Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:9][N:8]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[C:5]2=[N:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: CON(C)C(=O)c1n[nH]c2ncc(Br)cc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CON(C)C(=O)c1nn(C2CCCCO2)c2ncc(Br)cc12
Yield: 93.2 %

Procedure:
To a solution of 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (IX) (0.250 g, 0.88 mmol) in dry DCM (10 mL) was added 3,4-dihydro-2H-pyran (0.179 mL, 1.98 mmol) and PPTS (22 mg, 0.08 mmol) and refluxed 5 h under nitrogen. Another equivalent of 3,4-dihydro-2H-pyran (0.179 mL, 1.98 mmol) and PPTS (22 mg, 0.08 mmol) was added and the solution was further heated at refluxed overnight under nitrogen. The solution was cooled, diluted with DCM, washed subsequently with a saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 5-bromo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (X) as a viscous liquid (302 mg, 0.82 mmol, 93% yield). 1H NMR (CDCl3) δ ppm 1.51-1.62 (m, 2 H), 1.91-2.13 (m, 2H), 2.33-2.44 (m, 2H), 3.40 (s, 3 H), 3.66 (m, 1H), 3.75 (s, 3H), 3.87-3.98 (m, 1 H), 6.07 (dd, J=10.07, 2.52 Hz, 1 H), 8.57 (d, J=3.01 Hz, 1 H), 8.73 (d, J=3.01 Hz, 1 H); ESIMS found for C14H17BrN4O3 m/z 369.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=1)(=O)[CH3:12].CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:1]2
Reactant: CC(=O)c1ncccc1C(F)(F)F
Reactant: Nc1nccc(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cccnc1-c1ccc2c(Cl)ccnc2n1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (78 mg, 0.5 mmol) and 2-acetyl-3-trifluoromethylpyridine (95 mg, 0.5 mmol) in anhydrous THF (2.0 mL) and cool it to −20° C. under N2 atmosphere. Add in portion t-BuOK (112 mg, 1.0 mmol) to the reaction mixture and stir the mixture at 10° C. for 2 hours. Concentrate the reaction mixture under vacuum, dilute the residue with saturated aq. ammonium chloride (10 mL), filter the solid, wash the solid with water and dry under high vacuum to afford desired product as a cream colored solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]([F:18])([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1)[CH:6]([F:8])[F:7].CCOCC>O>[F:4][C:5]([F:18])([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][C:1]#[N:2])=[CH:12][CH:11]=1)[CH:6]([F:8])[F:7]
Reactant: FC(F)C(F)(F)Oc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: N#CCc1ccc(OC(F)(F)C(F)F)cc1
Reaction time: 0.67 h
Yield: 87.9 %

Procedure:
Over a period of 40 minutes, a hot solution of 75.1 g (1.15 mol) of potassium cyanide in 140 ml of water is added to a mechanically stirred 75° C. solution of 160.99 g (0.561 mol) of p-(1,1,2,2-tetrafluoroethoxy)benzyl bromide and 500 ml of anhydrous 2B alcohol. The resulting mixture is refluxed for 1.75 hours. After sitting overnight the reaction mixture is poured into 500 ml of cold water and 400 ml of ether. The combined ether solutions are washed twice with 500 ml of water, dried with sodium sulfate, filtered, and then evaporated on a rotary evaporator to give 114.95 g of an oil. A vacuum distillation of this oil gives, as one distillation fraction, 37.10 g (28%) of the nitrile, boiling point 85° C. to 100° C. at 0.29 mm Hg.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([NH2:21])[C:16]([NH2:20])=[CH:17][C:18]=1[Cl:19].[F:24][C:25]([F:36])([F:35])[C:26]([F:34])([F:33])[C:27]([F:32])([F:31])[C:28](O)=O>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:18]([Cl:19])=[CH:17][C:16]2[N:20]=[C:28]([C:27]([F:31])([F:32])[C:26]([F:33])([F:34])[C:25]([F:36])([F:35])[F:24])[NH:21][C:15]=2[CH:14]=1
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)c(C(F)(F)F)c1
Yield: 31 %

