Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][O:6][C:7]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH2:8][CH2:9][C:10](OCC)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:22][NH2:23].C(O)(C)C>O>[C:1]([O:5][O:6][C:7]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH2:8][CH2:9][C:10]([NH:22][NH2:23])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CCC(C)(OOC(C)(C)C)OOC(C)(C)C
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OOC(C)(CCC(=O)NN)OOC(C)(C)C
Reaction time: 20 h

Procedure:
4,4-Di-(t-butylperoxy)pentanohydrazide was prepared by reacting ethyl 4,4-di-(t-butyl-peroxy)pentanoate with 9 molar excess of 54% aqueous hydrazine. A 3-neck flask equipped with a magnetic stirrer, a thermometer and an addition funnel was charged with 125 mL of isopropanol (IPA), 15.3 g (0.05 mole) of 99% ethyl 4,4-di-(t-butylperoxy)pentanoate and 30 g (about 0.50 mole) of 54% aqueous hydrazine at 25° C. The solution was stirred for about 20 hours at 20°-25° C. Then the reaction mass was poured into 1000 mL of water and extracted once with 300 mL of methylene chloride. After drying over 10% by weight of anhydrous magnesium sulfate and separation of the spent desiccant by filtration, the methylene chloride was removed in vacuo leaving 14.4 g of liquid product. 30 mL of pentane were added and a solid was precipitated. The solid was separated by filtration and air dried, leaving 12.2 g (83.6% of theory, uncorrected) of a white solid having a melting point (mp) of 76°-78° C. An infrared (IR) spectrum of the product showed strong carbonyl absorption bands at 1640 cm-1 and at 1680 cm-1 and a strong NH band at 3300 cm-1. A DSC scan run on the product showed a peroxide decomposition exotherm at 170° C. These product data confirm that the product was 4,4-Di-(t-butylperoxy)pentano-hydrazide (I-1).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][NH2:8])#[CH:3].CN1CCOCC1.[CH3:25][C:26]1[C:31]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:30][CH:29]=[C:28]([C:37]([F:40])([F:39])[F:38])[N:27]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][NH:8][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[C:26]([CH3:25])=[N:27][C:28]([C:37]([F:38])([F:39])[F:40])=[CH:29][CH:30]=1)#[CH:3]
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: Cc1nc(C(F)(F)F)ccc1C=CC(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2C)cc(F)c1NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
To a suspension of 3-ethynyl-5-fluoro-4-methansulfonylaminobenzylamine hydrochloride (73 mg, 0.26 mmol) in THF (5 mL) was added N-methylmorpholine (43 μL, 0.39 mmol). After stirring for 5 minutes, 3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylic acid (60 mg, 0.26 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 73 mg, 0.26 mmol) were added. The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexane to give N-(3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl)-3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylamide (89 mg, 75.5%) as solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][CH:47]1[CH2:49][CH2:48]1.O>CN(C=O)C>[CH:47]1([CH2:46][N:13]2[C:12]3[C:7](=[N:8][C:9]([C:16]4[C:24]5[C:19](=[N:20][CH:21]=[CH:22][CH:23]=5)[N:18]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[F:32])[N:17]=4)=[N:10][CH:11]=3)[N:6]([CH2:5][C:4]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=3[O:2][CH3:1])[C:14]2=[O:15])[CH2:49][CH2:48]1
Reactant: BrCC1CC1
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(CC3CC3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
500 mg (0.980 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.270 mmol) of cesium carbonate and 150 mg (1.08 mmol) of 2-bromomethylcyclopropane were added and the mixture was stirred at RT for 18 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum. 482 mg (72% of theory, purity 82%) of the title compound were obtained.
Reaction SMILES: O[N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1.N.[H][H]>C(O)C.[Ni].O>[NH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccc(CC2CCCC2=NO)cc1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(CC2CCCC2N)cc1
Yield: 98.2 %

