Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23]([CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:40][C:18]1[CH:17]=[CH:16][C:15]([C:13]([N:11]2[CH2:12][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10]2)=[O:14])=[CH:20][C:19]=1[C:21]1[NH:22][C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][C:25]=1[CH3:26]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCNCC2)nc1C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3, 475 mg, 0.88 mmol) in 20 mL CH2Cl2, was added trifluoroacetic acid (4 mL). The reaction stirred for 1.5 hours and concentrated under reduced pressure, neutralized with 10 mL Na2CO3 (1M) and lyophilized to afford 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (135 mg, 0.31 mmol), formic acid (300 μL, 6.76 mmol), formaldehyde (37% in water, 300 μL, 3.41 mmol) and water (1.5 mL) was heated to reflux for 10 hours. The reaction was diluted with saturated NaHCO3 until pH 9 and extracted with CH2Cl2 (3×20 mL). The residue was purified by preparative TLC with 10% methanol and 1% ammonium hydroxide in dichloromethane and lyophilized to give 43 mg (30% two steps) of the title compound as a white solid. m/z (ES+) 540 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1F.[Cl:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:27][C:23]1[CH:22]=[C:21]([Cl:20])[CH:26]=[N:25][CH:24]=1
Reactant: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1F
Reactant: Oc1cncc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NCc1ccco1)c1cc([N+](=O)[O-])ccc1Oc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a 0.08 M solution of N-(2-furanylmethyl) 2-fluoro-5-nitrobenzamide (2.64 g, 10 mmol, from Example 35.1) in anhydrous DMSO was added 5-chloro-3-pyridinol (1.36 g, 10.5 mmol, Acros) followed by K2CO3 (1.38 g, 10 mmol). The resulting mixture was stirred at ambient temperature for 1 hr. The crude reaction mixture was diluted with a 1 M solution of aqueous hydrochloric acid (125 mL) and extracted 3× with EtOAc (125 mL). The organic layers were combined and washed twice with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to yield 3.7 g (100%) of N-(2-furanylmethyl) 5-nitro-2-(3-chloro-5-pyridyloxy)benzamide as a pale yellow foam which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[N-:39]=[N+:40]=[N-:41].[Li+]>CS(C)=O>[N:39]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)=[N+:40]=[N-:41]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a stirred suspension of 11.15 g (20 mmole) of 5-[4'-(bromomethyl)biphenyl-2-yl]-N-trityltetrazole [P. E. Aldrich, M. E. Pierce, and J. J. V. Duncia, European Patent Application 291,969 (1988)]in 55 ml of dry DMSO was added 1.23 g (25 mmole) of freshly pulverized lithium azide, and the mixture was stirred at room temperature under N2. Within a few minutes virtually all of the solid had dissolved, accompanied by a mild exotherm, and this was followed immediately by precipitation of product. After 4 hours the solid was collected on a filter and washed with some methanol, then with a relatively large volume of H2O, and finally again with methanol. The solid was air-dried overnight and-then dried further in a vacuum oven at 70° C. (<1 mm) to give 8.60 g (83%) of white crystals, mp 139°-140.5° C. dec., satisfactory purity by TLC (9:1 hexane-ethyl acetate) for use in the next step. From the combined filtrate and washes was recovered a less pure second crop (1.68 g of cream-colored crystals, mp 129°-132° C. dec.), which was also usable in the next step. Mass spectrum (FAB) m/e 243 (trityl cation); IR (Nujol) 2100 cm-1.
Reaction SMILES: ClC1C=[C:4]([NH:8][C:9]([NH:11][S:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:14])=[O:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.N1CCCC1>C(O)C>[N:8]1([C:9]([NH:11][S:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:14])=[O:13])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Nc1cccc(Cl)c1)NS(=O)(=O)C=Cc1ccccc1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C(NS(=O)(=O)C=Cc1ccccc1)N1CCCC1

