Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[F:28])[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cnccc2F)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnccc2F)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 116 mg, 0.25 mmol) and 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (116 mg, 0.5 mmol) were dissolved in DME (1 mL). A solution of 2 M Na2CO3 (0.375 mL, 0.75 mmol) was added, the mixture was flushed with argon and PdCl2(dppf) (9 mg, 0.013 mmol) was added and the RM was stirred at 120° C. for 1 h. Additional 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (80 mg) and PdCl2(dppf) (9 mg, 0.013 mmol) were then added and the RM was stirred at 120° C. for further 45 min. After cooling at RT, the RM was treated with EtOAc, washed with brine dried over Na2SO4. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, 12 g, EtOAc/2% MeOH in EtOAc, gradient 50 to 100% B, EtOAc/MeOH 10%) and treated with Si-Thiol (100 mg) in MeOH. The product was further purified by preparative SFC (Column Diol, from 21% to 26% in 6 min) to afford the title product as a beige foam. HPLC (Condition 4) tR=5.14 min, UPLC-MS (Condition 3) tR=0.98 min, m/z=479.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.94 (m, 2H) 2.89-3.00 (m, 1H) 3.14-3.23 (m, 1H) 3.23-3.42 (m, 3H) 4.20 (br. s, 1H) 4.88 (br. s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.47 (dd, J=9.78, 5.47 Hz, 1H) 7.81-7.90 (m, 2H) 8.05 (d, J=2.35 Hz, 1H) 8.62-8.79 (m, 2H) 8.81 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CS(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(C=O)cn1
Reaction time: 0.75 h
Yield: 77.9 %

Procedure:
5 (5-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (7.00 g, 31.2 mmol) was dissolved in dry DMSO (50 mL) and the reaction flask immersed in a waterbath at 15° C. TEA (13.1 ml, 94.0 mmol) was added, followed by sulfur trioxide pyridine complex (15.0 g, 94.0 mmol) in portions. The reaction mixture was stirred for further 45 min and poured onto crushed ice. The product was extracted with diethyl ether and the combined organic extracts were washed with brine, dried and concentrated under reduced pressure. Recrystallisation from hexane/CH2Cl2 afforded (5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (5.40 g, 78%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]([CH:17]=O)=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([CH2:17][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: O=Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=c1c(Br)c(OCc2ccc(F)cc2F)cc(CN2CCOCC2)n1-c1c(F)cccc1F
Yield: 28.4 %

