Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:22])[CH:3]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[F:22][C:4]1[CH:3]=[C:2]([C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=2)[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC(N2CCCC2)CC1
Product: O=C(c1c(F)cc(-c2ccc(OC(F)(F)F)cc2)cc1F)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-difluoro-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 39) was reacted with 4-trifluoromethoxy-phenyl boronic acid to give the title compound as light yellow amorphous solid. MS: 455.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[C:13]([OH:20])=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:18][C:17]([C:16]1[C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]=2[C:13]([OH:20])=[CH:14][CH:15]=1)=[O:19]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3)nc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3)nc12
Temperature: 25 °C
Yield: 80 %

Procedure:
2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (200 mg, 0.69 mmol) obtained in step 3 was dissolved in 5 ml of methanol, H2SO4 (0.18 ml, 3.45 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with 1M NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent—MeOH/CDCl3=5/95, Merck, Silicagel 60) to obtain the title compound (166 mg, 0.55 mmol) in a yield of 80%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][OH:18])[CH:16]=[C:10]3[C:9]2=[O:19])=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.CCOC(C)=O.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:16]=[C:10]3[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: Brc1cccnc1
Reactant: O=C1c2cc(CO)nn2CCN1c1ccc(F)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1c2cc(COc3cccnc3)nn2CCN1c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
Copper (I) iodide (7.3 mg, 0.038 mmol) was added to a stirred suspension of 5-(4-fluoro-phenyl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.19 mmol), 3-bromopyridine (0.073 mL, 0.76 mmol), cesium carbonate (0.25 g, 0.77 mmol) and N,N-dimethylglycine (7.89 mg, 0.077 mmol) in 1,4-dioxane (1 mL) in a sealed tube and under nitrogen. The mixture was stirred at 100° C. for 16 hours. More copper (I) iodide (7.3 mg, 0.038 mmol) was added, N,N-dimethylglycine (7.89 mg, 0.077 mmol), cesium carbonate (0.25 g, 0.77 mmol) 3-bromopyridine (0.073 mL, 0.76 mmol) were added and the mixture was stirred at 130° C. for another 24 hours. The mixture was diluted with AcOEt and washed with a 16% aqueous solution of NH4OH. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 0/100 to 5/95). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(4-fluorophenyl)-2-(pyridin-3-yloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (7 mg, 11% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 4.13-4.22 (m, 2H), 4.55 (dd, J=6.8, 5.3 Hz, 2H), 5.17 (s, 2H), 7.03 (s, 1H), 7.10-7.18 (m, 2H), 7.23 (dd, J=8.5, 4.8 Hz, 1H), 7.28-7.36 (m, 3H), 8.25 (dd, J=4.6, 1.2 Hz, 1H), 8.41 (d, J=2.9 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=4)[CH:16]=2)=[O:14])[CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[NH2:24][C:19]1[C:18]2=[C:17]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:29]=4)[CH:16]=[C:15]([C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[O:14])[N:23]2[N:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Nc1ncnn2c(C(=O)C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 12 h
Yield: 77.8 %

Procedure:
The product from Step 3 (0.51 g, 0.94 mmol) was dissolved in THF (15 mL) and HCl in dioxane (4N, 2.34 mL) was added. The mixture was stirred for 12 hours and then concentrated. The residue was suspended in EtOAc, sonicated for 10 min and the white solid was filtered. The solid was partitioned between NaHCO3 saturated solution and i-PrOH/CHCl3 (1:2) mixture. The organic layer was separated and washed with brine, dried over Na2SO4 filtered and concentrated to provide 320 mg (78%) of the title compound. 1H-NMR (CD3OD-d4) 8.41-8.39 (m, 1H), 8.05 (s, 1H), 7.87 (dd, 1H), 7.71-7.69 (m, 1H), 7.70 (s, 1H), 7.37-7.29, (m, 5 H), 7.24 (dd, 1 H), 5.67 (s, 1 H), 4.39-4.31 (m, 1 H), 3.28-3.21 (m, 2 H), 3.12-2.96 (m, 2 H), 2.25-2.07 (m, 2 H); LC-MS [M+H]+=438.4, RT=2.52 min.
Reaction SMILES: C([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C:16]=1OC)([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C)[C:4]([O:6]CC)=[O:5])#N.[C:31](O)(=O)C>I>[CH2:9]([CH:3]1[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:16]=2[O:6][C:4]1=[O:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:31]
Reactant: CC(=O)O
Reactant: CCCCCCC(C#N)(C(=O)OCC)c1cccc(Sc2ccccc2C)c1OC
Agent: I
Product: CCCCCCC1C(=O)Oc2c(Sc3ccccc3C)cccc21

