Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([CH:7]([F:9])[F:8])[CH2:5][OH:6].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:3][C:4]([F:10])([CH:7]([F:9])[F:8])[CH2:5][O:6][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: OCC(F)(F)C(F)F
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To sodium hydride (288 mg as 55-60% mineral oil dispersion, 6 mmol) in N,N-dimethylformamide (2 mL), a solution of 2,2,3,3-tetrafluoro-1-propanol (535 μL, 6 mmol) in N,N-dimethylformamide (8 mL) was added dropwise. The reaction mixture was stirred for thirty minutes at room temperature. Then, 4-fluorobenzaldehyde (429 μL, 4 mmol) was added slowly, and the reaction was heated to 80° C. for three hours. After cooling, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 674 mg of 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde; 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H), 7.88 (d, 2H), 7.06 (d, 2H), 6.06 (tt, 1H), 4.44 (tt, 2H) ppm.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH2:27])=[CH:25][C:20]=2[O:19][CH2:18]1>>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C:2]3[CH:16]=[CH:15][C:5]4[C:6](=[O:14])[NH:7][C:8]5[C:13]([C:4]=4[CH:3]=3)=[CH:12][CH:11]=[CH:10][N:9]=5)=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccc4c(c3)OCO4)ccc12
Yield: 16.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (266 mg, 1.15 mmol) and benzo[d]-[1,3]dioxol-5-ylmethanamine (697 mg, 4.61 mmol) to provide 476 (67 mg, 17% yield) as a white powder. LC-MS (M+H=346, obsd.=346). 1H NMR (400 MHz, DMSO-D6) δ 11.49 (s, 1H), 8.58 (d, J=6.6, 1H), 8.42 (dd, J=1.6, 4.7, 1H), 7.98 (d, J=8.7, 1H), 7.37 (d, J=2.1, 1H), 7.26 (dd, J=4.7, 7.9, 1H), 7.17 (t, J=6.1, 1H), 7.00 (d, J=1.5, 1H), 6.91 (m, 2H), 6.88 (d, J=7.9, 1H), 5.97 (s, 2H), 4.40 (d, J=5.9, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4]C(C#N)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:22])[C:15]([O:17]C(C)(C)C)=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[C:26](O)([C:28]([F:31])([F:30])[F:29])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:26]([C:28]([F:31])([F:30])[F:29])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:22])[C:15]([OH:17])=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
2.3 g (purity 91%, 5.2 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 2.6 g (purity 93%, quant.)
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][NH2:8])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCN1CCC(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
3-[4-(2-Pyridyl)-piperidine-1-yl]propylamine (Scheme 6). To 1-Benzyl -4-(2-pyridyl)-piperidine (3. 2 6 g, 12.9 mmol) in dry methanol (25 ml), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 ml EtOAc and 50 ml water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (Hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 ml chloroform and 5 ml water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ 1.45 (s, 9H),1.54-1.69 (m, 8H), 2.21-2.68 (m, 2H), 2.74-2.80 (m, 1H), 3.02-3.22 (m, 4H), 5.41 (s, 1H), 7.13-7.17 (m, 1H), 7.33 (d, J=7.93 Hz, 1H).7.63 (t, J=7.6 Hz, 1H), 8.54 (d, J=4.6 Hz, 1H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15 g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.098 g (100%) of 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step (step h).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Al:7]>O>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Al+3:7].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: [Al]
Reactant: CC(O)C(=O)O
Solvent: O
Product: CC(O)C(=O)[O-]
Product: [Al+3]

Procedure:
A polymeric aluminum lactate is prepared in a similar manner to that described in EXAMPLE 11 with the constituents following the formula Al2 (OH)5CH3CHOHCO2.2H2O. A typical batch comprises 106 grams of a 85% solution of lactic acid; 54 grams of activated aluminum and 381 grams of water. The mixture is left at room temperature until the activated aluminum has been substantially consumed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])/[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)c2ccccc2OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
