Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[C@@H:12]1(N2C=CC(=O)NC2=O)[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14].[N-]=[N+]=[N-].[K+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C@@H:12]3[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[CH:3]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: Clc1cc(Cl)c2nc[nH]c2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Product: OC[C@H]1O[C@@H](n2cnc3c(Cl)cc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
5,7-Dichloro-3H-imidazo[4,5-b]pyridine (0.0053 mole, 1.0 g) and uridine (0.00795 mole, 1.94 g), were suspended in 20 ml potassium phosphate, 0.01M at pH 7 with 0.04% potassium azide. The catalysts, purine nucleoside phosphorylase (1900 units) and uridine phosphorylase (1300 units) were added and the suspension mixed for 10 days at 35° C. The reaction was filtered and the cake dissolved in boiling methanol. After filtering, the volume was doubled with water then reduced to one quarter the volume in vacuo at 40° C. The resulting precipitate was collected by filtration and contained 1.3 g (0.0037 mole) of analytically pure 5,7-Dichloro-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine. M.p. 156°-158° C.; UV λmax nm (ε×10-3) at pH 1, 10% EtOH, 187(8.2), 256(4.2); at pH 13, 10% EtOH, 289(8.7 ), 260(5.0); [α]D20 =-15.6, (C=0.5, DMF); NMR (MC2SO-d6) δ 8.85 (s, 1H, H2), 7.68 (s, 1H, H6), 5.99 (d, 1H, J=5.49, H1'), 5.0 (m, 1H, H2'), 4.5 (m, 1H, H3'), 4.0 (m, 1H, H4'), 3.5 (b, 1H, H5')
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>>[CH2:15]([N:17]([CH2:18][CH3:19])[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1)[CH3:16]
Reactant: CCNCC
Reactant: Clc1nc2ccnn2c2ncccc12
Product: CCN(CC)c1nc2ccnn2c2ncccc12

Procedure:
2.04 g. of 5-chloropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine of Example 1c are added to 20 ml. of diethylamine. The solution is refluxed for 5 hours. The excess diethylamine is distilled off and the residue is treated with 5 ml. water and extracted three times with 10 ml. portions of ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered and evaporated to dryness. The residual N,N-diethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5-amine is recrystallized from ethyl acetate/petroleum ether, yield: 2 g. (83%); m.p. 102°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([CH:17]=[O:18])[NH:15][CH:16]=[C:10]2[C:9]1=[O:19])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[O:19]=[C:9]1[C:10]2=[CH:16][NH:15][C:14]([CH:17]=[O:18])=[C:11]2[CH2:12][CH2:13][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c[nH]c2C=O)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1[nH]cc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A mixture of 1-formyl-4-oxo-2,4,6,7-tetrahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (1.2 g, 4.54 mmol) in 50% of trifluoroacetic acid in dichloromethane was stirred at room temperature for 30 minutes. The reaction was concentrated and the residue was recrystallized from dichloromethane to give 400 mg (75%) of 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]2([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20]CCCC)[CH2:14][CH2:13]2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].B>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]2([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:4]([CH3:9])([CH3:5])[CH3:3])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCOC(=O)NC1CCN(C(=O)C(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(CC(c2ccc(Cl)c(Cl)c2)C2(O)CCCCC2)CC1
Temperature: 74 °C
Yield: 105.8 %

Procedure:
A solution of tent-butyl {1-[(3,4-dichlorophenyl)(1-hydroxycyclohexyl)acetyl]piperidin-4-yl}carbamate (364 mg, 0.75 mmol) in dry tetrahydrofuran (1 mL), under nitrogen, was treated with a solution of borane (1.0 M in tetrahydrofuran, 2.62 mL, 2.62 mmol). The reaction was heated at 74° C. for 2 h, after which time the reaction was cooled and quenched by the addition of methanol (4 mL). The solvents were removed in vacuo, and the products were purified via Biotage Horizon (FLASH 25 M, silica, gradient from 10% EtOAc/hexane to 90% EtOAc/hexane) to yield 187 mg (53%) tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate as a white foam which eluted first and 88 mg (31%) 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol as a colorless oil which eluted second. tert-butyl {1-[2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate: MS (ES) m/z 471.3 ([M+H]+); HRMS: calcd for C24H36Cl2N2O3, 470.2103; found (ESI), 471.2165. 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol: MS m/z 385/387/389 ([M+H]+). 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol was converted to the dihydrochloride salt with a methanolic solution of hydrochloric acid and diethyl ether to yield 45 mg (41%) 1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride as a white solid. HRMS: calcd for C20H30Cl2N2O.2.00 HCl, 456.1269; found (ESI), 385.183.
Reaction SMILES: CO[C:3](=[O:18])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH2:5].[CH3:19][N:20]=[C:21]=[S:22]>>[C:14]([O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:21](=[S:22])[N:20]([CH3:19])[C:3]1=[O:18])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: CN=C=S
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CN1C(=O)C(CCCCNC(=O)OC(C)(C)C)NC1=S

