Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:32][CH2:31][CH:30]=[CH:29][C:28]2=[CH:33][C:24](=[CH:25][CH:26]=[CH:27]2)[C@@H:23]([CH3:34])[NH:22][C:21](=[O:35])[C@H:20]2[NH:36][N:16]([CH2:17][CH2:18][CH2:19]2)[C:15](=[O:37])[C@H:14]([CH3:38])[NH:13][C:12](=[O:39])[C@H:11]([CH:40]([CH3:42])[CH3:41])[O:10][C:9](=[O:43])[C@@H:8]1[CH3:44])(C)(C)C.N1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:6][C@@H:7]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]2=[CH:33][C:24](=[CH:25][CH:26]=[CH:27]2)[C@@H:23]([CH3:34])[NH:22][C:21](=[O:35])[C@H:20]2[NH:36][N:16]([CH2:17][CH2:18][CH2:19]2)[C:15](=[O:37])[C@H:14]([CH3:38])[NH:13][C:12](=[O:39])[C@H:11]([CH:40]([CH3:42])[CH3:41])[O:10][C:9](=[O:43])[C@@H:8]1[CH3:44]
Reactant: CC(C)[C@@H]1OC(=O)[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)CCC=Cc2cccc(c2)[C@@H](C)NC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](C)NC1=O
Agent: [Pd]
Agent: CC(C)[C@@H]1OC(=O)[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)CC/C=C/c2cccc(c2)[C@@H](C)NC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](C)NC1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)[C@@H]1OC(=O)[C@H](C)[C@H](O)CCCCc2cccc(c2)[C@@H](C)NC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](C)NC1=O
Reaction time: 16 h

Procedure:
To (E)-(2R,5S,11S,14S,17R,18R)-18-(tert-butyl-dimethyl-silanyloxy)-14-isopropyl-2,11,17-trimethyl-15-oxa-3,9,12,28-tetraaza-tricyclo[21.3.1.1*5,9*]octacosa-1(26),21,23(27),24-tetraene-4,10,13,16-tetraone (50 mg, 0.08 mmol) in ethyl acetate (10 mL) at room temperature was added 10% palladium on carbon (50 mg). The system was purged with hydrogen gas and stirred vigorously for 16 h. The reaction mixture was filtered through Celite and the filter pad washed with methanol. The filtrate was concentrated in vacuo. The ensuing residue was dissolved in anhydrous tetrahydrofuran (5 mL) and transferred to a polypropylene vial. At room temperature hydrogen fluoride.pyridine (1.3 mL, 15.2 mmol) was added to the reaction mixture followed by stirring for 3 h. The reaction was diluted with ethyl acetate and quenched by cautious addition of saturated aqueous ammonium chloride. The organic layer was separated, dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/acetone 5/1 to afford the title compound as a white solid. This was further purified by triturating with diethyl ether, filtering and drying the solid in vacuo (20 mg, 48%, 2 steps). 1H NMR (300 MHz, CD3CN) 0.90-1.00 (m, 6H), 1.24-1.30 (m, 6H), 1.43 (d, J=6.9 Hz, 3H), 1.32-2.08 (m, 11H), 2.45-2.81 (m, 4H), 3.23-3.36 (m, 1H), 3.47-3.59 (m, 1H), 3.67 (d, J=10.3 Hz, 1H), 4.02 (d, J=11.8 Hz, 1H), 4.29 (d, J=13.8 Hz, 1H), 4.75 (d, J=5.4 Hz, 1H), 4.95-5.08 (m, 1H), 5.16-5.29 (m, 1H), 7.03-7.29 (m, 6H). LCMS (m/z)=545.3 [M+H], Tr=2.15 min.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])[CH:2]=[CH2:3].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][O:14][Si:19]([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the diol 14 (16.97 g, 84 mmol) in CH2Cl2 (235 mL) was treated with TEA (11.7 mL, 8.5 g, 84 mmol) and stirred for 15 minutes at room temperature. TBDMSCl (9.72 g, 64 mmol) and DBU (16.8 mmol, 2.51 mL, 2.56 g) were added and the reaction mixture stirred for a further 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with saturated NH4Cl (160 mL), brine (160 mL), dried (MgSO4), filtered and evaporated in vacuo to give an oil which was a mixture of the required product (major component), unreacted diol and the presumed disilyated compound by TLC (50% EtOAc/Petroleum Ether). Flash chromatography (20-100% EtOAc/Petroleum Ether) isolated the 3 