Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3(Cl)[N:22]=[C:21](Cl)[N:20]=[CH:19][NH:18]3)[CH:11]=2)[N:7]=[C:6](Cl)[N:5]=[CH:4][NH:3]1.[C:25]1([CH3:32])[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC.C(OCC)(=O)C>[CH3:32][C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][C:30]=1[C:4]1[N:5]=[C:6]([C:30]2[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[N:7]=[C:2]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[N:22]=[C:21]([C:30]4[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[CH3:32])[N:20]=[C:19]([C:30]4[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[CH3:32])[N:18]=3)[CH:11]=2)[N:3]=1
Reactant: ClC1=NC(Cl)(Oc2cccc(OC3(Cl)N=C(Cl)N=CN3)c2)NC=N1
Reactant: Cc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(Oc3cccc(Oc4nc(-c5ccc(C)cc5C)nc(-c5ccc(C)cc5C)n4)c3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Temperature: 25 °C

Procedure:
To a 500 mL round-bottomed flask fitted with a magnetic stirrer, a condenser and a nitrogen atmosphere are added 2.33 g (5.74 mmol) of the product of Example 11 and 25 mL of m-xylene. The mixture is stirred with warming and, when it becomes homogeneous at about 40° C., 1.84 g (0.0138 mol) of aluminum chloride are added all at once. The mixture is brought to reflux and stirred at this temperature for three hours. After cooling to room temperature, a 100 mL portion of 2N hydrochloric acid is added. The mixture is heated with stirring for 15 minutes and allowed to cool. Portions of ethyl acetate and heptane are added and the solids formed are collected by vacuum filtration. The solids are washed with ethyl acetate and water, then dried to afford 2.58 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: Clc1cnccn1
Reactant: CN1CCC[C@H]1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cnccn1
Reaction time: 0.17 h

Procedure:
A solution of (S)-1-methyl-2-pyrrolidinemethanol (1.15 g) in THF (45 mL) was treated with potassium tert-butoxide (1.2 g). After 10 min, chloropyrazine was added and the reaction stirred for 1.5 h. The reaction was quenched with 5N HCl (4 mL) and the solvent evaporated. The residue was suspended in water and extracted with ether. The aqueous fraction was made basic and extracted with CHCl3. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 20%-EtOH-2%-NH4OH-CHCl3 to give (S)-2-(1-methyl-2-pyrrolidinylmethoxy)pyrazine (1.1). The HCl salt crystallized from EtOAc as a white solid, m.p. 121-122° C. (Compound 28).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12.[CH3:12][O:13][C:14](=[O:30])[C:15](=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH3:12][O:13][C:14](=[O:30])[CH:15]([CH:23]([N:9]1[C:5]2=[N:6][CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]2[CH:11]=[CH:10]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17]
Reactant: COC(=O)C(=Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: COc1ccnc2[nH]ccc12
Product: COC(=O)C(C(=O)OC(C)(C)C)C(c1ccccc1)n1ccc2c(OC)ccnc21

