4](=[O:8])([OH:7])([OH:6])[OH:5]>>[P:4]([O-:8])([O-:7])([O-:6])=[O:5].[Ca+2:2].[Ca+2:2].[Ca+2:2].[P:4]([O-:8])([O-:7])([O-:6])=[O:5]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Product: O=P([O-])([O-])[O-]
Reaction time: 3 h

Procedure:
To a vigorously stirred calcium hydroxide suspension, an aqueous phosphoric acid solution was slowly added dropwise until the pH became 7 and the formed precipitate was calcined at 800° C. for 3 hours to obtain tricalcium phosphate, which was further ground by using a mortar and then passed through a sieve (average particle diameter: 45 μm) (calcium phosphate A).
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][C:3]=1[C:15]#[N:16].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:15]([C:3]1[O:4][C:5]2[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[C:2]=1[O:1][S:24]([CH3:23])(=[O:26])=[O:25])#[N:16]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(O)c(C#N)oc2c1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1c(C#N)oc2cc(S(C)(=O)=O)ccc12
Temperature: 25 °C

Procedure:
A suspension of 13 (3.9 g) in CH2Cl2 (200 mL) was treated with pyridine (10 mL), methanesulfonyl chloride (4 mL), and a catalytic amount of dimethylaminopyridine at 0° C., under an N2 atmosphere, for 2 h. The reaction was allowed to warm to ambient temperature overnight. The reaction was partitioned between 1:1 Et2O/hexanes and brine. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was purified by chromatography (silica gel, 1:1 EtOAc/hexanes) giving 1.05 g of methanesulfonic acid 2-cyano-6-methanesulfonyl-benzofuran-3-yl ester 14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]([CH2:75][F:76])([CH2:73][F:74])[O:71][B:70]([OH:77])[C:69]=2[CH:78]=1>CN(C=O)C>[F:76][CH2:75][C:72]1([CH2:73][F:74])[O:71][B:70]([OH:77])[C:69]2[CH:78]=[C:65]([CH2:64][NH:63][C:19](=[O:21])[C:18]3[CH:22]=[CH:23][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)([C:25]([F:27])([F:26])[F:28])[O:14][N:13]=4)=[CH:16][C:17]=3[CH3:24])[CH:66]=[CH:67][C:68]1=2
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(CF)CF
Reaction time: 0.17 h
Yield: 33 %

Procedure:
A solution of 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (100 mg, 0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5 mL) was stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (116 mg, 0.44 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by prep-TLC to provide the product (48 mg, 33%). 1H NMR (400 MHz, DMSO-d6): δ 8.89 (s, 1H), 7.82 (s, 2H), 7.59-7.57 (m, 2H), 7.49-7.44 (m, 3H), 7.33-7.31 (m, 2H), 4.61-4.31 (m, 8H), 2.36 (s, 3H) ppm; HPLC purity: 97.63% at 220 nm and 97.48% at 254 nm.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:29])=[CH:26][CH:25]=1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc(Cl)cc4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 62.6 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 4-chlorobenzoyl chloride (0.53 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O (50 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.80 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.97 min (97.05%); mp: 178-180° C.; 1H NMR (DMSO-d6) δ 1.92-2.15 (m, 1H, CHH), 2.54-2.71 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.65 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.5, 12.8 Hz, 1H, CH), 7.53-7.63 (m, 2H, Ar), 7.74-7.87 (m, 2H, Ar), 7.87-8.03 (m, 3H, Ar), 9.31 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.67, 48.99, 122.01, 123.55, 128.50, 129.21, 129.84, 131.62, 132.64, 133.47, 136.30, 147.38, 165.40, 166.96, 167.10, 169.80, 172.72; LCMS: MH=426/428; Anal Calcd for C21H16N3O5Cl: C, 58.98; H, 3.82; N, 9.83. Found: C, 58.67; H, 3.67; N, 9.53.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][CH2:21][CH2:22][N:23]=[C:24]([NH:26][N+]([O-])=O)[NH2:25])=[O:17])[C:8]3[C:13]([C:4]2=[CH:3][CH:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[NH:18]([C:16]([O:15][CH2:14][CH:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:17])[C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:26]
Reactant: NC(=NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)N[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 4 h

