Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[I:17]Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: ClI
Reactant: Clc1cnc2[nH]ccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (1, 15.00 g, 98.31 mmol) in 300 mL of dichloromethane under an atmosphere or nitrogen, pyridine (7.951 mL, 98.31 mmol) and iodine monochloride (110 mL, 1.0 M in dichloromethane, 110 mmol) are added slowly over 20 minutes. The reaction is stirred at room temperature for 2 hours, then quenched with 100 mL of 1 M aqueous sodium thiosulfate pentahydrate. The layers are separated, solids collected from the aqueous layer by filtration and combined with the organic layer. The aqueous layer is extracted with ethyl acetate, and the organic layers are combined and washed with brine, then concentrated under vacuum. The resulting solid is washed with 20% ethyl acetate in hexane to provide the desired compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1.[NH4+:33].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[NH2:33][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate (7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C. and treated with 5 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (3.33 g, 17.5 mmol) over a 10 min period. The reaction mixture was treated with an additional 5 mL concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 4 h. The reaction mixture was then cooled and treated with 100 mL of CH2Cl2. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 6.50 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a brown oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]1[C:23]2[C:18](=[C:19]([C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:14]1[C:23]2[C:18](=[C:19]([C:24]([CH3:29])([CH3:28])[C:25]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(SC(F)(F)F)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C)(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)-2-methylpropanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 405 (M+H)+; MS (ESI−) m/z 403 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (s, 3H), 1.64 (s, 3H), 4.33 (d, J 6.1, 2H), 6.57 (s, 1H), 7.18 (m, 1H), 7.33 (m, 1H), 7.52 (m, 2H), 7.82 (m, 1H), 8.11 (m, 1H), 8.36 (d, J 7.8, 1H), 8.57 (m, 1H), 9.42 (s, 1H), 10.08 (s, 1H); Anal. Calcd for C21H19F3N2OS+2HCl: C, 52.84; H, 4.43. Found: C, 52.66; H, 4.39.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[C:19]2[NH:20][C:21]3[C:22]([N:27]=2)=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.C(=O)([O-])[O-:31].[K+].[K+]>C(O)(=O)C.O>[C:1]1([S:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[C:19]2[NH:20][C:21]3[C:22]([N:27]=2)=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCSc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ncccc3[nH]2)c(OCCS(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.8 gm (0.0074 mol) of 2-[2-(2-phenylthioethoxy)-4-methoxyphenyl]imidazo[4,5-b]pyridine in 40 ml of glacial acetic acid was admixed with 0.84 gm of hydrogen peroxide (30%), and the mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was diluted with 20 ml of water, neutralized with potassium carbonate, extracted three times with 50 ml each of methylene chloride, and dried over magnesium sulfate. The purification was carried out on 70 gm of silicagel with methylene chloride/acetone (100:0 to 80:20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1NC(=O)C.[F:32]C1C=C2C(=CC=1)NC=C2CC(O)=O.ClN(Cl)CC1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:27])[CH:3]=1)[CH2:8][NH:9][C:10]([NH:11][C:12](=[O:25])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:32])[CH:21]=2)[NH:16][CH:15]=1)=[NH:26]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Agent: ClN(Cl)Cc1ccccc1
Product: N=C(NCc1cc(Cl)cc(Cl)c1)NC(=O)Cc1c[nH]c2ccc(F)cc12

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-fluoro-1H-indol-3-yl)acetic acid in step 4 (A) and dichlorobenzyl amine in step 4 (B), the title compound was prepared. MS (ESI) (M+H)+=393.24. 1H-NMR (500 MHz, CDCl3) δ 7.53 (s, 1 H), 7.08 (d, 1 H), 6.87 (bs, 3 H), 6.84 (bs, 4 H), 6.42 (m, 1 H), 4.38 (s, 2 H), 4.12 (s, 2 H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:32]=[CH:31][C:18]3[N:19]([CH3:30])[C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O.O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]2[N:19]([CH3:30])[C:18]3[CH:31]=[CH:32][C:15]([O:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:13]=4)=[CH:16][C:17]=3[N:21]=2)=[CH:24][CH:25]=1
Reactant: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(C(=O)O)c3)ccc21

