Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:43])([O-:42])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[CH:7][C:6]1=[O:33])=[O:2].C(O)(C)C>C(O)(=O)C>[P:1]([OH:43])([OH:42])([O:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[CH:7][C:6]1=[O:33])=[O:2]
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)c(=O)c1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Reaction time: 0.33 h
Yield: 82.7 %

Procedure:
To a 72 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer, and with a jacket temperature set at 40° C., was added di-tert-butyl((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl) phosphate (20, 2820.9 g, 4.49 moles, 1.0 eq) and isopropyl alcohol (25.4 liters, 9.0 volumes). The mixture was stirred at 200 rpm, and acetic acid (14.1 liters, 5.0 volumes) was added, resulting in a clear solution. The clear solution was polish filtered and transferred to a 50 liter jacketed glass reactor system with stirring at 100 rpm. Water (5.6 liters) was added, and the jacket temperature was ramped to 71° C. over 20 minutes. After 4.5 hours of stirring and heating, HPLC analysis indicated that the reaction was complete. The jacket temperature was ramped down to 19° C. over 3 hours, and the product began crystallizing out of solution. The solid was collected by filtration, rinsed with acetone (5 liters). The solid was added back into the reactor vessel, acetone was added (8.5 liters), the jacket temperature was ramped to 45° C. over 10 minutes, and the suspension was stirred. After 40 minutes, the jacket temperature was ramped to 20° C. over 30 minutes, and the crystalline solid was collected by filtration, rinsed with acetone (5 liters) and dried in vacuo at 50° C. to give 1917.7 g (83%) of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate (9) as a crystalline white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N:18]1([CH2:24][CH2:25][OH:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+].O>C1COCC1.CCOC(C)=O>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])=[CH:3][C:2]=1[O:26][CH2:25][CH2:24][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:10])=[O:9]
Reactant: O=c1ccccn1-c1ccc([N+](=O)[O-])c(F)c1
Reactant: OCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccccn1-c1ccc([N+](=O)[O-])c(OCCN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a suspension of 1-(3-fluoro-4-nitrophenyl)pyridin-2(1H)-one (0.70 g, 2.99 mmol) in anhydrous THF (6 mL) at room temperature, a pre-mixed solution of 1-piperidineethanol (0.40 mL, 3.02 mmol) and NaH (60%, 157 mg, 3.92 mmol) in anhydrous THF (8 mL) was added. After addition, the suspension became clear. The mixture was stirred at room temperature overnight. HPLC showed that the reaction was incomplete. Another pre-mixed solution of 1-piperidineethanol (0.40 mL, 3.02 mmol) and NaH (60%, 157 mg, 3.92 mmol) in anhydrous THF (5 mL) was added. After 1 h of stirring, the reaction was completed. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 1-(4-nitro-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (0.74 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10][S:11](=[S:14])([O-:13])=[O:12].[Na+].[CH3:16]N(C)C=O>>[CH3:10][S:11](=[S:14])([O:13][CH2:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:12]
Reactant: CN(C)C=O
Reactant: CS(=O)([O-])=S
Reactant: O=C(O)CCCCCBr
Agent: [Na+]
Product: CS(=O)(=S)OCCCCCCC(=O)O
Temperature: 55 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
6-Bromohexanoic acid (1.0 g, 5.1 mmol) and Sodium Methanethiosulfonate (750 mg, 5.6 mmol, 1.1 eq prepared according to Kenyon and Bruice, Methods Enzymol. (1977), 47, 407-430) were dissolved in 10 mL of dimethylformamide (DMF), warmed to 55° C. and stirred overnight. The reaction mixture was concentrated to syrup and taken up in CHCl3 (30 mL), washed with H2O (5×50 mL) and the organic phase was dried with anhydrous sodium sulfate. Concentration by rotary evaporation and elimination of residual solvent with high vacuum yielded 890 mg (78%) of white solid comprising 6-carboxyhexyl methanethiosulfonate. 1H NMR: δ 3.31 (s, 3H, CH3SO2S), 3.16 (t, J=7.5 Hz, 2H, SCH2), 2.37 (t, J=7.2 Hz, 2H, CH2COOH), 1.79 (m, 2H, CH2CH2S), 1.67 (m, 2H, CH2CH2COOH), 1.48 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][S-:12].[Na+]>C(O)C>[CH3:11][S:12][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])nc1

