Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1.O>CN(C=O)C>[C:1]1([N:7]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 17.0 g (88.1 mmol) of tert-butyl phenylcarbamate in 150 ml of hexanes 35.2 ml (88.1 mmol) of 2.5 M nBuLi in hexanes was slowly added at gentle reflux for ca. 15 min. This mixture was stirred for additional 30 minutes and then evaporated to dryness. The resulting white powder was added to a solution of 30.6 g (88.1 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 300 ml of DMF. This mixture was stirred for 20 minutes at 75° C. and then poured into 1200 cm3 of cold water. The product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed by 2×300 ml of water, dried over MgSO4, and then evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate=20:1, vol. then 10:1, vol.). Yield 28.0 g (69%) of yellowish oil. Anal. calc. for C28H34BNO4: C, 73.21; H, 7.46; N, 3.05. Found: C, 73.12; H, 7.62; N, 3.24. 1H NMR (CDCl3): 8.19 (m, 1H, 8-H in naphthyl), 7.85 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.77 (m, 1H, 5-H in naphthyl), 7.60 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.45 (m, 1H, 7-H in naphthyl), 7.40 (m, 1H, 6-H in naphthyl), 7.20 (m, 2H, 3,5-H in Ph), 7.13 (m, 2H, 2,6-H in Ph), 7.08 (m, 1H, 4-H in Ph), 5.21 (s, 2H, CH2N), 1.42 (s, 9H, tBu), 1.38 (s, 12H, CMe2CMe2).
Reaction SMILES: [OH:1][C:2]1[C:3](I)=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:1][C:2]1[C:3]([CH:37]=[CH:36][C:35]([O:39][CH2:40][CH3:41])=[O:38])=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCC
Reactant: OCc1ccc(O)c(I)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1nc(CO)ccc1O
Temperature: 120 °C

Procedure:
To a solution of 3-hydroxy-6-hydroxymethyl-2-iodopyridine (708 mg, 2.82 mmol) in DMF (5.7 ml) and water (0.3 ml) were added potassium acetate (0.74 g, 7.5 mmol), triphenylphosphine (63 mg, 0.24 mmol), ethyl acrylate (0.98 ml, 0.90 g, 9.0 mmol) and palladium acetate (27 mg, 0.12 mmol). The mixture was placed under nitrogen and stirred and heated at 120° C. for 5 h. The mix was cooled and poured into water (50 ml). The product was extracted into ethyl acetate (3×20 ml) and the combined extracts were washed with water (2×15 ml) with brine (15 ml), dried and evaporated. The etude product was purified by passage in ethyl acetate through a pad of silica, yielding after evaporation a yellow solid (295 g, 47%). mp (B.HCl) 199°-203° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:13])[CH2:11][CH3:12].[Li+].CC([N-]C(C)C)C.CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:34][CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>C1COCC1>[Si:38]([O:37][CH2:36][CH2:35][CH2:34][CH2:8][C:6]1[O:5][C:4](=[O:9])[C:3]([C:10](=[O:13])[CH2:11][CH3:12])=[C:2]([OH:1])[CH:7]=1)([C:41]([CH3:42])([CH3:43])[CH3:44])([CH3:40])[CH3:39]
Reactant: CCC(=O)c1c(O)cc(C)oc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(=O)c1c(O)cc(CCCCO[Si](C)(C)C(C)(C)C)oc1=O
Reaction time: 1 h

Procedure:
To 4-hydroxy-6-methyl-3-propionyl-2H-pyran-2-one (XII; 7 g, 38.5 mmol) in 60 ml anhydrous THF at −72° C. under argon, was added freshly prepared LDA (18.5 ml DIPEA in 150 ml THF with 52 ml 2.5 M n-butyllithium, Aldrich) in 150 ml anhydrous THF, and 20 ml HMPA (Aldrich). The reaction mixture was stirred for 1 h. 3-bromopropoxy-t-butyldimethylsilane (7 ml g; 27.7 mmol; Aldrich) in 50 ml anhydrous THF was added over 30 min, and stirred for an additional 5 min. The reaction mixture was quenched with saturated NH4Cl, extracted with 3×150 ml EtOAc, dried with brine and anhydrous Na2SO4, and evaporated to a yellowish oil. The product was purified via silica flash chromatography.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C1C=C[NH+]=CC=1.[Br:15][Br-]Br>C(O)(=O)C>[Br:15][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C(O)c1ccsc1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(O)c1csc(Br)c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 95.6 %

