Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1>C(N)C1C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:10][CH2:9][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Solvent: NCc1ccccc1
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(NCc3ccccc3)n2)cc1
Yield: 95 %

Procedure:
This compound was synthesize by refluxing 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in benzylamine overnight. The product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine, was obtained as a white solid in 95% yield; mp: 216-217° C.; Anal. Calc'd for C20H16FN5: C, 69.55; H, 4.67; N. 20.28. Found: C, 69.73; H, 4.69; N, 19.90.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:13]=1)(C)(C)C>Cl.O1CCOCC1>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([C:12]2[CH:13]=[C:8]([CH2:7][C:6]([OH:21])=[O:5])[CH:9]=[N:10][CH:11]=2)[CH2:15][CH2:16]1
Reactant: CN1CCN(c2cncc(CC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(c2cncc(CC(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[5-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-acetic acid tert-butyl ester (1.68 g, 5.77 mmol) is dissolved in 4 M HCl in dioxane (28 ml). After 1 h at 60° C., TLC analysis indicated complete consumption of starting material. The reaction mixture is cooled to RT and diluted with Et2O. The precipitate is filtered and washed with Et2O to yield the title compound, which is used in the next reaction without further purification. 1H NMR (d6-DMSO 400 MHz): δ 2.79 (s, 3H), 3.05-4.10 (br m, 8H), 3.81 (s, 2H), 8.04 (s, 1H), 8.22 (s, 1H), 8.45 (s, 1H). ES+−MS: 236.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[OH:25])[C:15]3=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1COCC1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[OH:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[N:14]1[CH2:13][C:12]2[C:16](=[CH:17][C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)=[CH:3][CH:4]=3)=[CH:10][CH:11]=2)[C:15]1=[O:18]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)ccc2CN1[C@@H]1CCCC[C@H]1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(Cc3ccc4c(c3)C(=O)N([C@@H]3CCCC[C@H]3O)C4)cn2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of rac-6-((6-chloropyridin-3-yl)methyl)-2-(trans-2-hydroxycyclohexyl)isoindolin-1-one (0.09 g) in a mixed solvent of THF (9.00 mL)-water (3.00 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.11 g), cesium carbonate (0.33 g) and bis(tri-tert-butylphosphine)palladium(0) (0.03 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (0.03 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:24])[C:10]([C:19]([O:21]CC)=[O:20])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[OH-].[K+].Cl>C(O)C.[Cl-].[Na+].O>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:24])[C:10]([C:19]([OH:21])=[O:20])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C)nn2c(CC)ccc2c1-c1cncc(C)c1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1ccc2c(-c3cncc(C)c3)c(C(=O)O)c(C)nn12
Yield: 94.7 %

Procedure:
To a solution of ethyl 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (682 mg) in ethanol (20 mL) was added potassium hydroxide (5 g) solution (10 mL) and the mixture was heated under reflux for 1 hour. The solution was acidified with 1 N hydrochloric acid to pH 3-4 and diluted with brine, and extracted with chloroform twice. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The crude product was triturated with ethyl acetate to give 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid as a yellow powder (590 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([N:12]([C:16](=O)[CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:5]2
Reactant: CCCN(C(=O)CC)C1COc2ccc(N)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCN(CCC)C1COc2ccc(N)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
To a solution of 6-amino-3-(N-propionyl-N-n-propylamino)chroman (18) (300 mg, 1.03 mmol) in anhydrous diethyl ether was added LiAlH4 (300 mg, 7.89 mmol). The mixture was stirred for 1.5 hours at room temperature. Excess hydride was quenched by addition water (0.5 ml), 15% sodium hydroxide (0.3 ml) and water (0.9 ml). The mixture was filtered and the solvent evaporated yielding 216 mg (85%) of 23 as an oil.
Reaction SMILES: C([O:4][C@@:5]1([C:13]#[CH:14])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)(=O)C.[H-].[Na+].O>CO>[C:13]([C@:5]1([OH:4])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)#[CH:14]
Reactant: C#C[C@@]1(OC(C)=O)CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#C[C@@]1(O)CN2CCC1CC2
Reaction time: 2 h
Yield: 98.6 %

