Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)(=O)C.C(O[CH2:29][CH3:30])(=O)C>>[N:9]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:30][CH2:29][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(C)=O
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Product: CC(CN1CCCCCC1)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
A solution of 2-(2-cyano-10-phenothiazinyl)propyl mesylate (9.05 g) in hexamethylenimine (28.2 cc) is brought to 90° C. for 16 hours. After cooling, the mixture is diluted with ethyl acetate (200 cc) and washed with distilled water (4×150 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is purified by chromatography on a column of 0.06-0.2 mm silica gel (height: 44 cm; diameter: 3.8 cm), eluting with mixture of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (500 cc) and 70:30 (1500 cc) and collecting 125-cc fractions. Fractions 7 to 15 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-2-phenothiazinecarbonitrile (5.27 g) in the form of a yellow product of honey-like consistency.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])=[N:25][CH:26]=1.CN(C)C=O>O>[CH3:34][C:33]1[O:32][C:31]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[N:30][C:29]=1[CH2:28][O:27][C:24]1[N:25]=[CH:26][C:21]([CH2:20][N:11]2[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:10]2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
Sodium hydride (60%, oily, 270 mg) was added to a mixture of ethyl 3-phenyl-1H-pyrazole-4-carboxylate (1.20 g), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (1.75 g), and N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-carboxylate (1.56 g, yield: 57%) as a colorless oily substance from the fraction eluted with diethyl ether-hexane (2:3, volume ratio).
Reaction SMILES: [NH2:1]C(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.C(N)CN.NC1C=CC=CC=1>>[NH2:1][CH2:30][CH2:29][NH:28][C:26](=[O:27])[NH:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]3=[C:13]([N:7]3[CH2:6][CH:5]4[O:12][CH:9]([CH2:10][CH2:11]4)[CH2:8]3)[N:18]=2)=[CH:20][CH:21]=1
Reactant: NC(N)=O
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Solvent: Nc1ccccc1
Solvent: NCCN
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NCCN)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing ethylenediamine as the aniline component. (31%, MS=550.3 (M+H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[C:11]([C:20]([OH:22])=[O:21])[C:12](=[O:19])[N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:20]([OH:22])=[O:21])[C:12](=[O:19])[N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(C(O)c2ccc(Cl)cc2)c2ccccn2c1=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cc2ccc(Cl)cc2)c2ccccn2c1=O
Reaction time: 1.5 h

Procedure:
To a solution of 1-[(4-chlorophenyl)(hydroxy)methyl]-4-oxo-4H-quinolizine-3-carboxylic acid (0.300 mg, 0.910 mmol) in 5 mL of CH2Cl2 was added triethylsilane (0.29 mL, 1.8 mmol) and trifluoroacetic acid (0.35 mL, 4.5 mmol). After 1.5 h, 10 mL of water was added, and the reaction was extracted with CH2Cl2, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was subjected to purification via reverse phase HPLC to yield the title compound that gave a mass ion (ES+) of 313.96 for M+H+. 1H NMR (400 MHz, CD3OD) δ 9.49 (d, J=7.1 Hz, 1H), 8.40 (s, 1H), 8.07 (d, J=9.1 Hz, 1H), 7.99-7.94 (m, 1H), 7.62-7.58 (m, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.8 Hz, 1H), 4.32 (s, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[OH:18])[CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[OH:18])[CH2:3][CH2:2]1
Reactant: O=C(OC1CCOCC1)c1ccc([N+](=O)[O-])cc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)OC2CCOCC2)c(O)c1
Yield: 35.1 %

Procedure:
2-Hydroxy-4-nitro-benzoic acid tetrahydro-pyran-4-yl ester (0.32 g, 1.20 mmol) was hydrogenated in ethanol (25 mL) with 10% palladium on charcoal catalyst (70 mg) until hydrogen uptake ceased. The mixture was filtered through Celite and concentrated to give a residue which was purified by flash column chromatography on silica, eluting with ethyl acetate/petroleum ether (5-35% gradient) to give 4-amino-2-hydroxy-benzoic acid tetrahydro-pyran-4-yl ester (100 mg, 35%).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:11].[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[C:22]1[N:23]=[CH:24][CH:25]=[C:26]2[C:30]([CH3:31])=[C:29]([CH3:32])[NH:28][C:27]=12>O1CCCC1>[ClH:11].[CH2:3]([N:28]1[C:27]2=[C:22]([N:13]3[CH2:14][CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:12]3)[N:23]=[CH:24][CH:25]=[C:26]2[C:30]([CH3:31])=[C:29]1[CH3:32])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nccc2c1C
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.6 %