Procedure:
A mixture of 3-thiophenecarboxylic acid (12.81 g), pyridinium bromide perbromide (35.54 g) and acetic acid (50 ml) was stirred at 45° C. for 48 hours. The mixture was poured into ice-water and precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-3-thiophenecarboxylic acid (19.78 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:40]12([CH2:50][NH:51][C:52]3[CH:57]=[CH:56][C:55]([S:58]([NH:61]C(=O)C4C=CC(I)=CC=4)(=[O:60])=[O:59])=[CH:54][C:53]=3[N+:71]([O-:73])=[O:72])[CH2:49][CH:44]3[CH2:45][CH:46]([CH2:48][CH:42]([CH2:43]3)[CH2:41]1)[CH2:47]2.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)(C)C.ClCCCl>[C:40]12([CH2:50][NH:51][C:52]3[CH:57]=[CH:56][C:55]([S:58]([NH:61][C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([C:6]5[CH:5]=[CH:4][S:3][C:2]=5[Cl:1])=[CH:15][CH:14]=4)(=[O:60])=[O:59])=[CH:54][C:53]=3[N+:71]([O-:73])=[O:72])[CH2:49][CH:44]3[CH2:43][CH:42]([CH2:48][CH:46]([CH2:45]3)[CH2:47]1)[CH2:41]2
Reactant: O=C(O)c1ccc(-c2ccsc2Cl)cc1
Reactant: O=C(NS(=O)(=O)c1ccc(NCC23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(I)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: O=C(NS(=O)(=O)c1ccc(NCC23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(-c2ccsc2Cl)cc1
Reaction time: 8 h

Procedure:
A room temperature mixture of Example 29A (39.4 mg, 0.17 mmol), resin-bound dicyclohexylcarbodiimide (225.0 mg, 1.83 mmol/g), and dimethylaminopyridine (60.0 mg, 4.95 mmol) was treated with a solution of Example 28A (40 mg, 0.11 mmol) in a 1:1 mixture of 1,2-dichloroethane and 2-methyl-2-propanol (3 mL), and agitated overnight on an Argonaut Technologies Quest 210. The mixture was treated with resin bound p-TsOH (990 mg, 1.44 mmol/g), agitated for 1 hour, decanted, and washed with dichloromethane. The combined extracts were concentrated and purified by HPLC using 0.1% TFA in H2O/CH3CN to provide the desired product. MS (APCI(+)) m/e 586 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.66 (d, 1H), 8.57 (t, 1H), 7.96 (d, 2H), 7.95 (dd, 1H), 7.71 (d, 2H), 7.59 (d, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.29 (d, 1H), 3.17 (d, 2H), 1.97 (s, 3H), 1.58 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: OCc1ccccc1
Reactant: CSc1nc(N)nc(Br)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nc(N)nc(OCc2ccccc2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. ES-MS m/e (%): 273 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:5]2([CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC(c2ccccc2)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CC(c2ccccc2)OC2(CCNCC2)C1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To tert-butyl 8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (540 mg, 1.50 mmol) in DCM (1.5 mL) was added 2,2,2-trifluoroacetic acid (1 mL, 12.98 mmol) and the solution was stirred for 30 minutes. The reaction mixture was concentrated in vacuo, diluted with DCM (50 mL), washed with 1:1 sat. aq. Na2CO3/NaHCO3 (10 ml) and the aqueous was extracted further with DCM (2×25 mL). The combined organics were dried (MgSO4) and evaporated to give 8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane (390 mg, 100%) as a pale yellow solid, which was used without further purification. ESI-MS m/z calc. 260.4. found 261.3 (M+1)+; Retention time: 0.3 minutes (3 min run).
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)=[O:21])=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)OC2CCCCO2)cc1

Procedure:
A mixture of 7 g. 4-(4-tetradecenylamino)benzoic acid, 2 g. dihydropyran and 100 mg. of anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and evaporated. The residue is collected and crystallized from methylcyclohexane to yield the product as white crystals.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH:19]=1)[C:9]([O:11]CC1C=CC=CC=1)=[O:10].C1COCC1.Cl>C(OCC)(=O)C.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH:19]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Temperature: 71 °C
Reaction time: 16 h