Procedure:
5-Chloro-2-nitropyridine (8.0 grams) was added to a solution of 2.5 grams of sodium methanethiolate in 100 milliliters of ethanol at a temperature of 0°C. to which solution excess sodium methanethiolate was added portionwise. The resulting reaction mixture was then heated to reflux and refluxed for 15 hours with constant stirring. At the end of the 15 hours, the reaction mixture was filtered and allowed to concentrate to 75 milliliters. The reaction mixture was then permitted to cool and filtered again, yielding the desired 5-(methylthio)-2-nitropyridine; it was recrystallized from ethanol, m.p., 100.5°-02.5°C.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[CH3:21])[CH2:6]1)C.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:21][C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[N:7]1[CH2:8][CH2:9][C:10]2[N:37]=[C:36]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:34][CH:33]=3)[N:38]=[CH:4][C:5]=2[CH2:6]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCC(=O)C(=CN(C)C)C1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1
Temperature: 25 °C

Procedure:
To a solution of 3-Dimethylaminomethylene-1-(2-methyl-5-nitrophenyl)-piperidin-4-one (12.06 gm, 41.7 mmol)[as prepared in reference 1] in Ethanol (250 ml) were added N-[4-(4-Methyl-piperazin-1-yl)-phenyl]-guanidine (38.9 gm, 167 mmol) and sodium acetate (27.32 gm, 334 mmol) and solution was heated under reflux for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was washed with brine, dried [sodium sulfate] and concentrated under vacuum. The crude product obtained was further purified by silica gel chromatography using 5-10% Methanol/Chloroform as eluent to give pure desired product [47] i.e., [6-(2-Methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as yellow solid. (Yield: 3.65 gm, 19.0%).
Reaction SMILES: [CH:1](=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:11]/1([CH3:12])[CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:13])\[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1>CCOCC>[C:14]([O:13][C@H:7]1[CH2:8][CH2:9][CH2:10][C@@:11]2([CH3:12])[C@H:6]1[CH2:5][CH2:4]/[C:3]/2=[CH:1]/[CH3:2])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: C/C=C1/CC[C@H]2[C@@H](O)CCC[C@]12C
Solvent: CCOCC
Solvent: c1ccncc1
Product: C/C=C1/CC[C@H]2[C@@H](OC(C)=O)CCC[C@]12C
Yield: 91 %

Procedure:
A solution of indenol 9 (100.5 g, 0.56 mmol), 6 mL of acetic anhydride and 5 mL of pyridine was stirred for 16 hr at rt. The reaction mixture was diluted with ether (80 mL), washed with 10% HCl (50 mL×4), saturated aqueous NaHCO3, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by chromatography (5% EtOAc/hexane) gave 112.8 mg (91%) of compound 10 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.20 (br d, J=2.4 Hz, IH), 5.08 (qt, J=7.2, 2.0 Hz, 1H), 2.33 (m, 2H), 2.18 (m,1H), 1.80 (m, 2H) 2.04 (s, 3H), 1.65 (dt, J=7.2, 2.4 Hz, 3H), 1.55 (m, 6H),1.08 (s, 3H); MS, m/z (70 eV, EI) 343 (M-tert-Bu+, 100%); HRMS Calcd. 343.1761 for C20H40O4 Si2 -tert-Bu+, found 313.1108.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][NH:17][CH2:18]3)[CH2:13]2)[CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[N:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[C:38]=1[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[N:47]=[CH:48][CH:49]=[CH:50][N:51]=2)[C:38]=1[C:39]([N:17]1[CH2:16][CH2:15][C@@H:14]2[C@@H:19]([N:12]([C:4]3[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=3)[CH2:13]2)[CH2:18]1)=[O:40]
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(C(F)(F)F)n1
Reactant: O=C(O)c1c(F)cccc1-c1ncccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-c4ncccn4)C[C@@H]32)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[8-(6-methyl-2-trifluoromethyl-pyrimidin-4-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 9) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (Intermediate 48) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. For C23H20F4N6O, 472.45; m/z found 473.0 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:23])[CH2:11][CH2:12][C@H:13]([C:20](=[O:22])[NH2:21])[NH:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24]1(=[O:41])[N:28]([CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:25]12.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([O:9][C:10](=[O:23])[CH2:11][CH2:12][C@H:13]([C:20](=[O:22])[NH2:21])[NH:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:24](=[O:41])[C:25]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:26]2[C:27]1=[O:36])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCCCN1C(=O)c2ccccc2C1=O
Reactant: C[C@H](N)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)CCCCN1C(=O)c2ccccc2C1=O)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
L-alanyl-D-isoglutamine benzyl ester hydrochloride (548 mg, 1.6 mmoles) and 5-phthalimidopentanoic acid (400 mg, 1.6 mmoles) were dissolved in N,N-dimethylformamide (8 ml). The solution was cooled to 0° C. and diphenylphosphoryl azide (495 mg, 1.8 mmoles) and triethylamine (323 mg, 3.2 mmoles) were added thereto. The reaction mixture was stirred for 1 hour at 0° C. and for 24 hours at room temperature. The reaction mixture was diluted by ethyl acetate (40 ml) and the organic phase was washed successively with citric acid (0.52M; 3×10 ml), water (3×10 ml), saturated NaCl solution (3×10 ml), saturated NaHCO3 solution (3×10 ml), water (3×10 ml) and saturated NaCl solution (3×10 ml). The organic phase was dried with MgSO4 and filtered, the filtrate was evaporated and the product was precipitated from n-hexane/diethyl ether. The compound was filtered off and crystallized from acetone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][CH2:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:24])[C:5]([CH:9]=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NCC(=O)Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)c(C=O)c(NCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a 25 mL round bottomed flask cooled to 0° C. was added 2-amino-4,6-di-chloro-5-formyl-pyrimidine (192 mg, 1.0 mmol, 1.0 eq.), THF (10 mL), DIEA (0.34 mL, 2.0 mmol, 2.0 eq.), and 2-amino-N-(3-trifluoromethyl-phenyl)-acetamide (245 mg, 1.0 mmol, 1.0 eq.). The reaction mixture was warmed to RT and allowed to stir overnight before quenching with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with brine, dried with Na2SO4, and concentrated to give crude product as a solid. The solid was then rinsed with 5:95 EtOAc:Hexanes to give pure 2-(2-Amino-6-chloro-5-formyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a yellow solid (159 mg, 43%). LC/MSD (HP Series 1100 MSD): Expected MW: 373, Observed M+H, 374.0, Retention time: 1.45 min. ANALYTICAL HPLC: >95%, Retention time: 4.15 min (8 minute run). 1H-NMR (d6-DMSO): 10.5 (s, 1H), 9.9 (s, 1H), 9.42 (t, 1H), 8.08 (s, 1H), 7.80 (d, 1H), 7.59 (t, 1H), 7.42 (d, 1H), 4.40 (d, 2H) ppm.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14]O)=[C:9]([CH3:16])[CH:8]=[CH:7][CH:6]=1>O1CCCC1.ClCCl>[Cl:4][C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][NH:3][CH2:1][CH3:2])=[C:9]([CH3:16])[CH:8]=[CH:7][CH:6]=1
Reactant: CCN
Reactant: Cc1cccc(Cl)c1NCCCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNCCCNc1c(C)cccc1Cl
Yield: 54.3 %

