Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:37][C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH2:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)([C:18](=[O:26])[NH:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.Cl.[CH3:44][NH:45][CH3:46].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:20]1([NH:19][C:18]([C:15]2([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:32](=[O:33])[N:45]([CH3:46])[CH3:44])=[CH:35][CH:36]=3)[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:37][C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH2:13][CH2:14]2)=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc(C(=O)O)cc2)(C(=O)NC2CCCCC2)CC1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)[C@@H](N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[1-(2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl)-4-cyclohexylcarbamoyl-piperidin-4-ylmethyl]-benzoic acid (0.201 mmol; 0.12 g) in DMF (1.5 mL) was added N,N-dimethylamine hydrochloride (0.241 mmol; 0.02 g), N,N-diisopropyl-N-ethylamine (0.502 mmol; 0.089 mL) and HBTU (0.241 mmol; 0.091 g), and the resulting mixture was stirred at room temperature overnight. The mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The resulting residue was dissolved in a 4N HCl solution in 1,4-dioxane (3 mL) and the resulting solution was stirred for 5 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-4-(4-dimethylcarbamoyl-benzyl)-piperidine-4-carboxylic acid cyclohexylamide as a hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([S:16][CH3:17])[N:9]=2)[N:3]=1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C@@H:20]1[CH2:15][C@H:14]1[C:12]1[CH:13]=[C:8]([N:4]2[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]2)[N:9]=[C:10]([S:16][CH3:17])[N:11]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(SC)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(SC)n1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)-6-vinylpyrimidine (1-3) (5.00 g, 20.0 mmol, 1.0 eq.) in degassed toluene (220 mL) was added ethyl diazoacetate (4.3 mL, 40.0 mmol, 2.0 eq.) and the reaction was heated to 120° C. The reaction was monitored by LC-MS and after 6 hours the mixture was cooled to room temperature and the toluene was removed by roto-evaporation. The resulting residue was purified by silica gel column chromatography (10-70% ethyl acetate in hexanes) to afford ethyl-trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropanecarboxylate (1-4) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 4.17 (q, 2H, J=7.1 Hz), 2.88 (s, 3H), 2.61-2.53 (m, 1H), 2.53 (s, 3H), 2.41 (s, 3H), 2.41-2.33 (m, 1H), 1.76-1.62 (m, 2H), 1.28 (t, 3H, J=7.1 Hz). LRMS m/z (M+H) 334 found, 334 required.
Reaction SMILES: [BrH:1].[O:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]1[CH2:8][NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:21])[C:16]=2[OH:20])[C:11]1=[O:22].[H][H]>[Pd].O>[BrH:1].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:21])[C:16]=2[OH:20])[CH:11]1[OH:22]
Reactant: [H][H]
Reactant: O=C1c2ccc(O)c(O)c2CCC1NCC1CCC=CO1
Agent: [Pd]
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1O)CCC(NCC1CCCCO1)C2O

Procedure:
In the presence of 2 parts of 5% palladium-on-carbon, 2 parts of 2-(3,4-dihydro-2H-pyran-2-yl)methylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide is catalytically reduced in 50 volume parts of water at ordinary temperature and pressure until no more hydrogen is absorbed. The catalyst is filtered off and the filtrate is freeze-dried. The above procedure yields 2 parts of 2-(tetrahydropyran-2-yl)methylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as colorless crystals melting at 155°-158° C (decomposition). The product was identified as that of Example 5 by mixed melting point)
Reaction SMILES: [O:1]=[S:2]1(=[O:41])[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14]3[CH:15]=[C:16]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][N:3]1CC1C=CC=CC=1>[Pd].C1COCC1.C(O)C>[O:41]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14]3[CH:15]=[C:16]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:28]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OCCN(Cc2ccccc2)S3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OCCNS3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
10% Palladium on carbon (30 mg) was added to 3-{[1,1-dioxido-2-(phenylmethyl)-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg; 0.17 mmol) in dry THF (4 mL) and dry ethanol (4 mL) under an argon atmosphere. The reaction was degassed and placed under a hydrogen atmosphere then stirred for 24 hours at 50° C. and 20 bar. The mixture was filtered through diatomaceous earth and the filtrate evaporated. Purification via column chromatography, eluting with 50-100% ethyl acetate in isohexane, yielded a colourless oil which solidified under vacuum to give the title compound as a white foam (21 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH:11]=[O:12])[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)CCO)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)CC=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (179 mg, 0.330 mmol, Example 574D) was taken up in DCM (3 mL) and the solution was cooled to 0° C. Dess-Martin periodinane (168 mg, 0.396 mmol) was added, and the reaction was stirred at 0° C. for 1 h. Some SM still remaining, so an additional 0.4 eq. (56 mg) of Dess-Martin was added, and the reaction was stirred for 30 min. The reaction was quenched with 2M K3PO4 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0%-60% EtOAc/Hex; 40 g column). 2-((2-chloro-5-cyano-3-(4-oxobutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (131 mg) was obtained as a yellow glass.
Reaction SMILES: O.O.[O-:3][Mo:4]([O-])(=O)=[O:5].[Na+].[Na+].[CH2:10]([N:12]([CH2:24][CH3:25])[C:13](=[O:23])[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])[CH3:11]>>[CH2:24]([N:12]([CH2:10][CH3:11])[C:13](=[O:23])[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])[CH3:25].[CH2:24]([N:12]([CH2:10][CH3:11])[C:13](=[O:23])[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])[CH3:25].[O:3]=[Mo+2:4]=[O:5]
Reactant: O=[Mo](=O)([O-])[O-]
Agent: CCN(CC)C(=O)CC(=O)c1ccccc1
Agent: [Na+]
Solvent: O
Product: O=[Mo+2]=O