Procedure:
The title compound was prepared by reacting 5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde (0.456 g, 1 mmol) with morpholine (0.13 ml, 1.5 mmol) and triacetoxy sodium borohydride (0.42 g, 2.0 mmol) in dichloromethane (7 mL) by using a similar procedure to the one described for Example 468. The crude product was purified by flash column chromatography. Elution with (50:50→0:100) hexanes-ethyl acetate to give 0.15 g (29% yield) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.57 (m, 2H), 7.43-7.31 (m, 3H), 7.20 (dt, J=8.64, 2.48 Hz, 2H), 6.85 (s, 1H), 5.44 (s, 2H), 3.37 (app t, J=4.37 Hz, 4H), 3.13 (s, 2H), 2.08 (t, J=4.19 Hz, 4H); ES-HRMS m/z 527.0600 (M+H calcd for C23H20BrF4N2O3 requires 527.0594).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH2:29][OH:30]>CN1C(=O)CCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:27][CH2:28][CH2:29][OH:30])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: NCCO
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(CNC(=O)c2cc(NCCO)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 1.5 h
Yield: 63 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and 2-aminoethanol (1 ml) in NMP (2 mL). The vessel was sealed and the reaction mixture was irradiated (microwave) at 130° C. for 1 h and then at 140° C. for 90 min. The mixture was evaporated under vacuum and the residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated yellow oil was treated with EtOAc, sonicated, and treated with hexanes. The solids were filtered, dissolved in DMF (1 mL), and a few drops of water were added. The solution was allowed to stand at room temperature overnight, and then sonicated. The filtered solid was washed with Hexanes/EtOAc (1:1), and then dried to afford the title compound (55 mg, 63%) as a light yellow solid. LCMS E-S (M+H)=399.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1 H) 8.44 (br. s., 1 H) 7.84 (s, 1 H) 7.20 (br. s., 1 H) 6.68 (s, 1 H) 5.89 (s, 1 H) 4.95 (dt, J=13.01, 6.38 Hz, 1 H) 4.72 (t, J=4.93 Hz, 1 H) 4.32 (d, J=4.80 Hz, 2 H) 3.58 (d, J=5.56 Hz, 2 H) 3.38-3.46 (m, 2 H) 2.21 (s, 3 H) 2.12 (s, 3 H) 1.43 (d, J=6.57 Hz, 6 H)
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].O[C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:23][C:21]([O:20][C:19]([NH:18][CH2:17][CH2:16][O:15][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])=[O:25])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)c1cccc(OC)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OC)c1OCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
DIAD (23.95 ml, 123 mmol) was added dropwise to a stirred solution of 1,1-dimethylethyl (2-hydroxyethyl)carbamate (18.05 g, 112 mmol), methyl 2-hydroxy-3-(methyloxy)benzoate (20.4 g, 112 mmol) and triphenylphosphine (32.3 g, 123 mmol) in THF (400 ml) with cooling in an ice/water bath. Stirred for 30 mins then evaporated and used without any purification. LC/MS showed essentially just product and triphenylphosphine oxide. Yield 98.9 g of crude material. MS (ES): C16H23NO6 requires 325; found 326 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12]3[C:17]([NH:18][C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.N1C2C(=CC=CC=2)C(=O)C1=O.[OH:30][CH2:31][CH2:32][NH:33][CH2:34][CH2:35][NH2:36].Cl>C(OCCO)C.CC(=O)OCC.CO>[ClH:1].[CH:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]1[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=1[C:2]([NH:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31][OH:30])=[N:3]2
Reactant: NCCNCCO
Reactant: Clc1nc2ccccc2c2[nH]c3ccccc3c12
Agent: Cl
Agent: O=C1Nc2ccccc2C1=O
Solvent: CCOC(C)=O
Solvent: CCOCCO
Solvent: CO
Product: OCCNCCNc1nc2ccccc2c2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of compound 4a as obtained from the above Synthesis Ex. 1 (0.50 g, 2 mmol) and N-(2-hydroxyethyl)ethylenediamine (0.63 g, 6 mmol) in 2-ethoxyethanol (5 mL) was heated at 140-150° C. for 24 hrs (by TLC monitoring). After cooling, the reaction mixture was evaporated in vacuo to give a residue, which was dissolved in EA (50 mL). The EA layer was washed with H2O and brine and then dried (MgSO4). Concentration of the EA layer gave a residue, which was dissolved in MeOH (10 mL) and then added with a solution of 6N HCl at 0° C., followed by stirring at room temperature for 8 hrs. The resultant precipitate was filtered off, washed with MeOH, and dried at 90° C. under reduced pressure for 24 hrs to give the title compound 9 (0.50 g, 70% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1
Reactant: COc1cc(CNc2ccccc2[N+](=O)[O-])cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(CNc2ccccc2N)cc(OC)c1OC
Temperature: 0 °C

Procedure:
[(2-Nitrophenyl)]-3,4,5-trimethoxybenzylamine (15.01 mmol, 5.0 g) in ethyl acetate (150 ml) is charged with SnCl22H2O (94.2 mmol, 7.84 ml), and is refluxed for four (4) hours. The mixture is poured into ice water (100 g), sodium bicarbonate is added to achieve pH 7. and the reaction mixture is extracted with ethyl acetate (3×50 ml). The organic layers are dried with MgSO4, are filtered and evaporated (45%)
Reaction SMILES: [C:1]1([CH2:9][C:10]([OH:12])=[O:11])([CH2:5][C:6]([OH:8])=O)[CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)(=O)C>>[CH2:2]1[C:1]2([CH2:5][C:6](=[O:8])[O:12][C:10](=[O:11])[CH2:9]2)[CH2:4][CH2:3]1
Reactant: O=C(O)CC1(CC(=O)O)CCC1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2(CCC2)CC(=O)O1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
2,2′-(cyclobutane-1,1-diyl)diacetic acid (0.7 g, 4.07 mmol) was dissolved in acetic anhydride (5.75 mL, 61.0 mmol) and refluxed overnight. The solution was cooled to r.t. Acetic anhydride was removed under reduced pressure to give a brown oil, which was then recrystallized by dissolving in ether/hexanes, cooling to 0° C. and collecting crystals by vacuum filtration. The crystals were dried under vacuum overnight producing 7-oxaspiro[3.5]nonane-6,8-dione (2.147 mmol, 52.8% yield) as a light brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C@H:8]([CH3:11])[CH2:9][OH:10].C(N(CC)C(C)C)(C)C.[S:21](Cl)(Cl)=[O:22]>ClCCl>[CH3:11][CH:8]1[CH2:9][O:10][S@@:21](=[O:22])[N:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: C[C@H](CO)Nc1ccccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CO[S@@](=O)N1c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of (R)-N-(2-pyridyl)-2-aminopropanol (20.0 g, 0.13 moles) and N,N-diisopropylethylamine (33.6 g, 0.13 moles) in dichloromethane (500 ml) was cooled to 5° C. Then thionyl chloride (15.5 g, 0.13 moles) in dichloromethane (100 ml) was added slowly whilst the temperature was kept below 10° C. The mixture was stirred for 0.5 h. and ice cold water (500 ml) was added. The organic phase was separated and washed with water (5×500 ml). The aqueous phase was back-extracted with dichloromethane (2×500 ml), the organic phases were combined, dried (MgSO4) and evaporated in vacuo to give a brown oil. This was purified on a silica column, eluting with diethyl ether to give (R)-4-methyl-3-(2-pyridyl)-[1,2,3]oxathiazolidine 2-oxide (15.4 g) as a clear oil.
Reaction SMILES: Cl.[CH:2]1([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(Cl)Cl.C(N(CC)CC)C>[C:19]([C:8]1([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)C1(C2CCCCC2)NCCc2ccccc21