Procedure:
A stirring solution of 4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid tert-butyl ester in trifluoroacetic acid was treated with two drops of water at room temperature for 3-4 hours or when the reaction was determined to be complete by HPLC. The reaction was evaporated under reduced pressure and then ether was added to the residue, which was then sonicated for 30 minutes. Filtration and washing with ether yields the desired acid in quantitative yield. LCMS m/z 379.4 (MH+), tR=1.74 mm.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[O:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]2=[O:31])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:28]3[CH2:29][CH2:30][N:25]([CH:22]4[CH2:21][CH2:20][O:19][CH2:24][CH2:23]4)[C:26](=[O:31])[CH2:27]3)=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: O=C1CNCCN1C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.3 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg, 0.57 mmol), in DMF (4 mL), was added 1-(tetrahydro-pyran-4-yl)-piperazin-2-one (116 mg, 0.63 mmol) and potassium carbonate (238 mg, 1.72 mmol). The mixture was stirred at RT for 4 h, then the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow solid (212 mg, 82%).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([C:23]3[CH:24]=[CH:25][C:26]4[O:39][CH2:38][N:29]5[C:30]6[CH:31]=[CH:32][CH:33]=[C:34]([F:37])[C:35]=6[CH:36]=[C:28]5[C:27]=4[N:40]=3)=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=O)[CH3:2].Cl.[CH3:42][O:43][NH2:44]>C(O)C.N1C=CC=CC=1>[F:37][C:34]1[C:35]2[CH:36]=[C:28]3[C:27]4[N:40]=[C:23]([C:14]5[C:15]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][C:6]6[O:5][C:4](/[C:1](=[N:44]/[O:43][CH3:42])/[CH3:2])=[C:8]([C:9]([NH:11][CH3:12])=[O:10])[C:7]=6[CH:13]=5)[CH:24]=[CH:25][C:26]=4[O:39][CH2:38][N:29]3[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: CNC(=O)c1c(C(C)=O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CNC(=O)c1c(/C(C)=N/OC)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a solution compound 2-acetyl-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.088 mmol) in ethanol (1.5 mL) was added O-methylhydroxylamine hydrochloride (25 mg, 0.26 mmol) and 2 drops pyridine. The resulting mixture was stirred at 70° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the product of (E)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(1-(methoxyimino)ethyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 9.56 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.48 (dd, J=10 Hz, 2H), 7.18˜7.23 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.84 (t, J=8.0 Hz, 1H), 5.99 (s, 2H), 4.12 (s, 3H), 3.41 (s, 3H), 2.99 (d, J=4.8 Hz, 3H), 2.66 (s, 3H), 2.41 (s, 3H). MS (M+H)+: 592.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)=[CH:3][CH:2]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:28][C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=3)=[CH:18][CH:19]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NCc1ccc(-c2cccc3c2oc2ccccc23)cc1
Product: FC(F)(F)c1ccc(CNCc2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Yield: 51 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step a) using 1-(4-dibenzo[b,d]furan-4-ylphenyl)methanamine and 4-(trifluoromethyl)benzaldehyde gave the title compound (51%). M+(LC/MS(ESI)): 432.4
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C1C=CC(C2C3C=C(Cl)C=CC=3NC(=O)CN=2)=CC=1.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:33]1([S:36]([NH:1][C:2]23[CH2:3][CH2:4][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:8][CH2:9]2)[CH2:6][CH2:7]3)(=[O:38])=[O:37])[CH2:35][CH2:34]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COC(=O)C12CCC(N)(CC1)CC2
Agent: CN(C)c1ccncc1
Agent: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: ClCCl
Product: COC(=O)C12CCC(NS(=O)(=O)C3CC3)(CC1)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.3 %

Procedure:
To a solution of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (500 mg, 2.73 mmol) (Yeh, V. S. C.; Kurukulasuriya, R.; Madar, D.; Patel, J. R.; Fung, S.; Monzon, K.; Chiou, W.; Wang, J.; Jacobson, P.; Sham, H. L.; Link, J. T. Bioorg. and Med. Chem. Let, 2006, vol. 16, #20 p. 5408-5413) in DCM (10 mL) at rt was added TEA (0.76 mL, 5.46 mmol) and DMAP (50 mg, 0.41 mmol). Cyclopropanesulfonyl chloride (764 mg, 5.46 mmol, Matrix) was added dropwise by syringe. The reaction mixture was stirred for about 15 h at rt. The mixture was washed with water (10 mL), and the aqueous layer was extracted with DCM (2×10 mL), the organic layers were combined and dried over anhydrous Na2SO4, filtered and concd in vacuo. The crude materials was purified by silica gel chromatography eluting with a gradient of 20-35% EtOAc in hexanes to afford methyl 4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate (410 mg, 52% yield). LC/MS (Table 1, Method p) Rt=1.68 min; MS m/z: 288 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Br)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2 carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (42.8 mg, 34%).
Reaction SMILES: N1C=CN=C1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[CH:44]=[CH:45]/[C:46]([NH:48][NH:49][C:50](=[O:63])[CH:51]([C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=2)[CH2:52][CH2:53][CH2:54][Cl:55])=O)[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1>C(Cl)Cl>[Cl:55][CH2:54][CH2:53][CH2:52][CH:51]([C:50]1[O:63][C:46](/[CH:45]=[CH:44]/[C:34]2[CH:35]=[CH:36][C:37]([N:38]3[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]3)=[C:32]([O:31][CH3:30])[CH:33]=2)=[N:48][N:49]=1)[C:56]1[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Agent: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(/C=C/c2nnc(C(CCCCl)c3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.4 %

