Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(=O)c1ccc(F)cc1
Product: CC(=O)c1ccc(N(C)C)cc1
Reaction time: 2 h

Procedure:
A mixture containing 50 g of p-fluoroacetophenone and 150 ml of 40% aqueous dimethylamine is warmed in a pressure bottle at 90°-100° C. After two hours, a pale yellow oil is formed. The mixture is cooled, and the oil solidifies. The solid is collected and washed well with H2O to give 54.93 of p-dimethylaminoacetophenone, mp 101°-103° C., after heptane recrystallization. A 72 g sample of this acetophenone is heated with 129 g of N-chlorosuccinimide in 700 ml of toluene to reflux temperature and maintained at this temperature for 35 minutes. The mixture is cooled and filtered. The filter cake is washed with 200 ml of toluene, and the filtrate and wash solution are evaporated to dryness in vacuo to afford 66 g of oil. This oil is chromatographed on SiO2 with 40% hexane/CH2Cl2 to give 38.9 g of 3.5-dichloro-4-dimethylaminoacetophenone as a yellow oil. A 5.22 g sample of this oil is added portionwise to 2.75 g of SeO2 in 20 ml of dioxane and 0.7 ml of H2O at 55°-60° C. This mixture is heated at reflux temperature for 4.5 hours, cooled and filtered through siliceous earth. The filter cake is washed with 20 ml of dioxane. The dioxane solutions are cooled to 15° C. and 2.77 g of t-butylamine is added dropwise to afford a tan precipitate. After stirring 15 minutes at room temperature, the mixture is diluted with 200 ml of ethanol, cooled to 5° C. and 7 g of NaBH4 is added portionwise. After 15 hours, the mixture is treated with 300-400 g of ice and 200 ml of H2O at below 10° C. The mixture is stirred to dissolve all solids and extracted with 300 ml of CH2Cl2 . The CH2Cl2 layer is washed with 100 ml of H2O, dried (MgSO4) and evaporated to dryness in vacuo to give 5.6 g of orange oil. This oil is dissolved in ethyl ether, decolorized with activated carbon and concentrated to 15 ml. On cooling, crystals are obtained. The title product is collected as white crystals, mp 96°-99° C.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:14]=1)[C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C>[Pd].C(O)C>[N:5]1[CH:4]=[C:3]([CH2:2][C:9]2[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:18])([CH3:19])[C:16]#[N:17])[CH:14]=2)[CH:8]=[N:7][CH:6]=1
Reactant: CC(C)(C#N)c1cc(C(Cl)c2cncnc2)cc(C(C)(C)C#N)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1cc(Cc2cncnc2)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,2'-[5-(1-chloro-1-(pyrimidin-5-yl)methyl)-1,3-phenylene]di(2-methylpropi ononitrile), (0.55 g), triethylamine (0.25 ml), 5% palladium-on-carbon (0.02 g) and ethanol (10 ml) was stirred under hydrogen at room temperature and atmospheric pressure for 10 minutes and then filtered. The filtrate was diluted with ethyl acetate (25 ml), and the solution washed with aqueous sodium hydrogen carbonate, dried and evaporated to dryness. The residue was purified by flash chromatography using 1% by volume of methanol in dichloromethane as eluant to give 2,2'-[5-(pyrimidin-5-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), mp 132°-134°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH:40]([CH3:46])[C:41]([O:43]CC)=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH:40]([C:41]([OH:43])=[O:42])[CH3:46])[N:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)Br
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC(C)C(=O)O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.50 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 12 ml DMF were added 670 μl ethyl 2-bromopropionate and 3.2 g cesium carbonate. After stirring at RT for 24 h the solution was diluted with ethyl acetate and extracted with aqueous LiCl (4 w/w). The crude product obtained after evaporation of the solvent was dissolved in THF and treated with 1 N NaOH. When conversion was complete (4 h) Amberlite IR-120®was added, the suspension filtrated and the filtrate evaporated to give the crude product (1.56 g)
Reaction SMILES: [OH:1][C:2]1([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.[Li+].CC([N-]C(C)C)C.C1CCCCC1.[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1>C1COCC1.CN(C=O)C>[C:32]([CH:33]1[CH:3]2[CH2:4][C:5](=[O:8])[CH:6]=[CH:7][C:2]2([C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:1][C:34]1=[O:35])(=[O:36])[CH3:31]
Reactant: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Reactant: C=C1CC(=O)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Temperature: -30 °C
Reaction time: 0.67 h
Yield: 53 %