Procedure:
A solution of ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]octanoate (5 g) in hydriodic acid (58%, 20 ml) and acetic acid (40 ml) was refluxed under heating for 24 hours. The reaction mixture was treated in a similar manner to that of Example 31-(7) to give oily 3-n-hexyl-7-(o-tolylthio)-2,3-dihydrobenzofuran-2-one (1.7 g).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH3:22]CO>>[Br:3][C:4]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=2)=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: CCO
Reactant: COc1ccc(COc2cccc(C=O)c2Br)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1ccc(COc2cccc(CO)c2Br)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
NaBH4 (0.38 g, 10 mmol) was added to a solution of 2-bromo-3-(4-methoxy-benzyloxy)-benzaldehyde (1.59 g, 4.95 mmol) in EtOH (15 mL) at 0° C. (bath temp). The mixture was stirred at 0° C. (bath temp) for 1.5 h and then concentrated in vacuo. H2O (10 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The organic fractions were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound as white solid: yield 1.50 g (94%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24](OCC)=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1.Cl.[NH2:31][C@@H:32]([CH3:40])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O1CCOCC1>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24]([NH:31][C@H:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH3:40])=[O:25])[C:17](=[O:23])[C:18]2([CH3:21])[CH3:22])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](NC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O)C(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
DIPEA (120 μL, 690 μmol, 1.5 eq) was added to a mixture of ethyl 7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-carboxylate (156 mg, 460 μmol, prepared in Example 53A-D) and (S)-tert-butyl 2-aminopropanoate hydrochloride (100 mg, 552 μmol) in dioxane (5 mL). The reaction mixture was stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo to give a yellow oil. The crude oil was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired ester as a transparent oil (137 mg). MS (m/e)=382.1 (M+H-tBu)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Yield: 67.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carboxamide (Intermediate 13) (180 mg, 0.4337 mmols), [3-(hydroxymethyl)phenyl]boronic acid (264 mg, 1.74 mmols), cesium carbonate (282 mg, 0.868 mmol), and Pd(PPh3)4 (22 mg, 0.021 mmol) in dioxane/water (2 mL/0.7 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (130 mg, 68%)
Reaction SMILES: [Na].[CH:2]([CH:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6])=O.Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[NH:12]([CH:2]=[C:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC(C=O)CNC=O
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N#CC(=CNc1ccccc1)CNC=O

Procedure:
74 parts of 75 percent pure sodium salt of α-formyl-β-formylaminopropionitrile are refluxed for 1 hour with 58.3 parts of aniline hydrochloride in 400 parts by volume of methanol, the reaction mixture is filtered, and the filtrate is concentrated to half its volume. 59.6 parts of α-anilinomethylene-β-formylaminopropionitrile are obtained, followed by a further 6.3 parts after concentrating the mother liquor; this corresponds in total to 87.4% of theory, based on the Na salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH2:38][F:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1>CO.ClCCl.[Pd]>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH2:38][F:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@]1(O)CF
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@]1(O)CF
Reaction time: 12 h
Yield: 103.3 %

Procedure:
The compound from Step B (16 mg) was dissolved in 1:1 methanol/dichloromethane, 10% Pd-C was added, and the suspension stirred under an H2 atmosphere for 12 h. The catalyst was removed by filtration through a celite pad and washed with copious amounts of methanol. The combined filtrate was evaporated in vacuo and the residue was purified by flash chromatography (SiO2, 10% methanol in EtOAc containing 0.1% triethylamine) to give the title compound (8 mg) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[N:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:34]#CBr.O>CS(C)=O>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[N:9]=[C:8]2[N:5]1[CH2:4][CH2:3][N:2]([C:1]#[N:34])[CH2:7][CH2:6]1
Reactant: N#CBr
Reactant: COc1ccc2c(c1)c(N1CCN(C)CC1)nn2S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)c(N1CCN(C#N)CC1)nn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.3 %

Procedure:
To a stirred mixture of 3-(4-methyl-1-piperazinyl)-5-methoxy-1-phenylsulfonyl-1H-indazole (55.0 g, 0.14 mol) of Example 5d, potassium carbonate (22.0 g, 0.16 mol) and dimethylsulfoxide (DMSO) [500 ml] under N2 was added dropwise, cyanogen bromide (16.0 g, 0.15 mol) dissolved in DMSO (125 ml). The reaction was stirred at room temperature for 4 hours and was then poured into H2O (2.5 l). The solid which formed was collected and washed well with H2O. The solid was dried and weighed to yield 41.0 g. A 5.0 g sample was recrystallized twice from ethanol (utilizing decolorizing carbon) to afford 3.5 g (50%) of 4-(5-methoxy-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazinecarbonitrile. m.p. 171°-173° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[N:21]1([C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[O:10][C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29])[CH2:26][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A solution of 2-chloro-4-morpholin-4-yl-furo[3,2-d]pyrimidine-6-carbaldehyde (300 mg, 1.12 mmol) and 2-piperazin-1-ylisobutyramide dihydrochloride (327 mg, 1.33 mmol) in DCE (12 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (358 mg, 1.69 mmol) was added and the mixture stirred for 6 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 90:10) to afford the title compound as a tan solid (390 mg, 82%). LCMS (Method H): RT=2.39 min, M+H+=423
Reaction SMILES: Cl.C([C:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[OH:6])#N.Br.FC1C=CC(CC(O)=O)=CC=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:4][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[O:6])=[CH:14][CH:15]=1
Reactant: N#CC(=C(O)c1ccncc1)c1ccc(F)cc1
Agent: Br
Agent: Cl
Agent: O=C(O)Cc1ccc(F)cc1
Product: O=C(Cc1ccc(F)cc1)c1ccncc1