Procedure:
2-[(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-phenyl-methyl]-malonic acid tert-butyl ester methyl ester was prepared from 4-methoxy-1H-pyrrolo[2,3-b]pyridine (WO03/082289) and 2-benzylidene-malonic acid tert-butyl ester methyl ester using the procedure of Example 7, and was used without purification.
Reaction SMILES: [N:1]1[C:6](C=O)=[CH:5][CH:4]=[CH:3][C:2]=1C=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)=O>C(O)C>[C:12]1([N:11]=[C:6]2[CH2:5][CH:4]=[CH:3][C:2](=[N:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc(C=O)n1
Reactant: Nc1ccccc1
Solvent: O=CO
Solvent: CCO
Product: C1=CC(=Nc2ccccc2)NC(=Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
2,6-pyridine dicarboxaldehyde (0.3071 g, 2.3 mmol) was added to a solution of aniline (0.5292 g, 5.7 mmol) in absolute ethanol (20 mL) at room temperature. 0.5 mL of formic acid was then added to the above solution. The mixture was stirred at room temperature for 65 hours. The product was filtered, washed with cold ethanol and dried in a vacuum oven (50° C.) overnight. Yield 0.2245 g (34.2%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>CN(C=O)C.C(N(CC)CC)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: C#CC(C)(C)C
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
To a solution of compounds 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (500 mg, 1.09 mmol) and 3,3-Dimethyl-but-1-yne (385 mg, 4.69 mmol) in DMF (0.5 mL), triethylamine (1.06 mL) and tris(dibenzylideneacetone) dipalladium (0) (70 mg, 0.08 mmol) are added and the reaction mixture is stirred under reflux conditions for 16 h under a N2 atmosphere. DMF and triethylamine are removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic layer is separated, dried (Na2SO4), concentrated and the residue is purified by column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid, 330 mg (66%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccccc1C(C)(C)C
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 150 g (1 mol) of 2-(1,1-dimethylethyl)phenol, 151.8 g (1.1. mol) of potassium carbonate and 115 g (1.05 mol) of allyl bromide dissolved in 500 ml of acetone was stirred at reflux temperature for 70 hours and then cooled to room temperature. Once cooled, all precipitates were removed by filtration and the resulting filtrate was concentrated to provide a residue. This residue was dissolved in ethyl acetate and the resulting solution was washed with a 1 N hydrochloric acid solution, water and then a saturated brine solution and then concentrated to dryness to provide a residue. This residue was purified by column chromatography, using hexane as eluent, to provide 167.1 g of title compound.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].C[O:9][C:10](=O)[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([N:19]([CH3:23])[C:20](=[O:22])[CH3:21])=[C:13]([O:24][CH3:25])[CH:12]=1.Cl>O.CS(C)=O>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([C:10](=[O:9])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:12]=[C:13]([O:24][CH3:25])[C:14]=1[N:19]([CH3:23])[C:20](=[O:22])[CH3:21]
Reactant: COC(=O)c1cc(OC)c(N(C)C(C)=O)c(OC)c1
Reactant: CS(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1N(C)C(C)=O
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A suspension of 35.7 g. of dimethylsulfone and 12.0 g. of sodium hydride (50% dispersion in oil) in 100 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 3 hours with the exclusion of moisture and subsequently treated with 34.0 g. of 3,5-dimethoxy-4-(N-methyl-acetamido)-benzoic acid methyl ester. After stirring at room temperature for 2.25 hours, the mixture was diluted with 1 liter of water. The resulting solution was made acidic with 3N hydrochloric acid and extracted with two 1 liter portions of ethyl acetate. The ethyl acetate extracts were washed with two 200 ml. portions of water, combined, dried over magnesium sulfate and evaporated in vacuo. Recrystallization of the residue from ethyl acetate gave 2',6'-dimethoxy-N-methyl-4'-[(methylsulfonyl)-acetyl]-acetanilide having a melting point of 141°-142° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH2:37][CH:38]1[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([NH:37][CH:38]2[CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41]2)=[O:29])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)NC2CN(C(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59.9 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (2.18 g) and tert-butyl 3-amino-1-azetidinecarboxylate (793 mg) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (1.07 ml), and the mixture was stirred under reflux for 40 hours. To the reaction mixture was added methylene chloride, and the solution was washed successively with 10% aqueous citric acid solution, 10% aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 10% methanol/methylene chloride to give tert-butyl 3-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-azetidinecarboxylate (1.52 g) as a solid.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[S:13][C:14]([C:18]([O:20]CC)=O)=[C:15]([CH3:17])[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].COC1C=C(C=CC=1OC)C([NH2:30])=O.ClC(C(C)=O)C(OCC)=O>C(O)CCC.C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[S:13][C:14]([C:18]([NH2:30])=[O:20])=[C:15]([CH3:17])[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C(N)=O)cc1OC
Reactant: CCOC(=O)c1sc(-c2ccc(OC)c(OC)c2)nc1C
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: N
Solvent: CCO
Solvent: CCCCO
Product: COc1ccc(-c2nc(C)c(C(N)=O)s2)cc1OC
Reaction time: 168 h
Yield: 65 %

Procedure:
Into a mixed solution of 50 ml of aqueous 28% ammonia and 450 ml of ethanol, 15.4 g of ethyl 2-(3,4-dimethoxyphenyl)-4-methylthiazole-5carboxylate which had been prepared by heating a mixture of 3,4-dimethoxybenzamide, ethyl α-chloroacetoacetate and n-butyl alcohol under a reflux for 5 hours was dissolved, and the solution was left at room temperature for 7 days. After condensing the solution to solid under a reduced pressure, the thus obtained residue was recrystallized from an aqueous ethanolic solution to obtain the object as colourless minute aciculate melting at 218° to 219.5° C. in an amount of 9.0 g corresponding to the yield of 65%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([BH3-])#[N:16].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:16])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)N)cc1OC
Temperature: 25 °C
Reaction time: 67 h
Yield: 96.5 %

