Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([F:29])[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=3)[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)c(OC)nc1C
Yield: 69 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:7]([C:6]2[S:5][N:4]=[N:3][C:2]=2[CH3:1])=[O:9])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1nnsc1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnsc1C(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 60 %

Procedure:
4-Methyl-1,2,3-thiadiazole-5-carboxylic acid (39.6 mg, 0.275 mmol) was suspended in DCM (2.0 mL). Bromotris(pyrrolydino)phosphonium hexafluorophosphate (128 mg, 0.27 mmol) and DIPEA (96 μL, 0.55 mmol) were added and premixed for 5 minutes. 3-Chloro-4-fluoroaniline (40 mg, 0.27 mmol) was added. The solution was stirred for 3 hrs, then purified by silica gel chromatography, (Hex/EA)-eluting at ˜60% EA in hexane to afford the desired product (44 mg). MF=C10H7ClFN3OS; LCMS calculated for C10H8ClFN3OS (M+H)+: m/z=272.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][C:19]=2[N:20]=1.Cl.Cl.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[CH:35]=[CH:34][C:33]=1[NH2:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)[CH:35]=[CH:34][C:33]=1[NH:45][C:25]([C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([C:3]3[CH:4]=[C:5]([C:8]4[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=4)[CH:6]=[CH:7][C:2]=3[OH:1])[NH:17][C:18]=2[CH:24]=1)=[O:26]
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C)CC2)ccc1NC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a solution of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 44 mg, 0.1 mmol), 2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamine di HCl salt (29.4 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (1.2 mL) was added DIEA (45 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 3 h, and then evaporated under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (26.4 mg, 39%). ESI-MS m/z 565.5 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:70]1[CH:83]=[CH:82][C:73]([O:74][CH2:75][CH:76]([OH:81])[C:77]([CH3:80])([CH3:79])[CH3:78])=[C:72]([CH3:84])[CH:71]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:58]2[CH:57]=[CH:56][C:55]([C:52]([CH2:50][CH3:51])([C:70]3[CH:83]=[CH:82][C:73]([O:74][CH2:75][CH:76]([OH:81])[C:77]([CH3:78])([CH3:79])[CH3:80])=[C:72]([CH3:84])[CH:71]=3)[CH2:53][CH3:54])=[CH:60][CH:59]=2)[CH:10]=1
Reactant: CCC(CC)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 33.5 mg, 0.145 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (62 mg, 0.291 mmol) and water (0.2 mL) were added to a solution of 1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol (Example 146-(1); 46.6 mg, 0.097 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (30.8 mg, 63%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[C:35]([O:39][C:40](=[O:45])[C@@H:41](O)[CH2:42][CH3:43])([CH3:38])([CH3:37])[CH3:36].CO>C(OCC)(=O)C>[C:35]([O:39][C:40](=[O:45])[C@H:41]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH2:42][CH3:43])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC[C@H](O)C(=O)OC(C)(C)C
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Agent: COC(=O)C(O)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC[C@@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C

Procedure:
Following the procedure for Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol, 2-hydroxy-3-methyl-butyric acid methyl ester and (S)-2-hydroxy-butyric acid tert-butyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (R)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid tert-butyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=4.05 min, [M+H]+=494
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH2:4]1.[H][H]>[Pd].CO>[CH3:30][N:2]([CH3:1])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CC=C(c2[nH]c3ccccc3c2CCCC(=O)O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCCC(=O)O)CC1

Procedure:
Palladium as the catalyst (Pd/C, 5%, 200 mg) was added to (±)-4-[2-(-4-dimethylamino-4-phenyl-cyclohex-1-enyl)-1H-indol-3-yl]butanoic acid (500 mg, 1.2 mmol) in abs. methanol (50 ml) and hydrogenation was carried out at RT for 6 h (hydrogen pressure: 3 bar). The catalyst was removed with the aid of a frit provided with a layer of Celite 1 cm high. The residue was rinsed thoroughly with methanol (500 ml). The solvent was distilled off in vacuo. 4-[2-(4-Dimethylamino-4-phenylcyclohexyl)-1H-indol-3-yl]butanoic acid was obtained in a yield of 340 mg (68%) as a white solid (one of the two possible diastereoisomers).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>C(OCC)(=O)C>[N+:17]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])c2ccccc12

Procedure:
To a cold (0° C.) suspension of 1-methylnaphthalene (5 g) in HNO3 was added H2SO4 (5 mL) dropwise. After stirring the reaction for one hour, the solution was diluted with ethyl acetate and washed with water (3×), aqueous saturated NaHCO3 (2×) and brine, dried over MgSO4, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate:hexane (5:95) and recrystallized from methanol to give yellow needles.
Reaction SMILES: CCN(C(C)C)C(C)C.CS([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1)(=O)=O.[OH2:45]>C(#N)C>[OH:45][C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[N:22]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:21]=2)[C:17]([C:43]#[N:44])=[CH:16][N:15]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reaction time: 1 h