Procedure:
1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (800 mg) was dissolved in methylene chloride (12 mL), to which triethylamine (1.1 mL) and acryloyl chloride (0.28 mL) were then added under ice-cooling, followed by stirring under ice-cooling for 30 minutes and then stirring at room temperature for 14 hours. Water was added to the reaction liquid which was then extracted with chloroform. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated to obtain 2 acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (856 mg).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([I:20])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[C@H:9]([OH:21])[C@@H:8]1[OH:22])([OH:4])([OH:3])=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.N1C=CC=CC=1SSC1C=CC=CN=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O.CN(C=O)C>[CH2:24]1[N:23]([P:1]([O:5][CH2:6][C@H:7]2[O:11][C@@H:10]([N:12]3[C:13](=[O:14])[NH:15][C:16](=[O:17])[C:18]([I:20])=[CH:19]3)[C@H:9]([OH:21])[C@@H:8]2[OH:22])([OH:3])=[O:4])[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)cc1I
Reactant: C1COCCN1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](COP(=O)(O)N3CCOCC3)[C@@H](O)[C@H]2O)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104.9 %

Procedure:
5-Iodouridine-5′-monophosphate 1 (292 mg, 0.65 mmol) was dissolved in dry DMSO, co-evaporated (3×) with dry DMF, and finally dissolved in 0.5 mL of dry DMSO. Morpholine (400 μL, 4.6 mmol) was added and the reaction mixture was stirred at room temperature for 5 min. Dipyridyl disulfide (500 mg, 2.3 mmol) and triphenylphosphine (600 mg, 2.3 mmol) were added in 5 min intervals, and the reaction mixture was stirred for another 60 minutes at room temperature. Upon quenching of the reaction with 0.1 M NaI in acetone a precipitate formed. The supernatant was removed, and the precipitate was washed repeatedly with cold acetone, to give 354 mg (99% yield) of 5-Iodouridine-5′-phosphoromorpholidate as a white powder. This material was used in the next step without further purification. δH (400 MHz, D2O) 3.04-3.16 (4H, m, H-Morpholine), 3.65-3.73 (4H, m, H-Morpholine), 4.00-4.15 (2H, m, H-5′), 4.24-4.26 (1H, m, H-4′), 4.27-4.32 (1H, m, H-3′), 4.36 (1H, t, J=5.4 Hz, H-2′), 5.94 (1H, d, J=5.8 Hz, H-1′), 8.17 (1H, s, H-6). δC (75.5 MHz, D2O) 64.3 (morpholine), 63.3 (d, J=5.4 Hz, C-5′), 66.3 (morpholine), 67.8 (C-5), 68.6 (C-3′), 73.2 (C-2′), 83.0 (d, J=8.4 Hz, C-4′), 88.2 (C-1′), 145.0 (C-6), 153.3 (C-2), 161.9 (C-4); OP (121.5 MHz, D2O) 11.0 ppm. m/z (ESI) 519.9968 [M+H]+, C13H19IN3O9P requires 519.9976.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])=[O:4].O[Li].O.Cl>C1COCC1.CO.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([N:23]2[C:19]3[CH:20]=[N:21][CH:22]=[C:17]([C:15]([NH:14][CH:11]([C:7]4[O:8][C:9]([CH3:10])=[C:5]([C:3]([OH:4])=[O:2])[N:6]=4)[CH2:12][CH3:13])=[O:16])[C:18]=3[CH:25]=[N:24]2)=[CH:31][CH:30]=1
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)OC)c(C)o1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)O)c(C)o1
Reaction time: 3 h