Procedure:
The acetate 49 (179 g, 0.926 mol) was treated with a solution of NaH (60% dispersion in oil, 100 mg, 2.7 mmol) in methanol (900 ml). After stirring for 2 hours at reflux, water (20 ml) was added and the solution concentrated. The residue was treated with ether and the white solid obtained was filtered off, dissolved in ethanol (2 L) and water (200 ml). The mixture was evaporated to dryness and dried under vacuum to give the (3R)-3-ethynyl-1-azabicyclo[2.2.2]octan-3-ol 50 as a white solid (138 g, 98%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:13]=O>O.O1CCCC1.CCOCC>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:13]=[N:2][OH:3]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: ON=Cc1ccc(Cl)c(Cl)c1
Temperature: 22 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A solution of hydroxylamine hydrochloride (2.73 g, 39.3 mmol) in water (35 ml) was treated with sodium acetate (2.74 g, 33.4 mmol) followed by a solution of 3,4-dichlorobenzaldehyde (4.0 g, 22.8 mmol) in tetrahydrofuran (15 ml) and the resulting mixture was stirred at 22° C. for 2 h. The reaction mixture was then diluted with ether (250 ml), washed with water, brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent gave 4.3 g of 3,4-dichlorobenzaldehyde oxime as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([OH:20])[N:17]=[C:16]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]=[C:16]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[N:17]=[C:18]([OH:20])[CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(O)nc(N3CCCCC3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1cc(C2CCNCC2)nc(N2CCCCC2)n1
Yield: 81 %

Procedure:
A suspension of 4-(6-hydroxy-2-piperidin-1-yl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.05 mol) in 15% HCl in dioxane (100 mL) was stirred at reflux for 2 hours. After reaction was completed the mixture was cooled, precipitate was filtered, washed with dry ether and dried to obtain 6-piperidin-4-yl-2-piperidin-1-yl-pyrimidin-4-ol, hydrochloride salt (12 g, 81%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:17][C:18]1([CH3:26])[C:20]([CH3:22])([CH3:21])[CH:19]1[C:23](O)=[O:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:17][C:18]1([CH3:26])[C:20]([CH3:22])([CH3:21])[CH:19]1[C:23]([N:12]1[CH2:11][CH2:10][N:9]([C:4]2[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13]1)=[O:24]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)C(C(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)C1(C)C
Yield: 67 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2,2,3,3-tetramethylcyclopropanecarboxylic acid (100 mg, 0.70 mmol) was carried out according to a similar procedure described for example 1A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 67% yield (166 mg) as colorless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([CH2:20][OH:21])[CH2:17][CH2:16][N:15]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:10]=[CH:11][C:12]=1[F:13].C(N(CC)CC)C.N12CCN(CC1)CC2>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([CH2:20][O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:16][N:15]2[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: O=C(OCc1ccccc1)N1CC[C@H](CO)C[C@@H]1c1ccc(F)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC[C@H]1CCN(C(=O)OCc2ccccc2)[C@@H](c2ccc(F)c(F)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
Methanesulfonyl chloride (74 mg, 0.65 mmol) was added to a mixture of (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (233 mg, 0.64 mmol), triethylamine (233 mg, 1.7 mmol), and 1,4-diazabicyclo[2.2.2]octane (15 mg, 0.13 mmol) in toluene (10 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 15 minutes, and at room temperature for another 15 minutes. The reaction mixture was then quenched with a cold mixture of water and ethyl acetate. The organic portion was separated, washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5% to 25% ethyl acetate in hexanes gradient) to give (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (271 mg, 96% yield). MS (EI) for C21H23F2NO5S: 440 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:9](=O)[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6](=O)[C:3]21[CH2:5][CH2:4]2.Cl.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][C:3]21[CH2:4][CH2:5]2
Reactant: CN1C(=O)CN(Cc2ccccc2)C(=O)C12CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccccc2)CC12CC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 105.2 %