Procedure:
2.05 g sodium molybdate dihydrate and 4.33 g N,N-diethyl-3-phenyl-3-oxopropanamide were reacted according to General Preparation Procedure B. The product consisted of 5.18 g of a yellow, microcrystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][C:26]([NH:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CNC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)CCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 48.5 %

Procedure:
A mixture of 5.0 g (0.017 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 3.0 g (0.025 mole) of 3-chloro-N-methylpropanamide, 15.0 g (0.142 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 100 ml of N,N-dimethylformamide was heated on a steam bath for 16 h. The mixture was poured into 1.5 L of water and extracted twice with 150 ml portions of ethyl acetate. The ethyl acetate fractions were combined, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a dark oil. The oil was purified by column chromatography using 150 g of silica gel on a 60 cm×3.5 cm column, eluted with 10% methanol in methylene chloride. The fractions containing the desired product were partitioned between 15% sodium hydroxide and methylene chloride. The methylene chloride layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a glass. Upon trituration with petroleum ether (30°-60° C.), the glass solidified. The solid was recrystallized from ethyl acetate/petroleum ether (30°-60° C.) to yield 3.2 g (50%) of white solid, mp 127°-129° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:19]1([C:22]#[CH:23])[CH2:21][CH2:20]1>C(NCC)C.C(Cl)CCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:23]#[C:22][CH:19]3[CH2:21][CH2:20]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1CC1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCNCC
Product: CN1Cc2c(C#CC3CC3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.37 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 75° for 16 hours with 1.47 g of cyclopropylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 20 mg of copper(I) iodide in 20 ml of diethylamine and 10 ml of ethylene chloride. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained a mixture of product and starting material. In order to remove the starting material, the mixture was heated under reflux for 4 hours with 1 ml of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 20 mg of copper(I) iodide in 10 ml of diethylamine and 10 ml of ethylene chloride. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate the byproduct can be separated from the desired product. After crystallization from ethyl acetate there was obtained 7-chloro-3-(cyclopropylethynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 177°-178°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:14])[CH2:12][CH3:13]
Reactant: COc1cccc(C)c1C
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred solution of 2,3-dimethylanisole (197.0 g) and propionyl chloride (147.0 g) in carbon disulfide (700 ml) is added anhydrous aluminum chloride (232.0 g) at 5°-10° C. over a period of 1.5 hours. Stirring is continued for 2 hours under cooling and additional 3 hours at room temperature. The reaction mixture is poured onto crushed ice--concentrated hydrochloric acid with stirring. The mixture is extracted with chloroform and the chloroform solution is washed successively with water, dilute sodium bicarbonate solution and water and then dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue is distilled at 121°-126° C. (1-2 mmHg) to give the title compound (255.0 g), which is crystallized from n-hexane, m.p. 39°-40° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH:31]([CH3:33])[CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CNC(C)C)C2

Procedure:
The title compound was prepared (0.064 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and isopropylamine (0.40 g, 6.76 mmol). mp 213-215° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=O)=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].CN(C)C=O.S(Cl)(Cl)=O.[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1>C(O)C.O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([N:35]4[CH2:40][CH2:39][S:38][CH2:37][CH2:36]4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: C1CSCCN1
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)N4CCSCC4)cc3)nc2n(CC)c1=O
Temperature: 0 °C
Yield: 96.6 %

