Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: N=C(OCC=Cc1ccc(Cl)cc1)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(Cl)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylene chloride in cyclohexane), p-chlorocinnamyl trichloroacetimidate (119 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 30 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (34 mg).
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C@H:42]([CH3:45])[CH2:43][OH:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:41][C@H:42]([CH3:45])[CH2:43][OH:44])=[O:40])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@@H](N)CO
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Product: C[C@H](CO)NC(=O)Nc1ccc(-c2cc(-c3cc(F)ccc3S(C)(=O)=O)nc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) and (R)-2-aminopropan-1-ol (20 mg, 0.267 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (59 mg, 61%)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[N:28]=[C:27]([CH2:29]O)[CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:29][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[N:28]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1cccc(CO)n1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 3.2 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (100 mg, 0.4 mmol), (6-methoxy-pyridin-2-yl)-methanol (example 10-75a) (101 mg, 0.7 mmol), tributylphosphine (147 mg, 0.7 mmol), and 1,1″″-azobis(N,N-dimethylformamide) (125 mg, 0.7 mmol) were dissolved in THF (5 mL) and stirred at room temperature for 15 hours. The reaction was diluted with brine (100 mL) and extracted with ethyl acetate (2×, 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was taken up in methanol (5 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient). The pure fractions were combined, concentrated then re-dissolved in ethyl acetate/hexane (1:9). The solution was cooled at 5° C. for 15 hrs, where a white solid formed. The precipitate was collected to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-((6-methoxypyridin-2-yl)methyl)imidazolidine-2,4-dione (5 mg, 4%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.37 (s, 3H), 3.74 (s, 3H), 4.17 (s, 2H), 4.54 (s, 2H), 5.17 (s, 2H), 6.69 (d, J=7.6 Hz, 1H), 6.96 (d, J=6.8 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.76 (s, 1H), 8.17 (s, 1H). MS M+H calculated 397.2; found 397.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.23 μM.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[N:9][C:10]2[N:11]([N:13]=[C:14]([CH3:16])[CH:15]=2)[CH:12]=1.CN([CH:20]=[O:21])C>>[Br:6][C:7]1[CH:8]=[N:9][C:10]2[N:11]([N:13]=[C:14]([CH3:16])[C:15]=2[CH:20]=[O:21])[CH:12]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn2cc(Br)cnc2c1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
POCl3 (1.84 mmol, 1.3 eq, 172 μl) is added dropwise to DMF (1 ml) at 0° C. and the resulting solution is stirred at 0° C. during 30 minutes. Then, a solution of 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine x14 (1.415 mmol, 1 eq, 300 mg) in DMF (1 ml) is added and the mixture is stirred for 30 minutes at room temperature. The reaction is quenched with water (100 ml). The resulting solid is filtered and washed with water to give 200 mg of 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde x21 as a solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=[C:7]([I:21])[N:6]=1.O>CS(C)=O>[I:21][C:7]1[N:6]=[C:5]([O:2][CH3:1])[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: C[O-]
Reactant: COc1ccc(COc2ccc(I)nc2Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(I)nc2OC)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
Sodium methoxide (11 g) was added to a solution of 2-bromo-6-iodo-3-[(4-methoxybenzyl)oxy]pyridine (17 g) in dimethyl sulfoxide (90 mL), and the mixture was stirred at 90° C. for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→70:30) to give 6-iodo-2-methoxy-3-[(4-methoxybenzyl)oxy]pyridine as a colorless powder (10 g, 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[O:14]1[CH:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1>C(O)C>[OH:14][CH:16]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: CC1CC(C)(C)NC2CCCCC12
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CCO
Product: CC1CC(C)(C)N(CC(O)COc2ccccc2)C2CCCCC12

Procedure:
1-(2'-hydroxy-3'-phenoxy propyl)-2,2,4-trimethyl decahydroquinoline was prepared using a process similar to those described above. 27.2 grams (0.15 mole) of about 75% cis structure 2,2,4-trimethyl decahydroquinoline was reacted with 22.5 grams (0.15 mole) of 1,2-epoxy-3-phenoxy propane in the presence of 0.5 gram of ethanol at 160° C. for 19 hours. The reaction mixture was distilled to yield 21.2 grams of a liquid product boiling at 168° C. at 0.2 mm Hg. The infrared and mass spectrometer spectra are consistent with the desired product. Calculated values for C21H34NO2 were 75.85% carbon, 10.31% hydrogen, and 4.21% nitrogen, while measured values were 74.67% carbon, 10.18% hydrogen, and 4.26% nitrogen.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2=[C:7]([CH:11]=O)[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>>[CH3:1][CH:2]1[CH2:6][C:5]2[C:7](/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1Cc2c(C=O)cccc2O1
Reactant: O=C(O)CC(=O)O
Product: CC1Cc2c(/C=C/C(=O)O)cccc2O1
Yield: 92 %