As in Example 115. (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid (1 g) and 4-nitrophenol (0.54 g) in 7 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (0.67 g). The mixture was stirred at room temperature for 2 hours. After the usual work up. the crude ester was crystallized from 2-propanol to give 0.825 g of (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 133.5°-135° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:16]([NH2:18])[CH3:17]>C1COCC1.C(OCC)(=O)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2](=[O:4])(=[O:3])[NH:18][CH2:16][CH3:17])[CH:6]=1
Reactant: CCN
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)c1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Methyl 2-(3-chlorosulfonyl-phenyl)acetate (0.29 g, 1.17 mmol) was dissolved in THF (10 mL) and to this solution 1 mL (2 mmol) of 2M ethylamine in THF was added. Let stir at room temperature 30 minutes, diluted with ethyl acetate and the organic layer was washed with 10% citric acid, brine, dried over sodium sulfate and concentrated to an oil. 0.28 g, 1.09 mmol, 93% yield. 1H NMR 500 MHz (CDCl3) 7.72 ppm, 2H, m; 7.41 ppm, 2H, m; 4.32 ppm, 1H, t; 3.68 ppm, 3H, s; 3.67 ppm, 2H, s; 2.98 ppm, 2H, m; 1.07 ppm, 3H, t.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]([O:9]B(OC(=O)C)OC(=O)C)(=[O:8])C.[C:19](O)(=O)[CH:20]=C>>[CH:5]12[O:1][CH:2]([CH:19]=[CH:20]1)[CH2:3][CH:4]2[C:6]([OH:9])=[O:8]
Reactant: CC(=O)OB(OC(C)=O)OC(C)=O
Reactant: c1ccoc1
Reactant: C=CC(=O)O
Product: O=C(O)C1CC2C=CC1O2
Temperature: -5 °C
Reaction time: 22 h
Yield: 43 %

Procedure:
Distilled furan (141.7 g, 2.08 mol) and triacetoxyborane (1.19 g, 6.63 mmol) were charged in a similar reactor as in Example 4, and the mixture was cooled to −5° C. To this mixed solution was added acrylic acid (30.4 g, 0.42 mol) and the mixture was stirred at an inner temperature of −5° C. for 22 hr. The resulting crystals were collected by filtration through a glass filter, washed with diisopropyl ether (60 ml) cooled to not more than 5° C. and dried under reduced pressure for 2 hr. to give 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as colorless crystals (11.4 g, endo form:exo form=98:2, purity >99%, yield 43% based on acrylic acid).
Reaction SMILES: [CH:1]1([N:7]2[C:20](=[O:21])[C:18]3=[C:19]4[C:14](=[CH:15][CH:16]=[CH:17]3)[C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=[C:10]4[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[N+:39]([O-:41])=[O:40].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C>[CH:1]1([N:7]2[C:20](=[O:21])[C:18]3=[C:19]4[C:14](=[CH:15][CH:16]=[CH:17]3)[C:13]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[N+:39]([O-:41])=[O:40])=[CH:12][CH:11]=[C:10]4[C:8]2=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: CC1(C)OB(c2ccc3c4c(cccc24)C(=O)N(C2CCCCC2)C3=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C1c2cccc3c(-c4ccc(Cl)cc4[N+](=O)[O-])ccc(c23)C(=O)N1C1CCCCC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
In a Schlenk tube, 2 g of N-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-naphthalene-1,8-dicarboximide (4.93 mmol), 1.75 g of 1-bromo-4-chloro-2-nitrobenzene (7.40 mmol) were dissolved in 80 mL of toluene, 1.6 g of potassium carbonate (11.6 mmol) in 8 mL of water and 0.8 mL of ethanol are added, and the mixture was thoroughly degassed. After addition of 800 mg of tetrakis(triphenyl-phosphine)palladium(0) (0.717 mmol), the mixture was degassed again and stirred at 80° C. under argon for 2 days.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[CH:8]=1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[CH:8]=1)(=[O:27])=[O:26]
Reactant: N#Cc1ccnc(-n2cc(CCO)cn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a mixture of 2-[4-(2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carbonitrile (700 mg, 3.3 mmol), Et3N (670 mg, 6.6 mmol) in DCM (15 mL) was added MeSO2Cl (410 mg, 3.6 mmoL) at 0° C., the mixture was then stirred for 2 hours at room temperature, water was added and extracted with DCM and concentrated give the title compound (830 mg, 87%). [M+H] Calc'd for C12H12N4O3S, 293. Found, 293.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]([NH:16][NH2:17])=O)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C(O)CCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:16]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:13][CH2:12]3)=[N:20][N:21]=2)[N:17]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NNC(=O)C1(c2ccc3ncccc3c2)CC1
Solvent: CCCCO
Product: Clc1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Temperature: 140 °C