Procedure:
Using an analogous procedure to Example 1 Nε-t-butyloxycarbonyl-L-lysine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.CO[C:15](OC)([N:17]([CH3:19])[CH3:18])C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:9](=[O:11])[CH:10]=[CH:15][N:17]([CH3:19])[CH3:18])=[C:6]([F:8])[CH:7]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1c(F)cc(Br)cc1F
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1c(F)cc(Br)cc1F

Procedure:
A mixture of 1-(4-bromo-2,6-difluorophenyl)ethanone (prepared according to the method described in PCT Patent Publication WO 2004/72070; 4.56 g, 19.4 mmol) and N,N-dimethylacetamide dimethyl acetal (6.94 g, 58.2 mmol) in toluene (45 mL) was refluxed for 16 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to yield the title compound (4.78 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:26])=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1.[ClH:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:28].[CH3:27][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:26][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CCCC(C)(c1ccccc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccccc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
1.0 g. (3.5 mmoles) of 4,4-dimethyl-9-hydroxy-7-(phenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta[c][1]benzopyran, 0.76 g. (3.63 mmoles) of γ-morpholinobutyric acid hydrochloride and 0.76 g. (3.70 mmoles) of dicyclohexylcarbodiimide are combined in 75 ml. of methylene chloride and stirred at room temperature for 24 hours. The insoluble by-product of dicyclohexylurea is removed by filtration and the methylene chloride solution is concentrated to 20 ml. Cyclohexane is added until the desired compound is obtained as a colorless solid. Recrystallization from methylene chloride/cyclohexane gives the desired crystalline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Yield: 56 %

Procedure:
Synthesis of the compounds of general class III begins with the reaction of 2-amino4-chloro-5-nitrophenol at 0-50° C., preferably at room temperature, with benzyl bromide in the presence of potassium carbonate and tetra-N-butylammonium iodide in DMF to give 2-benzyloxy-5-chloro-4-nitroaniline in 56% yield. Subsequent reaction of 2-benzyloxy-5-chloro-4-nitroaniline (25-80° C.), preferably refluxing, with benzoyl chloride in the presence of triethylamine provided N-(2-benzyloxy-5-chloro-4-nitrophenyl)benzamide in 85% yield. Reaction of N-(2-benzyloxy-5-chloro4-nitrophenyl)benzamide with sodium dimethyl malonate anion, generated from reaction of dimethyl malonate with sodium hydride in DMSO, in a DMSO solution at 80-150° C., preferably at 110° C., overnight gave dimethyl 2-(5-benzamido-4-benzyloxy-2-nitro)phenylmalonate in 36% yield. When dimethyl 2-(5-bybenzamido-4-benzyloxy-2-nitro)phenylmalonate was treated with NaOH in ethanol at 25-100° C., preferably refluxing, followed by acidification with HCl and mild heating at 25-100° C., preferably refluxing, provided the desired compound 2-(5-amino-4-benzyloxy-2-nitro)phenylacetic acid in 93% yield. Treatment of 2-(5-amino-4-benzyloxy-2-nitro)phenylacetic acid at 0-50° C., preferably at 5° C. then gradual warming to room temperature, with borane in THF selectively reduced the carboxylic acid group to an alcohol, 2-(5-amino-4-benzyloxy-2-nitro)phenylethanol in 52% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:39]2[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][O:33][CH2:32][CH2:31][OH:30])[CH2:37][CH2:38]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCOCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCOCCO)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-[2-(2-hydroxyethoxy)ethyl]piperazine (35 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC(O)=O.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:38]([CH3:40])[CH3:37])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 60 °C

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (20 mg, 0.04 mmol) in THF and AcOH (4.8 mg, 0.08 mmol) was added acetone (2.0 mL, 0.2 mmol) and sodium triacetoxy borohydride (85.0 mg, 0.4 mmol). The mixture was heated at 60° C. for one hour. Saturated sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with ethyl acetate and dried over sodium sulfate. Then the mixture was, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-isopropylpiperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=495)
Reaction SMILES: C[O-].[Na+].C([O:6][C:7](=O)[CH2:8][C:9](=O)[CH3:10])C.[N+]([O-])([O-])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:29][C:30]([NH2:32])=[NH2+:31])[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]>CO>[CH3:10][C:9]1[N:32]=[C:30]([NH:29][C:21]2[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=2)[NH:31][C:7](=[O:6])[CH:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Agent: C[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2nc(C)cc(=O)[nH]2)cc(OC)c1OC
Temperature: 25 °C
Yield: 47.9 %

Procedure:
To a solution of sodium methoxide (0.96 g, 1.79 mmol) in methanol was added ethyl-3-oxo-butanoate (0.23 g, 1.79 mmol) and 3,4,5-trimethoxyphenylguanidinium nitrate (0.5 g, 1.79 mmol). The mixture was stirred at reflux for 17 h. The reaction mixture was cooled to room temperature and evaporated in vacuo to give a dark grey solid. Recrystallisation from ethanol gave the title compound (0.25 g, 49%) as a light grey solid, m.p. 228-230° (dec). δH (d6DMSO) 2.12 (3H, s), 3.61 (3H, s), 3.74 (6H, s), 5.69 (1H, s), 7.02 (2H, s), 8.70 (1H, br s) and 10.47 (1H, br s).
Reaction SMILES: [C:1]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:47])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:46])[CH2:21][CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:45])[N:31]([CH2:33][CH2:34][CH2:35][N:36](C(OC(C)(C)C)=O)[CH3:37])[CH3:32])=[CH:26][CH:25]=2)[CH3:19])[CH2:12][CH2:11]1.Cl.O1CCOCC1>C(O)C>[C:1]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:47])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:46])[CH2:21][CH2:22][NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30](=[O:45])[N:31]([CH3:32])[CH2:33][CH2:34][CH2:35][NH:36][CH3:37])=[CH:28][CH:29]=2)[CH2:14][CH2:15]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCNc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CNCCCN(C)C(=O)c1ccc(NCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
The compound (150 mg, 0.21 mmol) obtained in Example 94b was dissolved in ethanol (0.5 mL), a 4 N hydrochloric acid-1,4-dioxane solution (5.1 mL, 20.6 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. Ethyl acetate was added under ice cooling, a saturated aqueous sodium hydrogencarbonate solution was further added to neutralize the mixture and separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (98 mg; yield, 76%) as a colorless oily substance.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH3:20]O>>[NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([O:13][CH3:20])=[O:12]
Reactant: CO
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1=C(C)CSC2C(N)C(=O)N12
Temperature: 75 °C

Procedure:
7-Amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1 g, 4.67 mmol) was suspended in methanol (20 mL) before treating with conc. sulphuric acid (0.1 ml, 1.876 mmol) and heated at reflux (75° C.) for 16 hours, under argon. After heating for 15 minutes all the remaining solid had dissolved to form a yellow solution. The solution turned from yellow to brown overnight. LCMS run. Desired product seen. Reaction cooled to RT, amount of solvent reduced in vacuo. Residue partitioned between EtOAc (40 ml) and saturated sodium bicarbonate solution (40 ml). Layers separated and aqueous layer was extracted with EtOAc (2×30 ml). Combined extracts were washed with brine (30 ml), dried over Na2SO4, filtered and evaporated to afford a brown gum of the desired product in 801 mg.
Reaction SMILES: S1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([F:13])[C:10]([C:14]3[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:15]=3[F:24])=[C:9]([F:25])[CH:8]=2)[CH2:3][CH2:2]1.O[O:27][S:28]([O-:30])=O.[K+]>C(Cl)Cl>[O:27]=[S:28]1(=[O:30])[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[C:11]([F:13])[C:10]([C:14]3[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:15]=3[F:24])=[C:9]([F:25])[CH:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C3=CCSCC3)cc2F)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3=CCS(=O)(=O)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 6-(4-(3,6-dihydro-2H-thiopyran-4-yl)-2,6-difluorophenyl)-5-fluoropicolinate (1.0 equiv.) in DCM (0.10 M) at rt was added oxone (6.0 equiv.) in one portion. The resulting mixture was stirred at RT overnight, and then refluxed at 40° C. for 4 hrs. 10.0 equiv. of oxone were added and the reaction was allowed to stir at 40° C. over the weekend. The reaction mixture was then diluted with DCM and washed with water the aqueous layer was then separated and extracted with DCM. The combined organic were then dried over MgSO4 and concentrated in vacuo to yield methyl 6-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2,6-difluorophenyl)-5-fluoropicolinate in 100% yield. LC/MS=398.0 (M+H), Rt=0.76 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22].[NH2:24][CH2:25][CH2:26][SH:27]>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]1[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[S:27][CH2:26][CH2:25][N:24]=1
Reactant: COc1cc(SC)ccc1/C=C/C(=O)c1c(O)cc(C)oc1=O
Reactant: NCCS
Solvent: CCO
Product: COc1cc(SC)ccc1C1CC(c2c(O)cc(C)oc2=O)=NCCS1
Temperature: 80 °C
Yield: 41.6 %

Procedure:
4-Hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one (41.8 mg, 0.126 mmol), prepared as in Reference 5, Step 5.1, was dissolved in absolute ethanol (5 mL) and then 2-aminoethanethiol (9.8 mg, 0.126 mmol) was added to the solution. The mixture was stirred at 80° C. The progress of the reaction was followed by analytical HPLC and when complete (approximately 12 hours) the solvent was removed in vacuo. Product was purified by silica flash column chromatography to provide 4-hydroxy-3-[7-(2-methoxy-4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one (20.5 mg) as a pale, yellow solid. LCMS: MH+ 392.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:41]([C:38]3[CH:37]=[CH:36][C:35]([C:32]4[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=4)=[CH:40][CH:39]=3)(=[O:43])=[O:42])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2N
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc(S(=O)(=O)N[C@@H]3CCCc4c(OCC(=O)OC(C)(C)C)cccc43)cc2)cc1

Procedure:
Starting from (R)-(5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (28 mg, 0.1 mmol), triethylamine (0.02 mL, 0.11 mmol) and 4′-methyl-biphenyl-4-sulfonyl chloride (29 mg, 0.11 mmol), using the method analogous to the one for example 1-1, method A, 4th step, crude [(R)-5-(4′-methyl-biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester was obtained, which was used in the next step without further purification. MS cald. for C29H33NO5S 507, obsd. 508 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([NH:11][C:12]1[C:13]([CH2:21][CH2:22][CH3:23])=[N:14][N:15]([CH3:20])[C:16]=1[C:17]([NH2:19])=[O:18])=O)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[NH:19][C:17](=[O:18])[C:16]2[N:15]([CH3:20])[N:14]=[C:13]([CH2:21][CH2:22][CH3:23])[C:12]=2[N:11]=1)[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1sccc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3sccc3OCC)nc12
Temperature: 80 °C
Yield: 57.4 %

Procedure:
A mixture of 3 (1.15 g, 3.42 mmol), NaOH (284 mg, 7.1 mmol) in ethanol (11 mL) and water (34 mL) was heated at 80° C. for 65 h. After cooling to r.t. a white precipitate was formed. Filtration and drying under vacuum gave 0.625 g of the product. The filtrate was extracted with CH2Cl2, and the organic phase was washed with 1N HCl and brine, dried with MgSO4. Evaporation of the solvent gave additional product; mp: 151-152° C.; 1H NMR (CDCl3) δ 1.00 (t, J=7 Hz, 3 H), 1.54 (t, J=7 Hz, 3 H), 1.82 (sxt, J=7 Hz, 2 H), 2.86 (t, J=7 Hz, 2 H), 4.23 (s, 3 H), 4.34 (q, J=7 Hz, 2 H), 6.87 (d, J=6 Hz, 1 H), 7.37 (d, J=6 Hz, 1 H); MS (m/z): 319 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[N+:10]([C:13]1[CH:14]=[CH:15][C:16](O)=[N:17][CH:18]=1)([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][N:17]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)nc1
Temperature: 120 °C
Yield: 48 %

Procedure:
A mixture of 3-flouro-benzyl alcohol (1.07 g, 8.48 mmol), 5-nitro-pyridin-2-ol (1.34 g, 8.48 mmol) and K2CO3 (1.41 g, 10.2 mmol) in DMA (10 ml) was heated at 120° C. for 7 h. The mixture was cooled to rt, diluted with MeOH(10 ml), filtered and purified by preparative HPLC to give 13A (1.01 g, 48%).