Procedure:
2-Methyl-2,3-dihydrobenzofuran-4-carboxaldehyde was reacted with malonic acid by the above procedures to give the desired acid (92%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([C@H:27]3[CH2:26][CH2:25][C@H:24]([OH:23])[CH2:29][CH2:28]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CC1(C)OB(c2ccc3c(c2)CN([C@H]2CC[C@H](O)CC2)C3=O)OC1(C)C
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN([C@H]4CC[C@H](O)CC4)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(trans-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=522.0.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)Cl>CCOCC>[CH:7]1[C:11]2[C:11](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc2ccccc2c1
Yield: 69.7 %

Procedure:
To a one-neck 50 mL round-bottomed flask equipped with a septum pierced with a needle and a stir bar, was added pyridinium chlorochromate (2.31 g, 10.7 mmol) and DCM (20 mL) with stirring. Alcohol S10 (0.600 g, 5.35 mmol) was added all at once via syringe, and the reaction turned dark brown and thick. The reaction was stirred at rt for 3.5 h until complete by TLC, followed by addition of Et2O (25 mL) and silica gel (10 g). The suspension was stirred for 30 min, filtered through a pad of silica gel with Et2O washings, and then concentrated under reduced pressure to yield the aldehyde xx as a yellow oil (0.478 g, 81%). The crude product was carried on without further purification. Compound S11 was previously characterized.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:11])[C:3]1=2.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C(Cl)Cl>[CH2:19]([NH:21][C:22]([NH:11][CH:10]1[C:3]2[S:2][CH:6]=[CH:5][C:4]=2[CH2:7][CH2:8][CH2:9]1)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: NC1CCCc2ccsc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)NC1CCCc2ccsc21