Procedure:
A mixture of a 2.0 M solution of ethylamine in tetrahydrofuran (139.5 mL) and the hydrobromide salt of Example 12, Step A (9.5 g) was stirred at ambient temperature under nitrogen for 48 hours. The tetrahydrofuran was removed in vacuo and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 95:5 to 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide) gave the title compound (3.4 g, 54.3%) as a yellow oil, which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[K+].[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18](Br)[CH2:17]1)[CH3:12]>C(O)C>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:17]1)[CH3:12]
Reactant: Sc1ccccc1Cl
Reactant: CCOC(=O)CC1CCC(=O)C(Br)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CCC(=O)C(Sc2ccccc2Cl)C1
Temperature: 25 °C

Procedure:
28 G. of 2-chlorothiophenol and a solution of 10.8 g. of 85% potassium hydroxide in 300 ml. of ethanol were each placed in a 3 liter three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 50.6 g. of 3-bromo-4-ketocyclohexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotovapor), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. A forerun was collected at 100°-190° (1 mm), while a main fraction was collected at 190° -222° (1 mm). The yield of 3-(2-chlorophenylthio)-4-ketocyclohexaneacetic acid ethyl ester from the main fraction was 33.9 g., b.p. 205°-215/0.7 mm.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:8][C:7]2([C:12]2[S:13][C:14]([S:17](=[O:24])(=[O:23])/[N:18]=[CH:19]\[N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:9]([C:7]1([C:12]2[S:13][C:14]([S:17](=[O:23])(=[O:24])/[N:18]=[CH:19]\[N:20]([CH3:21])[CH3:22])=[CH:15][CH:16]=2)[CH2:8][CH:6]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:11]
Reactant: Nc1nccs1
Reactant: CN(C)/C=N\S(=O)(=O)c1ccc(C2(C(=O)O)CC2C2CCCC2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: CN(C)/C=N\S(=O)(=O)c1ccc(C2(C(=O)Nc3nccs3)CC2C2CCCC2)s1
Yield: 50.5 %

