Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].N[C:16]1[N:24]([CH3:25])[C:23]2[C:18](=[N:19][C:20]([Cl:27])=[N:21][C:22]=2[Cl:26])[N:17]=1>N1C=CC=CC=1>[Cl:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]([CH3:25])[C:16]([NH:14][S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:1]([O:3][CH3:4])=[O:2])(=[O:13])=[O:12])=[N:17]2)=[C:22]([Cl:26])[N:21]=1
Reactant: Cn1c(N)nc2nc(Cl)nc(Cl)c21
Reactant: COC(=O)c1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1nc2nc(Cl)nc(Cl)c2n1C
Reaction time: 3 h

Procedure:
At 70° C., 6.60 g (28 mmol) of 2-carbomethoxybenzenesulfonamide was added to a suspension of 3.00 g (14.0 mmol) of 8-amino-2,6-dichloro-7-methylpurine in 150 ml of pyridine. After 3 hours at 70°-80° C., the reaction mixture was evaporated down in a rotary evaporator, and the residue was stirred into ice/H2O and acidified with dilute HCl. The desired product was obtained in the form of a brown powder having the following physical data (active ingredient 1.020)
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCCC1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(C2CCCC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 221° C. and MS: m/e=438.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and bromocyclopentane.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]([CH3:15])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH3:14][O:13][C:10]1[C:9]([CH3:15])=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[C:11]=1[CH3:12]
Reactant: COc1c(C)cnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cnc(CO)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
94.9 g of (4-methoxy-3,5-dimethyl-2-pyridyl)methyl acetate are dissolved in 570 ml of ethanol. 285 ml of 3N sodium hydroxide solution are then added dropwise thereto at 0° and the mixture is stirred at room temperature for 3 hours. The ethanol is subsequently removed in vacuo, whereupon the residual aqueous solution is extracted three times with 300 ml of methylene chloride. The organic extracts are dried over sodium sulphate and evaporated in vacuo. The residue is crystallized from petroleum ether and there is obtained 4-methoxy-3,5-dimethyl-2-pyridylmethanol of melting point 49°-51°.
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:24][CH3:25])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:24][CH3:25])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COCc1cc(Cl)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Solvent: CO
Solvent: CN(C)C=O
Product: COCc1cc(N)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH was added to a solution of 0.50 g (1.3 mmol) of 3-benzenesulphonyl-7-chloro-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 10:1) and crystallization from EtOH yielded 0.38 g (80%) of 3-benzenesulphonyl-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.00 g, 11.5 mmol) and sodium hydride (60%, 0.506 g, 12.6 mmol) in DMF (50 mL) was stirred at ambient temperature for 1 h then 4-fluorobenzaldehyde (1.36 mL, 12.6 mmol) was added. The reaction mixture was heated at 100° C. for 21 h. The reaction mixture was cooled to ambient temperature and the precipitate was collected by filtration, washed with DMF (30 mL) and ether (30 mL), and dried to afford 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde as a tan solid (2.80 g, 7.61 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 10.03 (1H, s), 8.46 (2H, d, J=8.4 Hz), 8.39 (1H, s), 8.09 (2H, d, J=8.8 Hz); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 9.71 min. MS: MH+ 365.8.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]([CH:10]2[C:19]([CH3:21])([CH3:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]([OH:24])=O)[CH:16]=3)[NH:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.Cl.CN(C)CCCN=C=NCC.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:25][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:10]2[C:19]([CH3:21])([CH3:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:24])[CH:16]=3)[NH:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CS(N)(=O)=O
Reactant: CN(C)c1cc(F)cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)c1cc(F)cc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)c1
Yield: 39.7 %

Procedure:
A mixture of 2-(3-dimethylamino-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (10 mg, 0.03 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.4 mg, 0.044 mmol), 4-dimethylaminopyridine (5.4 mg, 0.044 mmol), methane sulfonamide (8.3 mg, 0.09 mmol) in dichloromethane (3 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(3-dimethylamino-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (5 mg, 42%) as a light yellow solid: LC/MS m/e calcd for C21H26FN3O3S (M+H)+: 420.5, observed: 420.1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].O>O1CCCC1>[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=2)[CH2:18]1)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C2CCCNC2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)N1CCCC(c2ccc(OC)c(OC)c2)C1
Reaction time: 2 h