Procedure:
40.6 g (0.15 mol) of 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethen-1-ol hydrochloride were refluxed with vigorous stirring for 19 h in 130 ml of 48% strength hydrobromic acid. The reaction mixture was cooled in an ice bath, and the precipitate deposited (4-fluorophenylacetic acid) was filtered off and washed with dist. water. On neutralizing the filtrate with 80 ml of ammonia water, the title compound deposited as a dark-green precipitate. The precipitate was filtered off, washed with dist. water and dried over P2O5 in vacuo: pale gray-beige powder. Yield: 14.2 g (45%).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:10]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cc2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc(Cc2ccccc2)nc1-c1ccccc1
Yield: 40.8 %

Procedure:
A solution of methyl 2-(2-benzyl-4-methyl-6-phenylpyrimidin-5-yl)pentanoate (67 mg; 0.17 mmol) in ethanol (1 mL), tetrahydrofuran (1 mL) and 2N sodium hydroxide solution (0.895 mL; 1.789 mmol) was stirred for 40 h at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified with a 6N hydrochloric acid solution. The suspension was extracted twice with ethyl acetate and the organic layers were washed with water and dried by filtration over a phase separater filter (PS1). The crude material was purified first by flash chromatography on silica gel using a linear gradient of methanol (1-10%) in dichloromethane and then by preparative thick layer chromatography on silica gel eluting with 10% methanol in dichloromethane to give 25 mg (37%) of the title compound as a colorless oil. ESI/APCI(+): 361 (M+H).
Reaction SMILES: [P:1](Cl)(Cl)[O:2][C:3]1[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:16])=[CH:5][C:4]=1[C:36]([CH3:39])([CH3:38])[CH3:37].C(=O)=O.CC(C)=O.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[OH:56].C(N(CC)CC)C>C(Cl)Cl>[C:36]([C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:16])[CH:7]=[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:2][P:1]1[NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[O:56]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(OP(Cl)Cl)c(C(C)(C)C)c1
Reactant: Nc1ccccc1O
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(OP2Nc3ccccc3O2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
Into a cooled solution of 29.8 g (50 mmol) of 2,6-di-tert-butyl-4-[2-(n-octadecyloxycarbonyl)ethyl]-phenyl phosphorodichloridite in 100 ml of methylene chloride at dry ice/acetone temperature is added a solution of 5.46 g (50 mmol) of 2-aminophenol and 13.95 ml (100 mmol) of triethylamine in 25 ml of methylene chloride. After the addition is complete, the mixture is warmed to room temperature with continual stirring. After 16 hours, the reaction mixture is concentrated under reduced pressure, mixed with 50 ml of toluene and filtered to remove insoluble solids. The filtrate is reconcentrated, dissolved in hexane and treated with decolorizing charcoal. The resultant mixture is clarified and the filtrate concentrated under reduced pressure to give 27.6 g of the title compound as a white solid melting at 58°-65° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:37]=[CH:38][CH:39]=1)[CH2:7][O:8][C:9]1[CH:36]=[CH:35][C:12]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]3[CH:24]=[N:25][CH:26]=[C:27](/[CH:29]=[CH:30]/[C:31]([O:33]C)=[O:32])[CH:28]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:37]=[CH:38][CH:39]=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]3[CH:28]=[C:27](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])[CH:26]=[N:25][CH:24]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:35][CH:36]=1
Reactant: COC(=O)/C=C/c1cncc(OC(=O)N2CCC(Oc3ccc(OCc4cccc(F)c4)cc3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cncc(OC(=O)N2CCC(Oc3ccc(OCc4cccc(F)c4)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
An aqueous 1 M sodium hydroxide solution (1.11 ml) was added to a THF (5 ml) solution containing 5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]pyridin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (158 mg), followed by stirring at 60° C. for 3 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain (2E)-3-(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl)acrylic acid (88 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[NH2:21][C:22]1[CH:27]=[C:26]([C:15]2[C:14]3[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: Nc1cccc(B(O)O)c1
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1

Procedure:
The title compound was prepared from 4-chloro-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester and 3-aminophenylboronic acid according to the procedure of Example 1. MS (ES) m/z 361.0;