Procedure:
Sodium hydride (60%; 40 mg, 0.999 mmol) and benzyl bromide (0.475 ml, 0.399 mmol) were added at 0° C. to a solution of 7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride (92,3 mg, 0.333 mmol) prepared in Example 468 in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred for 12 hours at room temperature and ice was added thereto. The reaction mixture was extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 23.7 mg of the titled compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:36]=[CH:35][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[CH:22]=2)=[C:18]([Cl:37])[CH:17]=1.C(OCC)C>C(#N)C>[Cl:37][C:18]1[CH:17]=[C:16]([NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:11])[CH:36]=[CH:35][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)=[O:29])[CH:22]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(Cl)c1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
2-Phenylacetyl chloride (0.73 ml) was dissolved in acetonitrile (5 ml) under a nitrogen atmosphere, and then potassium thiocyanate (107 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and then a solution of 4-(4-amino-2-chlorophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine (122 mg) in acetonitrile (5 ml) was added thereto, followed by stirring at room temperature for 1.5 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:4, then ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which a small amount of diethyl ether was added to precipitate crystals. A suspension containing the crystals was diluted with a small amount of hexane. The crystals were filtered off and dried under aeration to provide the titled compound (66.7 mg, 36%) as pale yellow crystals.
Reaction SMILES: CI.C[C:4]1[C:13]2[C:8](=CC=CC=2)[CH2:7][CH2:6][N:5]=1.C[Mg][Cl:16].[CH3:17][C:18]1([CH3:29])[C:27]2C(=CC=CC=2)CCN1C>>[C:18]([N:5]1[CH2:4][CH2:13][CH:8]([Cl:16])[CH2:7][CH2:6]1)([CH3:29])([CH3:27])[CH3:17]
Reactant: CN1CCc2ccccc2C1(C)C
Reactant: CC1=NCCc2ccccc21
Reactant: C[Mg]Cl
Solvent: CI
Product: CC(C)(C)N1CCC(Cl)CC1

Procedure:
The imine bond can be activated by quaternization to allow the nucleophilic addition of Grignard reagent. Methyl iodide was added to 1-methyl-3,4-dihydroisoquinoline, generating the iminium salt 1,2-dimethyl-3,4-dihydroisoquinolinium iodide.20 This iminium salt is more reactive than the imine. Methylmagnesium chloride reacted with the iminium, generating 1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinoline. The reaction of methylmagnesium chloride with the iminium salt N-isopropylidene-4-chloropiperidinium chloride gave 1-tert-butyl-4-chloropiperidine.21
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21]>CN(C=O)C.O>[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:11][N:10]([CH2:26][O:25][CH2:24][CH2:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a 100 ml three necked round bottom flask, sodium hydride (60% in paraffin) (0.744 g, 0.0186 mole) was taken in DMF (10.0 ml). To this, 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-yl)-2,2-dimethyl propan-1-one (5.0 g, 0.1773 mole) in DMF (15 ml) was slowly added at 0° C. over 15 min under nitrogen atmosphere. After addition was complete, the reaction mixture was stirred for 10 min at same temperature followed by dropwise addition of SEM chloride (3.1 g, 0.0186 mole) at 0° C. After completion of the addition, the reaction mixture was warmed up to RT and stirred for 30 min. After completion of the reaction, the reaction mixture was poured in water and the aq. Layer was extracted with ethyl acetate. Organic layers were combined, washed with brine solution, dried over Na2SO4, filtered and concentrated to afford crude product which was subjected for the column purification. The crude compound was purified using column purification by eluting the compound with 10-15% ethyl acetate in hexanes to yield 7.0 g of 1-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl)-2,2-dimethylpropane-1-one.
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].O.[F:7][C:8]([F:18])([F:17])[C:9]1[CH:14]=[CH:13]C(C=C)=[CH:11][N:10]=1.S([O-])([O-])=[O:20].[Na+].[Na+]>CCOC(C)=O>[F:7][C:8]([F:18])([F:17])[C:9]1[N:10]=[CH:11][C:2]([C@@H:1]([OH:5])[CH2:3][OH:20])=[CH:13][CH:14]=1
Reactant: CC(C)(C)O
Reactant: O=S([O-])[O-]
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OC[C@H](O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C

