Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:12])[CH3:11].[N:13](OCCC(C)C)=[O:14].Cl>CC1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](=[N:13]\[OH:14])/[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Cc1ccc(F)cc1F
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CC1CCCCC1
Product: CC(=O)/C(=N/O)c1ccc(F)cc1F
Temperature: 32.5 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
A solution of 140.2 g (0.80 mol) of 1-(2,4-difluoro-phenyl)-propane-2-one in 550 g of methylcyclohexane is warmed up to 30-35° C. Over a period of 2 hours 96.6 g (0.80 mol) of isoamyl nitrite is added while a slow stream of dry hydrogen chloride is fed subsurface into the reactor. Following the end of the addition the batch is stirred for 15 minutes at 30-35° C. before the suspension is cooled to 0° C. The product is isolated by filtration and the filter cake is washed with 150 g of methylcyclohexane at 0° C.: 146.9 g of (E)-1-(2,4-difluoro-phenyl)-propane-1,2-dione 1-oxime (mp. 133-135° C.) are obtained in 89.5% yield.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:6]1=[O:15]
Reactant: NC1Cc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(N)Cc2ccccc21
Reaction time: 1 h
Yield: 100 %

Procedure:
Sodium hydride (60% in oil, 2.52 g, 63.0 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28, 1985, 1511-16; 5.0 g, 25.2 mmol), in anhydrous DMF (100 mL) at 0° C. over a period of 5 min keeping the internal temperature at <10° C. The reaction was stirred for a further 30 min before addition of methyl bromoacetate (2.85 mL, 30.2 mmol), then stirred for a further 60 min. The reaction was quenched by addition of 1M aqueous HCl (5 mL) and the volatiles were removed by evaporation. The residue was dissolved in DCM (250 mL) and washed with sat. aqueous NaHCO3 (100 mL) and the organic layer was dried (MgSO4), filtered and evaporated to yield the title compound (5.89 g, 25.2 mmol) as yellow paste which was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (50.00 g, 354.36 mmol) in DMF (450 ml) was added 3-hydroxypyridine (33.70 g, 354.36 mmol) under nitrogen. The reaction mixture was heated to 35° C. and then potassium carbonate (102.85 g, 744.15 mmol) was added in one portion. The reaction was very exothermic, and the temperature rapidly increased to 115° C., then gradually increased to 125° C. The mixture was then cooled to 90° C. and stirred at 90° C. for 2 h. The mixture was cooled to room temperature and poured into 2.5 L of water. The mixture was extracted with ethyl acetate (3×), and the combined organic phases were washed with water (3×) and brine (1×), dried over sodium sulfate, and evaporated at reduced pressure. The brown solid residue was stirred in MTBE at reflux, then filtered, and the filtrate was concentrated at reduced pressure to give a yellow crystalline solid that was triturated with ether to give 23.79 g (31%) of the desired product. The brown solids that did not dissolve in MTBE (43.89 g, 57%) were also of sufficient purity for use in the next step (i.e., total yield 88%). 1H-NMR (DMSO-d6) δ 8.50 (m, 2H), 8.24 (d, J=9.1 Hz, 2H), 7.67 (ddd, J=8.4, 2.9, 1.3 Hz, 1H), 7.52 (dd, J=8.3, 4.7 Hz, 1H), 7.18 (d, J=9.0 Hz, 2H); MS LC-MS [M+H]+=217, RT=1.67 min. In a subsequent experiment, the potassium carbonate was added to the 1-fluoro-4-nitrobenzene in DMF under nitrogen. To this stirred solution was dropwise added a solution of the 3-hydroxypyridine in DMF, and the exotherm caused the mixture to gradually warm up to 38° C. The reaction mixture was then heated to 60° C. for 2 h. Reaction work up as described above gave the desired product.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([C:13]1[C:14](=[O:38])[NH:15][C:16](=[O:37])[N:17]([CH:36]=1)[C@@H:18]1[O:35][C@H:22]([CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:20]([OH:21])[CH2:19]1)[CH3:12]>CN(C)C=O>[CH2:1]([S:8][CH2:23][C@H:22]1[O:35][C@@H:18]([N:17]2[CH:36]=[C:13]([CH2:11][CH3:12])[C:14](=[O:38])[NH:15][C:16]2=[O:37])[CH2:19][C@@H:20]1[OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CSCc3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 100.8 %