Procedure:
Solid LiOH (1.01 g, 42.1 mmol) was added in a single charge to a stirred solution of phenylmethyl 5-bromo-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 4, method B; 3 g, 7.55 mmol) in a 3:1 mixture of THF and water (40 ml) at 20° C. The reaction mixture was stirred at 71° C. for 16 h. After cooling to room temperature, it was diluted with ethyl acetate (200 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over Na2SO4, and concentrated to give a white solid. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (3:1) to yield the title compound as white solid. 2.1 g.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C@@H:7]1[CH2:11][C@@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:30](=[O:43])[NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1)=O.O>CO>[F:42][C:39]([F:40])([F:41])[O:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:30]([N:8]2[CH2:9][C@H:10]([O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C@H:7]2[CH2:5][OH:4])=[O:43])=[CH:33][CH:34]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](O[C@@H]1C[C@@H](CO)N(C(=O)Nc2ccc(OC(F)(F)F)cc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
NaBH4 (200 mg, 5.3 mmol) was added to a solution of (2S,4R)-4-(tert-Butyl-diphenyl-silanyloxy)-1-(4-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-2-carboxylic acid methyl ester (2.8 g, 4.8 mmol) in methanol (50 mL) portion-wise. The mixture was stirred at room temperature for 4 hours. Then the mixture was poured into water (50 mL), extracted with ethyl acetate (3×50 mL). The organic layers was combined, washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 2.35 g (88%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH3:11])=[N:9][NH:8][C:6]=2[N:7]=1.[CH:16]1(B(O)O)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1.[NH4+].[Cl-]>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:16]3[CH2:18][CH2:17]3)[C:6]=2[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc2[nH]nc(C)c12
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Product: COC(=O)c1cc(Cl)nc2c1c(C)nn2C1CC1
Temperature: 70 °C

Procedure:
To a suspension of methyl 6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (510 mg, 2.260 mmol), cyclopropylboronic acid (388 mg, 4.52 mmol), sodium carbonate (479 mg, 4.52 mmol) in 1,2-Dichloroethane (DCE) (150 mL) was added a suspension of copper(II) acetate (411 mg, 2.260 mmol), 2,2′-bipyridine (353 mg, 2.260 mmol) in hot 1,2-dichloroethane. The contents were heated at 70° C. for 16 hours. Added cyclopropylboronic acid (388 mg, 4.52 mmol), sodium carbonate (479 mg, 4.52 mmol) followed by copper(II) acetate (411 mg, 2.260 mmol), 2,2′-bipyridine (353 mg, 2.260 mmol) in hot 1,2-dichloroethane and heated at 70° C. for 16 hours. The contents were cooled to room temperature followed by addition of 100 mL of saturated NH4Cl solution and the phases were separated. The aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0% to 20% gradient EtOAc:Hex). The product was collected as 310 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.26 (m, 4 H), 2.53 (s, 3 H), 3.75-3.91 (m, 1 H), 3.96 (s, 3 H), 7.55 (s, 1 H). LCMS(ES) [M+H]+266.0
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(C)[CH:14]=CC=C[CH:10]=1>>[CH:10]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:1]=[CH:14][CH:9]=1
Reactant: Cc1ccccc1
Reactant: OCc1ccccc1
Product: c1ccc2ccccc2c1

Procedure:
About 18.4 liters, or about 15.95 Kg, of toluene were added to a steam jacketed blending vessel. About 4.0 kilograms of crystalline naphthalene were added to a separate vessel and slowly heated until the naphthalene was liquefied. The liquid naphthalene was then added to the toluene to produce a naphthalene:toluene weight ratio of about 0.25. The mixture was stirred until a homogeneous solution was obtained. About 0.6 liters, or about 0.62 Kg, of benzyl alcohol were then added to the homogeneous solution to produce a naphthalene:benzyl alcohol weight ratio of about 6.45. The solution was then allowed to stand for 72 hours before use.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26]CC)=[O:25])[CH:17]=[N:16]2)=[CH:11][CH:10]=1)#[N:8]>C1COCC1>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:21])([F:22])[F:23])=[C:18]([C:24]([OH:26])=[O:25])[CH:17]=[N:16]2)=[CH:11][CH:10]=1)#[N:8]
Reactant: CCOC(=O)c1cnn(-c2ccc(C#N)cc2)c1C(F)(F)F
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2ncc(C(=O)O)c2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Potassium trimethylsilanolate (3.32 g, 23.28 mmol) was added in one portion to ethyl 1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Intermediate#126) (2.4 g, 7.76 mmol), in THF (50 mL), under nitrogen. The resulting suspension was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (100 mL), and washed sequentially with 0.1M HCl (50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude solid was triturated with isohexane to give a solid which was collected by filtration and dried under vacuum to give 1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1.600 g, 73.3%) as a orange solid. Used directly in next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2CCCN(C(=O)OC(C)(C)C)C2)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC2CCCN(C(=O)OC(C)(C)C)C2)ccc1C(=O)O