Procedure:
A solution of 4-[2,4-bis(trifluoromethyl)phenyl]-5-chlorobenzene-1,2-diamine (300 mg, 0.85 mmol) in heptafluorobutanoic acid (20 ml) was stirred overnight at 80° C. in an oil bath and then quenched with water (100 ml). The pH value of the solution was adjusted to 8 with sodium carbonate and extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 6-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a pink solid (137.7 mg, 31%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:12]=[C:13]([C:19]2(O[Si](C)(C)C)[CH2:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>ClCCl.O>[Br:10][C:11]1[CH:12]=[C:13]([C:19]2([F:7])[CH2:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2(O[Si](C)(C)C)CC2)cc1Br
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2(F)CC2)cc1Br
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Diethylaminosulfur trifluoride (2.4 ml) was added to a solution of [1-(3-bromo-4-methoxyphenyl)cyclopropyloxy]trimethylsilane (3.84 g) in dichloromethane (68 ml). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.88 g).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH2:12])[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:26]([NH:12][CH:5]1[CH:4]2[CH2:10][CH:8]3[CH2:9][C:2]([OH:1])([CH2:11][CH:6]1[CH2:7]3)[CH2:3]2)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC12CC3CC(C1)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C3)C2
Reaction time: 0.17 h

Procedure:
5-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine (2.0 g; 0.012 mole) is dissolved in 70 ml of dichloromethane with gentle heating. To this is added triethylamine (2.4 g; 0.024 mole) and cooled in an ice bath. To this is added triphenylmethyl chloride (3.34 g; 0.012 mole) in dichloromethane (10 ml) all at once. The reaction is stirred for 10 minutes with ice cooling and then 5 hours at room temperature. The reaction mixture is heated to reflux overnight, cooled, filtered and evaporated to dryness. Purification is accomplished via HPLC (eluting with 20% ethyl acetate/hexane) to obtain N-trityl-5-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine (m.p. 166°-170° C.) which is used directly in step E.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24](OC)=[CH:23][CH:22]=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1.[F:31]C1C=CC(CBr)=CC=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:31])=[CH:23][CH:22]=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)c(Cl)c2=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of Intermediate 3 (120 mg, 0.39 mmol) in N,N-dimethylformamide (2 mL) was added 4-fluorobenzyl bromide (0.05 mL, 0.39 mmol), potassium carbonate (81 mg, 0.58 mmol) and 18-crown-6 (10 mg). The slurry was stirred at ambient temperature for two hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a colorless oil. (63 mg, 38% yield). MS (M+H): 417
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[CH2:13][C:14](O)=O.[CH3:17][NH:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[CH2:13][C:14]1[N:18]([CH3:17])[C:19]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:20]=2[N:26]=1
Reactant: CNc1c(N)cccc1N
Reactant: O=C(O)Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Product: Cn1c(Cc2c(Cl)cc(C(F)(F)F)cc2Cl)nc2cccc(N)c21
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
To a solution of [2,6-dichloro-4-(trifluoromethyl)phenyl]acetic acid (273 mg, 1.00 mmol) in toluene (2.0 mL) was added N,N′-carbonyldiimidazole (162 mg, 1.00 mmol) at room temperature. After the reaction mixture was stirred at 50° C. for 15 min, N2-methylbenzene-1,2,3-triamine (137 mg, 1.00 mmol) in toluene (2 mL) was added to the mixture, and the mixture was refluxed for further 60 hr. After the reaction mixture was cooled, the solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography eluting with 40-60% ethyl acetate/n-hexane gradient mixture to give the title compound (170 mg, 0.455 mmol, 45%) as a colorless solid. The resulting solid was recrystallized from n-hexane/ethyl acetate to give the title compound (137 mg, 0.38 mmol).
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:30][O:29][C@H:28]([CH2:31][OH:32])[C@@H:27]([O:33][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[CH:9][C:8]=2[Cl:41])=[CH:3][CH:2]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:30][O:29][C@H:28]([CH:31]=[O:32])[C@@H:27]([O:33][Si:34]([CH2:37][CH3:38])([CH2:39][CH3:40])[CH2:35][CH3:36])[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[CH:9][C:8]=2[Cl:41])=[CH:3][CH:2]=1
Reactant: CC[Si](CC)(CC)O[C@H]1C[C@@H](Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)CO[C@@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H]1C[C@@H](Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)CO[C@@H]1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ((2R,3 S,5R)-5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-3-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol (56 mg, 0.080 mmol) in anhydrous DCM under nitrogen was added pyridine (13 μL, 12.7 mg, 0.161 mmol) and Dess-Martin periodinane (51 mg, 0.121 mmol). After stirring at room temperature for 2 hours, the mixture was directly loaded onto a Biotage™ 10 g silica gel cartridge and eluted with 0-20% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The desired SEM regioisomeric product fractions were combined and concentrated under reduced pressure to provide the title compound as a clear oil. LC-MS: calculated for C36H48ClN3O5Si2 693.28, observed m/e: 694.25 (M+H)+ (Rt 3.23/4 min, minor isomer), 694.23 (M+H)+ (Rt 3.31/4 min, major isomer).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:11][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7.0 g (0.045 mol) of 3-fluoro-4-nitrophenol and 6.7 g (0.067 mol) of triethylamine in 20 ml of methylene chloride cooled to 0° is added 6.5 g (0.054 mol) of pivaloyl chloride in a dropwise manner. The reaction is allowed to warm to room temperature and stirred overnight. The reaction is quenched with water and extracted with ethyl acetate. The organic layer is washed successively with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over magnesium sulfate. Filtration and removal of the solvents gives crude 2-fluoro-4-pivaloyloxy-nitrobenzene which is dissolved in 200 ml of absolute ethanol. To the solution is added 0.9 g of 5% palladium on carbon, and the mixture is then hydrogenated under 30 psi hydrogen for two hours. The catalyst is filtered and the solvent removed to give 2-fluoro-4-pivaloyloxyaniline.
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])C(O)=O)#[N:2].O>CC(N(C)C)=O>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[CH2:7][CH2:3][C:1]#[N:2]
Reactant: N#CC(Cc1c(Cl)cccc1Cl)C(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#CCCc1c(Cl)cccc1Cl
Temperature: 150 °C
Yield: 93.7 %

Procedure:
2-Cyano-3-(2,6-dichlorophenyl)propanoic acid (447 mmol, 109 g) was dissolved in DMA (179 ml) and heated for 2 hours at 150° C. After cooling, the reaction mixture was poured into water and extracted with ether. The organic layer was washed with a saturated solution of sodium hydrogen carbonate and then with a saturated solution of sodium chloride. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to afford 3-(2,6-dichlorophenyl)propanenitrile (94% yield, 83.8 g).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]2.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:44][CH:45]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]([CH2:55][CH2:56][CH2:57][O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[C:46]1=[O:66]>C(Cl)Cl>[Si:59]([O:58][CH2:57][CH2:56][CH2:55][N:47]1[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:54][CH:45]([NH:44][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=3)=[O:23])[C:46]1=[O:66])([C:62]([CH3:64])([CH3:65])[CH3:63])([CH3:61])[CH3:60]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCCCN1C(=O)C(N)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Yield: 82.3 %

Procedure:
Prepared exactly as in Method 7 using HOBT (174 mg, 1.3 mmol), 5-chloroindole-2-carboxylic acid (250 mg, 1.3 mmol), DIPEA (0.22 mL, 1.3 mmol), EDCI (308 mg, 1.6 mmol) and 3-amino-1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3,4-dihydroquinolin-2(1H)-one (Method 14, 432 mg, 1.3 mmol) in DCM (10 mL). This gave the title compound (548 mg, 82%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][N:5]([CH:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[OH-].[Na+].Cl>CO>[C:23]([O:22][C:20]([CH:14]([C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)[N:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:4][C:3]([OH:27])=[O:2])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)CN(Cc1ccccc1C)C(C(=O)OC(C)(C)C)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1CN(CC(=O)O)C(C(=O)OC(C)(C)C)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-(N-2-methylbenzyl)-glycine methyl ester (41.85 g, 0.111 mol) was dissolved in CH3OH (300 mL) at 0° C. and treated with 2N NaOH solution (111 mL, 0.222 mol) and allowed to stir at ambient temperature for 3 hr. 1N HCl (235 mL, 0.235 mol) was added, the CH3OH was removed on a rotary evaporator, and the residue was extracted with EtOAc (2×1.5 L), washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound as a white solid. 1H NMR (CD3OD) δ 7.56 (d, 1H, J=7.5 Hz), 7.15-7.36 (m, 3H), 4.70 (d, 1H, J=13 Hz), 4.27 (d, 1H, J=13 Hz), 4.1-4.2 (m, 1H), 3.73 (d, 1H, J=16 Hz), 3.59 (d, 1H, J=16 Hz), 3.15-3.5 (m, 4H), 2.49 (s, 3H), 2.1-2.2 (m, 1H), 1.7-1.9 (m, 2H), 1.6-1.7 (m, 1H), 1.46 (s, 9h).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:10]=1[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:10]=1[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CCCc1c(OCc2ccccc2)cccc1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCc1c(O)cccc1C(=O)O
Yield: 110.8 %

Procedure:
A solution of 4-[2-benzyloxy-6-carboxy-phenyl]butanoic acid (5 g, 15.9 mmol) in ethanol was hydrogenated at 60 psi for 4 hr over 10% Pd/C (1 g). The mixture was filtered, and the filtrate was concentrated in vacuo to give a white solid (3.95 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrazol-1-yl-benzylamino)-methyl-phenoxy}-acetic acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, 1H), 7.86-7.49 (m, 8H), 7.07 (m, 3H), 6.73 (m, 1H), 6.60 (d, 1H), 6.56 (s, 1H), 6.42 (m, 1H), 4.33 (s, 2H), 4.32 (s, 2H), 4.27 (s, 2H), 1.46 (s, 9H); MS 534 (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[CH3:24])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7]>C(O)C>[CH3:3][S:4][CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:29][CH:30]=2)[CH3:24])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)SC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSC(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
5.05 ml of a 1N aqueous sodium hydroxide solution was added to a solution of 1.20 g of ethyl 2-methylthio-3-[4-[2-[[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 17 in 20 ml of ethanol, and the mixture was stirred at 50° C. for 30 minutes. After the reaction, the ethanol was evaporated under reduced pressure, and 5.05 ml of 1N hydrochloric acid was added to the residue thus obtained, followed by extraction of the precipitated product with ethyl acetate. The extract thus obtained was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residual powder thus obtained was washed with isopropyl ether to obtain 0.95 g of the desired compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=2[O:14][CH:13]=1)C>C1COCC1>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH2:11][CH2:10][OH:9])=[CH:13][O:14][C:15]=2[CH:20]=1
Reactant: CCOC(=O)Cc1coc2cc(OC)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(CCO)coc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(6-methoxy-1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4, filtered and concentrated. The product, 2-(6-methoxy-1-benzofuran-3-yl)ethanol, was obtained as a white oil and was pure enough to be taken to the next step without purification. Yield: 850 mg (88%); (M+H): 193.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH2:23])[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]2[CH:11]=[C:10]([NH:23][S:36]([C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=3)(=[O:38])=[O:37])[CH:9]=[C:8]([O:7][C:6]3[CH:24]=[CH:25][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:13]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(Oc2cc(NS(=O)(=O)c3ccc4ccccc4c3)cc(Oc3ccc(C#N)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
[3,5-Bis-(4-cyano-phenoxy)-phenyl]-amine (0.35 g, 1.07 mmol) and 2-naphthyl-sulphonyl chloride (0.29 g, 1.28 mmol) were dissolved in 10 ml of dichloromethane and cooled to 0° C. Further 0.18 ml (2.14 mmol) of pyridine and 15 mg (0.107 mmol) of DMAP was added to the reaction mixture and allowed to stirred overnight at RT. After completion, reaction mixture was diluted with 50 ml of dichloromethane and washed with 50 ml 1N HCl solution and then with brine. Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuo. Thus obtained crude product was subjected to column chromatography and eluted with ethylacetate and hexane mixture to afford 0.4 g of the required product. Percentage purity (LCMS): 90.4% M+1=517.1+1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[N:5]=[C:6](Cl)[C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1>CO.[Pd]>[CH3:17][O:16][CH:3]([O:2][CH3:1])[C:4]1[N:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1
Reactant: COC(OC)c1nc(Cl)c2c(n1)NC(=O)CC2
Agent: [Pd]
Solvent: CO
Product: COC(OC)c1ncc2c(n1)NC(=O)CC2
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To crude 2-[bis(methyloxy)methyl]-4-chloro-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (presumed 6.78 mmol) dissolved in MeOH was added 10% Pd/C (0.15 g). The solution was stirred under an atmosphere of H2 (balloon) overnight. The Pd/C was filtered off and the solution concentrated under vacuum. The crude residue was purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as a white solid (0.873 g, 58% over 2 steps).