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (10.0 g, 0.0274 moles) and N,N-dimethylformamide (300 ml) is cooled to 0° C. and treated with thionyl chloride (6.5 g, 0.055 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature and stirred vigorously until a thick slurry results. To this slurry is added thiomorpholine (14.2 g, 0.137 moles) in one portion. The resulting mixture is stirred one hour, poured into three liters of water, and filtered. The solids thus obtained are tritruated with ethanol and dried at 48° in a vacuum oven to yield 11.9 grams of 4-[[4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)phenyl]sulfonyl]thiomorpholine, mp 340°-350° C.(d).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(O)[CH2:32][CH2:33][OH:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]([F:29])([F:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH2:26][CH2:32][CH2:33][OH:34])=[O:24])=[CH:21][CH:20]=1
Reactant: OCCCO
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(OCCCO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate, 280 mg. of 1,3-propanediol and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[N:22]=[CH:21]1)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C([O-])(C)=O.[NH4+]>C1COCC1>[OH:8][CH2:9][CH:10]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[N:22]=[CH:21]1)[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1
Reactant: Cc1ccc(CCC(CO[Si](C)(C)C(C)(C)C)n2cnc(C(N)=O)c2)cc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(CCC(CO)n2cnc(C(N)=O)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To an ice cooled solution of 1-[1-(tert-butyldimethylsilyloxy)-4-(4-methylphenyl)-2-butyl]imidazole-4-carboxamide (obtained in Example 3(4))(194 mg, 0.50 mmol) in THF (5 ml) was added dropwise 1.0 M Bu4NF in THF (1.0 ml). After the addition was completed, the reaction mixture was stirred at ice-bath temperature for 1 h. 25% AcONH4 (4 ml) was added, and the resulting mixture was stirred for several minutes and then extracted with chloroform. The organic layer was washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel (5 g) column chromatography eluting with chloroform/methanol (20:1) to give 1-[1-hydroxy-4-(4-methylphenyl)-2-butyl]imidazole-4-carboxamide (44.9 mg, 32.9%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N=CC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOCc1nc2cnc3ccccc3c2n1NCC(C)C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
A solution of N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isobutylideneamine (1.15 g, 3.88 mmol) in 15 mL of methanol was treated with NaBH4 (0.44 g, 11.6 mmol) and stirred under an atmosphere of nitrogen. After 18 h, the reaction was concentrated under reduced pressure. The residue was partitioned between CHCl3 and water, and the phases were separated. The organic portion was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield an orange oil. Chromatography (SiO2, 97:3 CHCl3:MeOH), gave N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isobutylamine (0.69 g) as clear, colorless crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Brc1nccs1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3nccs3)CC2)c(Cl)c1Cl
Yield: 60.2 %

Procedure:
3,4-Dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1; 1 g, 3.2 mmol) was dissolved in NMP (10 ml). Bromothiazole (2.65 g; 16 mmol) was added followed by the addition of N,N-diisopropylethylamine (2.75 ml, 16 mmol). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for a total of 3 h. The mixture was diluted with EtOAc and washed well with water, NaHCO3, brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (692 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][SH:21])=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[N:7]=1)[CH3:2]
Reactant: COc1ccc(CS)cc1
Reactant: CCOC(=O)Cc1cccc(Br)n1
Product: CCOC(=O)Cc1cccc(SCc2ccc(OC)cc2)n1

Procedure:
Prepared according to the procedure described in Example 16, Step 2, using the following starting materials: (6-bromo-pyridin-2-yl)-acetic acid ethyl ester and 4-methoxybenzyl mercaptan.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:21])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].Cl(O)(=O)(=O)=O>[Pt](=O)=O.C(O)(=O)C>[C:1]([CH:6]1[CH2:7][CH2:8][CH:9]([CH2:12][CH:13]([CH3:21])[CH2:14][N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:10][CH2:11]1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(CC(C)CN2CCCCC2)cc1
Agent: O=[Pt]=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCC(C)(C)C1CCC(CC(C)CN2CCCCC2)CC1

Procedure:
7 G. of platinum dioxide and 7 g. of active carbon are suspended in 500 ml. of glacial acetic acid and prehydrogenated. Subsequently, there is added a solution of 37.4 g. of 1-[3-(p-tert.-amyl-phenyl)-2-methyl-propyl]-piperidine in 1000 ml. of glacial acetic acid and 67 ml. of perchloric acid and the mixture is hydrogenated at 25° C. The hydrogenation solution is filtered to remove the catalyst and the filtrate is treated with 110 g. of potassium acetate dissolved in 100 ml. of water. The precipiated potassium perchlorate is removed by filtration and the filtrate is evaporated on a rotary evaporator. The crystalline residue is made alkaline with 2 N sodium hydroxide, the free base is extracted with 500 ml. of ether, washed neutral with water, dried over sodium sulfate and evaporated. By distillation, there is obtained pure 1-[3-(4-tert.-amylcyclohexyl)-2-methyl-propyl]-piperidine, having a boiling point of 128°-132° C./0.04 Torr.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:35])([F:34])[C:26]=3[C:25]([CH:36]([F:38])[F:37])=[N:24]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.BrC1C([C@@H](NC(=O)CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1.[O:81]1[C:85]2([CH2:90]CN[CH2:87][CH2:86]2)[O:84][CH2:83][CH2:82]1>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:34])([F:35])[C:26]=3[C:25]([CH:36]([F:37])[F:38])=[N:24]2)[CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[N:4][C:5]([N:8]2[CH2:87][CH2:86][C:85]3([O:84][CH2:83][CH2:82][O:81]3)[CH2:90][CH2:9]2)=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: C1CC2(CCN1)OCCO2
Agent: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(N2CCC3(CC2)OCCO3)ncc1Br

Procedure:
The title compound (19A) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 12C and 1,4-dioxa-8-azaspiro[4.5]decane. MS (m/z) 740.04 [M+H]+.