Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:11][CH3:12])=[CH:3][CH:2]=1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23]CC)=[O:22])C.[OH-].[K+].C>O>[CH2:11]([N:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=2)[C:19](=[O:18])[C:20]([C:21]([OH:23])=[O:22])=[CH:26]1)[CH3:12]
Reactant: CCNc1cccc(-c2ccncc2)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccncc3)cc21
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 29.3 %

Procedure:
A mixture of 100 mg of 3-(4-pyridyl)-N-ethylaniline (90% pure) and 108 mg of diethyl ethoxymethylenemalonate was heated at 165° C. for 0.5 hour. Then 2 g of polyphosphoric acid were added to the mixture, and heating was continued for another hour. A solution of 3 g of potassium hydroxide in 40 ml of water was then added to the reaction mixture, bringing it to a pH of 12-13; and the solution was heated on a steam bath for 30 minutes until it became clear. A pinch of activated charcoal was added, and the reaction mixture was stirred while hot for another 10 minutes and filtered. The residue was taken into 20 ml of methanol, heated, and then cooled. Filtration yielded 43 mg of 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3-quinolinecarboxylic acid as a slightly impure white solid. Another 19 mg of the product were found in the filtrate, bringing the total yield to 47%, based on the amount of 3-(4-pyridyl)-N-ethylaniline employed.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[CH:37]=[CH:36][C:21]([C:22]([N:24]2[CH2:30]C[C:28]3[O:31][C:32]([CH2:34][OH:35])=[N:33][C:27]=3[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.[C:38]([Si:42]([CH3:52])([CH3:51])[O:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)([CH3:41])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.[OH-].[Na+]>[Si:42]([O:43][C:44]1[CH:45]=[CH:46][C:47]([O:35][CH2:34][C:32]2[O:31][C:28]3[CH2:30][N:24]([C:22]([C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:37][CH:36]=4)=[O:23])[CH2:25][CH2:26][C:27]=3[N:33]=2)=[CH:48][CH:49]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:52])[CH3:51]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Reactant: O=C(c1ccc(F)cc1)N1CCc2nc(CO)oc2CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2nc3c(o2)CN(C(=O)c2ccc(F)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 151.9 %

Procedure:
Di-tert-butyl azodicarboxylate (0.1 g, 0.43 mmol) was added to a stirred solution of 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepine-2-methanol (0.1 g, 0.36 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-phenol (0.097 g, 0.43 mmol) and triphenylphosphine (0.114 g, 0.43 mmol) in THF (0.5 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. Additional di-tert-butyl azodicarboxylate (0.1 g, 0.43 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-phenol (0.097 g, 0.43 mmol) and triphenylphosphine (0.114 g, 0.43 mmol) were added at 0° C. The mixture was stirred at 120° C. for 20 minutes under microwave irradiation. The mixture was diluted with a 1M aqueous solution of NaOH and washed with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)methyl]-5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine (264 mg, 66% purity, 99% yield) as a colorless oil. C26H31FN2O4Si.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].C=O.[OH-].[K+].[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O)([O-:18])=[O:17].S(Cl)([Cl:29])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][Cl:29])([O-:18])=[O:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Agent: C=O
Agent: O=[N+]([O-])c1cccc(CO)c1
Agent: [K+]
Product: O=[N+]([O-])c1cccc(CCl)c1

