Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24]
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1OCC
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.44 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (1.0 g), anhydrous potassium carbonate (0.58 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (1.57 g, 72%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7](I)=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].[F:19][C:20]([F:25])([F:24])C([O-])=O.[Na+].CN1CCCC1=O>CCOCC.[Cu]I>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:20]([F:25])([F:24])[F:19])=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCc1nc(-c2ccccc2)n(CC)c(=O)c1I
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCc1nc(-c2ccccc2)n(CC)c(=O)c1C(F)(F)F
Temperature: 175 °C
Yield: 47.3 %

Procedure:
A mixture of 1.00 g (2.5 mmol) of 3,6-diethyl-5-iodo-2-phenyl-4(3H)-pyrimidinone, 1.08 g (5.7 mmol) of copper (I) iodide, 1.54 g (11.3 mmol) of sodium trifluoroacetate and 8 mL of anhydrous N-methylpyrrolidinone was heated at 175° C. for 2 h. The mixture was cooled, diluted with 175 mL of ether, washed with four 50 mL portions of water and dried over MgSO4. Removal of the solvent on the rotovap afforded 0.92 g of crude product as a brown oil. This material was purified by flash chromatography on a 25 g column of silica gel eluting with 100 mL portions of 0, 10, 20, 30, 40, 50 and 75% ether in hexanes to afford 0.35 g of 3,6-diethyl-2-phenyl-5-trifluoromethyl-4(3H)-pyrimidinone (compound 185) as a white solid. 1H-NMR (CDCl3) 1.25(3H,t), 1.30(3H,t), 2.8(2H,q), 4.0(2H, q), 7.5(5H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]([CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:8][OH:9]>N1C=CC=CC=1>[CH3:1][S:2]([O:9][CH2:8][CH:7]([CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)Cc1ccc2ccccc2c1
Solvent: c1ccncc1
Product: CC(COS(C)(=O)=O)Cc1ccc2ccccc2c1
Yield: 66 %

Procedure:
11 g (0.1 mole) of methanesulphonyl chloride are added dropwise to 14 g (0.074 mole) of 2-methyl-3-β-naphthylpropanol (crude) in 80 ml of absolute pyridine at 0° C., with stirring, the mixture is stirred for a further 16 hours at room temperature when the addition has ended, excess pyridine is removed by distillation in vacuo, the residue is taken up in water, the mixture is extracted several times with methylene chloride, the extract is dried over sodium sulphate and the solvent is removed in vacuo. 13.6 g (66% of theory) of 1-methanesulphonyloxy-2-methyl-3-β-naphthyl-propane are obtained as an oil. (IR: η=1345 and 1180 cm-1). ##STR48##
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH3:16])=[C:9]([C:12](=[O:15])[CH2:13]Br)[CH:10]=2)[C:5]([CH3:18])([CH3:17])[CH:4]([CH3:19])[CH2:3]1.[C:21]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CCO>[C:21]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:18])([CH3:17])[CH:4]([CH3:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:7][C:8]=2[CH3:16])=[O:15])[CH2:32][CH2:31]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc2c(cc1C(=O)CBr)C(C)(C)CC(C)C2(C)C
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2c(cc1C(=O)CN1CCC(NC(=O)c3ccccc3)CC1)C(C)(C)CC(C)C2(C)C
Yield: 24.1 %

