Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][C:4](=[S:6])[NH:3][C:2]1=[S:7].[OH-].[Na+].Cl.[Cl:11][CH2:12][C:13]([NH2:15])=[NH:14]>C(O)C>[ClH:11].[C:13]([CH2:12][S:6][C:4]1[N:3]=[C:2]([SH:7])[S:1][CH:5]=1)(=[NH:14])[NH2:15]
Reactant: S=C1CSC(=S)N1
Reactant: N=C(N)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)CSc1csc(S)n1
Yield: 19.9 %

Procedure:
In 20 ml of ethanol was suspended 1.49 g of thiazolidine -2,4-dithione, and 20 ml of 1N-sodium hydroxide solution was added under ice-cooling and stirring. To the mixture was added 1.29 g of α-chloroacetamidine hydrochloride, and the resultant was stirred at room temperature for 2.5 hours and concentrated. The precipitating crystals were collected by filtration, suspended to water, and hydrochloric acid was added to the suspension to dissolve the crystals. Thereafter this solution was subjected to a column chromatography on XAD-II (450 ml) being eluted with water. The eluate was evaporated to dryness and treated with ethanol. The resultant crystals were washed with a (1:2) mixture of ethanol and ethyl acetate to give 0.48 g of 4-amidinomethylthio-2-mercaptothiazole hydrochloride as colorless crystals. mp 178°-181° C. (decomp.)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][CH2:35][CH2:36][CH:37]=[O:38])[C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(=CC)C.Cl([O-])=[O:47].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][CH2:35][CH2:36][C:37]([OH:47])=[O:38])[C:24](=[O:33])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CCCC=O)C(=O)c3ccc(OC)cc3)cc2)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CCCC(=O)O)C(=O)c3ccc(OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirring solution of 4-((4-methoxy-N-(4-oxobutyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-8 (264 mg, 0.484 mmol) in tert-butanol (12 mL) was added 2-methylbut-2-ene (4.7 ml, 44.4 mmol). A solution of sodium chlorite (400 mg, 4.42 mmol) and sodium dihydrogen phosphate (400 mg, 3.33 mmol) in H2O (2.5 mL) were added and the reaction stirred for 1 h at room temperature. The reaction was quenched with aq. Na2S2O5 (10 mL) and brine (10 mL). The aqueous phase was extracted with DCM and the combined organic phases were dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to provide 150 mg (55%) of 4-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-4-methoxybenzamido)butanoic acid 88. LCMS-ESI (m/z) calculated for C33H39NO7: 561; found 560 [M−H]−, tR=9.53 min (Method 4).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>C(Cl)Cl.O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[N:19]([CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)=[O:18])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a mixture of 1-(4-benzyloxy-phenyl)-2-bromo-ethanone (28.55 g; 93.6 mmol) in CH2Cl2 (300 mL) and water (30 mL) was added nBu4NBr (1.51 g; 4.7 mmol) and NaN3 (6.69 g; 102.9 mmol) in one portion. After 4 h at RT, the layers were separated. The organic layer was washed water, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-azido-1-(4-benzyloxy-phenyl)-ethanone (23.64 g)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[CH:22]=[C:21]([Cl:23])[C:18]([C:19]#[N:20])=[C:17](Br)[C:16]=3[O:25][CH2:26][CH3:27])[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:28][N:29]([CH3:41])[C:30]([C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].O.ClCCl>>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[C:16]([O:25][CH2:26][CH3:27])=[C:17]([C:35]4[CH:34]=[CH:33][C:32]([C:30]([N:29]([CH3:41])[CH3:28])=[O:31])=[N:37][CH:36]=4)[C:18]([C:19]#[N:20])=[C:21]([Cl:23])[CH:22]=3)[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C#N)c1Br
Reactant: CN(C)C(=O)c1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Yield: 24.1 %