Procedure:
In an autoclave, a solution of 75.1 g (0.27 mole) of ethyl 4-[(2-hydroxyiminocyclopentyl)methyl]benzeneacetate in 800 ml of anhydrous ethanol saturated with NH3 is combined with about 37.5 g of Raney Nickel in water. The mixture is stirred under 80 atmospheres of hydrogen, at 80° C. during 4 hours. After cooling, the catalyst is filtered and rinsed with ethanol. The concentrated filtrate under reduced pressure, gives 69.3 g (yield=98.3%) of an orange oil which crystallizes but which is used without any other purification.
Reaction SMILES: C([O:5][C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)C(O)=O)(C)(C)C.[Br:29][C:30]1[C:39]([C@H:40]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:41][OH:42])=[C:38]([CH3:48])[CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34]([CH3:49])=[N:35]2>>[Br:29][C:30]1[C:39]([C@H:40]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[C:41]([OH:5])=[O:42])=[C:38]([CH3:48])[CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34]([CH3:49])=[N:35]2
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Reactant: Cc1ccc2c(Br)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Product: Cc1ccc2c(Br)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
Compound 5G was prepared following the procedure used to prepare compound 1L of Example 1, except that (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethanol (5F) was used instead of compound 1K. LCMS-ESI+ (m/z): 366.1, 368.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[CH:5][N:4]=1.[C:10]([C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20](=[O:22])[CH3:21])[CH:19]=1)[NH2:16])(=[O:12])[CH3:11].Cl.[OH-].[K+]>O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:16][C:15]2[CH:14]=[C:13]([C:10](=[O:12])[CH3:11])[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[CH:17]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: CSc1nccc(Cl)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CSc1nccc(Nc2cc(C(C)=O)cc(C(C)=O)c2)n1
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
Illustrative compound 62 was synthesized by mixing 803 mg (5 mmol) 2-methylmercapto-4-chloropyrimidine and 886 mg (5 mmol) 3,5-diacetylaniline in 20 ml of water. In addition, 0.42 ml concentrated HCl was added. This reaction mixture was heated at 90°-100° C. for 4 hours, and then cooled down in an ice bath. The cooled mixture had 5 ml of 1N KOH added to neutralize the acid pH from the HCl. The mixture was stirred for 10 minutes in an ice bath to form a precipitate. The precipitate was filtered out to give 1.44 g dry pale brown crude product. A thin layer chromatography (TLC) analysis in methanol:CH2 Cl2 (1:25) showed only one spot. The crude precipitate was recrystalized from methoxyethanol and dried under vacuum to give 1.42 grams of pure 2-methylmercapto-4-(3',5'-diacetylphenyl) aminopyrimidine (compound 62) with an overall yield of 94%. The NMR analysis found the formula C15H15N3O2S with a molecular weight of 301.38.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[N+]=[N-])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N=[N+]=[N-])c2)COC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N)c2)COC1

Procedure:
A solution of [5-(3-azido-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (497 mg, 1.50 mmol) in EtOAc (37 ml) was hydrogenated using Lindlar catalyst (10 h, room temperature). The mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure yielding the title compound in the form of a colourless solid.
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].[CH:6]([O:9][C:10](=[O:12])[CH3:11])(C)C.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].CC(C(Cl)=O)C(Cl)=O>>[O:4]=[C:1]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:14]([F:13])([F:22])[F:23])[CH:16]=1)[CH2:11][C:10]([O:9][CH3:6])=[O:12]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)C
Reactant: O=C([O-])O
Agent: CC(C(=O)Cl)C(=O)Cl
Agent: [Na+]
Product: COC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 5 °C
Yield: 91 %

Procedure:
Sodium hydrogen carbonate (36.3 kg, 1.7 mol eq) was charged followed by iso-propylacetate (102.5 L, 2.5 rel vol). 3-(trifluoromethyl)aniline (41.0 kg, 1 mol eq, limiting reagent) charged followed by a line rinse of iso-propylacetate (20.5 L, 0.5 rel vol). The reaction was cooled to 5° C.-10° C. Methyl malonyl chloride (36.5 kg, 1.05 mol eq) was charged maintaining the temperature below 10° C. followed by a line rinse of iso-propylacetate (10.3 L, 0.25 rel vol). The mixture was stirred until the reaction was complete as judged by HPLC. The temperature was adjusted to 20° C. and further iso-propylacetate (71.8 L, 1.75 rel vol) charged followed by water (205 L, 5 rel vol). The layers were separated & the organic layer further extracted with brine (41 L, 1 rel vol). The solvent was swapped from iso-propylacetate to cyclohexane by reduced pressure distillation. Following seeding, cooling to 5° C. and stirring, the product was isolated by filtration, washed twice with cyclohexane (2×41 L, 2×1 rel vol) and dried to constant weight to yield the title compound (60.6 kg, 232.2 mol, 91%).
Reaction SMILES: O.ClS(N=[C:7]=[O:8])(=O)=O.C[Si]([CH:13]([OH:15])[CH3:14])(C)C.[I:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C(Cl)Cl>[CH3:7][O:8][C:13](=[O:15])[CH2:14][NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([I:16])[CH:18]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1cccc(I)c1
Reactant: CC(O)[Si](C)(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)CNc1cccc(I)c1
Reaction time: 1 h