components, to provide the monosilylated compound 15 as a slightly yellow transparent oil (13.85 g, 52%): [α]21D=−58.6° (c=1.14, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ 6.01-5.86 (m, 1H, NCO2CH2CH═CH2), 5.34-5.18 (m, 2H, NCO2CH2CH═CH2), 4.59-4.49 (m, 3H, NCO2CH2CH═CH2 and NCHCH2OTBDMS), 4.06-3.50 (m, 5H, NCH2CHOH, NCH2CHOH and NCHCH2OTBDMS), 2.20-2.01 (m, 2H, NCH2CHOHCH2), 0.87 (s, 9H, SiC(C3)2), 0.0 (s, 6H, Si(CH3)2); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ 155.0 (NC═O), 133.1 (NCO2CH2CH═CH2), 117.6 and 117.1 (NCO2CH2CH═CH2), 70.3 and 69.7 (NCH2CHOH), 65.9 and 65.6 (NCO2CH2CH═CH2), 63.9 and 62.8 (NCHCH2OTBDMS), 57.8 and 57.4 (NCHCH2OTBDMS), 55.7 and 55.2 (NCH2CHOH), 37.3 and 36.6 (NCH2CHOHCH2), 25.9 (SiC(CH2)2), 18.2 (SiC(CH3)3), −5.5 (Si(CH3)2); MS (EI), m/z (relative intensity) 316 (M+.+1, 29), 315 (M+., 4), 300 (M-CH3, 26), 284 (4), 261 (8), 260 (50), 259 (100), 258 (M-OC3H3 or M-tBu, 100), 218 (13), 215 (10), 214 (52), 200 (12), 170 (M-CH2OTBDMS, 100), 156 (40), 126 (58), 115 (33), 108 (41), 75 (35); IR (Neat) 3422 (br, OH), 2954, 2858, 1682 (C═O), 1467, 1434, 1412 (SiCH2), 1358, 1330, 1255 (SiCH2) 1196, 1180, 1120, 1054, 995, 919, 837, 776, 669 cm−1; exact mass calcd for C15H29NO4Si m/e 315.1866, obsd m/e 315.1946.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH:10](O)=O>>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][CH:10]=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: O=CO
Reactant: Nc1cc(Br)cnc1N
Product: Brc1cnc2nc[nH]c2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A suspension of 2,3-diamino-5-bromopyridine (3.0 g, 16.00 mmol) in formic acid (30 mL) was heated to reflux for 3 hours. After cooling the reaction mixture to room temperature it was concentrated and the residue was taken into 50% ethyl acetate in toluene (100 mL) then concentrated and the process repeated once more to remove excess formic acid. The resulting solid was triturated with ethyl acetate and the solid residue collected by filtration to give 6-bromo-1H-imidazo[4,5-b]pyridine (3.7 g, 95%). GCMS (EI) for C6H4BrN3: 198 (M+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:38][CH:39]([F:41])[F:40])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH:31]=3)[N:10]=2)[CH:8]=1.[O:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(#N)C.O>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:38][CH:39]([F:41])[F:40])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH:32]4[CH2:33][CH2:34][N:35]([CH:45]5[CH2:46][CH2:47][O:42][CH2:43][CH2:44]5)[CH2:36][CH2:37]4)[CH:31]=3)[N:10]=2)[CH:8]=1
Reactant: O=C1CCOCC1
Reactant: O=C(Nc1cn(Cc2cn(C3CCNCC3)nn2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=C(Nc1cn(Cc2cn(C3CCN(C4CCOCC4)CC3)nn2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (200 mg, 0.330 mmol) in dichloromethane (30 mL) was added oxan-4-one (264.9 mg, 2.646 mmol). The resulting solution was stirred at room temperature overnight. Then NaBH(OAc)3 (280.8 mg, 1.325 mmol) was added. The resulting solution was stirred at room temperature for 6 h and concentrated under vacuum. The residue was applied onto a silica gel column eluting with DCM/MeOH (80:20). The crude product (150 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O (10 mmol NH4HCO3)=20% increasing to ACN/H2O (10 mmol NH4HCO3)=49% within 8 min; Detector, UV 254 nm. 56.9 mg product was obtained. This resulted in 56.9 mg (26%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-([1-[1-(oxan-4-yl)piperidin-4-yl]-1H-1,2,3-triazol-4-yl]methyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=653.3, RT=1.74 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.67-8.66 (m, 2H), 8.39 (s, 1H), 8.26 (s, 1H), 7.65-7.62 (m, 2H), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.4 Hz), 5.48 (s, 2H), 4.58-4.45 (m, 1H), 3.90-3.87 (m, 2H), 3.32-3.25 (m, 2H), 3.04-2.98 (m, 2H), 2.51-2.33 (m, 1H), 2.30-2.24 (m, 2H), 2.09-2.06 (m, 2H), 1.99-1.91 (m, 2H), 1.70-1.67 ((m, 2H), 1.49-1.40 (m, 2H).