Yield: 27 %

Procedure:
A microwave tube was charged with 1-quinolin-6-yl-cyclopropanecarboxylic acid hydrazide (513 mg, 2.26 mmol), 3,6-dichloropyridazine (437 mg, 2.93 mmol) and n-butanol (5 mL). The mixture was heated at 140° C. for 12 h. The solvent was removed in vacuo and the residue was purified by flash chromatography in silica gel eluting with ETOAC/methanol gradient to afford 196 mg (41%) of the title compound. LCMS (method A): [MH]+=322, tR=4.38 min.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.N1C=CC=CC=1.CCCCCC>ClCCl>[F:15][C:16]([F:24])([F:25])[C:17]1[CH:18]=[CH:19][C:20]([NH:21][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])=[CH:22][CH:23]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C1Cc2cc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
A suspension of 2.1 g of 5-chlorosulphonyl-2-oxindole, 1.6 g of 4-trifluoromethylaniline and 1.4 g of pyridine in 20 mL of dichloromethane was stirred at room temperature for 4 hours. The precipitate which formed was collected by vacuum filtration, washed twice with 5 mL of water and dried under vacuum at 40° C. overnight to give 2.4 g of crude product containing some impurities by thin layer chromatography. The crude product was chromatographed on silica gel eluting with ethyl acetate:hexane (1,2) to give 1.2 g (37% yield) of 5-(4-trifluoromethylphenyl-aminosulfonyl)-2-oxindole.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]1[N:15]([CH3:23])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:4])([CH3:3])[CH3:2].ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]1[N:15]([CH3:23])[C:16]2[C:21]([C:22]=1[C:31]#[N:30])=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(-c2cnccc2C(C)(C)O[SiH2]C(C)(C)C)cc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(-c2cnccc2C(C)(C)O[SiH2]C(C)(C)C)c(C#N)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of 2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indole (0.263 g, 0.747 mmol) in DCM (5 mL) is added chlorosulfonyl isocyanate (0.162 mL, 1.867 mmol). After 5 min, DMF (1 mL) is added. After another 30 min, the reaction is concentrated under vacuo to afford 2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile as a light yellow solid, which is redissolved in DCM (3 mL). 4 M HCl in 1,4-dioxane (1 mL) is added, and the mixture is stirred at room temperature for 30 min. Purification by reverse phase HPLC with Xbridge Shield RP18 column and a 0.1% aqueous NH4OH in acetonitrile gradient affords 2-(4-hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.67 (s, 3H), 4.44-4.67 (m, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.47 (t, J=8.3 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.87 (d, J=5.3 Hz, 1H), 8.60 (s, 1H), 8.80 (d, J=5.3 Hz, 1H). HRMS (ESI) m/z 264.1142 [(M+H)+ Calcd for C16H14N3O: 264.11379].
Reaction SMILES: [CH2:1]([N:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)[O:8][C:7]1=[O:20])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH3:21][C:12]1([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:14][CH2:15][C:9]2([O:8][C:7](=[O:20])[N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:10]2)[CH2:11]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C1CCCC2(C1)CN(CC(C)(C)C)C(=O)O2
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a 78° C. solution of methyl 3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-carboxylate (15.0 g, 52.9 mmol) in THF (41.0 mL) under N2 was added sodium bis(trimethylsilyl)amide, 1 M in THF (238 mL, 238 mmol) over 1 h using an addition funnel. The reaction mixture was stirred at −78° C. for 3 h. Iodomethane (14.9 mL, 238 mmol) was added, and the reaction was stirred at −78° C. for an additional 2 h. The reaction was quenched at −78° C. with water (5 mL) and diluted with brine (200 mL). The product was extracted into EtOAc (3×200 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to a light yellow solid. The solid was suspended in Et2O (75 mL) and collected in a frit. The collected solids were washed with cold Et2O (4×10 mL) and dried to afford the title compound (13.4 g, 81% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.40 (d, J=8.78 Hz, 1H), 3.29 (d, J=8.78 Hz, 1H), 3.06 (d, J=14.05 Hz, 1H), 2.92 (d, J=14.05 Hz, 1H), 2.16 (d, J=14.05 Hz, 1H), 1.77-1.93 (m, 4H), 1.43-1.69 (m, 3H), 1.35 (s, 3H), 0.96 (s, 9H). MS (m/z) 298.1 (M+H+).