Procedure:
To a cooled (ice/salt/water bath) solution of chlorosulfonylisocyanate (3.23 mL, 37.1 mmol) in CH2Cl2 (100 mL) is added trimethylsilylethanol (5.32 mL, 37.1 mmol). After 1 h, a solution of (3-Iodo-phenylamino)-acetic acid methyl ester (2.7 g, 9.28 mmol) (obtained by alkylation of 3-iodoaniline using the method of Tohru Fukuyama et. al., Tett. Lett. 38 (33) pp. 5831-34,1997) and TEA (5.3 mL, 38.04 mmol) in CH2Cl2 (50 mL) is added and the reaction is stirred for 2.5 h. The mixture is poured into 400 mL of 1N aqueous HCl and extracted with EtOAc. The EtOAc layer is washed with 1N aqueous HCl, dried over anhydrous Na2SO4, filtered and concentrated. Chromatography on a 110 g silica gel RediSep (Isco Inc.) column with a 30 mL/min gradient elution of 10:90 (EtOAc:hexane) to 40:60 over 55 min gives an oil. Trituration with Et2O yields N-(2-trimethylsilylethoxycarbonyl-sulfamoyl)-N-(3-iodo-phenyl)glycine methyl ester as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH2:17][C:18]#[CH:19])[CH:6]=1)(=[O:3])[CH3:2]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CCCCCC>[C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]2[C:6]=1[CH:19]=[CH:18][CH2:17][O:16]2)(=[O:3])[CH3:2]
Reactant: C#CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCC=C2
Temperature: 65 °C
Yield: 64.8 %

Procedure:
A stirred solution of methyl 4-acetylamino-5-chloro-2-(prop-2-ynyloxy)benzoate (25 grams, 88.8 mmol, obtained in above step) in dowtherm A (127 mL) was heated to 220° C. for 3 hours. The reaction mixture was cooled to 60-70° C. and dumped in hexane. The solids precipitated were filtered and washed with hexane to obtain methyl 5-acetylamino-6-chloro-2H-chromene-8-carboxylate (16.2 grams).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]2[N:6]=[CH:7][CH:8]=[C:2]12.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[N+:9]([C:8]1[CH:7]=[N:6][N:3]2[CH2:4][CH2:5][NH:1][C:2]=12)([O-:11])=[O:10]
Reactant: c1cc2n(n1)CCN2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of 2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (1 g, 9.17 mmol) in conc. H2SO4 (aq.) at 0° C. was added conc. HNO3 (aq.) portion-wise over 15 min. The reaction was warmed to room temperature and the mixture was stirred for 18 h. The mixture was poured into ice water (200 mL) with stirring. The product was extracted into DCM and the combined organics were washed with saturated aqueous NaHCO3. The organic layer was separated, passed through a phase separator cartridge and concentrated under reduced pressure. The crude residue was triturated with diethyl ether to yield 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole as a pale brown solid (0.52 g, 34%). Sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.62 mmol) was added in 2 portions to a stirred solution of 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.21 g, 1.35 mmol) in anhydrous DMF (10 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 10 min. before di-tert-butyl dicarbonate (0.68 mL, 2.75 mmol) was added. The reaction was stirred for 45 min. Water (5 mL) was added dropwise and the mixture concentrated under reduced pressure. The residue was diluted with water and the product extracted into diethyl ether. The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazole-1-carboxylate as a grey solid (0.22 g, 63%). 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 4.60-4.53 (m, 2H), 4.38-4.30 (m, 2H), 1.50 (s, 9H)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.390 g. of caprylic acid chloride as in Example 1. The 0.671 g. of yellowish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.586 g. of colorless crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl octanoate obtained melts at 77.5°-77.9° and is liquid crystalline (monotrope) upon cooling to 74.1°. UV (EtOH): ε272 = 26,500.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:2].[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:33](=[O:34])[N:32]([CH3:36])[CH3:31])[CH2:19][CH2:18]2)[C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)=[O:15])=[N:10][CH:9]=1)[CH3:2].[CH3:31][N:32]([CH3:36])[C:33]([N:20]1[CH2:19][CH2:18][CH:17]([N:16]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:3])=[O:30])=[CH:9][N:10]=2)[CH2:22][CH2:21]1)=[O:34]
Reactant: CCOC(=O)CCSc1cnc(NC(=O)N(C2CCNCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: CN(C)C(=O)Cl
Product: CCOC(=O)CCSc1cnc(NC(=O)N(C2CCN(C(=O)N(C)C)CC2)[C@H]2CC[C@H](C)CC2)s1
Product: CN(C)C(=O)N1CCC(N(C(=O)Nc2ncc(SCCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
3-{2-[3-(1-Dimethylcarbamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester was prepared in a similar manner to Example 554 using 3-{2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester and dimethylcarbamoyl chloride. Hydrolysis using general procedure (F) gave the title compound
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:11]([CH:14]=1)[C:12]#[N:13].FC(F)(F)C(O)=[O:35].S(=O)(=O)(O)O.[OH-].[Na+]>O>[O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:21][CH2:22]2)=[O:16])=[C:11]([CH:14]=1)[C:12]([NH2:13])=[O:35]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3C#N)CC2)nc1C
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3C(N)=O)CC2)nc1C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
5-(2-Oxoimidazolidin-1-yl)-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (418 mg) described in Example 445 was added to a solution of trifluoroacetic acid (1.12 mL) and concentrated sulfuric acid (0.28 mL) under cooling, and the mixture was stirred at 10° C. for 1 hr. Then, the reaction mixture was added to water under ice-cooling, neutralized with 4N aqueous sodium hydroxide solution and the to mixture was stirred for 1 hr. The obtained precipitate was collected by filtration to give the title compound (363 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[CH3:12][C:13]1[C:14]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:24][CH2:25]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Yield: 94.5 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (310 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (383 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (620 mg) was obtained.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].S(Cl)(Cl)=O.[CH3:18]O>ClCCl>[CH3:18][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([NH:1][C:2]([NH2:4])=[NH:3])=[CH:6][CH:7]=1
Reactant: CO
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NC(=N)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred suspension of 4-guanidino benzoic acid (20.0 g, 93mmol) in methanol (600 mL) was added thionyl chloride (12 mL) drop wise. The reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo to give a white powder. The crude material was dissolved in dichloromethane and evaporated to provide the title compound as a white powder (17.95 g, 100% yield): HPLC Retention Time; 1.27 min (Method A). M+1; 193.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[CH2:2].Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+]>CC(O)C.C(OCC)(=O)C>[OH:13][N:12]=[C:7]([NH2:8])[C:6]1[CH:9]=[CH:10][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1
Reactant: NO
Reactant: C=Cc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C=Cc1ccc(C(N)=NO)cc1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
To a mixture of 4-vinylbenzonitrile (4.36 g, 33.8 mmol) and hydroxylamine hydrochloride (4.69 g, 67.5 mmol) in 2-propanol (50 mL) was added sodium bicarbonate (11.34 g, 135 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4, filtered, and concentrated to yield 5.3 g of N′-hydroxy-4-vinylbenzimidamide. MS (m+1)=163. HPLC Peak RT=0.53 minutes (Analytical Method B).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](O)(=[O:16])[CH2:11]CCCC>C(O)(=O)C>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:16])[CH3:11]
Reactant: CCCCCCCCO
Reactant: CCCCCC(=O)O
Solvent: CC(=O)O
Product: CCCCCCCCOC(C)=O