Procedure:
A mixture of 3,4-dimethoxyphenylactone (51.1 g., 0.26 m.) is dissolved in methanol (780 ml.), sodium cyanoborohydride (11.3 g., 0.18 m) is added and the mixture is stirred at room temperature for 67 hours. The reaction mixture is adjusted to pH 2 with concentrated HCl and the solvent is evaporated under reduced pressure. The residue is dissolved in H2O (250 ml.), the aqueous layer is extracted with ether (3X) and then rendered alkaline with KOH and extracted with CH2Cl2 (3X). After drying, the solvent is evaporated under reduced pressure and the product is distilled at 112°-5°/0.5 mm. to yield (VIII) (33.88 g., 67%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].Cl.[O:27]1CCC[CH2:28]1>O>[CH3:13][O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH:28]=[O:27])[C:18]=1[F:24]
Reactant: C1CCOC1
Reactant: COC(=O)Nc1ccc(F)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)Nc1ccc(F)c(C=O)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Into a reaction flask under nitrogen, diisopropylamine (24.87 g, 250 mmol) is combined with 160 mL of anhydrous tetrahydrofuran and the solution is cooled to −78° C. n-Butyllithium (154 mL, 1.6 M in hexanes, 250 mmol) is added dropwise, maintaining the temperature below −70° C. After stirring at −78° C. for 1 hour, (2,4-difluoro-phenyl)-carbamic acid methyl ester (2, 20.00 g, 110 mmol) in 40 mL of tetrahydrofuran is added dropwise, maintaining the temperature below −70° C. The reaction is stirred at −78° C. for 1 hour, then warmed to room temperature and stirred for 1 minute. The reaction is poured into 250 mL of water, the pH is adjusted to 1 with addition of 2M hydrochloric acid, and the mixture is extracted with 3×250 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is slurried in hexane and the resulting solid is collected by filtration and dried to provide the desired compound (3, 19.38 g, 84%).
Reaction SMILES: [Br:1]Br.[CH:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15][CH:16]=[O:17])[CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([Br:1])=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15][CH:16]=[O:17])[CH2:6]1)=[O:4]
Reactant: O=CNC1Cc2ccccc2N(C=O)C1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=CNC1Cc2cc(Br)ccc2N(C=O)C1
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
Bromine (10.2 g, 0.064 tool) was added to a stirred solution of N-(1-formyl-1,2,3,4-tetrahydro-3-quinolyl)formamide (14.0 g, 0.065 tool) in acetic acid (70 mL) containing anhydrous sodium acetate (10.2 g, 0.12 mol). The solution was stirred for 30 minutes and water (500 mL) was added. The precipitate was filtered off and air dried to give 15.8 g (86%) of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-3-quinolyl)formamide, mp 174°-178° C. A sample was recrystallized from ethanol for analysis; mp 178°-181 ° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:18])[S:12][C:13]=2[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>>[CH2:14]([C:13]1[S:12][C:11]([NH:18][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:21]([O:20][CH3:19])[CH:22]=2)=[N:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCCCc1sc(N)nc1-c1ccc(OC)cc1
Product: CCCCc1sc(NC(=O)c2ccc(OC)c(OC)c2)nc1-c1ccc(OC)cc1
Yield: 62.8 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-n-butyl-thiazol-2-ylamine prepared in Example 62 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was recrystallized with petroleum ether and ethyl acetate at a ratio of 2:1 (V:V) to obtain a product as a white solid in a yield of 62.8%, mp: 150-151 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.93 (3H, t, J=7.2 Hz, CH3), 1.41 (2H, sextuple, J=7.20 Hz, CH2), 1.72 (2H, quintuple, J=7.20 Hz, CH2), 2.88 (2H, t, J=7.2 Hz, CH3), 3.80 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.94 (3H, s, OCH3), 6.72˜6.82 (3H, m, ArH), 7.25˜7.40 (4H, m, ArH), 11.16 (1H, br, CONH); EI-MS m/e (%): 426.1 (M+, 50), 383.1 (7), 165.1 (100); HREI-MS Calcd. for C23H26N2O4S: 426.1613. found: 426.1613. Anal. Calcd. for C23H26N2O4S: C, 64.77; H, 6.14; N, 6.57. found: C, 64.56; H, 6.23; N, 6.61.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([C:11]1[N:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)#[N:10]>CC(C)=O>[C:9]([C:11]1[N:16]=[CH:15][C:14]([C:17]([O:19][CH3:1])=[O:18])=[CH:13][CH:12]=1)#[N:10]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C#N)nc1
Yield: 80.2 %