Procedure:
4-Hydroxy-4-(phenylethynyl)-2,5-cyclohexadien-1-one, the product of Example 2A, (10.5 g, 0.05 mole) was dissolved in dry THF (100 mL). The reaction was cooled to -30° C. and treated with 1.96M LDA in cyclohexane (25.5 mL, 0.05 mole). During the addition of the LDA solution, a beige-colored slurry formed. The reaction was cooled to -78° C. and stirred at that temperature for 40 min. Dry DMF (10 mL) was added. The reaction immediately became homogeneous. Diketene (6.3 mL, 0.08 mole) was added rapidly and the reaction was stirred for 20 min before an additional portion of diketene (4.0 mL 0.05 mole) was added. The stirred reaction was allowed to warm slowly to 0° C., then quenched into ice (300 g) and concentrated hydrochloric acid (45 mL). The resulting mixture was extracted with CH2Cl2. The combined extracts were washed with water, dried over anhydrous sodium sulfate overnight, filtered and concentrated. The resulting solution was concentrated in vacuo. The residue was treated with Et2O (300 mL) and cooled to 0° C. for 1 hr. The resulting solid was isolated by filtration and washed with Et2O to yield 7.8 g (53%) of the title compound as a light tan solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([SiH](CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2[nH]cc(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A solution of 5-cyanoindole (10.00 g, 70.34 mmol) in acetonitrile (120 ml) was added to a solution of 1-benzyloxycarbonyl-4-piperidone (8.20 g, 35.17 mmol) and trimethylsilyl trifluoromethanesulfonate (6.80 ml, 35.17 mmol) in acetonitrile (230 ml) via addition funnel at 0° C. over 1.5 h. Triethylsilane (4.2 ml, 26.28 mmol) was added at 0° C. and reaction mixture was allowed to gradually warm to RT over 2 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, dried over MgSO4, and concentrated in vacuo. The residue was diluted with acetonitrile (300 ml) and hexanes (200 ml) and stirred for 20 min. The organics were removed in vacuo and the residue was chromatographed (SiO2, 20-40% ethyl acetate/hexanes) to give 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine as a white crystalline solid (59%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1.O.[OH-].[Na+]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 101.5 %

Procedure:
Methyl 4-(1H-benzimidazol-2-yl)benzoate (Step A) (2.63 g) is stirred in THF (50 mL) and water (10 mL) with sodium hydroxide (2.08 g) at reflux for 4 hours. The solvent is evaporated and the residue treated with 2N hydrochloric acid (100 mL). The resulting suspension is collected, washed with methanol/ethyl acetate and dried to give 2.52 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].ClCCl.O>C(O)C>[CH2:1]([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(c1)C(=NCc1ccccc1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Fc1ccc2c(c1)C(NCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Dissolve benzyl-(6-fluoroindan-1-ylidene)-amine (23.22 g, 97.03 mmol) in ethanol (1200 mL). Cool the mixture to 0° C. under nitrogen. Add sodium borohydride (11.01 g, 291.10 mmol) to the mixture. After one hour, add dichloromethane (150 mL) and water (150 mL). Stir for 14 hours under nitrogen and concentrate in vacuo to remove ethanol. Extract the residue with dichloromethane and saturated aqueous sodium chloride. Dry the resulting organics with magnesium sulfate, filter, and concentrate in vacuo to give the title compound as a red oil (22.12 g, 94%). MS (ES) m/z=242 [M+1].
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[N:17][C:12]3[O:13][CH2:14][CH2:15][NH:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(N(CC)CC)C.O>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([N:16]2[CH2:15][CH2:14][O:13][C:12]3[N:17]=[CH:18][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=4)=[CH:10][C:11]2=3)=[O:26])[CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32]
Reactant: FC(F)(F)c1ccc(-c2cnc3c(c2)NCCO3)cc1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(C(F)(F)F)cc4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
In a 10 ml flask, 7-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (67 mg, 0.24 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (118 mg, 0.36 mmol) were dissolved in dichloromethane. Triethylamine (0.17 ml, 1.20 mmol) was added thereto and then stirred at room temperature for 2 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=19:1. The fractions containing the product were collected and evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(4-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (122 mg, 89%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]#[N:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)CC)C.[N-:40]=[N+:41]=[N-:42].[Na+].O>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:24]3[NH:42][N:41]=[N:40][N:25]=3)[CH:16]=2)[C:11](=[O:26])[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:9]=1[CH2:8][NH:7][C:6](=[O:31])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:21][CH2:22][CH3:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C#N)cc12
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nnn[nH]3)cc12
Yield: 53.1 %