Procedure:
To a mixture of 4-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (20 mg, 0.04 mmol) and {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (13 mg, 0.069 mmol) in acetonitrile (2 mL, 40 mmol) was added sodium carbonate (10 mg, 0.09 mmol) in water (0.5 mL, 30 mmol). The reaction was degassed with bubbling nitrogen. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2 mg, 0.002 mmol) was added and degassed more with N2. Reaction was heated at 100° C. for 1 h. The crude product was purified on preparative LC-MS (acetonitrile, water, TFA) to give the desired product (0.005 g, 20%) as white amorphous solid. The product was isolated as a racemic mixture. LCMS calculated for C26H24ClN7O3(M+H)+: m/z=518.1; found: 518.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9].C(OC)(OC)OC.Cl.[CH2:18](O)[C:19](=[CH2:21])[CH3:20].CS(O)(=O)=O>CC(O)=O.CO>[CH3:1][C:2]1([CH2:20][C:19]([CH3:21])=[CH2:18])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9]
Reactant: CC1CCCC(C)C1=O
Reactant: C=C(C)CO
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(OC)OC
Product: C=C(C)CC1(C)CCCC(C)C1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2,6-Dimethyl-cyclohexanone (1 kg, 4 mol), trimethyl orthoformate (TMOF, 880 g), and methanol (800 mL) were charged to a 5 L reaction flask. HCl was added quickly. Reaction exothermed and the temperature increased from 14° C. to 20° C. The reaction mixture was heated to 60° C. and aged for 7 hours. When the reaction was about 75% complete, the reaction mixture was quenched with NaOCH3 (25%, 25 g), heated to 90° C., and applied to a Bidwell-Sterling trap. The reaction mixture was then cooled to room temperature followed by sequential addition of methallyl alcohol (1.25 Kg, 8.5 moles), HOAc (50 g), and methane sulfonic acid (MSA, 10 g). The resulting mixture was heated to 110° C., applied to a Bidwell-Sterling trap, and aged for 4 hours until gas chromatograph analysis indicated that the reaction was 95% completed. The reaction mixture was then cooled and washed with saturated sodium carbonate solution (3 L) to provide the crude product 2,6-dimethyl-2-(2-methyl-allyl)-cyclohexanone.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15]SC)[C:7]2=[O:18].O[O:20][S:21]([O-:23])=O.[K+].[CH3:25]O>O>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][S:21]([CH3:25])(=[O:23])=[O:20])[C:7]2=[O:18]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSCCCn1c(=O)[nH]c2c(I)cccc2c1=O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)CCCn1c(=O)[nH]c2c(I)cccc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 150 mL round-bottomed flask was added 8-iodo-3-(3-(methylthio)propyl)quinazoline-2,4(1H,3H)-dione (1.34 g, 3.56 mmol) in MeOH (15 mL) and oxone monopersulfate (3.28 g, 5.34 mmol, Sigma Aldrich) in water (15 mL) was added. The mixture was stirred at RT for 24 h. Another 0.5 equiv. of oxone was added and the mixture was stirred at 35° C. for 24 h. The mixture was diluted with water (30 mL) and extracted with DCM (60 mL×3). The combined organic layers were dried (MgSO4), filtered and concentrated to give the crude product (1.09 g). MS (ESI, pos. ion) m/z: 408.8 (M+1).
Reaction SMILES: C(C[CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH3:11])(=[O:9])=[O:8])#N.Cl.[C:13]([OH:16])(=[O:15])[CH3:14]>>[CH3:11][NH:10][S:7]([CH2:6][CH2:5][CH2:4][CH2:14][C:13]([OH:16])=[O:15])(=[O:9])=[O:8]
Reactant: CNS(=O)(=O)CCCCC#N
Reactant: CC(=O)O
Agent: Cl
Product: CNS(=O)(=O)CCCCC(=O)O
Yield: 58 %

Procedure:
A mixture of 4-cyano-N-methylbutane-1-sulfonamide (Example 9; 100 mmol), acetic acid (100 ml) and concentrated hydrochloric acid (100 ml) was refluxed for 5 hours and then concentrated in vacuo. The residue was taken on THF and then filtered off. The filtrate was concentrated and the residue was washed with dichloromethane to give the pure product (11 g; 58% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:16]=2)=[C:4]([O:17]C)[CH:3]=1.[C:19]([O-])(=O)/C=C/C([O-])=O>>[OH:17][C:4]1[CH:3]=[C:2]([O:1][CH3:19])[CH:7]=[CH:6][C:5]=1[C:8]1[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N:16]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: COc1cc(O)ccc1-c1nc2cnccc2[nH]1
Product: COc1ccc(-c2nc3cnccc3[nH]2)c(O)c1

Procedure:
2-(4-Hydroxy-2-methoxyphenyl)imidazo(4,5-c)pyridine, fumarate, m.p. 255°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12])=O.[CH3:15][O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[NH2:23]>O>[CH3:15][O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:24][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]([F:14])([F:13])[F:12])[N:23]=1
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Reactant: COC(=O)CCCCC(N)=O
Solvent: O
Product: COC(=O)CCCCc1nc(-c2ccccc2C(F)(F)F)co1