Procedure:
A solution of 0.5 g of benzyl mercaptan in 10 ml of dry dimethylformamide was treated with 60 mg of a 80% dispersion of sodium hydride in mineral oil. After the effervescence had ceased a solution of 1.64 g of 2'-deoxy-5-ethyl-5'-O-(p-toluenesulphonyl)uridine in 20 ml of dry dimethylformamide was added. The mixture was stirred and heated at 100° C. under a nitrogen gas atmosphere. The course of the reaction was followed by thin layer chromatography. After 4 hours the mixture was evaporated to give an oily residue. This was purified by flash column chromatography on silica gel using methanol/dichloromethane (1:9) for the elution. The fractions containing the product were combined and evaporated to yield an oil which solidified and was recrystallized from diethyl ether to give 1.46 g of 5'-benzylthio-2',5'-dideoxy-5-ethyluridine, mp 149°-151° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])[CH:14]=1)[C:7]([O:9]CC)=[O:8])#[N:2].O.[OH-].[Li+].Cl>C(O)C.O>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([C:15]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])=[O:16])[CH:14]=1)[C:7]([OH:9])=[O:8])#[N:2]
Reactant: CCCN(CCC)C(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(CC#N)cc(C(=O)O)c1

Procedure:
A mixture of ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate (1.5 g) and phosphorous tribromide (0.95 mL) is stirred in dichloromethane (10 mL) and heated at 50 degrees C. for 4 hours and then cooled and partitioned between dichloromethane and water. The organic phase is separated and washed with aqueous sodium bicarbonate and then dried over magnesium sulfate and taken to dryness to give ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate, high resolution MS MH+=370.1020. Ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate (1.4 g) and sodium cyanide (0.2 g) are stirred in dry DMSO (25 mL) at 20-25 degrees C. for 3.5 hours and the mixture is then partitioned between ethyl acetate, water and saline. The organic layer is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate. Ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate (0.6 g) is hydrolyzed with lithium hydroxide monohydrate (0.1 g) in ethanol and water at 20-25 degrees C. overnight and then added to water (50 mL). The pH is adjusted to 4 using concentrated hydrochloric acid and the mixture is partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid, MS M+H=287.2.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Br[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH3:17][O:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:1][CH2:2][CH2:3][OH:4])=[CH:15]2
Reactant: OCCS
Reactant: COc1ccc2ncc(Br)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCO)cc2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
2-Mercaptoethanol (0.11 mL, 1.51 mmol, 2.0 eq) is added at room temperature to a stirred solution of 3-bromo-6-methoxy-quinoline (200 mg, 0.76 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL), followed by sodium hydride (50%, 174 mg, 3.78 mol, 5.0 eq). After 4 hours stirring at 80° C., solvent is evaporated and the residue is extracted with ethyl acetate (3×50 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: ethyl acetate:hexane, 1:4 to 1:2, v/v) to afford 2-(6-methoxy-quinolin-3-ylsulfanyl)-ethanol as a yellow viscous oil (140 mg, 79% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])[O-:3].[K+].C[Si](C)(C)O[Si](C)(C)C.[F:16][C:17]([F:25])([C:21]([F:24])([F:23])[F:22])[C:18](F)=[O:19]>>[C:21]([C:17]([C:18]([O:3][Si:2]([CH3:5])([CH3:4])[CH3:1])=[O:19])([F:25])[F:16])([F:24])([F:23])[F:22]
Reactant: O=C(F)C(F)(F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: C[Si](C)(C)OC(=O)C(F)(F)C(F)(F)F
Temperature: 125 °C