Procedure:
A mixture of 3.4 g. of N-(N-[m-chlorophenyl]carbamoyl)-2-phenylethenesulfonamide and 2.15 g. of pyrrolidine in 100 ml. of ethanol is heated under reflux for 20 hours. The solution is cooled, and then it is concentrated in vacuo to ca. 25 ml. A small amount of starting material precipitates and it is filtered off. To the ethanol filtrate is then added 75 ml. of ether and 75 ml. of water. The layers are separated, and the aqueous layer is acidified using concentrated hydrochloric acid. This causes the crude product to precipitate. It is filtered off, and when dry it weighs 1.5 g. The ether layer is washed with 50 ml. of 1N hydrochloric acid, followed by 25 ml. of water. After being dried using anhydrous sodium sulfate, the ether is evaporated in vacuo to give a second crop of product (0.70 g.). The first crop of product is recrystallized from acetone to 0.60 g. of pure-N-(pyrrolidinocarbonyl)-2-phenylethenesulfonamide, m.p. 201°-204° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1>C(O)(=O)CC>[F:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2cc(F)ccc12
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(F)ccc2c1O
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
Nitric acid (20 mL of 70%) was added to a hot (125° C.) solution of 7-fluoro-4-quinolinol (35 g, 214 mmol) in propionic acid (200 mL). The reaction mixture was stirred at 125° C. for about 1.5 hours and then allowed to cool to ambient temperature. The resulting yellow precipitate was isolated by filtration, rinsed with water and then with ethanol, and then recrystallized from N,N-dimethylformamide/water to provide 18 g of 7-fluoro-3-nitro4-quinolinol.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:22](Br)[CH3:23].CO>O1CCOCC1>[CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([O:14][CH2:22][CH3:23])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(O)C(=CC1CCCCC1)n1cncn1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(C(=CC1CCCCC1)n1cncn1)C(C)(C)C
Temperature: 50 °C
Yield: 37.7 %

Procedure:
A solution of 26.3 g (0.1 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol (Example 2) in 50 ml of dioxan was added dropwise to a suspension of 3 g of 80% strength sodium hydride in 100 ml of dioxan. When the addition had ended, the mixture was warmed to 50° C. for 1 hour. After cooling, 10.9 g (0.1 mol) of ethyl bromide were added dropwise and the reaction mixture was heated under reflux overnight. After cooling, 10 ml of methanol were added and the mixture was concentrated in a rotary evaporator. The residue was taken up in methylene chloride and the methylene chloride mixture was washed with water. After drying the organic phase over sodium sulphate, it was filtered and the filtrate was concentrated. The residue was distilled. 11.0 g (37.8% of theory) of 1-cyclohexyl-3-ethoxy-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene of boiling point 110° C./0.07 mm Hg were obtained.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[F:22][C:23]1[CH:24]=[C:25]([CH:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc(C(Br)c2cccc(F)c2)c1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3cccc(F)c3)c3cccc(F)c3)nc1-2
Yield: 47 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]acetate and bis(3-fluorophenyl)methylbromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 47%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:35]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH2:40])[CH3:36]>CN(C=O)C>[CH2:35]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:18][CH:17]=1)[CH3:36]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A solution containing about 1.26 g of Compound 39 in about 20 ml anhydrous DMF under nitrogen was cooled in an ice-salt bath. About 0.55 ml of N-methylmorpholin was added to the cooled solution, followed 5 minutes later by about 0.65 ml isobutylchloroformate. After stirring for a period of about 20 minutes, 1.20 g diethyl-L-glutamate hydrochloride was added, followed immediately by about 0.55 ml N-methylmorpholin. The reaction mixture was warmed to room temperature and stirred for 12 hours. At this time, the activation cycle was repeated using 1/2 the amounts of reagents indicated above, after which the reaction mixture was warmed to room temperature and stirred for an additional 12 hours. The solvents were removed under reduced pressure, and the residue was dissolved in about 100 ml CH2Cl2, washed with about 75 ml water, 50 ml 0.1 NHCl, and about 50 ml saturated NaCl. The organic layers were dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure and the residue was flash chromatographed on silica gel (2.4×24 cm), eluting first with CH2Cl2 and then with 1% methanol in CH2Cl2. Fractions showing a single spot corresponding to the product were pooled and evaporated under reduced pressure to yield about 1.29 g of Compound 34.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])[CH3:8].O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[NH2:23][C:22]1[C:3]2[C:2](=[CH:21][CH:20]=[CH:19][C:4]=2[O:5][CH2:6][C:7]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12])([CH3:8])[CH3:9])[N:1]=[C:25]([CH3:32])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(COc1cccc(N)c1C#N)NC(=O)C1CCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)cyclohexanecarboxamide (Example 37b) and ethyl 3-oxobutanoate as a bright yellow solid (55%). MS 428 (MH+).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[ClH:13].Cl.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22][C:23]([NH:25][C:26]([NH2:28])=[NH:27])=[NH:24])=[CH:19][CH:18]=1>C(O)C>[ClH:13].[NH2:28][C:26]1[NH:25][C:23]([NH:22][CH2:21][C:20]2[CH:29]=[CH:30][C:17]([C:16]([F:15])([F:31])[F:32])=[CH:18][CH:19]=2)=[N:24][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:27]=1
Reactant: N=C(N)NC(=N)NCc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCC1N=C(N)NC(NCc2ccc(C(F)(F)F)cc2)=N1