Procedure:
To a 5 mL reaction vial equipped with stir bar was added approximately 200 μL of 3-butyl-1-(butyl-4-sulfonyl)imidazolium trifluoromethanesulfonate (1.9 M). Added next via syringe was 1-octanol (60 μL, 0.38 mmol) followed by hexanoic acid (48 μL, 0.38 mmol). The resulting monophase was allowed to stir at room temperature for a period of 7 days at which time the oil was washed with toluene (5×2 mL). Shorter reaction times using higher reaction temperatures also afforded excellent conversion of acid to ester. Reaction of 1-octanol and acetic acid resulted in 89% conversion to n-octyl acetate at 40° C. for a period of 72 h whereas 83% conversion was observed at 40° C. for 48 h. The collected organic washes were concentrated in vacuo to afford 76 mg of n-octyl hexanoate. GC analysis of the crude product revealed only trace amounts of starting material in the organic washes. Purification of the crude colorless oil by bulb-to-bulb distillation afforded the desired compound in 72 mg (0.31 mmol, 82% yield) as a clear and colorless oil (bp 130° C./3 mm Hg (air bath temp)). 1H NMR (300 MHz, CDCl3); δ 4.04, J=6.6, 2H), 2.27 (t, J=7.4, 2H), 1.63–1.58 (m, 4H), 1.30–1.25 (m, 14H), 0.87–0.80 (m, 6H). 13C NMR (75.5 MHz, CDCl3); δ 174.10, 64.47, 34.42, 31.84, 31.39, 29.26, 28.72, 26.00, 24.78, 22.70, 22.38, 14.13, 13.96. IR (thin film) 2956, 2929, 2858, 1739, 1466, 1173 cm−1. GC ((HP-1 methyl siloxane; f=1.0 mL/min) 100° C. (2 min), 10° C./min, 275° C. (10 min)) 11.05 min.
Reaction SMILES: [CH3:1][O:2]S([O-])(=O)=O.[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=1[C:10](O)=[O:11].CCN(CC)CC>CN(C=O)C>[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=1[C:10]([O:2][CH3:1])=[O:11]
Reactant: COS(=O)(=O)[O-]
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol). The reaction mixture was stirred at rt for 48 h. The mixture was quenched with water, extracted with EtOAc and dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5% EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56% yield). 1H NMR (300 MHz, DMSO) δ 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (m, 3H), 3.77 (s, 3H).