Procedure:
4-Methyl-7-(phenylmethyl)-4,7-diazaspiro[2.5]octane-5,8-dione (1.535 g, 6.284 mmol) was dissolved in THF (100 mL) and the mixture was cooled to 0° C. Borane-THF complex (25.13 mL, 25.13 mmol) was added portionwise over 10 min. The mixture was heated to 60° C. for 4 h and was then checked by LCMS. If greater than 15% of the starting material remained, an additional portion of Borane-THF complex (12.56 mL, 12.56 mmol) was slowly added, and the reaction was allowed to stir for an additional 45 min. When the reaction was complete as determined by LCMS, the reaction mixture was cooled to room temperature. 1N HCl (25 mL) was added, and the mixture was heated to 80° C. for 1 h. The reaction mixture was then cooled to room temperature, and 6 N aq. NaOH was added to adjust the pH to 14. The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude product was purified via reverse phase HPLC to provide 4-methyl-7-(phenylmethyl)-4,7-diazaspiro[2.5]octane (1.43 g, 94%). LCMS: (M+H)+:217.2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[N:12]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[N:15][CH:14]=[N:13]1.Br[C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[N:29][CH:30]=1>O>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([O:23][C:20]2[CH:19]=[CH:18][C:17]([N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[CH:22][CH:21]=2)=[CH:30][N:29]=1)([O-:33])=[O:32]
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(-n3cncn3)cc2)cn1
Temperature: 70 °C
Yield: 31.9 %