Procedure:
Combine 2-bromo-1-(2-trifluoromethyl-phenyl)-ethanone (6.6 g, 24.7 mmol) with 5-carbamoyl-pentanoic acid methyl ester (7.8 g, 49 mmol) and heat the neat mixture in a sealed vessel at 140-150° C. for about 4.5 hours. Cool the mixture, dilute with water, and extract with EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatography over silica gel (CH2Cl2) allows for recovery of 5-[4-(2-trifluoromethyl-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.47 g, 43%). MS (ES): (M+1)+ 328.2 m/z.
Reaction SMILES: [CH3:1][C:2]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])=[N:19][N:18]=1)([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][C:6]=1[C:14]([NH2:16])=[O:15])[CH3:3].O.C(=O)(O)[O-].[Na+].[NH3:39].[CH3:40][C:41]([N:43](C)C)=[O:42]>C(O)C>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([O:4][C:2]([CH3:1])([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:31])([F:32])[F:30])=[N:19][N:18]=2)[CH3:3])=[C:6]([C:14]2[O:15][N:39]=[C:40]([C:41]([NH2:43])=[O:42])[N:16]=2)[CH:7]=1)(=[O:10])[NH2:11]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C(N)=O)cc1C(N)=O
Reactant: CC(=O)N(C)C
Reactant: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C(N)=O)cc1-c1nc(C(N)=O)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-oxyiminooxalate (298 mg) was added to the reaction solution B obtained in Example 55 (1), followed by stirring overnight. Water and saturated aqueous sodium bicarbonate were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (after washing with ethyl acetate, chloroform-methanol=95:1) to obtain a white solid. The resulting solid was dissolved in dimethylacetamide (10 ml), followed by stirring at 150° C. for 8 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 100:3) to obtain a white solid. The resulting solid was dissolved in ethanol (5 ml) and an aqueous ammonia solution (1 ml) was added thereto, followed by stirring for 30 minutes. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1). The resulting solid was washed with diisopropylether to obtain, as a white solid, 5-[5-carbamoyl-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl-1,2,4-oxadiazole-3-carboxamide (36 mg).
Reaction SMILES: [OH-].[Li+].O1CCCC1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1)[CH:13]=O.C(OP([CH:32]1[CH2:40][CH2:39][C@@H:38]2[N:34]([C@H:35]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[CH2:36][CH2:37]2)[C:33]1=[O:48])(=O)OCC)C>O.C(O)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C@H:35]2[N:34]3[C@H:38]([CH2:39][CH2:40]/[C:32](=[CH:13]\[C:12]4[CH:15]=[CH:16][C:17]([N:18]5[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]5)=[C:10]([O:9][CH3:8])[CH:11]=4)/[C:33]3=[O:48])[CH2:37][CH2:36]2)=[CH:46][CH:45]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(Cl)cc3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@@H]3CC[C@@H](c4ccc(Cl)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
Lithium hydroxide (355 mg) was added to a solution mixture of tetrahydrofuran (8 mL)-ethanol (30 mL) of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (875 mg) and [(3S,8aR)-3-(4-chlorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonic acid diethyl ester (2.5 g). The resulting reaction solution was stirred under light-shielded conditions at room temperature for 5 hr and then poured into iced-water. The resulting mixture was extracted with ethyl acetate. The extract solution was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to give 1.43 g of the title compound as a colorless solid. The physical property values of this compound were as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Yield: 97 %

Procedure:
A mixture of 2-fluoro-4-nitrophenol (15gr, 95.5 mmol) and benzyl bromide (18 g, 105 mmol) in acetone (125 ml) containing potassium carbonate (26.5 gr, 190 mmol) was refluxed for 2 hours. The volatiles were removed and the residue was partitioned between 2N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed under vacuum. The solid was triturated with petroleum ether to give 2-fluoro-4-nitro-benzyloxybenzene (23g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:5])[CH3:4].[Br:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[C:11]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[CH:12]=1.COC(=O)[C:22](=[CH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH:23]([CH3:27])[C:24]([OH:26])=O>>[CH3:1][O:2][C:3](=[O:5])[CH2:4][C:22]1[C:23]([CH3:27])=[C:24]([O:26][C:8]2[C:7]([Br:6])=[CH:12][C:11]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:10][N:9]=2)[C:30]2[C:29](=[CH:34][CH:33]=[C:32]([F:35])[CH:31]=2)[CH:28]=1
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Reactant: CCS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: COC(C)=O
Product: CCS(=O)(=O)c1cnc(Oc2c(C)c(CC(=O)OC)cc3ccc(F)cc23)c(Br)c1
Yield: 73.9 %