Procedure:
A mixture of 1,1,3,4,4,6-hexamethyl-7-bromacetyl-1,2,3,4-tetrahydronaphthalene (7 g.), 4-benzamidopiperidine (4.27 g.) and triethylamine (3.5 g.) was refluxed in100 ml. EtOH for 2 hours. The resulting yellow solution was cooled, whereupon the product crystallised. This was recrystallised twice from EtOH/water to give the title compound (2.3 g.) as a pale yellow solid, m.p. 153°(dec.). Analysis Calculated for C30H40N2O2 ; C, 78.22%; H, 8.75%; N, 6.08%. Found: C, 78.29%; H, 8.92%; N, 6.14%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[C:16]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:17]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Br)cc1Nc1ccnc(Cl)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloropyrimidin-4-amine (8.83 g, 68.18 mmol) in THF (250 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 4.36 g, 181.82 mmol) portionwise. The reaction mixture was stirred at 0° C. to RT for 10 minutes before addition of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.45 mmol). The reaction mixture was stirred at 65° C. for 1 hr, then after cooling to RT, water was added resulting in formation of a yellow precipitate. The solid was collected by suction filtration and was washed with water. The filtrate was extracted with DCM. The organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Isolute column, 1% MeOH in DCM) then combined with the solid collected by suction filtration to give the title compound: 1HNMR (250 MHz, DMSO) δ 6.91 (1H, d, J=5.79 Hz), 7.61 (1H, dd, J=8.76, 2.21 Hz), 7.91-8.05 (2H, m), 8.29 (1H, d, J=5.79 Hz), 10.40 (1H, s); LC-MS: m/z=+328.9, 330.8 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH:20]1([Mg]Br)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:20]1([CH:8]([C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=3)[S:4][C:3]=2[CH2:1][CH3:2])[OH:9])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophene-3-carbaldehyde (2.00 g) synthesized above in tetrahydrofuran (40 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (14.1 mL) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to ethyl acetate:hexane=1:4, volume ratio) to give the title compound (2.29 g, 88%) as a yellow oil.
Reaction SMILES: Cl.CC(OC(=O)N[C:9]1[CH:10]=[N:11][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:13]=1[I:14])(C)C>O1CCOCC1>[I:14][C:13]1[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cnn(-c2cccc(F)c2)c1I
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cccc(-n2nccc2I)c1
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Hydrochloric acid in dioxane (4 N, 3 mL) was added to 5-iodo-1-(3-fluorophenyl)-1H-pyrazol-4-yl-carbamic acid 1,1-dimethylethyl ester (348 mg, 0.864 mmol) at ambient temperature. The reaction was stirred overnight at the same temperature. Solvent was removed under reduced pressure. The crude material was dissolved in ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude material was purified using silica gel column chromatography (20-60% ethyl acetate in hexanes) to afford 5-iodo-1-(3-fluorophenyl)-1H-pyrazol (210 mg, 0.695 mmol, 80% yield).
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CC(C)=O>[C:15]([C:14]1[CH:18]=[CH:19][C:11]([N:10]2[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([CH3:1])[C:7]2=[O:8])=[CH:12][CH:13]=1)([OH:17])=[O:16]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1=C(C)C(=O)OC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC1=C(C)C(=O)N(c2ccc(C(=O)O)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
37.8 g (0.3 mol) of dimethylmaleic anhydride was slowly added to a solution of 41.1 g (0.3 mol) of p-aminobenzoic acid and 300 ml of acetone in a 250 ml flask at 10° C. The mixture was stirred for 2 hours to obtain a yellow precipitate. Thereafter, the precipitate was collected by filtration under reduced pressure and recrystallized from a solution of DMF/water (50:50 (w/w)) to give an intermediate. The intermediate was treated with sodium acetate and acetic anhydride at 85° C. for 4 hours, cooled to room temperature, and placed in an ice bath to obtain a precipitate. The precipitate was collected by filtration under reduced pressure and recrystallized from a solution of ethanol/water (50:50 (w/w)) to give N-(p-carboxyphenyl)dimethylmaleimide.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[C:16]([NH2:18])=[O:17])[CH:13]=2)OC1.Br[C:26]1[N:30]2[CH:31]=[CH:32][C:33]([C:35]([F:38])([F:37])[F:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:23][C:11]1[CH:10]=[CH:9][C:8]([C:26]2[N:30]3[CH:31]=[CH:32][C:33]([C:35]([F:36])([F:37])[F:38])=[N:34][C:29]3=[N:28][CH:27]=2)=[CH:13][C:12]=1[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cnccc3C(N)=O)c2)OC1
Product: NC(=O)c1ccncc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-[5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]isonicotinamide (100 mg, 0.41 mmol) was coupled to 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (121 mg, 0.46 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 4% methanol, then recrystallisation from toluene, gave 3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]isonicotinamide as a yellow solid: δH (400 MHz, d6-DMSO) 7.50-7.60 (3H, m), 7.65 (1H, s), 7.80-7.86 (2H, m), 8.02 (1H, s), 8.30 (1H, s), 8.73-8.76 (2H, m), 9.33 (1H, d, J 7); m/z (ES+) 402 (M++H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][S:39]([CH3:38])(=[O:41])=[O:40])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2ccc(Cl)cc2C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a cooled solution (0°-5° C.) of 5.24 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-(6-hydroxyhexyl)urea and 4.0 ml of triethylamine in 65 ml of dichloromethane was added dropwise a solution of 1.2 ml of methanesulfonyl chloride in 10 ml of dichloromethane. The resulting solution was gradually warmed to room temperature, then was stirred for 16 hours. The procedure of Example 515 was continued and gave 6.0 g of the desired product as a light brown oil in 97% yield.
Reaction SMILES: [Si]([O:8][CH:9]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:10][CH2:11][CH:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:13]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:9]([OH:8])[CH2:10][CH2:11][CH:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:13]2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.5 g of 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (3) were dissolved in 65 ml of tetrahydrofuran. 0.74 ml of acetic acid and 8.03 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran were added and the mixture was stirred at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoride solution were then added, and the mixture was stirred at reflux temperature for another 3 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using n-heptane/ethyl acetate 2/1. This produced 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C26H23FN2O3); MS (ESI): 431.24 (M+H+).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[O:9])=[CH:6][N:5]=1)[NH2:3].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.C(=O)([O-])[O-].[K+:37].[K+]>O.C(O)C>[CH2:26]([O:25][C:23]([C:22]1[CH:28]=[N:3][N:2]([C:4]2[CH:17]=[CH:16][C:7]([C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:6][N:5]=2)[C:21]=1[O-:20])=[O:24])[CH3:27].[K+:37]
Reactant: COCCCNC(=O)c1ccc(NN)nc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCCCOC)cn2)c1[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
A mixture of 6-hydrazinyl-N-(3-methoxypropyl)nicotinamide hydrochloride (7.5 g, 28.8 mmol), diethyl 2-(ethoxymethylene)malonate (14 mL, 69 mmol), and potassium carbonate (9.94 g, 71.9 mmol) in water (150 mL) and ethanol (25 mL) and stirred at 25° C. for 3 h and then at 60° C. for 18 h. The mixture was cooled to 20° C. to give a precipitate which was collected by filtration and washed with water to give the title compound (8.14 g, 73.2% yield) as a yellow solid. MS m/z 349 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.1 Hz, 3 H) 1.77 (quin, J=6.7 Hz, 2 H) 3.25 (s, 3 H) 3.27-3.34 (m, 2 H) 3.38 (t, J=6.3 Hz, 2 H) 4.02 (q, J=7.1 Hz, 2 H) 7.52 (s, 1 H) 8.10 (dd, J=8.8, 2.5 Hz, 1 H) 8.42 (dd, J=8.8, 0.5 Hz, 1 H) 8.48 (t, J=5.6 Hz, 1 H) 8.78 (dd, J=2.4, 0.6 Hz, 1 H).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(CCC(=O)O)cc(C(C)(C)C)c(O)c1C