Procedure:
Cesium carbonate (1.3 g, 4.03 mmol) was mixed with 3 ml of dry dimethylformamide, 4-(1H-1,2,4-triazol-1-yl)phenol (0.5 g, 3.1 mmol) and 5-bromo-2-nitropyridine (0.63 g, 3.1 mmol) and the reaction mixture was heated at stirring at 70° C. in a closed vial. The reaction mixture was then mixed with 40 ml of water and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine, dried over magnesium sulfate and concentrated by rotary evaporation. The resulting greenish-brown solid was washed thoroughfully with methylene chloride to give 280 mg of desired compound (32% yield).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:26][CH3:27])[C:24]=1[OH:25])[CH:18]=[CH:19][C:20]#[N:21].[CH:28](OCC)=[O:29].Cl>O1CCCC1>[CH:28]([C:19](=[CH:18][C:17]1[CH:22]=[C:23]([O:26][CH3:27])[C:24]([OH:25])=[C:15]([O:14][CH3:13])[CH:16]=1)[C:20]#[N:21])=[O:29]
Reactant: COc1cc(C=CC#N)cc(OC)c1O
Reactant: CCOC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(C=C(C#N)C=O)cc(OC)c1O
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
A 4.0 ml of n-butyllithium (1.6M) was added to a tetrahydrofuran (20 ml) solution of diisopropylamine (0.9 ml) at -70° C. under nitrogen atmosphere. After 15 minutes, to the solution was added a tetrahydrofuran (8 ml) solution of 1.24 g of 3,5-dimethoxy-4-hydroxycinnamonitrile at -60° C. or less, and the solution was stirred for 1 hour. A 0.7 ml of ethyl formate was added to the solution, and the mixture was further stirred for 1 hour. A 1N hydrochloric acid was added to the mixture and a temperature of the mixture was elevated to room temperature. The mixture was extracted with 250 ml of ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A crystal formed was washed with ethanol to give 430 mg (yield 43.6%) of α-formyl-3,5-dimethoxy-4-hydroxycinnamonitrile. The compound thus obtained was dissolved in 20 ml of tetrahydrofuran- To the solution 3.2 g of carbethoxymethylenetriphenylphosphorane was added. The mixture was stirred at room temperature for 32 hours, and concentrated under reduced pressure. A 80 ml of ethyl ether was added to the residue. The solution was washed with water and 1N hydrochloric acid in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A crystal formed was washed with ethanol to give 320 mg (yield 57.3%) of γ-cyano-6-(3,5-dimethoxy-4-hydroxy)phenyl-2,4-pentadienic acid ethyl ester, which was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and methanol (10 ml). To the solution, an aqueous potassium hydroxide solution (140 mg/5 ml) was added. The mixture was stirred at room temperature for 48 hours, concentrated under reduced pressure. A 70 ml of water was added to the residue. The aqueous solution was washed with ethyl acetate and acidified with conc. hydrochloride. The aqueous layer was extracted with 200 ml of ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 190 mg (yield 65.1%) of a desired γ-cyano-β-(3,5-dimethoxy-4-hydroxy)phenyl-2,4-pentadienic acid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:29][CH2:28][C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: O[C@H](CNCc1ccc(C(F)(F)F)cc1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 4-(trifluoromethyl)benzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=95%, [M+H]+=461.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@H:9]1[NH:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=2)[N:19]=3)[CH2:10]1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([N:14]1[C@@H:9]([CH3:8])[CH2:10][N:11]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([C:31]2[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=2)[N:19]=3)[CH2:12][C@H:13]1[CH3:15])(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1[C@H](C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
Triethylamine (73.8 μl, 0.53 mmol) was added to a methylene chloride solution (9.0 ml) of 5-[8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (108.7 mg, 0.22 mmol) at room temperature followed by the addition of acetic anhydride (25.0 μl, 0.26 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 3 days followed by the addition of acetic anhydride (8.3 μl, 0.09 mmol) and the resulting mixture was stirred for 1 day. Acetic anhydride (4.2 μl, 0.04 mmol) was further added to the resulting mixture, the resulting mixture was stirred for 1 day, and the reaction mixture was poured into methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (109.8 mg, 93%) as a pale yellow solid.
Reaction SMILES: S(O)(O)(=O)=O.[CH2:6]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18](O)=O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:7][CH3:8].C([C:24]1[NH:25][C:26]2[CH:32]=[C:31](C(O)=O)[CH:30]=[CH:29][C:27]=2[N:28]=1)CC.Cl.Cl.CNC1C=CC=CC=1N.N>O>[CH2:6]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[N:25]([CH3:24])[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[N:28]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:7][CH3:8]
Reactant: CCCc1nc2ccc(C(=O)O)cc2[nH]1
Agent: CNc1ccccc1N
Agent: Cl
Agent: N
Solvent: O
Product: CCCc1nc2ccc(-c3nc4ccccc4n3C)cc2[nH]1

Procedure:
A solution of 6.7 g (25 mMol) of 2-n-propyl-benzimidazole-5-carboxylic acid-hemisulphate and 4.9 g (25 mMol) of 2-methylaminoaniline-dihydrochloride in 200 g of polyphosphoric acid is stirred for 5 hours at 150° C., then poured onto 600 ml of water and made alkaline with concentrated ammonia whilst cooling with ice. The resulting solution is extracted three times with 200 ml of ethyl acetate, the crude product thus obtained is purified by column chromatography (300 g of silica gel; eluant: methylene chloride/methanol=15:1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3].[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: COCC(=O)Cl
Agent: Cl
Product: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)COC)CC3)c(C)[nH]c12

Procedure:
Starting from 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f34) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][C:61]1[CH:66]=[CH:65][C:64]([CH2:67][NH2:68])=[CH:63][CH:62]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][C:64]3[CH:65]=[CH:66][C:61]([CH3:60])=[CH:62][CH:63]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: Cc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 1-(4-methylphenyl)methanamine (63.8 mg, 0.526 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=459 [M+H]+.