Procedure:
A 100 mL flask was charged with tert-butyl alcohol (49 mL), water (49 mL), and AD-mix-(3 (13.78 g). Stirring at room temperature produced two clear phases. The mixture was cooled to 0° C. and 2-(trifluoromethyl)-5-vinylpyridine (1.7 g, 9.8 mmol) was added at once. The heterogeneous slurry was stirred vigorously at −20° C. overnight. TLC indicated completion of the reaction. While the mixture was stirred at 0° C., solid sodium sulfite (15 g, 0.12 mol) was added and the mixture was allowed to warm to rt and stirred for 1 hour. EtOAc was added to the reaction mixture, and after separation of the layers, the aqueous phase was further extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel column (MeOH/CH2Cl2: 0-10%) to afford the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O.CCOCC>[OH:12]/[N:11]=[C:3](/[C:2](=[O:1])[CH2:9][CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)/C(=N\O)C(=O)CC
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
A solution of ethyl 3-oxopentanoate (50 g) in acetic acid (66 ml) was cooled to 0° C. and treated dropwise with 2/3 portion of a solution of sodium nitrite (52.6 g) in water (170 ml). After dropping (40 minutes), the reaction mixture was diluted with water (170 ml) and stirred for 1.5 hours. The mixture was treated with the residual solution of sodium nitrite at room temperature and stirred for more 1.5 hours. The reaction mixture was diluted with ether and quenched by aqueous sodium bicarbonate. The organic phase was washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure to afford ethyl 2-(Z)-hydroxyimino-3-oxopentanoate (43.77 g).
Reaction SMILES: C1(C)C=CC([S:7](O)(=O)=O)=CC=1.[CH2:12]([O:14][CH:15]=[CH2:16])[CH3:13].ClCCl.P([O-])([O-])([O-])=O.[C:25]([O:28]CC)(=[O:27])[CH3:26]>O>[CH2:15]([O:14][CH2:12][CH2:13][S:7][CH2:26][C:25]([OH:28])=[O:27])[CH3:16]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=COCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CCOCCSCC(=O)O
Reaction time: 1 h

Procedure:
To a solution of 17.38 g of p-toluenesulfonic acid maintained between -18° C.-25° C., 23.9 mL of ethylvinyl ether in. 125 mL of dichloromethane is added in drops over a period of 1-1.5 hours. When the addition is complete, the mixture is stirred for another 1 hour. To the above cold solution 250 mL of pH 7 phosphate buffer is added and the cold mixture is poured into a mixture of 800 mL of ethyl acetate and 200 mL of water. The organic layer is removed and the aqueous layer is extracted with 2×200 mL of ethyl acetate. The combined layers were washed with brine, dried over anhydrous MgSO4 and evaporated to give S-(1-ethoxy)ethylmercaptoacetic acid 11 in 100 mL of dry tetrahydrofuran were added 4.85 g of N-hydroxysuccinimide and 8.7 g of N,N'-dicyclohexycarbodiimide. The mixture is stirred for 2-3 hours. TLC in EtOAc:hexanes:acetic acid 49:50:1 (p-anisaldehyde stain) showed the completion of the reaction. Dicyclohexylurea is removed by filtration and the filtrate is evaporated. The oily residue is dissolved in 50 mL of ethyl acetate and washed with water. The solution is dried over anhydrous MgSo4 and evaporated and the product is purified by silica gel flash column chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCOCC3)nc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 241.3, 290 mg, 0.87 mmol) in methanol (6 mL). Then a solution of sodium hydroxide (139 mg, 3.48 mmol) in water (3 mL) was added to the reaction. The reaction mixture was stirred for 1 h at 60° C., then concentrated under reduced pressure. The pH of the solution was adjusted to 1 with hydrogen chloride (2 M). The resulting mixture was concentrated under reduced pressure. Methanol (10 mL) was added to the residue. The salt was filtered off, and the filtrate was concentrated under reduced pressure to give 300 mg of the title compound as a brown solid.
Reaction SMILES: C1(=O)CCCCC1.C(N)CN.O.[CH:13]1([NH:19][CH2:20][CH2:21][NH:22]C2CCCCC2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>[Pt]>[CH:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCC(NCCNC2CCCCC2)CC1
Agent: [Pt]
Solvent: O=C1CCCCC1
Solvent: O
Solvent: NCCN
Product: NCCNC1CCCCC1
Reaction time: 7 h
Yield: 95 %