Procedure:
A solution of tert-butyl(4-butoxy-6-cyano-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.85 g, 2 mmol), triethylamine hydrochloride (0.34 g, 2.5 mmol) and sodium azide (0.16 g, 2.5 mmol) in toluene (20 ml) was stirred at 90° C. for 24 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl [4-butoxy-2-isobutyl-1-oxo-6-(1H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.50 g, 53.2%) as crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:30][N:31]1[CH:35]=[C:34]([CH:36]=O)[C:33]([CH3:38])=[N:32]1.C(O)(=O)C.[H][H].[OH-].[Na+]>[Pd].O.O1CCCC1>[CH3:30][N:31]1[CH:35]=[C:34]([CH2:36][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:12])=[CH:9][CH:8]=3)[CH2:3][CH2:2]2)[C:33]([CH3:38])=[N:32]1
Reactant: Cc1nn(C)cc1C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Temperature: 40 °C
Yield: 83.5 %

Procedure:
tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 4 above; 108.1 g, 273.3 mmol), 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (35.6 g, 287 mmol) and palladium on charcoal (3.09 g, 1.37 mmol) were charged to a suitable pressure vessel. Tetrahydrofuran (920 ml), water (54 ml) and acetic acid (32.8 g, 546.7 mmol) were charged and the stiffed mixture heated to 60° C. under 3 bar of hydrogen until the reaction deemed complete. The mixture was then cooled to 40° C. and 2 M sodium hydroxide solution (410 ml, 820 mmol) added. On cooling to 25° C. the mixture was filtered to remove catalyst before tetrahydrofuran (650 ml) was added and the organic phase separated. The organic phase was partially concentrated by distillation before toluene (575 ml) was added. The distillation was continued whilst maintaining the reaction volume with further addition of toluene (690 ml). The reaction mixture was allowed to cool to ambient temperature over about 3 hours during which the product crystallizes. The solid was collected by filtration, washed with toluene (460 ml), then ethyl acetate (230 ml) before being dried in vacuo at 45° C. to constant weight to give the title compound (114.9 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C(C=CC=1F)N.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[C:12]([NH2:13])=[N:32][N:31]=1
Reactant: N#CC(C#N)=NNc1ccc(F)c(F)c1
Reactant: NN
Agent: Nc1ccc(F)c(F)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc(F)c(F)c1
Yield: 38 %

Procedure:
This compound was prepared using 103 mg (0.5 mmol) of 2-[(3,4-difluorophenyl)-hydrazono]malononitrile, which was derived from 3,4-difluoroaniline (99 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 45 mg (38%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 6.18 (br s, 4H), 7.28-7.55 (m, 2H), 7.70-7.82 (m, 1H), 10.80 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:30]#[N:31])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[C:30]([C:13]1[CH:14]=[C:9]([CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:10]=[CH:11][N:12]=1)#[N:31]
Reactant: C[Si](C)(C)C#N
Reactant: CCOC(=O)C(C)Cc1ccncc1
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.6 %