Procedure:
260 mg of sodium carbonate were added under a nitrogen atmosphere to a mixture of 500 mg of 3-(3',4'-dimethoxyphenyl)-piperidine in 5 ml of tetrahydrofuran and while cooling the mixture on an ice bath, 0.21 ml of propionyl chloride was added dropwise over 5 minutes. After the temperature rose to room temperature, the mixture was stirred for 11/2 hours and was then poured into 10 volumes of ice and water. The mixture was extracted with methylene chloride and the extracts were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The 460 mg of residue was chromatography over silica gel and was eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture. The product was crystallized to get 270 mg of amorphous N-propionyl-3-(3',4'-dimethoxyphenyl)-piperidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH2:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[N:7]=2)=[CH:12][N:11]([CH3:13])[N:10]=1
Reactant: COc1ccc(N)cc1OC
Reactant: Cn1cc(-c2ccnc(Cl)n2)c(-c2ccc(Cl)cc2Cl)n1
Product: COc1ccc(Nc2nccc(-c3cn(C)nc3-c3ccc(Cl)cc3Cl)n2)cc1OC

Procedure:
The title compound is prepared as described in Example 1 but using 2-chloro-4-[3-(2,4-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidine and 3,4-dimethoxy-phenylamine.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([NH:17][CH2:11][C:10]3[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:15][CH3:16])[CH2:1][CH3:2])=[CH:8][CH:9]=3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN(CC)CCOc1ccc(CNc2ccc3ncccc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.3 %

Procedure:
To a stirred solution of 1.0 gram (0.0045 mole) of 4-(2-(diethylamino)ethoxy)benzaldehyde and 0.65 gram (0.0045 mole) of 6-aminoquinoline (available from Aldrich Chemical Company) in 25 mL of 1,2-dichloroethane (DCE, available from Aldrich Chemical Company) was added 0.3 mL (0.0045 mole) of glacial acetic acid (available from J. T. Baker Inc.) followed by 1.4 grams (0.0068 mole) of sodium triacetoxyborohydride (available from Aldrich Chemical Company). Upon completion of addition, the reaction mixture was stirred at ambient temperature for three hours. At the conclusion of this period, 50 mL of 10% aqueous sodium hydroxide was added dropwise. The resulting solution was extracted with three 25 mL portions of diethyl ether. The extracts were combined, washed with one 25 mL portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.25 grams of a dark brown paste. The dark brown paste was purified by column chromatography on silica gel, yielding 0.13 gram of Compound 15. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:9]1[CH2:20][N:12]2[C:13](=[O:19])[N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:22][CH2:23][CH3:24]>>[C:1]([C:9]1[N:10]=[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[N:14]([CH2:22][CH2:23][CH3:24])[C:13](=[O:19])[N:12]2[CH:20]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: COc1cc2n(c(=O)n1)CC(C(=O)c1ccccc1)=N2
Product: CCCn1c(OC)cc2nc(C(=O)c3ccccc3)cn2c1=O

Procedure:
Using the procedure of Example 2, 2-benzoyl-7-methoxyimidazo[1,2-c]pyrimidin-5-one and iodopropane were reacted to obtain 2-benzoyl-7-methoxy-6-propyl-imidazo[1,2-c]pyrimidin-5-one. Spectral, yield and melting point data are given in Table I.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH2:16])[CH2:6]1)[CH:2]=[CH2:3].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C@H:26]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:27]2[CH2:29][O:28]2)[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:29][C@@H:27]([OH:28])[C@@H:26]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:25][C:20]2[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OC)ccc21
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OCc2ccccc2)c2cc(OC)ccc21
Yield: 34 %