Procedure:
To a solution of 2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-oxazole-4-carboxylic acid methyl ester (95.0 mg, 0.217 mmol) in a mixture of THF/Methanol/water (3 mL, 3:1:1) was added LiOH.H2O (36.5 mg, 0.869 mmol). After 3 hours, the reaction mixture was acidified to pH 3-4 with 2 M aqueous hydrochloric acid and concentrated. The mixture was diluted with ethyl acetate (25 mL) and water (25 mL) and stirred vigorously. After 5 hours, the heterogeneous mixture was filtered and the solid was washed with water (until the pH of the filtrate was 5), ethyl acetate (3×10 mL), and air dried to afford the title compound as a white solid. MS m/z 424.74 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH:36]3[CH2:38][CH2:37]3)=[N:19][C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:21][C:22]=2[CH2:23][O:24][CH3:25])=[CH:11][C:10]=1[CH3:39])([CH3:7])[CH3:6])C.[Li+].[OH-]>O1CCCC1.CCOCC>[CH:36]1([C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[C:10]([CH3:39])[CH:11]=3)=[C:22]([CH2:23][O:24][CH3:25])[N:21]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)[N:19]=2)[CH2:38][CH2:37]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1COc1ccc(OC(C)(C)C(=O)O)c(C)c1
Yield: 80.3 %

Procedure:
A solution of 215 mg (0.385 mmol) 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester and 1.1 ml 1N LiOH-solution in 2.5 ml tetrahydrofurane was stirred for 2 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude residue was suspended in AcOEt/heptane 1:19. The resulting amorphous crystals were filtered off to provide 164 mg of pure 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>C(#N)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[C:10](=[O:15])[C:11]([CH3:13])([CH3:14])[O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)OC(C)(C)C2=O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)OC(C)(C)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a stirred solution of 5-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (600 mg, 1.93 mol) in acetonitrile (50 mL) was added K2CO3 (800 mg, 5.8 mol). 2-Chloromethyl quinoline (500 mg, 2.32 mol) was added dropwise under an inert atmosphere. The reaction mixture was stirred at 80° C. for 16 h and then partitioned between water and EtOAc (200 mL). The organic layer was separated, washed with water, dried over Na2SO4 and then concentrated in vacuo to obtain a residue. The residue was purified via silica gel column chromatography to afford 4-(4-methoxyphenyl)-2,2-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (0.51 g, 58%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.45 (d, J=7.2 Hz, 1H), 8.02-7.97 (m, 2H), 7.85-7.77 (m, 1H), 7.76-7.68 (m, 2H), 7.59-7.51 (m, 2H), 7.19-7.11 (m, 4H), 6.95 (d, J=7.4 Hz, 2H), 5.41 (s, 2H), 3.75 (s, 3H), 1.45 (s, 6H). MS: M+H: m/z=452.1.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1ccc(CC2CCCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)cc1
Yield: 53 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-methylbenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 53% yield: mp 110-113° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.37-7.22 (m, 5H), 7.12-6.99 (m, 4H), 6.09 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.28-4.19 (m, 1H), 3.99-3.86 (m, 1H), 3.43-3.29 (m, 1H), 2.82-2.66 (m, 2H), 2.63 (s, 3H), 2.29 (s, 3H), 2.06-1.69 (m, 3H), 1.61-1.43 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 172.2, 162.7, 157.0, 152.1, 138.0, 136.1, 135.8, 129.2, 129.1, 128.8, 127.9, 127.6, 119.4, 48.1, 44.2, 44.0, 37.1, 24.8, 21.2, 21.1, 17.4; MS (ES+) m/z 434.3 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][CH2:16][CH2:17][CH:18]([OH:24])[C:19]([CH3:23])([CH3:22])[C:20]#[N:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CCOCC>[CH2:8]([O:15][CH2:16][CH2:17][CH:18]([O:24][C:1](=[O:3])[CH3:2])[C:19]([CH3:22])([CH3:23])[C:20]#[N:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)C(O)CCOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC(CCOCc1ccccc1)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
14.56 g (42.64 mmol) of acetic acid anhydride is added at 0° C. to a solution that consists of 25.6 g (109.7 mmol) of 5-benzyloxy-2,2-dimethyl-3-hydroxy-pentane-nitrile of the title compound of Example 1a, 14.43 g (142.64 mmol) of triethylamine and 200 mg of 4-dimethylaminopyridine (DMAP), dissolved in 128 ml of MTB-ether, and it is stirred for 5 hours at room temperature. The reaction mixture is poured onto 2 l of ice water and extracted twice with 300 ml each of MTB-ether. The combined MTB-phases are washed once with 300 ml of 5% hydrochloric acid and then with water. It is evaporated to the dry state in a vacuum.