Procedure:
A solution of 9-fluorenylmethyloxycarbonyl-Ng -nitro-L-arginine (from step 2, 26.8 mmol), BOP (30 mmol), HOBt (30 mmol) and NMM (55 mmol) in 40 mL of DMF was mixed with 10 g of PAC resin (α-methylphenacyl linker attached to polystyrene-1% divinylbenzene, substitution 0.97mmol/g, supplied by Bachem Bioscience, Philadelphia, Pa.) and stirred for 4 h. The resin was filtered off, washed with DMF, DCM and MeOH and dried to yield the final product Fmoc-Arg (NO2 )-Resin (11.1 g). The resin, Fmoc-Arg (NO2 )-Resin (11.1 g) was treated with 100 ml of a solution containing piperidine (30%), DMF (35%) and toluene (35%) and stirred for 2.5 hrs. The Fmoc removed resin was filtered and consecutively washed with DCM/DMF (50:50) and MeOH to yield the title product (9.2 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([N:10]([CH3:12])[CH3:11])=O)[CH:4]=1.[H-].[Al+3].[H-].[H-].O>O1CCCC1.Cl>[CH3:12][N:10]([CH2:8][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[S:7][CH:6]=1)[CH3:11]
Reactant: CN(C)C(=O)c1csc(CO)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1csc(CO)c1
Reaction time: 2 h

Procedure:
A solution of 5-(hydroxymethyl)-N,N-dimethyl-3-thiophenecarboxamide (1.7 g) in dry tetrahydrofuran (150 ml) was treated with a 0.5M solution of aluminium hydride in tetrahydrofuran (26 ml). After 2 h at room temperature, water (5 ml) was cautiously added and the mixture was filtered through diatomaceous earth. The filtrate was evaporated to leave an oily residue, which was dissolved in 2M hydrochloric acid (20 ml). The aqueous solution was washed with diethyl ether, basified with 5M sodium hydroxide and extracted with ethyl acetate.
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:8][CH:9]=[CH:10][C:11]=1[Br:12].[NH:13]1[C:21](=[O:22])[C:19](=O)[C:17](=[O:18])[NH:16][C:14]1=[O:15]>CCOCC.O1CCCC1>[Br:12][C:11]1[CH:10]=[CH:9][O:8][C:7]=1[CH:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Brc1ccoc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2occc2Br)C(=O)N1
Temperature: -20 °C

Procedure:
n-Butyl lithium is reacted with 2,3-dibromofuran in ether at -70° C. according to the procedure of Zaluski et al. [Bull. soc. chim. Fr., p. 1843 (1970)] and Sornay et al. [loc. cit., p. 990 (1971)]. The reaction mixture is warmed to -20° C. and an equivalent of anhydrous alloxan in tetrahydrofuran is added dropwise. Reaction is allowed to proceed to completion by warming to room temperature for 2 hours. The product, 5-(3-bromo-2-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione is isolated according to the method of Example 5.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]([Cl:39])[C:33]=4[Cl:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,3-dichloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=630.5)=70%.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([CH3:22])=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[C:38](OC(=O)C)(=O)C>N1C=CC=CC=1>[C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]2[C:21]([CH3:22])=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])[N:18]=2)=[O:16])[CH2:12][CH2:13]1)(=[O:7])[CH3:38]
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(NC(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Yield: 81 %

Procedure:
tert-Butyl-4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (1 eq, 34 mg, 0.073 mmol) was stirred in pyridine (1 mL) and acetic anhydride (1 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure N-(1-acetylpiperidin-4-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide (30 mg, 81%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.28-1.49 (m, 2H) 1.87-2.13 (m, 5H) 2.30 (s, 3H) 2.62-2.82 (m, 1H) 3.05-3.24 (m, 1H) 3.75 (d, J=13.56 Hz, 1H) 3.98-4.25 (m, 1H) 4.49 (d, J=13.37 Hz, 1H) 6.80 (d, J=8.01 Hz, 1H) 6.99 (d, J=8.48 Hz, 2H) 7.13-7.29 (m, 4H) 7.36 (d, J=1.51 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]2[CH:11]=[N:12][NH:13][C:7]=2[CH:6]=1.[I:19]I.[OH-].[K+]>CN(C=O)C>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]2[C:11]([I:19])=[N:12][NH:13][C:7]=2[CH:6]=1
Reactant: II
Reactant: Fc1ccc(Oc2cc3[nH]ncc3cn2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2cc3[nH]nc(I)c3cn2)c(F)c1
Reaction time: 5 h
Yield: 72.9 %

Procedure:
To a room temperature solution of 6-(2,4-difluorophenoxy)-1H-pyrazolo[4,3-c]pyridine (0.10 g) in DMF was added 0.11 g of iodine and 0.049 g of potassium hydroxide. After 5 hours, additional 10% of iodine was added and a reaction mixture was stirred for an additional one hour. The mixture was quenched with 1 M sodium bisulfite (50 mL) solution and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over MgSO4, and concentrated to give 0.11 g of 6-(2,4-difluorophenoxy)-3-iodo-1H-pyrazolo[4,3-c]pyridine (71% yield). Mass Spec. M+H=374.