Procedure:
Ethyl 2-methyl-3-(4-pyridyl)propionate (5.9 g, 30.5 mmol) was dissolved in ethyl acetate (25 ml) and 3-Chloroperbenzoic acid (ca. 77%, 7.5 g, 33.4 mmol) was added thereto. The reaction mixture was stirred at room temperature for 14 hrs and subjected to a silica gel (120 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (3:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (18 ml), and trimethylsilyl cyanide (4.5 g, 45.0 mmol) and N,N-dimethylcarbamoyl chloride (3.5 g, 32.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (50 g) column chromatography. The fractions eluted with hexane-ethylacetate (4:1, v/v) were collected and concentrated to give the titled compound (3.7 g, 76%).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1O>>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(F)cc1F
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)cc2F)C1
Yield: 98.4 %

Procedure:
The title compound (D127) (95 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 2,4-Difluorophenol (0.032 ml, 0.338 mmol).
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30]>CCO.O>[CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=[N:29][OH:30])[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=C1CCN(CCc2ccccc2)C(=O)C1c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1C(c2ccccc2)C(=NO)CCN1CCc1ccccc1
Temperature: 0 °C
Yield: 59.6 %

Procedure:
Phenethyl-3-phenyl-piperidine-2,4-dione (781 mg), sodium acetate (1.15 g) and hydroxylamine hydrochloride (925 mg) were suspended in EtOH/water 1:1 (25 ml) and the mixture was refluxed for 4 hours. The mixture was then poured into ice/water/1N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated to give the crude product that was purified by flash chromatography (DCM/MeOH/NH4OH 98:2:0.25) to give the compound as a white foam (489 mg). MS (ESI): 309.4 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].Cl.[CH3:10][NH:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+].[C:19]([C:26]([O:28][CH2:29]C)=[O:27])#[C:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(OCC)(=O)C.O.C(O)C>[CH2:24]([O:23][C:21]([C:20]1([CH2:19][C:26]([O:28][CH3:29])=[O:27])[O:12][N:11]([CH3:10])[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:2]1)=[O:22])[CH3:25]
Reactant: N#Cc1ccccn1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CC(=O)OC)N=C(c2ccccn2)N(C)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 111.8 %

Procedure:
To a stirred solution of 2-cyanopyridine (2.08 g, 20 mmol) and N-methylhydroxylamine hydrochloride (1.66 g, 20 mmol) in 1:1 water/ethanol (30 mL) was added sodium carbonate (1.04 g, 10 mmol) in small portions. LCMS analysis after 5 min indicated that the reaction was complete. To this was added diethyl acetylenedicarboxylate (3.2 mL, 20 mmol) and the reaction mixture stirred for additional 20 min at room temperature. LCMS analysis of the resulting dark-green reaction showed that the reaction was complete. The reaction mixture was taken up into ethyl acetate (200 mL) and washed successively with water (2×25 mL) and brine (25 mL), and the organic layer dried (Na2SO4), filtered and concentrated to give brown oil which was passed through a plug of silica gel (1:1 hexanes/ethyl acetate). The filtrate was concentrated to give the title compound as a yellow oil (6.87 g). LCMS calcd for C15H20N3O5 (M+H): 322.14; found: 322.08.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[C:6]([OH:41])(=[O:7])[CH3:37].[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@H:24]3[CH2:29][CH2:28][C@@H:27]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:38][CH:37]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CN)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CNS(C)(=O)=O)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34 %

Procedure:
Cis-3-{4-[4-(aminomethyl)phenoxy]phenyl}1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.051 g, 0.0001 mol) was dissolved in anhydrous pyridine (1 mL), methanesulfonyl chloride (0.011 g, 0.0001 mol) was added and the resulting solution was stirred at ambient temperature for 20 hours. The solvent was removed under reduced pressure and the resulting residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-N-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]methanesulfonamide acetate (0.011 g, 0.000017 mol) as a white solid.