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:16]1[O:27][C:26]2[C:18](=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=O)[O:17]1.[NH2:28][C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[NH:31][N:30]=1>C1COCC1.O>[Cl:45][C:41]1[CH:40]=[C:39]([NH:38][C:36]2[N:35]=[CH:34][N:33]=[C:32]3[NH:31][N:30]=[C:29]([NH:28][C:20](=[O:22])[C:19]4[CH:23]=[CH:24][CH:25]=[C:26]5[O:27][CH2:16][O:17][C:18]=45)[C:37]=23)[CH:44]=[CH:43][CH:42]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=C(O)c1cccc2c1OCO2
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12)c1cccc2c1OCO2
Reaction time: 0.75 h

Procedure:
Under a nitrogen atmosphere, 320 μl (2.9 mmol) of NMM and 210 1 (1.6 mmol) of isobutyl chloroformate are added at −20° C. to 250 mg (1.5 mmol) of 2,3-methylenedioxybenzoic acid [for preparation see: Chem. Ber. 104 (1971) 2347] in 3.2 ml of THF and then stirred for 45 min. 378 mg (1.45 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine (see Step 1.6) are then added and the reaction mixture is allowed to rise to RT and is stirred for 1 hour to complete the reaction. The reaction mixture is poured into 100 ml of water and stirred for 1 hour, and the crude product is filtered off and washed with water and ethanol. Dissolution in 3 ml of DMSO at =110° C., cooling, filtering and washing with ethanol yield 4-(3chloro-phenylamino)-3-(2,3-methylenedioxy-benzoylamino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100/20)=16.5; FAB-MS: (M+H)+=409.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[CH:15]=O.[C:22](#[N:26])[CH2:23][C:24]#[N:25].N1CCCCC1>C(O)C.O>[NH2:26][C:22]1[O:10][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:9][C:8]3=[CH:7][C:6]=2[CH:15]([C:14]2[CH:13]=[C:12]([F:11])[C:19]([F:20])=[C:18]([F:21])[CH:17]=2)[C:23]=1[C:24]#[N:25]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: N#CC1=C(N)Oc2cc3c(cc2C1c1cc(F)c(F)c(F)c1)OCO3
Temperature: 80 °C

Procedure:
3,4-Methylenedioxyphenol (166 mg, 1.2 mmol), 3,4,5-trifluorobenzaldehyde (160 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μL) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml, stirred for 1 h, solids were collected by filtration, washed with 60% aq ethanol and dried (303 mg, 0.88 mmol, 88%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Brc1cccnc1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccn(C)n2)n1
Agent: [Pd]
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared in accordance with the general method of example 4, step 2 using 1-Methyl-1H-pyrazol-3-ylamine instead of 2-chloro-4-aminopyridine to yield [6-Methyl-2-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester as an off-white solid. MS (ISP): m/e=332.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide as an off-white solid, MS (ISP): m/e=232.3 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a light brown solid, MS (ISP): m/e=309.1 (M+H+).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].[OH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)C>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)[C:2]#[C:3][CH3:4]
Reactant: CCOC(=O)CO
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(C)c(=O)c21
Solvent: CCO
Product: CC#CCn1c(N2CCNCC2)nc2nc(OCC(=O)OCC)n(C)c(=O)c21

Procedure:
Ethyl [7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetate trifluoroacetate and [7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetic acid trifluoroacetate [MS m/e (ESI) 361 (MH+-CF3COOH)] were obtained by treating t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate using ethyl 2-hydroxyacetate, instead of ethanol, by the same method as used in Example 11. Ethyl [7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetate trifluoroacetate was purified by chromatography using NH-silica gel. Thus, ethyl [7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetate [1H-NMR (CDCl3) δ 1.29 (t, J=7.22 Hz, 3H) 1.83 (t, J=2.4 Hz, 3H) 3.02-3.06 (m, 4H) 3.38-3.41 (m, 4H) 3.55 (s, 3H) 4.22 (q, J=7.2 Hz, 2H) 4.90 (q, J=2.4 Hz, 2H) 5.03 (s, 2H); MS m/e (ESI) 389 (MH+)] was obtained from the fraction eluted with ethyl acetate-methanol (20:1)