Reaction SMILES: [CH:1](=O)[CH3:2].[CH:4]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[K+]>>[CH:1](=[N:11][CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: CC=O
Reactant: NC1CCCCCC1
Agent: [K+]
Agent: [OH-]
Product: CC=NC1CCCCCC1
Yield: 86 %

Procedure:
90% Acetaldehyde (19.55 g) was added dropwise to cycloheptylamine (45.28 g) with ice bath cooling over about 2 hours. After the completion of the dropwise addition, potassium hydroxide, in solid form, was added and the organic layer was separated by a separatory funnel. This liquid was distilled under reduced pressure to obtain pure N-ethylidenecycloheptylamine (47.92 g). b.p. 100°-104° C./106.4 mbar.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:5].Br[Mg][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([F:28])[CH:22]=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>O1CCCC1>[F:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[CH3:27])[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:5]
Reactant: Cc1ccc([Mg]Br)cc1F
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (2.35 g, 9.10 mmol) in tetrahydrofuran (10 mL), 0.5 M solution of bromo(3-fluoro-4-methylphenyl)magnesium in tetrahydrofuran (20 mL, 10 mmol) was added dropwise under an argon atmosphere and ice cooling. Upon the completion of the dropwise addition, the mixture was stirred for 16 hours at room temperature, and then added with saturated aqueous citrate solution (40 mL). The mixture obtained was extracted with ethyl acetate (30 mL×3) and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=6/4) to give the title compound as a brown oily substance (1.35 g, yield 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1Cl
Product: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1Cl

Procedure:
8.10 g (37.6 mmol) of (2-chloro-4-nitrophenyl)acetic acid is suspended in 40 mL of thionyl chloride and refluxed for 2 hours. The product is reacted further without any more purification. Crude yield: 8.80 g (100% of theory); C8H5Cl2NO3.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[H][H]>CO>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]([OH:11])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCOc2ccccc21
Solvent: CO
Product: O[C@@H]1CCOc2ccccc21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
In a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl(R,R)—O-HT-Tsdpen) was placed, and the autoclave was purged with nitrogen. Subsequently, 0.74 g (5.0 mmol) of 4-chromanone and 4.4 ml of methanol were added thereto, and the pressure was raised with hydrogen up to 3.0 MPa. Subsequently, the mixture was stirred for 18 hours at 60° C. The reaction liquid was subjected to a GC analysis, and as a result, (R)-4-chromanol was obtained at a conversion rate of 98.6% with an optical purity of 99.1% ee.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[C@H:21]1[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:54](O)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([O:25][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:21]1[CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1COCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)[C@H]1COCc1ccccc1
Reaction time: 14 h
Yield: 78.5 %

Procedure:
A solution of 0.52 ml (3.31 mmol) of diethyl azodicarboxylate in 5 ml of tetrahydrofuran was slowly added at room temperature to a solution of 1.00 g (3.25 mmol) of (2R, 3R)-1-t-butoxycarbonyl-2-benzyloxymethyl-3-hydroxypyrrolidine [prepared as described in step (a) above], 0.87 g (3.31 mmol) of triphenylphosphine and 0.42 g (3.47 mmol) of benzoic acid in 5 ml of tetrahydrofuran, and the mixture was stirred for 14 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash chromatography through silica gel, using a 20:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.05 g of the title compound as an oil.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH:1]1([CH2:7][C:8]([Cl:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To cyclohexylacetic acid (23a) (89, 56.25 mmol) in DCM (160 mL) at room temperature was added the oxalyl chloride (6.4 mL, 73.14 mmol) and 2 drops of DMF. The reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure to give cyclohexylacetyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[H-].[Na+].Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[N:17]=1>CN(C=O)C.O>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:19][N:20]=3)[N:17]=2)=[N:5][CH:4]=[N:3]1
Reactant: Cn1ncnc1CO
Reactant: Clc1ccc2nnc(-c3ccccc3)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1ccc2nnc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-methyl-2 H-1,2,4-triazol-3-yl)methanol (0.9 g, 8.0 mmol) (prepared using the conditions described in EP-A-421210) in DMF (30 ml) was added sodium hydride (0.32 g of a 60% dispersion in oil, 1.6 mol eq.) and the reaction mixture was stirred at room temperature for 30 minutes. After this time the product from Example 88 Step a) (1.15 g, 5.0 mmol) was added as a solution in DMF (20 ml) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (200 ml) and the aqueous extracted with dichloromethane (4×150 ml). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using 4% MeOH in dichloromethane as eluent to give the required product, (1.5 g, mp=254° C.). 1H NMR (360 MHz, CDCl3) δ3.98 (3 H, s), 5.61 (2 H, s), 6.90 (1 H, d, J=9.8 Hz), 7.51-7.60 (3 H, m), 7.94(1 H, s), 8.12 (1 H, d, J=9.8 Hz), 8.39 (2 H, dd, J=9.6, 1.5 Hz); MS (ES+) m/e 308 [MH]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11](Br)[C:10]([C:15]#[N:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:32])([CH3:31])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)=[O:20].C(O)CC.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC)(C)(C)C.O>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:19](=[O:20])[C:18]([CH3:31])([CH3:17])[CH3:32])[C:10]([C:15]#[N:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccccc1B(O)O
Reactant: Cc1c(Br)c(C#N)nn1Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCCO
Product: Cc1c(-c2ccccc2NC(=O)C(C)(C)C)c(C#N)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
1-Benzyl-4-bromo-5-methyl-1H-pyrazole-3-carbonitrile (3.00 g, 10.9 mmol) was treated with triphenylphosphine (85 mg, 0.32 mmol), 2-[(2,2-dimethylpropanoyl)amino]phenylboronic acid (prepared as described in Part G of Example 23, 2.15 g, 16.3 mmol), 1-propanol (22 mL), palladium (II) acetate (24 mg, 0.11 mmol), aqueous sodium carbonate (6.5 mL of 2 M, 13 mmol), and water (4.4 mL) according to the general procedure described in Example 34. The reaction time was approximately 16 hours and no additional reagents were added. The reaction was allowed to cool to ambient temperature and methyl tert-butyl ether (25 mL) was added. After the mixture was stirred for about 10 minutes, the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield a brown oil. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution 1-30% ethyl acetate in hexanes). The appropriate fractions were combined, dried over magnesium sulfate, filtered, and concentrated to yield 2.40 g of N-[2-(1-benzyl-3-cyano-5-methyl-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamide as an oil that solidified upon standing at ambient temperature.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[NH:6][C:5]1=O)[CH2:2][CH3:3].[NH4+].[Cl-:32]>O=P(Cl)(Cl)Cl>[Cl:32][C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[N:6]=1