Procedure:
To a 850 cc glass liner for a rotating autoclave was charged 12.25 g (0.125 mole) cyclohexanone, 3.7 g of a catalyst consisting of 0.3 weight percent platinum (sulfided) on alpha alumina, and an 80 weight percent solution of ethylenediamine in de-ionized water (37.5 g (0.63 mole) ethylenediamine and 9.37 g (0.52 mole) water). An exotherm was generated immediately associated with the formation of Schiff bases from the reaction of cyclohexanone and ethylenediamine. The liner was placed into a rotating autoclave, purged with nitrogen, charged to 1,000 psig with hydrogen or 500 psig each of hydrogen and nitrogen, and then the autoclave was rotated at approximately 30 rpm for 6-8 hours at 160°-180° C. The cooled liner was vented, flushed with nitrogen to avoid catalyst ignition, and the cooled product mixture was removed to afford a clear to pale yellow viscous liquid containing some solids which were principally N,N'-dicylohexyl ethylenediamine (DICEDA). The product mixture was filtered through diatomaceous earth to remove catalyst and DICEDA, and the resulting filtrate contained, in addition to unreacted ethylenediamine, CEDA with only traces of DICEDA. The liner and filter cake were rinsed with methanol and subsequent removal of volatile material at 80° C. afforded product which was principally DICEDA. Removal of volatiles at 80° C. at 30 inches vacuum afforded 15 grams CEDA. Conversion of cyclohexanone amounted to 99+% with a 95% yield of CEDA and 5% DICEDA.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(CN)OC
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCNCC(OC)OC
Reaction time: 16 h
Yield: 78.1 %

Procedure:
Hexyl iodide (50 mmol, 7.38 ml) was added to a mixture of 2-amino acetaldehyde dimethyl acetal (100 mmol, 11 ml) and potassium carbonate (50 mmol, 6.9 g) in DMF (10 ml) at 0° C. Stirring was continued for 16 h before diluting with ethyl acetate (200 ml), and filtering the solution through a plug of celite. Concentration in vacuo was follwed by column chromatography (eluant ethyl acetate) to give N-hexyl 2-amino acetaldehyde dimethyl acetal (7.39 g, 78%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([O:8][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F

Procedure:
A mixture of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (2.2 g), 2-chloronitrobenzene (1.3 g) and potassium carbonate (1.4 g) in N,N-dimethylformamide (100 ml) was heated at reflux for 3 hours under an atmosphere of nitrogen. The resulting mixture was poured into water (200 ml) and acidified by the addition of a small portion of conc. hydrochloric acid. The solution was extracted with a mixed solvent (ethyl acetate:hexane, 1:1,400 ml) and the organic phase dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromatographed on silica gel eluting with ethyl acetate:hexane, 1:1, to give 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-18) as an amorphous solid (1.0-g).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]1[C:13]2[CH:20]=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][N:17]=1.[NH4+].[Cl-]>C1COCC1>[C:3]1([CH2:2][CH2:1][C:12]2[C:13]3[CH:20]=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(CCc2ncnc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
Phenethyl magnesium bromide (0.5 M solution in THF, 12 mL, 6.15 mmol) was added dropwise to a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.210 g, 1.37 mmol) and Fe(acac)3 (0.1 g 0.273 mmol) in THF (5.0 mL) under Ar. The resulting reaction mixture was stirred at r.t. for 8 h. The mixture was poured onto a mixture of ice (10 mL) and NH4Cl (0.5 g) and the product was extracted with CHCl3. The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0 to 10% MeOH/DCM) to afford the title compound (0.166 g, 54%).