Procedure:
A 200 mL Hastelloy® pressure vessel was heated for 6 hr at 150° C. under a nitrogen purge. At room temperature, the vessel was charged with potassium trimethylsilanolate (0.65 g, 5.1 mmol) and hexamethyldisiloxane (81 g, 0.50 tool) and then sealed, cooled and evacuated. Pentafluoropropionyl fluoride (47.4 g, 0.27 mol) was transferred from a cycinder to the pressure vessel. Once sealed, it was heated at 125° C. (barricade). The pressure rapidly increased to 1.79 MPa and then dropped to 0.62 MPa during a 1.5 hr period. The pressure vessel was heated for a total of 24 hr. The cooled pressure vessel was pressurized with nitrogen and the contents were transferred to a dried bottle. The crude product was transferred under vacuum and subsequently fractionated by spinning band distillation to remove most of the trimethylsilyl fluoride. The remaining 100 g of colorless liquid was a mixture of three components: trimethylsilyl pentafluoropropionate (49.7%) , hexamethyldisiloxane (42.6%) , and trimethylsilyl fluoride (7.6%) as determined by GC analysis, 1H and 19F NMR analyses. 19F NMR(CDCl3): -83.4 (s, CF3), -122.28 (s, CF2), -158.2 (m, SiF). 1H NMR: 0.40 (s, CO2SiMe3), 0.22 (d, Me3SiF), and 0.06 (s, Me6Si2O). GC/MS analysis of a previously prepared sample of CF3CF2CO2SiMe3 featured a component with m/z@220.989868 (calcd forC5H6F5SiO2 =221.005722), consistent with M--CH3.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:40]([O:39][C:37]([N:31]1[CH2:36][CH2:35][N:34]([CH2:14][C:11]2[C:12](=[O:13])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:30][CH:29]=3)[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)[CH:10]=2)[CH2:33][CH2:32]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 78.8 %

Procedure:
Following the procedure of Example 1(10), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 78.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[N:23]=[C:22]([CH3:24])[O:21][N:20]=4)=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[N:23]=[C:22]([CH3:24])[O:21][N:20]=4)=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc3c(=O)n(-c4ccc(F)cc4)c(SCC(=O)OC(C)(C)C)nc3c2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2ccc3c(=O)n(-c4ccc(F)cc4)c(SCC(=O)O)nc3c2)no1
Yield: 70.8 %

Procedure:
A solution of tert-butyl 2-(3-(4-fluorophenyl)-7-(5-methyl-1,2,4-oxadiazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10C, 25 mg, 0.0534 mmol), was treated with 5 mL 20% TFA in DCM for 14 hours. The reaction was concentrated and purified by reverse phase prep LC to yield 2-(3-(4-fluorophenyl)-7-(5-methyl-1,2,4-oxadiazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetic acid (10, 15.6 mg, 64% yield). MS (M+H)=413.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.[H-].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: CSc1ccc(C(=O)CCC(=O)O)cc1
Agent: CC[SiH](CC)CC
Agent: [H-]
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(CCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
In a 500 ml round-bottomed flask, 0.088 mol of the compound obtained in Step A is dissolved in 0.881 ml of trifluoroacetic acid. The solution is cooled to 0° C. with the aid of an ice bath and 0.220 ml of triethylsilane hydride is added with the aid of a dropping funnel. The reaction mixture is stirred for 18 hours at ambient temperature and is then hydrolysed. The precipitate formed is filtered off under suction, is washed with water and with cyclohexane and is then dissolved in ethyl acetate. The organic phase is dried over MgSO4 and evaporated to obtain the title product in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]([NH2:39])([CH2:37][CH3:38])[CH3:36].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:35]([NH:39][C:27]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[O:33])([CH2:37][CH3:38])[CH3:36]
Reactant: CCC(C)N
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, sec-butylamine (23 μl) was added, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 33 mg (yield 49%) of the title compound.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:3]1.[NH2:22][CH:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([NH2:26])=[O:25].Cl>>[NH2:26][C:24](=[O:25])[CH:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([N:4]2[CH2:5][C:2]([F:1])([F:21])[CH2:3]2)=[CH:11][N:10]=1)=[O:13])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Reactant: CC(C)(C)C(N)C(N)=O
Agent: Cl
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 223b) and 2-Amino-3,3-dimethyl-butyramide; hydrochloride (CAN 113582-42-6) as starting materials and isolated (32 mg, 47%); MS (ESI, m/z): 425.3 (M+H+).
Reaction SMILES: [C:1]([NH:11][C:12](=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])SC)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40]>>[C:16]([N:15]=[C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: NCCCCCC(=O)O
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
A methanolic (350 mL) solution of N, N'-dicarbobenzyloxy-S-methyl-isothiourea(60 g, 0.18 mol), triethylamine(18.2 g, 0.18 mol), and 6-aminocaproic acid (23.3 g, 0.18 mol) was refluxed for 30 min and subsequently stirred at room temperature for 4 h. The solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4), and concentrated. The residual solid was recrystallized from ethyl acetate/hexane to afford 52.3 g (66%) of the title product, mp 93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[CH:5]=[C:4]([F:20])[C:3]=1[S:21]([N:24](CC1C=CC(OC)=CC=1OC)C(=O)OC(C)(C)C)(=[O:23])=[O:22].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:20][C:4]1[CH:5]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[CH:7]=[C:2]([F:1])[C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2c(F)cc(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(N)(=O)=O)c(F)c1
Yield: 53.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the t-butyl [(2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}phenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate (0.74 g, 1.22 mmol) prepared in Example 111b, triethylsilane (0.97 mL), trifluoroacetic acid (1.2 mL) and dichloromethane (12 mL), to yield the title compound (232.9 mg, 54%) as a colorless solid.
Reaction SMILES: IC.[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:10][CH:11]([C:13]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][C:35]([S:38]([NH:41][CH2:42][CH2:43][N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)(=[O:40])=[O:39])=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)[O:15][N:14]=1)[CH3:12].[OH-].[K+]>CCO>[C:5]([OH:7])([C:4]([F:9])([F:8])[F:3])=[O:6].[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:4][N:41]([CH2:42][CH2:43][N:44]1[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)[S:38]([C:35]1[CH:36]=[CH:37][C:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH:21]3[CH2:20][CH2:19][N:18]([C:16]4[O:15][N:14]=[C:13]([CH:11]([CH3:10])[CH3:12])[N:17]=4)[CH2:23][CH2:22]3)=[CH:27][CH:28]=2)=[CH:33][CH:34]=1)(=[O:40])=[O:39]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCN5CCOCC5)cc4)cc3)CC2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)N(C)CCN5CCOCC5)cc4)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.7 %