Reactant: CCCn1c(=O)[nH]c2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: [Cl-]
Agent: [NH4+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 122.5 °C
Yield: 56.6 %

Procedure:
A mixture of 1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (7.2 g, 0.017 mol), NH4Cl (4.54 g, 0.085 mol) and POCl3 (220 ml) were heated at 120-125° C. for 72 h. Reaction mixture was cooled to 20-25° C. It was then concentrated under vacuum and quenched with cold water slowly and solid material was separated. It was filtered off and washed with water. The solid material was dried under vacuum. The crude product was purified by column chromatography using silica gel (230-400 mesh) and 0.5 to 4% methanol in chloroform as an eluent to obtain 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (4.2 g, 58%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]CC#C)[C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[C:4]([F:24])[CH:3]=1.[F-].[Cs+].C(N(CC)[C:30]1[CH:35]=CC=C[CH:31]=1)C>>[Cl:1][C:2]1[C:7]2[CH:31]=[C:30]([CH3:35])[O:8][C:6]=2[C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=2)=[C:4]([F:24])[CH:3]=1
Reactant: CCN(CC)c1ccccc1
Reactant: C#CCOc1cc(Cl)cc(F)c1-c1ccc(C(F)(F)F)n(C)c1=O
Agent: [Cs+]
Agent: [F-]
Product: Cc1cc2c(Cl)cc(F)c(-c3ccc(C(F)(F)F)n(C)c3=O)c2o1
Yield: 21 %

Procedure:
2.78 g (7.73 mmol) of 3-[4-chloro-2-fluoro-6-propargyloxyphenyl]-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 2.35 g (15.46 mmol) of cesium fluoride was heated to 180° C. in 50 ml of N,N-diethylaniline and reacted for 1 hour. The solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.58 g (yield: 21%) of the desired product. Melting point: 138-140° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5]([Cl:23])=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[C:27]([O:34][CH3:35])(=[O:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+].[Cl-].[NH4+]>CN1CCCC1=O>[Cl:23][C:5]1[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:7][C:2]([CH:28]([C:27]([O:34][CH3:35])=[O:33])[C:29]([O:31][CH3:32])=[O:30])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2cc(Cl)c([N+](=O)[O-])cc2Cl)CC1
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: COC(=O)C(C(=O)OC)c1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 57 °C
Yield: 48 %

Procedure:
2,5-Dichloro-4-(2-[4-(t-butoxycarbonyl)-1-piperazinyl]ethyl)-nitrobenzene (5 g, 13 mmol) and dimethyl malonate (3.8 ml, 33 mmol) were stirred in N-methyl pyrrolidone (75 ml), at room temperature under nitrogen, while sodium hydride (1.33 g, 33 mmol, 60% in oil) was added. The reaction mixture was heated to 57° C. for 7 hours. The reaction mixture was cooled and poured into saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with water three times, one time with brine and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave an oil which was chromatographed over flash silica gel with ethyl acetate/hexanes followed by ethyl acetate. The fractions containing the desired product were combined and evaporated to give an oil, 2.5 g, 48% yield. NMR (CDCl3) δ 8.09 (s, 1), 7.45 (s, 1), 5.31 (s, 1), 3.79 (s, 6), 3.43 (m, 4), 2.98 (t, 2), 2.61 (t, 2), 2.47 (m, 4), 1.43 (s, 9).