Procedure:
Imidazole (211 mg), carbon tetrabromide (1.0 g) and triphenylphosphine (244 mg) were added to a solution of 5-chloro-2-(4-fluorophenyl)pentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (300 mg) in methylene chloride (5 mL), and the reaction solution was stirred at room temperature for 14 hours. The reaction solution was purified as is by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 264 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)=[O:16])=[CH:12][C:11]([CH:28]([CH3:30])[CH3:29])=[N:10]2)=[CH:5][CH:4]=1.[CH2:31](Cl)Cl>O=[Mn]=O>[C:28]([C:11]1[CH:12]=[C:13]([NH:14][C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:16])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=2)[N:10]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2ccc(CO)cc2)n1
Reactant: ClCCl
Agent: O=[Mn]=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2ccc(C=O)cc2)n1
Reaction time: 2 h

Procedure:
To a solution of Example 204 (200 mg) in CH2Cl2 (50 mL) was added MnO2 (450 mg) at RT. The suspension was stirred for 2 h then filtered through celite. The filtrate was concentrated under reduced pressure to afford 150 mg of 1-[5-t-butyl-2-(4-formyl-phenyl)-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea, which was used without further purification.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:19]([CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([OH:25])=O)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:44][C@@H:45]([CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:46]([N:48]([CH3:64])[CH2:49][CH2:50][NH:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=1)=[O:53])=[O:47]>C(Cl)Cl>[C:40]([O:39][C:37]([NH:36][CH2:35][CH2:34][N:18]([CH2:17][CH2:16][NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:14])[C:19]([CH2:21][C@H:22]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:23](=[O:25])[NH:44][C@H:45]([C:46](=[O:47])[N:48]([CH3:64])[CH2:49][CH2:50][NH:51][C:52]([C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:62])([F:63])[F:61])=[CH:58][CH:59]=1)=[O:53])[CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:20])=[O:38])([CH3:41])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@@H](N)CCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@H](CCc1ccccc1)NC(=O)[C@H](CC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
A solution of CDMT (0.22 g, 1.26 mmol) in DCM (30 mL) was cooled to 0° C. before adding N-methylmorpholine (0.3 mL, 2.62 mmol). After 15 min, (2S)-3-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}propanoic acid CXXIV (0.62 g, 1.20 mmol) was added and the solution was stirred for additional 40 min. After that time, (2S)-2-amino-N-methyl-4-phenyl-N-(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)butanamide CXXIII (0.56 g, 1.26 mmol) was added and the mixture stirred at r.t. overnight. The mixture was washed with 1 M HCl (5×), 1 M K2CO3 (5×), brine and dried over MgSO4. The solvent was evaporated under vacuum and the residue was purified on a silica gel column (50:1 DCM/methanol) to give tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1S)-1-[methyl(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)carbamoyl]-3-phenylpropyl]carbamoyl}ethyl]carbamate as yellow solid (0.78 g, 0.86 mmol, 68% yield). ESIMS found for C44H64F3N7O10 m/z 908 (M+H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][S:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])(=[O:20])=[O:19])[CH:11]=1.BrCBr>CN(C)C=O>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:1][N:17]([S:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:12]=2[CH:11]=1)=[O:30]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Agent: [K+]
Solvent: BrCBr
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CO2
Temperature: 80 °C
Yield: 99.3 %

Procedure:
Potassium carbonate (3.87 g, 28.0 mmol) was added to a solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (2.08 g, 5.59 mmol) and dibromomethane (2.92 g, 16.5 mmol) in N,N-dimethylformamide (35 mL), and the suspension was heated at 80° C. for 48 h, then the reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid methyl ester (2.13 g, 99%). White solid, MS (ISP)=384.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[C:14](=O)[NH:13][C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:11][C:5]=1[NH:6]2.O=P(Cl)(Cl)[Cl:25].C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl.CO>[Cl:25][C:14]1[C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][C:5]=2[N:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1cccc(Cl)c12
Temperature: 115 °C
Yield: 70 %

Procedure:
To 9 (2 g, 6.274 mmol) was added 30 mL of POCl3 in a 250 mL round bottom flask. The reaction mixture was refluxed at 110-120° C. for 4 hours. After this the POCl3 was evaporated and the mixture was neutralized using NH4OH. The aqueous mixture was filtered (the precipitate being the compound). The filtrate also contained some compound. Therefore, it was extracted using chloroform and ethyl acetate. The precipitate obtained was dissolved in chloroform and methanol. Both the dissolved precipitate and extracted filtrate were dried using sodium sulfate overnight. To the solution was added silica, and solvent was removed under reduced pressure to provide a silica gel plug. The plug was transferred on top of a column packed with silica gel, twenty times the weight of plug, eluted with chloroform, 1% methanol in chloroform and 5% methanol in chloroform. Fractions containing the product 10 (TLC) were pooled and evaporated to give a solid. The overall yield was 70%. TLC Rf 0.86 (chloroform-methanol 5:1), m.p. 245.6-246.1° C., 1H NMR: δ 1.24 (s, 9H, pivaloyl); 7.37-7.63 (m, 3H, phenyl); 10.32 (s, 1H, 9-NH, exch); 12.96 (s, 1H, 2-NH, exch).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2ccnc(F)c2)c(F)c1
Product: CN1c2cc(OCc3ccc(Oc4ccnc(F)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-fluoropyridin-4-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimeth-yl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.