Procedure:
100 ml of ethanol, 5.3 ml (25.7 mmol) of 1-undecanal and 0.7 ml of concentrated hydrochloric acid were added to 5.01 g (16.9 mmol) of N1-(4-trifluoromethylbenzyl)-biguanide hydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The first main fraction eluted with a mixture of chloroform and methanol (9:1.5) was recrystallized from 80% aqueous acetonitrile to obtain 1.41 g of colorless crystals (1) having a melting point of 163 to 166° C., and the second main eluate was recrystallized from 80% aqueous acetonitrile to obtain 0.87 g of colorless crystals (2) having a melting point of 208 to 211° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:15][CH2:16][CH3:17])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][C:27]#[C:28][CH3:29]>CN(C=O)C>[CH2:16]([O:15][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=[C:9]2[N:12]([CH2:29][CH2:28][C:27]#[C:26][CH3:25])[N:13]=[CH:14][C:8]=12)[CH3:17]
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Reactant: CC#CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCCn1ncc2c(OCC)c(C(=O)OCC)cnc21
Reaction time: 4.5 h

Procedure:
A mixture of the ethyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate of Example 19c (8.13 g.), pulverized anhydrous potassium carbonate (14.3 g.) and 1-bromo-3-pentyne (10.7 g.) in dry DMF (58 ml.) was stirred at 55°-60° for 4.5 hours. Additional quantities of 1-bromo-3-pentyne (5.3 g.) and potassium carbonate (14.3 g.) were added after 1 hour. The mixture was cooled and filtered and the filtrate evaporated at 45°-50°. The residue was diluted with water and extracted with ether and EtOAc. The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel using EtOAc/hexane 1:1 v/v as eluant to give the title compound, m.p. 93°-95°, after recrystallization from toluene.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:21]([O:11][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH2:3][C:2]([Cl:19])([Cl:1])[Cl:20])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: OC(Cn1cncn1)(CC(Cl)(Cl)Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OC(Cn1cncn1)(CC(Cl)(Cl)Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Five (5) g (0.0141 mol) of 4,4,4-trichloro-2-(4-chlorophenyl)-2-hydroxy-(1,2,4-(1H)-triazolyl)butane (prepared as in Example I) was slurried in 75 mls of benzene, 4.31 g (0.0422 mol) of acetic anhydride and 2.6 g (0.0211 mol) of 4-dimethylaminopyridine. This mixture was stirred at room temperature for 30 hours and then diluted with 75 mls of benzene. The mixture was washed thrice with 100 mL portions of water. Evaporation of the solvent under reduced pressure and purification of the residue by preparative high pressure liquid chromatography (HPLC) in a 1:1 mixture of ethyl acetate and hexane gave the desired product as a white solid in a yield of 2.2 g (39 percent of theoretical) melting at 112°-114° C.
Reaction SMILES: C[Si]([I:5])(C)C.O[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH2:26][CH3:27])[CH:20]=2)[NH:13][C:12]1=[O:28].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[I:5][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH2:26][CH3:27])[CH:20]=2)[NH:13][C:12]1=[O:28]
Reactant: CCc1cc(Nc2cc(=O)n(CCCCO)c(=O)[nH]2)ccc1C
Reactant: C[Si](C)(C)I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Nc2cc(=O)n(CCCCI)c(=O)[nH]2)ccc1C