Procedure:
m-Nitro-benzyl alcohol was prepared by subjecting m-nitro-benzaldehyde to the Cannizarro Reaction at 45° C., with an aqueous formalin solution and potassium hydroxide. The m-nitro-benzyl alcohol was reacted with thionyl chloride to form m-nitro-benzyl chloride (m.p. 45° C.). By refluxing m-nitro-benzyl chloride with sodium cyanide in aqueous-ethanolic solution for five hours in the presence of potassium iodide, m-nitro-benzyl cyanide (m.p. 58° C.) was prepared which was subsequently hydrolized by boiling with concentrated hydrochloric acid to form m-nitrophenyl-acetic acid. The m-nitrophenyl-acetic acid thus obtained was then converted into 1-(m-nitro-phenyl)-propanone-(2), m.p. 62° C., by the method of Shtacker et al, J. Med. Chem. 15, 1174 (1972), and the 1-(m-nitro-phenyl)-propanone-(2) was reduced in water with nascent hydrogen generated by iron powder and concentrated hydrochloric acid, followed by 3 hours' stirring. The reduction product, 1-(m-amino-phenyl)-propanone-(2), was recovered from the reaction mixture by extraction with ether. Since the product thus obtained was not distillable without decomposition, it was purified via its oxalate, m.p. 127°-129° C., which was prepared by dissolving the base in acetonitrile and adding oxalic acid to the solution. By adding aqueous sodium hydroxide to the oxalate and extracting the aqueous mixture with ether, the free base was again obtained.
Reaction SMILES: B(F)(F)F.CCOCC.CO[C:12]1[C:13](=[O:27])[C:14]2[C:23]([C:24](=[O:26])[CH:25]=1)=[CH:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:15]=2.[CH:28]([OH:31])([CH3:30])[CH3:29]>>[CH:28]([O:31][C:25]1[C:24](=[O:26])[C:23]2[C:14]([C:13](=[O:27])[CH:12]=1)=[CH:15][C:16]1[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:22]=2)([CH3:30])[CH3:29]
Reactant: CC(C)O
Reactant: COC1=CC(=O)c2cc3ccccc3cc2C1=O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)OC1=CC(=O)c2cc3ccccc3cc2C1=O
Reaction time: 8 h

Procedure:
17 ml of cold borontrifluoride etherate was added to a suspension of 7 g of 2-methoxy-1,4-anthraquinone in 120 ml of isopropanol. The reaction was carried at 70°-80° C. overnight. After partially concentrated, the reaction mixture was left at room temperature and the crude product was obtained as dark brown precipitate. Recrystallization from isopropanol yielded 5 g of pure yellow needles of IPAQ.
Reaction SMILES: C1CO[C:3]2([CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=[O:10])[CH:4]2[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15])[O:2]1.O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:9]([CH2:8][CH:5]1[CH2:6][CH2:7][C:3](=[O:2])[CH:4]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15])=[O:10]
Reactant: CC/C=C\CC1C(CC=O)CCC12OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC/C=C\CC1C(=O)CCC1CC=O
Yield: 47.9 %

Procedure:
A mixture of 47.6 g of 1,1-ethylenedioxy-3-formylmethyl-2-(cis-2-n-pentenyl)-cyclopentane, 80 ml of dioxane, 64 ml of water and 0.38 g para-toluenesulphonic acid is refluxed for 3 hours. It is then cooled, 120 ml of water added and extracted three times with 100 ml of benzene. The benzene solutions are washed to neutrality and concentrated under reduced pressure. There is obtained a crude product which is carefully rectified to yield 18.6 g of pure 3-formylmethyl-2-(cis-2-n-pentenyl)-1-cyclopentanone exhibiting: b.p.0.5 = 96°C. It can be represented by the formula ##SPC24##
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[N:7][NH:6][C:5]2=[S:10].[Na].[CH3:12]I>C(O)C>[CH3:12][S:10][C:5]1[N:4]2[CH:3]=[CH:2][N:1]=[C:9]2[CH:8]=[N:7][N:6]=1
Reactant: S=c1[nH]ncc2nccn12
Reactant: CI
Agent: [Na]
Solvent: CCO
Product: CSc1nncc2nccn12

Procedure:
A 66.7 gm. portion of imidazo[1,2-d]-as-triazine-5(6H)-thione is added to 250 ml. of ethanol. A solution of 10.1 gm. of sodium reacted in 250 ml. of ethanol is added with swirling. A 27.7 ml. portion of methyl iodide is added slowly with swirling. The mixture is stored in a chillroom overnight, filtered and dried giving 56.5 gm. of the desired final product, m.p. 147°-149° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]1.CS([C:25]1[N:30]=[C:29]([C:31]2[C:39]3[C:34](=[C:35]([O:40][CH2:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:36]=[CH:37][CH:38]=3)[NH:33][N:32]=2)[CH:28]=[CH:27][N:26]=1)=O.O>CN1C(=O)CCC1>[CH3:47][S:44]([CH2:43][CH2:42][CH2:41][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:34]=1[NH:33][N:32]=[C:31]2[C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)[N:30]=1)(=[O:46])=[O:45]
Reactant: CS(=O)c1nccc(-c2n[nH]c3c(OCCCS(C)(=O)=O)cccc23)n1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCCOc1cccc2c(-c3ccnc(NC4CCC(NS(C)(=O)=O)CC4)n3)n[nH]c12
Temperature: 130 °C
Reaction time: 2.5 h

Procedure:
DIEA (0.31 mL) and N-(4-aminocyclohexyl)-methanesulfonamide (348 mg) were stirred in NMP (1 mL) at RT for 1 hour. 3-(2-Methanesulfinyl-pyrimidin-4-yl)-7-(3-methane-sulfonyl-propoxy)-1H-indazole (200 mg, 0.5 mmol) was added to the mixture and stirred at 130° C. for 2.5 h. The reaction mixture was then poured into water and the precipitate purified on a silica column using flash chromatography, eluting with hexane:EtOAc:MeOH 5:4.5:0.5 to yield N-(-4-{4-[7-(3-methanesulfonyl-propoxy)-1H-indazol-3-yl]-pyrimidin-2-ylamino}-cyclo-hexyl)-methanesulfonamide (Compound 315).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[C:20]([F:25])[CH:19]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1ccc(Cl)cc1F
Product: O=c1[nH]c2nccc(Nc3ccc(Cl)cc3F)c2c2ccccc12
Yield: 79.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 4-chloro-2-fluoroaniline (95 mg, 0.65 mmol) to provide 195 (116 mg, 79% yield) as a white solid. LC-MS (M+H=340, obsd.=340).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[F:27])[NH:16][S:17]([CH2:20][C:21](O)=[O:22])(=[O:19])=[O:18]>C(O)(=O)C>[NH2:12][C:13]1[CH:14]=[C:15]([NH:16][S:17]([C:20]2[C:21](=[O:22])[O:11][C:6]3[C:7]([CH:8]=2)=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:19])=[O:18])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1cc(NS(=O)(=O)CC(=O)O)ccc1F
Reactant: COc1ccc(O)c(C=O)c1
Solvent: CC(=O)O
Product: COc1ccc2oc(=O)c(S(=O)(=O)Nc3ccc(F)c(N)c3)cc2c1

Procedure:
A solution of 5-methoxysalicylaldehyde (1 mmol) and 3-amino-4-fluoroanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 255-260° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[OH:3].C(N(CC)CC)C.ClCCl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[CH3:1])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
(a-1) To a stirred solution of 50.2 parts of α-methyl-4-nitrobenzenemethanol and 48.6 parts of N,N-diethylethanamine in 390 parts of dry dichloromethane was added dropwise a solution of 37.8 parts of methanesulfonyl chloride in 65 parts of dry dichloromethane at -5~0° C. The whole was stirred for 1 hour at 0° C. 75 Parts of cold water were added and the dichloromethane layer was decanted, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The solid residue was shaked with 2,2'-oxybispropane. The product was filtered off and dried, yielding 67.1 parts (91%) of [1-(4-nitrophenyl)ethyl] methanesulfonate; mp. 70° C. (int. 112).
Reaction SMILES: P([O-])([O-])([O-])=O.[C@@H:6]1(N2C(C(O)=O)=CC(=O)NC2=O)[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:7]1[OH:8].[NH:26]1[CH:30]=[N:29][C:28]([C:31]([NH2:33])=[O:32])=[N:27]1>>[CH:30]1[N:26]([C@@H:6]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:7]2[OH:8])[N:27]=[C:28]([C:31]([NH2:33])=[O:32])[N:29]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: O=C(O)c1cc(=O)[nH]c(=O)n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
prepared by culturing the same in a manner similar to Example 1 was added to 5 ml of 0.3 M phosphate buffer (adjusted final pH to 7.0) containing 50 mM of orotidine or orotidic acid and 50 mM of 1,2,4-triazole-3-carboxamide. The whole amount of washed cells (corresponding to 5 ml of the culture solution) of microorganisms shown in Table 5 prepared by culturing them in a manner similar to Example 1 was added to each reaction solution to prepare 28 kinds of reaction solutions shown in Table 5. Each reaction solution followed was reacted at 60° C. for 5 hours. The concentration of ribavirin produced was measured in a manner similar to Example 2. The results are shown in Table 5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C1COCC1.C([Li])CCC.CCCCCC.[N:33]1([C:39]2[N:44]=[CH:43][C:42]([CH:45]=[O:46])=[CH:41][N:40]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CCOC(C)=O.O>[Si:7]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:45]([C:42]2[CH:43]=[N:44][C:39]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[N:40][CH:41]=2)[OH:46])[CH:16]=[CH:15][CH:14]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Reactant: O=Cc1cnc(N2CCOCC2)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(C(O)c2cnc(N3CCOCC3)nc2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
[(3-Bromobenzyl)oxy](tert-butyl)dimethylsilane (860 mg) was mixed with THF (10 ml), followed by cooling to −78° C. under argon atmosphere. A 1.60M n-butyl lithium/hexane solution (1.8 ml) was added dropwise thereto, followed by stirring at −78° C. for 10 minutes, and then 2-morpholin-4-ylpyrimidine-5-carboaldehyde (500 mg) was added thereto. The mixture was warmed to 0° C. over 1 hour and then stirred again at 0° C. for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl][2-(morpholin-4-yl)pyrimidin-5-yl]methanol (914 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:29]([NH:31][C@H:32]([C:38]([NH:40][C@H:41]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:59]([NH:61][C@H:62]([C:68]([NH:70][C@H:71]([C:84]([NH:86][C@H:87]([C:92]([OH:94])=[O:93])[CH2:88][C:89](=[O:91])[NH2:90])=[O:85])[CH2:72][C:73]1[C:81]2[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=2)[N:75](C=O)[CH:74]=1)=[O:69])[CH2:63][CH2:64][CH2:65][CH2:66][NH2:67])=[O:60])[CH3:58])=[O:55])[C@@H:51]([CH3:53])[OH:52])=[O:48])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[O:30])[CH2:27][OH:28])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:22])[NH2:21])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6])[CH2:3][OH:4]>C(=O)([O-])O.[NH4+]>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:29]([NH:31][C@H:32]([C:38]([NH:40][C@H:41]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:59]([NH:61][C@H:62]([C:68]([NH:70][C@H:71]([C:84]([NH:86][C@H:87]([C:92]([OH:94])=[O:93])[CH2:88][C:89](=[O:91])[NH2:90])=[O:85])[CH2:72][C:73]1[C:81]2[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=2)[NH:75][CH:74]=1)=[O:69])[CH2:63][CH2:64][CH2:65][CH2:66][NH2:67])=[O:60])[CH3:58])=[O:55])[C@@H:51]([CH3:53])[OH:52])=[O:48])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[O:30])[CH2:27][OH:28])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:22])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:6])[CH2:3][OH:4]
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)O)[C@@H](C)O
Agent: O=C([O-])O
Agent: [NH4+]
Product: CC(C)[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)O)[C@@H](C)O
Reaction time: 24 h

Procedure:
H-Ser-Val-Arg-Ser-Lys-Lys-Thr-Ala-Lys-Trp(CHO)-Asn-OH (2) (965 mg) was dissolved in 0.1M ammonium hydrogen carbonate (90 ml) and the solution was stirred at 37°-38° C. for 24 hours, followed by addition of 0.1M ammonium hydrogen carbonate (4.5 g). The mixture was further stirred at 43° C. for 24 hours and then concentrated. The concentrate was chromatographed on a Sephadex G-25 column (3.2×65 cm), elution being carried out with 1N acetic acid, to give crude H-Ser-Val-Arg-Ser-Lys-Lys-Thr-Ala-Lys-Trp-Asn-OH (3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>O.CO.[Fe]>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[CH2:12][CH2:11][CH2:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CCCc2nccs2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(CCCc2nccs2)nc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of compound 138 (2.32 g, 9.3 mmol), NH4Cl (7.46 g, 140 mmol) and Iron Powder (5.19 g, 93 mmol) in water (100 mL) and CH3OH (100 mL) was stirred at 90° C. for 1 h. After cooling, the reaction mixture was filtered and the solid was washed by DCM. The filtrates were separated, the organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 139 (2.0 g, 83%) as a light yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH3:17])=[C:11]([N+:18]([O-])=O)[CH:10]=1)=[O:7])(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][CH2+:40]1SC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][C:40]1=[N:18][C:11]1[CH:10]=[C:9]([NH:8][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:7])[CH:14]=[CH:13][C:12]=1[NH:15][CH2:16][CH3:17])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCNc1ccc(NC(=O)COC(C)=O)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-acetoxy-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.73 (1H, br s), 7.44–7.51 (3H, m), 7.23–7.34 (5H, m), 7.16 (1H, t), 7.08 (1H, dd), 7.00 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.67 (2H, s), 3.74 (3H, s), 2.98 (2H, q), 2.20 (3H, s), 1.00 (3H, t); MS(ESI): 588(MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]2)=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:37])([F:35])[F:36])(=[O:25])=[O:26])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:40][CH2:41][S:42](=[O:46])(=[O:45])[CH2:43][CH2:44]2)=[O:18])[CH2:14][CH2:15]1)#[N:12]
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCS(=O)(=O)CC2)CC1
Reactant: Cc1cc(B(O)O)ccn1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC4CCS(=O)(=O)CC4)[C@@H](C(=O)NC4(C#N)CC4)C3)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2,4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 181) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 624.3 (M−H)−.
Reaction SMILES: ClC1C=C([CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])C=CC=1Cl.N1[C:33]2[C:28](=[CH:29][C:30]([S:34](N)(=O)=O)=[CH:31][CH:32]=2)CC1.C1(SCC(O)=O)C=CC=CC=1>>[C:30]1([S:34][CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:31]=[CH:32][CH:33]=[CH:28][CH:29]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(O)CSc1ccccc1
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)CSc1ccccc1
Yield: 45 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 64, indoline-5-sulfonamide (Intermediate 54A, 120 mg, 0.60 mmol) and 2-(phenylthio)acetic acid (117 mg, 0.70 mmol) were converted to the title compound (100 mg, 45%). 1H NMR (DMSO-d6) δ 8.09 (d, J=8.4 Hz, 1H), 7.67-7.62 (m, 2H), 7.43-7.40 (m, 2H), 7.34-7.30 (m, 2H), 7.22-7.19 (m, 3H), 4.29 (t, J=8.6 Hz, 2H), 4.17 (s, 2H), 3.23 (t, J=8.5 Hz, 2H); MS(ESI+) m/z 348.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23].[CH2:24]([N:26]([CH2:37][CH3:38])[CH2:27][CH2:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:25]>ClCCl.CO.C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:24][CH3:25])=[CH:36][CH:35]=3)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23]
Reactant: CN1C(=O)N(c2ccccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2ccccc2Br)C3)cc1
Temperature: 180 °C
Yield: 8.4 %

Procedure:
A mixture of 200 mg (0.5 mmol) of 3-(2-bromophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 208 mg (1 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 30 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 22 mg (8%) of 3-(2-bromophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a cream colored solid of melting point 144° C.