Procedure:
Under nitrogen, a solution of methyl 3-(5-tert.-butyl-2,3-dimethyl-4-hydroxyphenyl)propionate (71.5 g) in 150 ml of ethanol was treated with a solution of 98% sodium hydroxide (12.1 g) in 15 ml of water, and the mixture was heated under reflux for 3 hours. The cold solution was diluted with water to about 1200 ml and then acidified with concentrated hydrochloride acid. The precipitated solid was filtered off and washed with water. Recrystallization from 600 ml of acetonitrile gave the acid, m.p. 191° to 193° C.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](N)=[O:5].S(=O)(=O)(O)[OH:15]>>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:15])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: Cc1c(F)c(F)cc(C(N)=O)c1F
Product: Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4,5-trifluoro-3-methylbenzamide (0.38 g) in 18N sulfuric acid (3 ml) was stirred on an oil bath (100° to 110° C.) for 2 hours. After cooling, to the reacting mixture was added ice-water (10 ml), the resulting precipitate was collected by filtration and recrystallized from hexane to give the title compound (0.30 g) as colorless needles, mp 103°-105° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:6](F)[CH:5]=1.C(NC([O:23][CH2:24][CH3:25])=O)C>O1CCOCC1.O>[Br:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:6]([O:23][CH2:24][CH3:25])[CH:5]=1
Reactant: CCNC(=O)OCC
Reactant: Fc1cc(Br)ccc1CN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(Br)ccc1CN1CCCCC1
Temperature: 140 °C
Yield: 73.4 %