Procedure:
Trimethylsilyl iodide (19.4 g, 47 mmol) was added to a stirred solution of 3-(4-hydroxybutyl)-6-(3-ethyl-4-methylanilino)uracil (7.7 g, 24.3 mmol) in dry chloroform (300 ml). The reaction mixture was stirred at reflux for 12 h, until disappearance of starting material (TLC). A saturated solution of aqueous sodium sulfite was added to decolorize the brown-purple solution. After separation of layers, the aqueous solution was extracted with chloroform, and the combined organic extracts were reduced to about one fourth volume. The solid was filtered and washed with water and acetone to give 9.9 g (95%) of IB-EMAU.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.Cl.[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1.O>CN(C)C=O>[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:35][CH2:36]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1
Reactant: ClCCCCCOc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOc2ccccc2)CC1
Reaction time: 7.5 h
Yield: 44.1 %

Procedure:
Potassium carbonate (2.2 g) and 5-phenoxypentyl chloride (1.2 g) were added to a solution of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) in dimethylformamide (40 ml), an the mixture was stirred at 70°-80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give crystals. The obtained crystals were recrystallized from ethyl acetate to give 0.82 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-phenoxypentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=O)#[N:2].[NH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:16]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: Nc1cccnc1N
Reactant: CCOC(=O)CC#N
Product: N#CCc1nc2cccnc2[nH]1
Temperature: 25 °C

Procedure:
Ethyl cyanoacetate (1.5 eq) and 2,3-diaminopyridine (1 eq) were heated at 185° C. for 30 minutes. The reaction mixture was cooled to room temperature and the black solid was triturated with ether. The desired product was thus obtained as a dark brown powder. LC/MS m/z 159.1 (MH+), Rf 0.44 minutes.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)(Cl)=O.[CH2:26](OC1C=CC(CO)=CC=1)[CH2:27]CCCCCCCCCCCC>C(Cl)Cl>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Reactant: CCCCCCCCCCCCOc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(CCl)cc1

Procedure:
This one was synthesized following the same general procedure as that for the preparation of 4-dodecyloxybenzyl chloride; thionyl chloride (7.45 g, 63.1 mmol), 4-tetradecyloxybenzyl alcohol (18.4 g, 57.4 mmol), CH2Cl2 (150 mL). 16.28 g (84%) white solid which decomposes upon melting.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]>>[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=3[CH:17]=2)=[CH:24][CH:23]=1)(=[O:20])[CH3:19]
Reactant: O=C1Nc2ccc(OCCCCCl)cc2CO1
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1.[CH3:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:3]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:9]=1)=[O:18]
Reactant: COC(=O)c1ccc(OCc2ccccn2)cc1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2ccccn2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 4-(Pyridin-2-ylmethoxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 380.2
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2C)=[CH:13][C:12]([I:22])=[N:11][CH:10]=1.[F:34]C(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(C)C(=O)C1C(C2C=CC(F)=CC=2)=CC(Cl)=NC=1>>[F:29][C:28]([F:30])([F:31])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:32])([F:1])[F:33])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:34])=[CH:19][CH:20]=2)=[CH:13][C:12]([I:22])=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(Cl)cc1-c1ccc(F)cc1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(I)cc1-c1ccc(F)cc1

Procedure:
The title compound is prepared according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) using N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-4-(4-fluoro-phenyl)-N-methyl-nicotinamide (Example 36) instead of N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide.