Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([O:18]/[N:19]=[C:20](\[C:32]1[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][N:33]=1)/[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[OH:31])([CH3:17])([CH3:16])[CH3:15].O>C(Cl)(Cl)Cl>[C:14]([O:18]/[N:19]=[C:20](\[C:32]1[C:37]([O:38][C:7](=[O:9])[CH3:8])=[CH:36][CH:35]=[CH:34][N:33]=1)/[C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[OH:31])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)O/N=C(/c1cc(C(F)(F)F)ccc1O)c1ncccc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccnc1/C(=N\OC(C)(C)C)c1cc(C(F)(F)F)ccc1O
Reaction time: 0.83 h

Procedure:
Pyridine (0.30 ml) was dissolved in chloroform (10 ml). To the solution was added acetic anhydride (0.18 ml), and the mixture was stirred for 50 minutes. To the reaction mixture was then added (Z)-2-(2-hydroxy-5-trifluoromethylbenzoyl)-3-hydroxypyridine O-t-butyloxime (0.21 g), and the mixture was stirred for 3 hours at room temperature. To the reaction mixture were added water and chloroform for extraction. The organic layer was dried (anhydrous magnesium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane, then with ethyl acetate/THF) to give (Z)-3-acetoxy-2-(2-hydroxy-5-trifluoromethylbenzoyl)pyridine O-t-butyloxime (0.20 g) (Compound 46).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:24])=[C:4]([CH:19]=[C:20]([C:22]#[N:23])[CH:21]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Cl[C:26]1[N:31]=[C:30]([N:32]([CH:42]2[CH2:44][CH2:43]2)[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:29]2=[N:45][CH:46]=[C:47]([C:48]#[N:49])[N:28]2[N:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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.[Fe+2]>[Cl:24][C:3]1[C:2]([NH:1][C:26]2[N:31]=[C:30]([N:32]([CH:42]3[CH2:44][CH2:43]3)[CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:29]3=[N:45][CH:46]=[C:47]([C:48]#[N:49])[N:28]3[N:27]=2)=[CH:21][C:20]([C:22]#[N:23])=[CH:19][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(C#N)cc(N)c2Cl)CC1
Agent: [Fe+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 41.6 %

Procedure:
A mixture of tert-butyl 4-(3-amino-2-chloro-5-cyanobenzyl)piperazine-1-carboxylate (28 mg, 0.079 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (28 mg, 0.079 mmol), Cs2CO3 (51.4 mg, 0.158 mmol), DPPF (4.4 mg, 7.9 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (4.6 mg, 7.9 μmol), and in a microwave vial was flushed with nitrogen. Dioxane (0.7 mL) was added and the vial was sealed and heated at 100° C. for 3 hr. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed and radial silica gel chromatography with hexane containing 5 to 40% EtOAc afforded tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)benzyl)piperazine-1-carboxylate (22 mg) as an oil.
Reaction SMILES: O=S(Cl)[Cl:3].[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1>C(Cl)Cl>[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:3])=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1
Reactant: Cc1nc(N)nc(O)c1Sc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(N)nc(O)c1Sc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
SOCl2 (20 ml) was added slowly to a stirred mixture of the product from step (i) (6.7 g) in DCM (50 ml) and stirred at rt for 24 h. The solvent was evaporated under reduced pressure to give the title compound, 8.7 g.
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:30][CH:29]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([O:6]CC1C=CC=CC=1)=[O:5].[H][H]>C(O)C.[Pd]>[OH:1][CH:2]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:32][CH:33]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(OCc1ccccc1)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccn2)cc1
Reaction time: 2 h

Procedure:
To a solution of benzyl (2RS,3RS)-3-hydroxy-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (4.99 g, 8.95 mmol) in ethanol (500 ml) was added 10% palladium/carbon (containing water by 50%, 500 mg), and the mixture was stirred under a 1 atm hydrogen stream for 2 hrs. The reaction solution was filtered with celite and the filtrate was concentrated to give the objective substance (4.50 g, 100%, crude). The present compound was used for the next reaction as a crude compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:15](OCC)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:25])(=O)C.[CH2:26]([N:33]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:15](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:41][CH:42]=1)[CH3:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)ccc21)c1ccccc1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Product: COc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolinone and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)#[N:7]
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1f with 2c produced 3r. MS found M+H=467. The oxalate salt of 3r was recrystallized from ethyl acetate; mp 111-112° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:6]([CH2:12][OH:13])[CH:5]=[C:4]([CH:14]2[CH2:16][CH2:15]2)[C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:6]([CH:12]=[O:13])[CH:5]=[C:4]([CH:14]2[CH2:16][CH2:15]2)[C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: CC(C)Oc1c(CO)cc(C2CC2)c(-c2ccc(F)cc2F)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)Oc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2F)c1Cl
Reaction time: 1 h
Yield: 77 %

Procedure:
Manganese dioxide (5.37 g) was added at room temperature to a toluene (30 mL) solution of (2-chloro-6-cyclopropyl-2′,4′-difluoro-3-isopropoxybiphenyl-4-yl)methanol (2.18 g), and the mixture was stirred at 60 C for 1 hour in a nitrogen atmosphere. The solid was filtered off, and then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.67 g)
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH3:15])[C:9]2=[O:16])=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:18]#[C:17][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[C:9]1=[O:16]
Reactant: CN1C(=O)C(c2ccc(I)cn2)CC1(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(c2ccc(C#Cc3ccccc3)cn2)CC1(C)C
Temperature: 60 °C
Yield: 80.6 %

Procedure:
A solution of (RS)-3-(5-iodopyridin-2-yl)-1,5,5-trimethylpyrrolidin-2-one (140 mg, 0.42 mmol), ethynylbenzene (65.0 mg, 69.9 μl, 0.64 mmol), triethylamine (129 mg, 177 μl, 1.27 mmol), bis(triphenylphosphine)palladium (II) chloride (17.9 mg, 25.4 μmol) and triphenylphosphine (3.34 mg, 12.7 μmol) in 4 ml of THF was purged with argon. Then copper (I) iodide (2.42 mg, 12.7 μmol) was added and the reaction was heated for 3 h at 60° C. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue was taken up in ethyl acetate, adsorbed onto 3 g of silicagel which was loaded onto a 20 g prepacked flash chromato-graphy column. After elution with a 0% to 65% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 103 mg (72%) of the title compound as an amorphous yellow solid, MS: m/e=305.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[C@H:19]12[CH2:25][C@H:22]([NH:23][CH2:24]1)[CH2:21][N:20]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:23]3[CH2:24][C@@H:19]4[CH2:25][C@H:22]3[CH2:21][N:20]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 96 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (Example 57, step B) (0.63 g, 2.5 mmol), 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 5.0 mmol), HOAc (0.23 g, 3.8 mmol), TEA (0.25 g, 2.5 mmol) in DCM (20 mL) is added sodium triacetoxyborohydride (0.81 g, 3.8 mmol). The mixture was stirred for 1 h then poured into saturated NaHCO3 solution (30 mL). The layers are separated and the aqueous layer washed with DCM. The organics are combined, dried (MgSO4), filtered and rotovaped. DCM and silica are added and the solvent removed by rotovap. After purification by silica gel chromatography, the title compound of step A (1.0 g, 2.4 mmol, 96%) is obtained as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=9.3 Hz, 1H), 6.39 (dd, J=9.3, 2.0 Hz, 1H), 6.28 (d, J=2.0 Hz, 1H), 4.36-4.20 (m, 1H), 3.91 (s, 3H), 3.79-3.40 (m, 4H), 3.16-3.01 (m, 4H), 2.64-2.37 (m, 2H), 1.93-1.68 (m, 4H), 1.61-1.49 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: COC1C=CC(C=O)=CC=1.Cl[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17](C)[C:16](=[O:22])[CH2:15]2.N1CCCC1>CO>[N:17]1[C:16](=[O:22])[CH:15]=[C:14]2[C:18]=1[CH:19]=[CH:20][CH:12]=[CH:13]2
Reactant: CN1C(=O)Cc2cc(Cl)ccc21
Agent: COc1ccc(C=O)cc1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1C=c2ccccc2=N1
Temperature: 25 °C
Yield: 11 %

Procedure:
3-(exo-Bicyclo 2.2.1!hept-2-yloxy)-4-methoxybenzaldehyde (677 mg, 2.75 mmol; disclosed in WO 87/06576 published Nov. 5, 1987), and 5-chloro-1-methyloxindole (500 mg, 2.75 mmol; Chemical Abstracts registry number 41192-33-0, were dissolved in 10 ml of methanol under an inert atmosphere. To this brown, homogeneous mixture was added 0.23 ml of pyrrolidine (2.75 mmol) via syringe. The reaction mixture was stirred at room temperature for ten hours. The solvent was then stripped off and the resulting yellow oil was purified via flash chromatography (1:1 ethyl ether/hexane) to provide the desired Z-adduct 3- 3-(bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-5-chloro-1,3-dihydro-1-methyl- 1α,2α(Z),4α!-2H-indol-2-one (125 mg, 11% yield) as a yellow solid (Example 1): m.p. 149°-151°. Analysis calculated for C24H24ClNO3 : C, 70.32; H, 5.90; N, 3.42. Found: C, 70.26; H, 5.87; N, 3.38. The corresponding E-adduct 3- 3-(bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-5-chloro-1,3-dihydro-1-methyl- 1α,2α(E),4α!-2H-indol-2-one (Example 2) was also obtained in 6% yield, m.p. 142°-144° C. Analysis calculated for C24H24ClNO3 : C, 70.32; H, 5.90; N, 3.42. Found: C, 70.34; H, 5.85; N, 3.36.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.[Cl:22][CH2:23][CH2:24][CH2:25]I>C1COCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:19]([OH:21])=[O:20]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: ClCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
Step AC (1): NaHMDS (1.0 M in THF, 100 mL, 100 mmol) was added to a stirred solution of 2-(4-fluorophenyl)acetic acid (7.71 g, 50.0 mmol) in THF (100 mL) at 0° C. The resulting mixture was aged for 20 min at 0° C. and neat 1-chloro-3-iodopropane (5.27 mL, 50.0 mmol) was added. The mixture was allowed to warm to rt. After 16 hr, the reaction was quenched with water (3 mL). The crude mixture was concentrated in vacuo. Aqueous NaOH (1 M, 150 mL) was added to the residue and the resulting mixture was extracted with Et2O (2×100 mL). The basic layer was acidified with aqueous HCl (1 M, 200 mL) and the resulting solution was extracted with Et2O (2×100 mL). The combined organic layers from the acidic extraction were washed with mixture of brine/1N HCl/sodium sulfite, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography (0-10% EtOAc/hexane, linear gradient). The pure fractions were combined and concentrated to afford 5-chloro-2-(4-fluorophenyl)pentanoic acid (7.59 g, 29.6 mmol, 59% yield) as a light brown solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.30 (dd, J=8.55, 5.19 Hz, 2 H) 7.04 (t, J=8.70 Hz, 2 H) 3.58 (t, J=7.78 Hz, 1 H) 3.53 (t, J=5.80 Hz, 2 H) 2.21 (dddd, J=13.35, 10.45, 7.78, 5.34 Hz, 1 H) 1.90-2.01 (m, 1 H) 1.65-1.84 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(NC(=O)OC(C)(C)C)cc4)no3)cc2C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}phenyl)carbamate (Example 101, 1.0 g, 2.25 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the residue was re-dissolved in ethyl acetate. After washing with saturated aqueous sodium bicarbonate, the solvent was removed and the title compound was obtained as an off-white solid (770 mg, 99%): 1H NMR (400 MHz, CDCl3) 8.00 (d, 2H), 7.13 (d, 2H), 7.07 (d, 2H), 6.76 (s, 1H), 6.73 (d, 2H), 5.40 (s, 2H), 3.92 (broad, 2H), 2.32 (s, 3H), 2.23 (s, 3H); ES-MS m/z 346, HPLC RT (Method D) 2.48 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([C:25]3[CH:37]=[CH:36][C:28]4[O:29]C(C)(C)[O:31][C:32](=[O:33])[C:27]=4[CH:26]=3)[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[C:25]3[CH:37]=[CH:36][C:28]([OH:29])=[C:27]([CH:26]=3)[C:32]([OH:33])=[O:31])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C(C)(C)C)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C(C)(C)C)c3ccc(O)c(C(=O)O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-2,2-dimethylpropionamide and NaOH 5M aq. in the presence of EtOH as a white powder (70%). 1H NMR (CDCl3, 300 MHz) δ 10.62 (s, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.43 (m, 4H), 7.15 (m, 4H), 7.08 (dd, J=8.7, 2.6 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 4.83 (s, 2H), 2.62 (t, J=7.8 Hz, 2H), 1.61 (m, 2H), 1.36 (m, 2H, 1.08 (s, 9H), 0.93 (t, J=7.4 Hz, 3H). M− (ESI): 482.4; M+ (ESI): 484.3. HPLC, Rt: 5.39 min (Purity: 100%).
Reaction SMILES: O1CCCC1.C(N(CC)CC)C.[C:13]([CH:16]([N:20]1[CH2:23][CH:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]1=[O:34])[CH:17]([CH3:19])[CH3:18])(O)=[O:14].ClC(OCC)=O.[N-:41]=[N+:42]=[N-:43].[Na+]>O>[N:41]([C:13]([CH:16]([N:20]1[CH2:23][CH:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]1=[O:34])[CH:17]([CH3:19])[CH3:18])=[O:14])=[N+:42]=[N-:43]
Reactant: CC(C)C(C(=O)O)N1CC(NC(=O)Cc2ccccc2)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(C(=O)N=[N+]=[N-])N1CC(NC(=O)Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 91.2 %

Procedure:
A tetrahydrofuran solution (5 ml) containing triethylamine (1.02 g) was added to a tetrahydrofuran solution (40 ml) containing 1-(1-carboxy-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone (3.04 g) at -20° C. with stirring. To this solution, there was dropwise added a tetrahydrofuran solution (5 ml) containing ethyl chloroformate (1.14 g) at -10° C. in the course of 5 minutes, whereafter the mixture was stirred at -10° to 0° C. for 2 hours. To the resultant mixture, there was all at once added water (8 ml), in which sodium azide (1.23 g) was dissolved at the same temperature, and the stirring was continued for additional half an hour. The reaction mixture was poured into ice-water (200 ml) and the resultant mixture was extracted with three portions of 100 ml methylene chloride. The extracts were washed with three portions of 100 ml water and dried over calcium chloride. The solution was evaporated to dryness under reduced pressure to give oily 1-(1-azidocarbonyl-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone (3.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[CH:12][C:11]=1[CH3:21]>>[CH:18]1([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9](=[O:22])[CH2:6][C:2]#[N:1])=[C:11]([CH3:21])[CH:12]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(OCC2CC2)cc1C
Reactant: Nc1cc[nH]n1
Product: Cc1cc(OCC2CC2)ccc1C(=O)CC#N
Yield: 69 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis from 4-cyclopropylmethoxy-2-methyl-benzoic acid methyl ester (route Albis). 0.54 g of the title product was extracted from water and dried (yield 69%) and used directly for the next step.
Reaction SMILES: [OH-:1].[K+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)=[CH:7][CH:6]=1)#[N:4].OO>O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)=[CH:9][CH:10]=1)(=[O:1])[NH2:4]
Reactant: [OH-]
Reactant: Cc1[nH]n(Cc2ccc(C#N)cc2)c2nc(-c3ccncc3)nc(=O)c1-2
Agent: OO
Agent: [K+]
Solvent: O
Product: Cc1[nH]n(Cc2ccc(C(N)=O)cc2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.2 %

Procedure:
A solution of potassium hydroxide (0.24 g, 3.7 mmol) in water (10 ml) was stirred in an ice-bath for 30 minutes and 1-(4-cyanophenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one (0.42 g, 1.2 mmol) was added, followed by 30% hydrogen peroxide (0.6 ml, 6.1 mmol). The reaction mixture was stirred for 4 hours, warmed to room temperature and stirred for 24 hours. The reaction mixture was filtered, and the filtrate was neutralized with acetic acid to afford a white precipitate. The product was collected by filtration and washed with water, ethanol and ether. The product was recrystallized in DMF to afford 0.2 g (46%) of 1-(4-carbamoylphenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as a fluffy white powder, m.p. >300° C. when dried at 120° C. for 24 hours in high vacuum.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])#[N:2].[CH:13](OCC)(OCC)[O:14][CH2:15][CH3:16]>C(OC(=O)C)(=O)C>[C:1]([C:3](=[CH:13][O:14][CH2:15][CH3:16])[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: N#CCC(=O)NC1CCCCC1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(=O)NC1CCCCC1
Yield: 35.4 %

Procedure:
2-cyano-N-cyclohexyl-acetamide (Intermediate #18) (1.35 g, 8.09 mmol) was suspended in acetic anhydride (20 mL). Triethyl orthoformate (3.91 g, 21 mmol) was added and the mixture heated to reflux for 5 h. The reaction mixture was cooled to ambient and to volatiles removed by evaporation in vacuo to leave a brown oil which was which was purified by chromatography on silica gel eluting with an EtOAc/DCM gradient (0-10%) to give the title compound as a solid (637 mg, 35%)