Procedure:
To a stirred solution of methyl 2-methoxy-4-(1-tert-butyloxycarbonyl-3-piperidinyloxy)benzoate from Step 3 above (1.35 g, 3.69 mmol) in methanol (25 mL) was added 2N NaOH (9.2 mL, 18.5 mmol). The reaction mixture was heated to reflux for 30 minutes and then cooled in an ice water bath. The solution was acidified with 5% citric acid and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (2×75 mL). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated to give 2-methoxy-4-(1-tert-butyloxycarbonyl-3-piperidinyloxy)benzoic acid as a white solid which was used without further purification.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:19]1[CH:20]=[CH:21][C:22]2[NH:28][C:27]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:26]=3[CH2:25][N:24]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:23]=2[CH:50]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:7][O:6][C:1](=[O:5])[C:2]([C:19]1[CH:20]=[CH:21][C:22]2[NH:28][C:27]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:26]=3[CH2:25][N:24]([S:37]([C:40]3[CH:41]=[CH:42][C:43]([C:46]([CH3:48])([CH3:47])[CH3:49])=[CH:44][CH:45]=3)(=[O:39])=[O:38])[C:23]=2[CH:50]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)C(C)C
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
To methyl isobutyrate (128 mg, 1.25 mmol) in toluene (5 mL) was added 1.46 mL of LiHMDS (1.0 M in PhMe, 1.46 mmol) at 0° C. After stirring at rt for 10-15 min, the mixture was transferred via cannula to a mixture of intermediate 53 (225 mg, 0.416 mmol), Pd(dba)2 (24 mg, 0.042 mmol), and tri-t-butylphosphonium tetrafluoroborate (12 mg, 0.042 mmol). After stirring at rt for 48 hrs, the reaction was quenched with aqueous NH4Cl (20 mL) and the product was extracted with EtOAc (50 mL). The extracts were washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on silica gel column eluting with 5-30% EtOAc in hexanes to afford the title compound. LCMS: m/e 562.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].C(N(C(C)C)C(C)C)C.[CH3:20][O:21][CH2:22][CH2:23][OH:24]>CCOC(C)=O>[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: COCCO
Reactant: N#Cc1cccc(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCOCc1cccc(C#N)c1
Yield: 81 %

Procedure:
A solution of 3-(bromomethyl)benzonitrile (1 g, 5.1 mmol) in 2-methoxyethanol (10 mL) and n-ethyldiisopropylamine (0.89 mL, 5.1 mmol) was heated under microwave irradiations for 2 hours at 150° C. After this time, reaction mixture was diluted with EtOAc (200 mL), washed with water and brine to give the title compound as a colorless oil (800 mg, 81%). 1H NMR (DMSO-d6, 300 MHz) δ 7.76-7.74 (m, 2H), 7.68-7.65 (m, 1H), 7.59-7.54 (m, 1H), 4.54 (s, 2H), 3.59-3.56 (m, 2H), 3.51-3.47 (m, 2H), 3.25 (s, 3H). HPLC (Method A) Rt 3.09 min (Purity: 82.9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: Cc1ccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2,4-dimethylbenzeneboronic acid (CAS RN 55499-44-0). Colorless solid (52%). MS (ESI): m/z=453.4 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:23]=3[F:22])=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(F)c1F
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Product: O=C(NCC1CCCCC1)c1cnc(Nc2cccc(F)c2F)nc1C(F)(F)F
Yield: 24.8 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-dioxan (1 ml) was added 2,3-difluoroaniline (Aldrich) (113 mg) and the mixture was stirred at reflux for 47 hours using a Radleys Greenhouse Parallel Synthesiser. The dioxan was removed using a nitrogen blow down unit. The residue was taken up into methanol (0.5 ml) and dimethylsulfoxide (0.5 ml) and purified using a mass directed auto-preparative system to give the title compound (16 mg)