Procedure:
Sodium hydride (306 mg, 60%, 7.6 mmol) was added in portions to a solution of 1-(4-bromo-2-fluorobenzyl)-piperidine (520 mg, 1.9 mmol) and ethyl urethane (0.91 mL, 7.6 mmol) in dioxane (10 mL) under an atmosphere of nitrogen. The reaction mixture was then sonicated for 30 minutes until gas evolution ceased then heated at 140° C. overnight in a sealed tube. The reaction mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a colourless oil that was then purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (416 mg, 74%). 1H NMR (CDCl3, 400 MHz): 7.23 (d, J=8.1 Hz, 1H), 7.03 (dd, J=8.1, 1.9 Hz, 1H), 6.95 (d, J=1.9 Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.47 (s, 2H), 2.46-2.35 (m, 4H), 1.61-1.53 (m, 4H), 1.45-1.36 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:18]([CH2:19][CH3:20])[CH2:16][CH3:17]
Reactant: CCNCC
Reactant: COc1ccc(N)c(CO)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)Cc1cc(OC)ccc1N

Procedure:
2-Amino-N,N-diethyl-5-methoxy-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and diethylamine analogous to Example 1. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][CH:5]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([NH2:8])=[O:7].[CH:31]([CH:33]=[CH2:34])=O.CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][C:5]1([S:9]([CH3:12])(=[O:10])=[O:11])[CH2:34][CH:33]=[CH:31][NH:8][C:6]1=[O:7]
Reactant: C=CC=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(C(N)=O)S(C)(=O)=O)c(Cl)cc2F)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3(S(C)(=O)=O)CC=CNC3=O)c(Cl)cc2F)c1=O
Reaction time: 3.5 h
Yield: 39.2 %

Procedure:
To a mixture of 1.3 g of 2-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(methylsulfonyl) acetamide, 0.21 g of acrolein and 20 ml of THF, 0.03 g of potassium t-butoxide was added at room temperature, and stirred for 3.5 hours. Then, 0.1 g of p-toluenesulsonic acid was added and the reaction mixture was refluxed under stirring for 4 hours. The reaction liquid was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give 0.55 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-3-(methylsulfonyl)-3,4-dihydro-1H-pyridin-2-one.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.O=C1C2C(=CC=CC=2)C(=O)[N:28]1[CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40].NN>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][S:39]([CH2:38][CH2:37][NH2:28])(=[O:41])=[O:40])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: NN
Product: Cc1ccc(NC(=O)Nc2nc(CNS(=O)(=O)CCN)cs2)c(C(=O)C2CCCC2)c1
Yield: 89.3 %

Procedure:
2-Amino-ethanesulfonic acid {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-amide (104 mg, 83%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (70 mg, 0.25 mmol) following the general procedure T. This intermediate was deprotected by heating with excess of hydrazine (0.2 mL, 1.0 M. in THF).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH2:44][CH2:45][CH2:46][NH:47]C(=O)OC(C)(C)C)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[N:18](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:19]=[C:20]([C:21]([F:24])([F:23])[F:22])[C:13]=34)[CH:11]=2)[CH2:5][CH2:4]1)#[N:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][CH2:46][CH2:45][CH2:44][C:8]1[CH:7]=[C:6]([C:3]2([C:1]#[N:2])[CH2:5][CH2:4]2)[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][N:19]=[C:20]([C:21]([F:23])([F:24])[F:22])[C:13]=23)[CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cc(-c2ccnc3c2c(C(F)(F)F)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc(C2(C#N)CC2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2cc(CCCN)cc(-c3ccnc4[nH]nc(C(F)(F)F)c34)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
tert-Butyl 3-(3-(1-cyanocyclopropyl)-5-(3-(trifluoromethyl)-1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)propylcarbamate (72 mg, 0.09893 mmol) was dissolved in DCM (3 mL) and cooled to 0° C. Triethylsilane (46.01 mg, 63.20 μL, 0.3957 mmol) was added followed by TFA (0.5 mL). The reaction was stirred at 0° C. for 1 hour then the solvent removed under reduced pressure. The crude product was dissolved in DMSO and purified by FractionLynx. The fractions were passed through bicarbonate cartridges to obtain free base and lyophilised to give 1-(3-(3-aminopropyl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)cyclopropanecarbonitrile as a white solid (22 mg, 57%).