Procedure:
Step W (1): (1S,3R)-3-(Allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine from Step U(2) was reacted with benzyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate according to the conditions described in Step V (1). The crude product was purified using silica gel column chromatography (1-10% MeOH (with 0.1% triethylamine)/chloroform, linear gradient) to provide 1.72 g mg (34% yield) of benzyl (2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate. HRMS (M+H)+=553.2534; 1H NMR (500 MHz, DMSO-d6) δ 7.21-7.35 (m, 4H) 7.14-7.21 (m, 2H) 7.03 (t, J=9.46 Hz, 1H) 6.87-6.99 (m, 3H) 6.83 (dd, J=8.24, 2.14 Hz, 1H) 5.88-6.00 (m, 1H) 5.30 (dd, J=17.09, 1.83 Hz, 1H) 5.14 (dd, J=10.53, 1.98 Hz, 1H) 4.96-5.02 (m, 1H) 4.83-4.95 (m, 2H) 4.75 (t, J=6.41 Hz, 1H) 4.01-4.13 (m, 2H) 3.91-4.00 (m, 1H) 3.72-3.76 (m, 3H) 3.64-3.72 (m, 1H) 3.44-3.53 (m, 1H) 3.06 (dd, J=13.73, 3.05 Hz, 1H) 2.65-2.75 (m, 1H) 2.54-2.65 (m, 2H) 1.92-2.02 (m, 1H) 1.57-1.67 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[CH:22]1([C:25]2[N:29]=[C:28]([CH2:30][N+:31]#[C-:32])[O:27][N:26]=2)[CH2:24][CH2:23]1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH:22]1([C:25]2[N:29]=[C:28]([C:30]3[N:31]=[CH:32][N:3]4[C:4]5[C:9](=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=[CH:6][CH:5]=5)[C:10]([N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)=[N:11][C:2]=34)[O:27][N:26]=2)[CH2:24][CH2:23]1
Reactant: FC(F)(F)c1cccc2nc(Cl)nc(N3CCOCC3)c12
Reactant: [C-]#[N+]Cc1nc(C2CC2)no1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2c1c(N1CCOCC1)nc1c(-c3nc(C4CC4)no3)ncn12
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a stirred solution of 2-chloro-4-morpholino-5-trifluoromethyl-quinazoline (600 mg, 1.9 mmol) and 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole (440 mg, 2.9 mmol) in dry DMF (15 ml) under nitrogen at 5°-10° C. was added solid potassium t-butoxide (330 mg, 2.9 mmol). The mixture was stirred at 5°-10° C. for 0.5 h and triturated with water (20 ml). The crystals were filtered off and washed with water (10 ml) and ethyl acetate. A final purification was done by stirring the crystals in acetone (10 ml) to give 330 mg of the title compounds, m.p. 197°-199° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:15]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C(O)CCCCCBr
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCBr

Procedure:
A solution of 6-bromohexanoic acid (10 g) in 50 ml of methanol to which was added 1.0 ml of concentrated sulfuric acid is heated under reflux for 8 hours. The methanol is distilled off, the residue is dissolved in ether. The ether solution is washed free of acid with water, dried over sodium sulfate and evaporated to dryness. Distillation at 0.8 mm Hg gives methyl 6-bromohexanoate, b.p. 85°-90°/0.8 mm.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccnc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ncccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.6 %

Procedure:
To a solution of (2-fluoro-3-pyridinyl)methanol (ASYNCHEM, 505 mg, 3.97 mmol) in dry DCM (15 mL), under N2 atmosphere, were added triphenylphospine (ALDRICH, 1042 mg, 3.97 mmol) and carbon tetrabromide (ALDRICH, 1318 mg, 3.97 mmol) in an ice-water bath. Reaction mixture was stirred at room temperature overnight. 0.3 eq. of carbon tetrabromide (ALDRICH, 409 mg, 1.19 mmol) and 0.3 eq. of triphenylphospine (ALDRICH, 323 mg, 1.19 mmol) were added. Reaction mixture was stirred until starting material was not detected. Solvent was evaporated to dryness. Residue was purified by silica gel chromatography using a linear gradient of hexane-EtOAc. Collected fractions afforded title compound (812 mg, 4.27 mmol, quantitative yield) as yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.20-8.21 (m, 1H), 8.06-8.12 (m, 1H), 735-7.39 (m, 1H), 4.69 (s, 2H). [ES+MS] m/z 190 (M).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:12]=[CH:11][C:9]([N:10]2[C:18]([CH3:19])=[CH:17][CH:13]=[C:14]2[CH3:16])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-n2c(C)ccc2C)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-ethoxycarbonylaniline (82.6 g), acetonylacetone (68.5 g) and concentrated sulfuric acid (one drop) were heated at 150° C. for one hour. The reaction mixture was diluted with ethyl acetate and washed with water, followed by drying and concentrating, whereby 1-(4-ethoxycarbonylphenyl)-2,5-dimethylpyrrole was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:30]([OH:31])=[CH:29][CH:28]=[C:27]([CH3:32])[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:30]4[C:25]([CH3:24])=[N:26][C:27]([CH3:32])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)c(C)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Yield: 74.3 %