Procedure:
Equivalent amounts of 4,5,6,7-tetrahydrobenzo[b]thiophen-7-amine hydrochloride, triethylamine, and ethyl isocyanate in methylene chloride are stirred at room temperature for an hour and then heated to reflux for half an hour. The product is collected, washed well with water, and dried to afford the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:29]=[N:30][N:31]([CH2:33][C@H:34]5[O:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]5)[CH:32]=4)[N:22]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:29]=[N:30][N:31]([CH2:33][C@H:34]5[O:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]5)[CH:32]=4)[N:22]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C(=O)c6ccccc6)cn5)CC4)n3)cn2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C(O)c6ccccc6)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (80 mg, 0.127 mmol) in THF/methanol was added sodium borohydride (20 mg, 0.51 mmol). The mixture was stirred at room temperature for 1 hour, and LCMS showed the reaction was completed. The solvents were removed to give (S)-tert-butyl 2-((4-(4-(4-(5-(hydroxy(phenyl)methyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (80 mg, crude) as a yellowish solid. (MS (ES+) C31H39N11O4 requires: 629, found: 630 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.C1([Li])C=CC=CC=1.[C:24](=[O:26])=[O:25].Cl>O1CCCC1.O>[Br:7][C:5]1[N:6]=[C:2]([C:24]([OH:26])=[O:25])[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Br:8]
Reactant: O=C=O
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C(=O)O)nc(Br)c1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4,5-tribromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (5.0 g, 11.5 mmol) in tetrahydrofuran (200 ml) at −78° C. is added phenyl lithium (7.0 ml, 12.6 mmol, 1.8 M in THF). After 30 minutes stirring at −78° C. CO2-pellets (˜3.0 g) are added. The mixture is allowed to warm to room temperature, water is added, and the pH is carefully adjusted with 6N HCl (aqueous) to pH=5. The mixture is extracted with ethyl acetate (2×50 ml) and the combined organic layer is washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude 4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid is obtained as a yellow oil, and used without further purification 4.2 g, 91%, LC/MS ESI m/z (M−H)−398.8.
Reaction SMILES: ClCCl.CC1(C)C(C)(C)OB([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[N:16][CH:17]=2)O1.[Cl:23][CH:24]([Cl:40])[C:25]([NH:27][C@H:28]([CH2:38][F:39])[C@H:29]([OH:37])[C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:23][CH:24]([Cl:40])[C:25]([NH:27][C@H:28]([CH2:38][F:39])[C@@H:29]([C:30]1[CH:31]=[CH:32][C:33]([C:12]2[CH:17]=[N:16][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=2)=[CH:34][CH:35]=1)[OH:37])=[O:26]
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Reactant: CC1(C)OB(c2ccc(CCC#N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 60 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (30.2 mg, 0.037 mmol) is added to a degassed mixture of the product of step 1, Example 21 along with 2,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamide (150 mg, 0.369 mmol), and cesium carbonate (482 mg, 1.48 mmol) in N,N-dimethylformamide (2.76 mL) at room temperature. The reaction mixture is heated at 60° C. for 4 hours. After cooling to room temperature the reaction mixture is concentrated under high vacuum, and the residue slurried in ethyl acetate. The slurry is filtered through solka floc washing the cake with ethyl acetate. The combined filtrates were concentrated and the brown residue purified by chromatography on silica gel eluting with a gradient of 50-80% ethyl acetate in hexanes to afford the title compound (72.5 mg): 1H NMR (300 MHz, DMSO-d6) δ 2.92-2.97 (m, 2H), 3.08-3.13 (m, 2H), 4.23-4.28 (m, 1.5 H), 4.41-4.46 (m, 0.5H), 4.54-4.58 (m, 0.5H), 4.69-4.74 (m, 0.5H), 4.89-4.92 (m, 1H), 5.98 (d, 1H), 6.53 (s, 1H), 7.42-7.49 (m, 3H), 7.79 (d, 2H), 8.03-8.06 (dd, 1H), 8.62 (d, 1H), 8.83-8.84 (m, 1H). MS (ESI+) m/z of 410.0/412.0 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]=1[S:27][CH3:28])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]=1[S:27]([CH3:28])=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(3-benzyloxy-2-methylsulfanylphenoxy)-butyl]-carbamic acid tert-butyl ester (600 mg, 1.44 mmol) in methylene chloride (15 mL) is added mCPBA (355 mg, 1.44 mmol) and the mixture is stirred at RT for 2 h. Water is added the organic phase is washed with saturated NaHCO3, water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1cccc(Cl)c1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(Cl)cccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichlorobenzene and isolated as white solid (5.2 mg, 29%). MS (m/e): 441.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.[C:11](OCC)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].N1CCCCC1>CCO>[CH2:16]([O:15][C:13]([C:12]1[C:11](=[O:18])[NH:1][C:2]2[C:7]([CH:8]=1)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=2)=[O:14])[CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ncc(Br)cc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)cnc2[nH]c1=O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carbaldehyde (4.00 g, 14.2 mmol), diethyl malonate (21.6 mL, 142 mmol) and piperidine (7.00 mL, 71.0 mmol) in EtOH (70 mL) was heated to reflux overnight. The mixture was cooled to room temperature and the solid was collected by filtration to give the title compound (2.41 g, 57%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 12.65 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.45 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH2:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH3:30].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH3:30])=[CH:32][CH:33]=1)[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(CC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 67.4 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 4-ethylphenol (0.34 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.59 g, 67%).
Reaction SMILES: CO[CH2:3][N:4]([CH2:13][Si](C)(C)C)[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[C:18]([O:22][CH3:23])(=[O:21])[C:19]#[CH:20]>ClCCl.FC(F)(F)C(O)=O>[C:7]1([C@H:5]([N:4]2[CH2:3][CH:20]=[C:19]([C:18]([O:22][CH3:23])=[O:21])[CH2:13]2)[CH3:6])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C#CC(=O)OC
Reactant: COCN(C[Si](C)(C)C)[C@H](C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=CCN([C@H](C)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
To a stirred solution of (1R)-N-(methoxymethyl)-1-phenyl-N-[(trimethylsilyl)-methyl]ethanamine (55.83 mL, 205.62 mmol) and methyl prop-2-ynoate (22.5 mL, 252.9 mmol) in dichloromethane (500 mL) at 0° C. under nitrogen was added trifluoroacetic acid (800 μL, 10.45 mmol). The reaction mixture was allowed to stir at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was purified by FCC, eluting with 0-70% EtOAc in heptane, to afford the title compound (26.5 g, 56%) as a yellow oil. δH (500 MHz, CDCl3) 7.41-7.29 (m, 4H), 7.28-7.21 (m, 1H), 6.77-6.70 (m, 1H), 3.72 (s, 3H), 3.71-3.65 (m, 1H), 3.65-3.42 (m, 4H), 1.40 (d, J 6.6 Hz, 3H). Method F HPLC-MS: MH+ m/z 232, RT 1.62 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:5][C:6]=1[F:9]
Reactant: Cc1c(F)cc(S(N)(=O)=O)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: NS(=O)(=O)c1cc(F)c(CBr)c(F)c1
Yield: 30.5 %

Procedure:
A mixture of 3,5-difluoro-4-methylbenzenesulfonamide (1.237 g, 6 mmol), N-bromosuccinimide (1.4 g, 1.3 eq) and benzoyl peroxide (87 mg, 0.1 eq) in carbon tetrachloride (24 mL) was heated to reflux for 6 h under a halogen light. After the reaction was determined to be complete by GC-MS, the mixture was concentrated and purified by column chromatography (silica, EtOAc-hexane, 1:4 to 4:1) to give the title compound (524 mg). 1H NMR (400 MHz, CD3OD) δ 7.75 (d, 2H), 4.83 (s, 3H); GC-MS (ES) m/z 285 (M+), 287 (M+2).