Procedure:
Iodomethane (0.004 mL, 0.07 mmol) was added to a solution of 4′-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-N-[2-(4-morpholinyl)ethyl]-4-biphenylsulfonamide trifluoroacetate (Example 109, 46 mg, 0.07 mmol) and KOH (12 mg, 0.21 mmol) in EtOH (1 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight. The mixture was charged with additional iodomethane (0.006 mL, 0.11 mmol), and stirred at ambient temperature overnight. The mixture was charged with additional iodomethane (0.006 mL, 0.11 mmol) and stirred at ambient temperature overnight. The mixture was quenched with MeOH and concentrated. The crude product was purified by reverse-phase preparative HPLC using a CH3CN:H2O gradient (0.5:99.5 to 90:10) with 0.05% TFA as a modifier to give 19 mg (39%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.80-7.75 (m, 2H), 7.71-7.66 (m, 2H), 7.52 (d, 2H, J=8.8 Hz), 6.97 (d, 2H, J=8.8 Hz), 4.25-4.15 (m, 2H), 4.07-3.83 (m, 6H), 3.78-3.55 (m, 3H), 3.51-3.32 (m, 4H), 3.17-2.97 (m, 3H), 2.95-2.85 (m, 1H), 2.80 (s, 3H), 2.14-2.02 (m, 1H), 2.01-1.91 (m, 2H), 1.54-1.39 (m, 2H), 1.27 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 584 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([NH:15][CH2:16][C:17](O)=[O:18])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:11]([N:15]1[CH2:16][C:17](=[O:18])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]1=[S:10])[CH2:12][CH2:13][CH3:14]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCCCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCN1CC(=O)N(c2ccc(F)cc2)C1=S
Yield: 44.1 %

Procedure:
The title compound was prepared by the procedure described in Example 54 using 7.7 g of 4-fluorophenyl-isothiocyanate, 12.0 g of N-butyl glycine, 15.0 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (5.9 g) as an off-white solid, m.p. 92°-93° C. Anal. Calcd. for. C13H15F N2O S: C, 58.62; H, 5.68; N, 10.52. Found: C, 58.23; H, 5.65; N, 10.56. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[OH:17])([O-:3])=[O:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:7][C:6]=2[N+:14]([O-:16])=[O:15])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2c([N+](=O)[O-])cc(C(C)(C)C)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-dinitro-4-t-butyl-phenol (80 mmol; 10) and tosyl chloride (80 mmol) were dissolved in 300 ml CH2Cl2. Diisopropylethylamine (DIEA, 80 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solution was washed with 10% citric acid, saturated aqueous NaCl (sat. NaCl), and dried with MgSO4. The solvent was removed under reduced pressure, and the product was obtained as a bright yellow solid in quantitative yield. 1H NMR (500 MHz, CDCl3): δ=8.12 (s, 2H), 7.80 (d, 2H), 7.40 (d, 2H), 2.51(s, 3H), 1.41 (s, 9H). ESI-MS: m/z: 417.2 (M+Na+).