Procedure:
According to method 16h was used (±)-(Z)-2-cyclopentyl-1-[5-(dimethylaminomethylene-sulfamoyl)-thiophen-2-yl]-cyclopropanecarboxylic acid (65 mg, max. 0.344 mmol), 2-amino-thiazole (19 mg, 0.188 mmol), TBTU (60 mg, 0.188 mmol) and triethylamine (57 μL, 0.402 mmol) to give 43 mg of purified product. MS (m/e): 453.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:18]=[N:19][C:20](F)=[CH:21][CH:22]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:18]=[N:19][C:20]([N:30]5[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]5)=[CH:21][CH:22]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(F)nc1
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(N2CCC(O)CC2)nc1
Temperature: 100 °C

Procedure:
A mixture of (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 4-hydroxypiperidine (50 mg, 0.49 mL) in anhydrous DMSO (3 mL) was heated at 100° C. under nitrogen for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-{4-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 55 mg, 89%.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.[OH-].[Na+].CN([CH:29]=[O:30])C>O1CCOCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:1][C:2]2[C:10]([O:11][CH2:4][C:3]3[CH:7]=[CH:8][C:9]([O:30][CH3:29])=[CH:10][CH:2]=3)=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CBr)cc1
Reactant: O=C(O)c1cccc(O)c1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(COc2cccc(C(=O)O)c2OCc2ccc(OC)cc2)cc1

Procedure:
A catechol protecting group other than methyl, that is, one that could be removed concurrently with the BOC functionality while leaving the disulfide intact, was required. Thus, 2,3-dihydroxybenzoic acid (18) was converted to its trianion with NaH in DMF and treated with excess 4-methoxybenzyl bromide to make ester 19 in 62% yield. Hydrolysis of 19 with NaOH (aqueous) in dioxane produced 2,3-bis(4-methoxybenzyloxy)benzoic acid (20) in 90% recrystallized yield (Scheme 1: Synthesis of 20a. aReagents: (a) 60% NaH, 4-methoxybenzyl bromide (3.5 equivalents), DMF, 62%; (b) 2N NaOH, dioxane, 90%). Activation of an equivalent of carboxylic acid 20 with CDI and stirring with N12-(phthaloyl) thermospermine (12) in CH2Cl2 and NEt3 afforded diamine 21 in 57% yield (FIG. 6).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19].[NH2:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[N:46]1([NH-:52])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(Cl)Cl>[NH:16]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:17]([C:21]([NH:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:23])[CH:18]([CH3:19])[CH3:20].[N:46]1([NH-:52])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [NH-]N1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.75 g of DCC are added to a solution of 2.14 g of Z-(L)-Val-OH in 80 ml of absolute ice-cooled methylene chloride and after stirring for 20 minutes at that temperature a solution of 2 g of H-(L)-Phe-morpholin-4-ylamide is added dropwise thereto over a period of 15 minutes. The reaction mixture is stirred for a further 24 hours at room temperature and the urea that forms is filtered off. The filtrate is washed in succession with aqueous sodium hydrogen carbonate solution and brine and, after drying over sodium sulfate, concentrated. Stirring with ether and removal of the insoluble residue by filtration yields, after concentration, the title compound which is processed further without additional purification. TLC Rf (D )=0.7.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]N)=[CH:8][CH:7]=1.[C:18]([O:22][C:23]([NH:25][C:26](=[N:29][C:30]([C:32]1[C:37]([NH2:38])=[N:36][C:35]([NH2:39])=[C:34]([Cl:40])[N:33]=1)=[O:31])SC)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1COCC1.C([N:48](CC)CC)C>>[C:18]([O:22][C:23]([NH:25][C:26]([N:29]([C:30]([C:32]1[C:37]([NH2:38])=[N:36][C:35]([NH2:39])=[C:34]([Cl:40])[N:33]=1)=[O:31])[CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])=[CH:11][CH:10]=1)=[NH:48])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CSC(=NC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OC(C)(C)C
Reactant: CN(C)CCOc1ccc(CCCCN)cc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(CCCCN(C(=N)NC(=O)OC(C)(C)C)C(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
A suspension of compound 63 (0.22 g, 0.93 mmol) and 64 (0.33 g, 0.92 mmol) in THF/triethylamine (11 mL, 10/1) was stirred at room temperature for 48 h. After this time, a clear solution was formed. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, 10:1:0.1 chloroform/methanol/concentrated ammonium hydroxide) to provide the guanidine 65 (0.3 g, 60%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.42 (s, 9H), 1.55 (m, 4H), 2.19 (s, 6H), 2.58 (m, 4H), 3.99 (m, 2H), 6.83 (d, 2H), 7.12 (d, 2H), 7.40 (br s, 2H), 9.02 (m, 2H).