Procedure:
Potassium carbonate (6.1 g, 43.9 mmol) and methyl iodide (21 mL, 338 mmol) were added sequentially to a solution comprising 6-cyanopyridine-3-carboxylic acid (5 g, 33.8 mmol) in acetone (300 mL). The mixture was heated at reflux for 15 hours and concentrated under reduced pressure. The residue was partioned between ether and saturated sodium bicarbonate. The organic layer was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to provide methyl 6-cyanopyridine-3-carboxylate (4.4 g, 27.1 mmol) as a tan solid. 1H-NMR (300 Mhz, DMSO-d6): 3.9 (s, 3H), 8.2 (d, 1H, J=7.5 Hz), 8.5 (d, 1H, J=7.5 Hz), 9.2 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC1N(C)CC[NH+]1C.[OH:41][C:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][C:44]([NH2:52])([CH2:45]3)[CH2:43]1)[CH2:49]2>ClCCl>[OH:41][C:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][C:44]([NH:52][C:7]([C:5]4[N:6]=[C:2]([CH3:1])[N:3]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:4]=4[CH3:10])=[O:9])([CH2:45]3)[CH2:43]1)[CH2:49]2
Reactant: Cc1nc(C(=O)O)c(C)n1-c1ccccc1
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Agent: CN1CC[NH+](C)C1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)NC23CC4CC(CC(O)(C4)C2)C3)c(C)n1-c1ccccc1
Yield: 67.1 %

Procedure:
To a magnetically stirred solution of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.66 gram, 0.00306 mol) in dichloromethane (35 ml) was successively added diisopropylethylamine (DIPEA) (3.1 ml), CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophosphate). (2.55 gram) and 3-hydroxyadamantane amine (0.612 gram, 0.00366 mol). The resulting mixture was reacted at 20° C. for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with 5% aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichoromethane/methanol=98/2 (v/v)) to give N-(3 hydroxyadamant-1-yl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (0.75 gram, 67% yield). Rf (silica gel/dichoromethane/methanol=98/2 (v/v))˜0.6. Melting point: 215-220° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[CH:8](OC)(OC)[O:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:8][O:9][CH:10]1[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: COC(OC)OC
Reactant: OCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC1OCC(CO)CO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.1 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (1.7 g, 16 mmol), trimethyl orthoformate (7 ml, 64.1 mmol), and p-toluenesulfonic acid monohydrate (275 mg, 1.6 mmol) was stirred at room temperature for 22 hours. To the reaction mixture, triethylamine (447 μl) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (1.4 g, 59.1% yield), which is a cis and trans (1:1) mixture, as a light yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].[CH3:13]O>S(=O)(=O)(O)O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1Cc2ccccc2N1

Procedure:
Indoline-2(S)-carboxylic acid (10 g, 64 mmol) was refluxed in a mixture of methanol (50 ml) and sulphuric acid (8 ml) for 5 h. The solvent was removed to give the product in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[CH:4][CH:3]=1.[CH3:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](Cl)=[O:11].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[Br:1][C:2]1[S:6][C:5]([C:10](=[O:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH3:7])=[CH:4][CH:3]=1
Reactant: Brc1cccs1
Reactant: CC(C)(C)CC(=O)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)CC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Stir overnight at room temperature a mixture of 5-bromothiophene (1 g, 6.1 mmol), 3,3-dimethylbutyryl chloride (1.3 mL, 9.1 mmol) and ytterbium(III) trifluoromethanesulfonate (378 mg, 0.6 mmol) in nitromethane (15 mL). Wash the mixture sequentially with water, saturated aqueous NaHCO3 and water. Extract with chloroform, dry over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane to obtain the desired intermediate (1.3 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl.O>CS(C)=O>[C:10]([C:9]1([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:11]
Reactant: ClCCOCCCl
Reactant: N#CCc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2cc(F)cc(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
To a solution of 3,5-difluorophenylacetonitrile (24.2 g, 0.158 mol) in DMSO (240 ml) was added sodium hydride (60% w/w dispersion in mineral oil, 13.3 g, 0.332 mol) portionwise over 10 min. The reaction mixture was stirred for 40 min at room temperature and then bis-(2-chloroethyl)ether (24.9 g, 0.174 mol) was added slowly and stirring continued for an additional 1 h. The reaction mixture was poured into water (500 ml) and the mixture was extracted with an ethyl acetate-toluene mixture (2:1 v/v, 400 ml×3). The combined extracts were washed with 2N aqueous HCl (300 ml), water (300 ml) and brine (300 ml), dried (MgSO4) and concentrated to 100 ml. The precipitated solids were collected and washed with cold Et2O (50 ml) to afford 26.3 g (71%) of the titled compound as off white solids.