Procedure:
Starting with 6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (124 mg, 0.50 mmol) and 3-bromo-2-chloro-5-ethanesulfonyl-pyridine (157 mg, 0.55 mmol), using a method analogous to the one described for the methyl ester of example 2-1, [4-(3-bromo-5-ethanesulfonyl-pyridin-2-yloxy)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (183 mg, 73.9%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@@H:11]1[CH2:26][OH:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@@H:11]1[CH2:26][O:27][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1CO)c1ccccc1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1COCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.5 %

Procedure:
The compound (3.37 g, 9.07 mmol) synthesized in Example 1 (1h) was dissolved in methylene chloride:cyclohexane (1:2, 180 mL) and benzyl trichloroacetoimidate (2.0 mL, 10.88 mmol) and trifluoromethanesulfonic acid (2.57 mL, 15.3 mmol) were added thereto, followed by stirring of the mixture at room temperature for 1 hour. After saturated aqueous sodium hydrogencarbonate solution (20 mL) was added to the reaction mixture at 0° C. and the mixture was diluted with ethyl acetate (200 mL), it was washed with water (300 mL) and saturated aqueous sodium hydrogencarbonate solution (300 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-2:1, V/V) to obtain 4.71 g of pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22].[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34](O)=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:24])[CH3:23])=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a stirred solution of N1-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-alaninamide (6g) (765 mg, 2.351 mmol) in dichloromethane (10 mL) was added 3,5-difluorophenylacetic acid (450 mg, 2.614 mmol), HOBt (441 mg, 3.265 mmol), NMM (330 mg, 3.267 mmol) and EDAC-HCl (626 mg, 3.265 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated and then washed in succession with 1N aqueous HCl and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 2:1 (v/v) ethyl acetate:hexanes to afford the title compound (968 mg, 86%) as a white solid. TLC Rf=0.30 (2:1 ethyl acetate:hexanes). 1H NMR (300 MHz, DMSO-d6) δ1.11 (d, 3H, J=7.0 Hz), 3.46 (q AB, 2H, J=14.4 Hz), 4.24 (m, 1H), 4.95 (m, 1H), 5.61 (d, 1H, J=6.6 Hz), 6.94 (m, 2H), 7.02-7.29 (m, 5H), 7.32-7.40, (m, 6H), 8.32 (m, 1H), 10.29 (br, 1H). MS APCI, m/z=480 (M+1). LC/MS: 2.31 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH2:8][CH2:9][CH3:10].[N:12]1([C:18]2[N:25]3[C:21](=[N:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=43)[S:20][N:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(#N)C>C1COCC1.CS(C)=O>[CH2:7]([N:15]1[CH2:14][CH2:13][N:12]([C:18]2[N:25]3[C:21](=[N:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=43)[S:20][N:19]=2)[CH2:17][CH2:16]1)[CH2:8][CH2:9][CH3:10]
Reactant: c1ccc2c(c1)nc1snc(N3CCNCC3)n12
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCCN1CCN(c2nsc3nc4ccccc4n23)CC1

Procedure:
A mixture of potassium carbonate (700 mg, 5.06 mmol), butyl bromide (0.43 mL, 0.4 mmol), 3-piperazinyl-1,2,4-thiadiazolo[4,5-a]benzimidazole (798 mg, 3.07 mmol) in THF (15 mL) and DMSO (2 mL) was refluxed for 16 h. The solution was evaporated to dryness, the residue partitioned between dichloromethane and water. The organic layer was washed five times with water, dried over sodium sulfate and evaporated to give an oil. This oil was mixed with acetonitrile, an insoluble solid was formed which was filtered (595 mg). The solid was purified by chromatography to give the title compound which was recrystallized from hexane (5:95) (440 mg, 41%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=3[S:23][C:14]=12>CN(C)C=O>[Cl:3][C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH:6][C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=3[S:23][C:14]=12
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A mixture of 160 mg (4.00 mmol) of sodium hydride (60% dispersion in oil) and 648 mg (4.00 mmol) of 2,4-dichloroaniline in 10 mL of dimethylformamide is stirred at room temperature for 1 hour. 4-Chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 578 mg (2.00 mmol), is added and the suspension is heated at 130° C. overnight. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is washed with water then dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration. The solid is suspended in diethyl ether and filtered. The filtrate is concentrated to a small volume and filtered to give 80 mg (29%) of 4-(2,4-dichloroanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile as an off-white solid, mp 210–213° C.