Procedure:
4-[4-(2,6-Dimethyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (41 mg, 65%) was prepared using the procedure described for the preparation of Example 96, by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol) with 2,6-dimethyl-3-hydroxypyridine (Apollo Scientific Ltd., Stockport, Cheshire, UK; 16 mg) in the presence of potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL). Mass spectrum (ES) MH+=425. HRMS Calcd. for C22H29N6O3 (MH+): 425.2296. Found: 425.2294.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25](=O)[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:36]([NH:39][NH2:40])([CH3:38])[CH3:37].C(N(CC)CC)C>C(O)C>[Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:39]([CH:36]([CH3:38])[CH3:37])[N:40]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=2)[CH2:20]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Reactant: CC(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C2C3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC32)n(C(C)C)n1
Reaction time: 16 h
Yield: 44.9 %

Procedure:
To a solution of ethyl 4-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-2,4-dioxobutanoate (0.40 kg, 84 mmol) in ethanol (500 mL) was added N-isopropylhydrazine hydrochloride (9.7 g, 84 mmol) at room temperature. After 16 h, triethylamine was added, and the resulting mixture was concentrated in vacuo. Purification of the residue by flash column chromatography (9% ethyl acetate in petroleum ether) afforded ethyl 5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazole-3-carboxylate (19.5 g, 45%) as a colorless oil. LRMS: [M+H]+=517.1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([OH:17])([CH3:16])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[H-].[Na+].[CH3:22]I>C1COCC1>[F:19][C:2]([F:1])([F:18])[C:3]([O:17][CH3:22])([CH3:16])[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: CC(O)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirring solution of 2-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)isoindoline-1,3-dione (250 mg, 0.915 mmol)) at 0° C. in THF (8 ml), NaH (80 mg, 2 mmol) was added. After 30 minutes methyl iodide (1.299, 9.15 mmol) was added. The reaction mixture was left stirring in a ice-bath and allowed to warm to 25° C. over 3.5 hours. The reaction was quenched with sat. NH4Cl and the mixture extracted with DCM. The organic extract was separated using a phase separator and purification by chromatography on silica, eluting in a 0% to 30% iso-hexane:EtOAc afforded the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.91 (2H, m), 7.85 (2H, m), 3.97 (2H, m), 3.44 (3H, s), 1.42 (3H, s);
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([O:17][C:18](=O)[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:20]=O)C>CC(O)=O>[C:1]([N:5]1[C:9]2[NH:10][C:18](=[O:17])[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:8]=2[C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C=O)c1ccccc1
Reactant: CC(C)(C)n1nc(C2CCC2)cc1N
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2cc(-c3ccccc3)c(=O)[nH]c21
Temperature: 110 °C
Yield: 0.9 %

Procedure:
To a stirring solution of crude 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (1.0 g, 5.2 mmol) in AcOH (5 mL) was added 3-oxo-2-phenyl-propionic acid ethyl ester (1.0 g, 5.2 mmol). The reaction was then heated to 110° C. for 18 hr, at which time the reaction was cooled to room temperature, concentrated under reduced pressure to remove HOAc, diluted with EtOAc, and quenched with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of the resulting material was accomplished by flash chromatography with a Biotage® 35L column (A Dynax Corp., Charlottesville, Va.), eluting with a gradient of 5%, 10%, 20% EtOAc/hexanes. The product was collected and concentrated under reduced pressure to give the title compound (15 mg, 9% yield). LRMS m/z (APCl) 322 (M+1).