Procedure:
DIPEA (7.421 g, 10.00 mL, 57.42 mmol) was added to a suspension of 2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (1 g, 1.918 mmol) in acetonitrile (20 mL). The reaction mixture was stirred for 1 hour then water (5 mL) was added. The mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give the desired product (880 mg, quantitative yield).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CSCCOc1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Cyclohexyl{3-methyl-5-[2-(methylsulfanyl)ethoxy]-1-benzofuran-2-yl}methanone (0.73 g) synthesized in the above-mentioned (1) was dissolved in a tetrahydrofuran (10 mL) and methanol (5 mL), and sodium borohydride (90%, 0.18 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (0.67 g, 91%) as a pale-yellow oil.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[CH3:9][O:10][C:11](=[O:15])[CH2:12][C:13]#[N:14]>C1COCC1>[CH3:9][O:10][C:11](=[O:15])[C:12]([C:13]#[N:14])=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8]1
Reactant: COC1=NCCCC1
Reactant: COC(=O)CC#N
Solvent: C1CCOC1
Product: COC(=O)C(C#N)=C1CCCCN1
Temperature: 70 °C
Yield: 79.9 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-6-methoxypyridine (1.1 g, 9.72 mmol) and cyanoacetic acid methyl ester (1 g, 10.1 mmol) in 40 mL THF was heated at 70° C. overnight. The reaction was cooled, and solvent was removed in vacuo. The resulting residue was purified on flash column to afford cyano-2-piperidinylidene-ethanoic acid methyl ester (1.4 g, 80%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54]1[NH:58][N:57]=[C:56]([C:59]([NH:61][CH2:62][C:63](O)=[O:64])=[O:60])[CH:55]=1>CN(C=O)C.O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:63](=[O:64])[CH2:62][NH:61][C:59]([C:56]2[CH:55]=[C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[OH:47])[NH:58][N:57]=2)=[O:60])[CH2:24][CH2:25]1)=[O:19]
Reactant: O=C(c1cc(F)ccc1Br)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2Br)CC1)c1cc(-c2ccccc2O)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 68.5 %

Procedure:
DIPEA (100 mg, 0.13 mL, 0.7 mmol) was added to a stirred solution of (2-Bromo-5-fluoro-phenyl)-piperazin-1-yl-methanone; hydrochloride salt (prepared by the method as described above)(68 mg, 0.21 mmol) in DMF (4 mL). HOBT (31 mg, 0.23 mmol) and EDCI (91 mg, 0.47 mmol) were then added at room temperature. After 2 minutes, {[5-(2-Hydroxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (50 mg, 0.19 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 68.5 mg (68.5% yield) 5-(2-Hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 95.24%. 1H NMR (DMSO-d6): δ 13.4-13.2 (bs, 1H), 10.4-10.2 (bs, 1H), 8.2-8.0 (bs, 1H), 7.8-7.64 (m, 2H), 7.46-7.34 (bs, 1H), 7.34-7.2 (t, 2H), 7.02-6.84 (m, 4H), 4.26-4.1 (bd, 2H), 3.76-3.46 (bt, 6H), 3.24-3.1 (bd, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:32])([F:33])[F:19])[CH:22]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.FC(F)(F)C(O)=O.[Br:22][C:23]1[CH:24]=[C:25]([CH2:28][NH2:29])[O:26][CH:27]=1.C(N(CC)CC)C>C(O)C>[Br:22][C:23]1[CH:24]=[C:25]([CH2:28][NH:29][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])[O:26][CH:27]=1
Reactant: NCc1cc(Br)co1
Reactant: COCCNc1nonc1C(Cl)=NO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCCNc1nonc1C(=NO)NCc1cc(Br)co1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
N-Hydroxy-4-(2-methoxyethylamino)-1,2,5-oxadiazole-3-carbimidoyl chloride [prepared according to the procedure of Example 1, steps A through E] (4.5 g, 20.3 mmol) was stirred in ethanol (20 mL) at room temperature. To this, a solution of 1-(4-bromo-2-furyl)methanamine trifluoroacetate (6.5 g, 22.4 mmol) in ethanol (24 mL) was added and the mixture was stirred for 15 minutes. Triethylamine (6.3 mL, 44.8 mmol) was added dropwise over 10 minutes and the reaction was stirred for an additional 15 minutes. The solvent was removed in vacuo and after adding water (50 mL), the product was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated to give the desired product (7.5 g, 100%). LCMS calculated for C11H15BrN5O4 (M+H)+: m/z=359.9, 361.9.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:9](#[N:12])[CH2:10]O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([CH:3]([CH2:10][C:9]#[N:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: N#CCO
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)CC#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl cyanoacetate (916.0 g, 8.10 mol) in N,N-dimethylformamide (2.5 L) was added slowly glycolonitrile (700.0 g, 6.75 mol) in water (55% solution). To the mixture was added potassium carbonate (932.7 g, 6.75 mol), over 1.5 h, ensuring that the reaction temperature did not rise above 30° C. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was filtered and the filtrate adjusted to pH 3 by addition of acid. The organic phase was separated and partially concentrated in vacuo. To the concentrate was added diethyl ether (1 L) and the solution was washed with water (5×1 L), dried (MgSO4) and concentrated in vacuo to give Preparation 46 (803 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([CH3:17])[CH:9]=2)=[C:4]([F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.CN.[CH2:28]([N:30](CC)CC)C>ClCCl.O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:30][CH3:28])=[O:15])=[CH:12][N:11]=[C:10]([CH3:17])[CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2F)c(C(=O)O)cn1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)-6-methylnicotinic acid (500 mg, 1.88 mmol) in dichloromethane (10 mL) at 0° C. was added oxalyl chloride (0.988 mL, 11.29 mmol) drop wise followed by DMF (0.2 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was evaporated to dryness. The residue was taken in dichloromethane (50 mL) and cooled to 0° C. Methylamine hydrochloride (1.27 g, 18.82 mmol) and triethylamine (2.62 mL, 18.82 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N,6-dimethylnicotinamide (520 mg, 1.43 mmol, 76% crude yield) as yellow solid. The material was carried forward without further purification. LC/MS (ESI) m/e 279.0 [(M+H)+, calcd for C14H13ClFN2O 279.1]; LC/MS retention time (Method I): tR=1.82 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23]I)([CH2:19][CH2:20]2)[CH2:17][O:16]3)[CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1.C1OCCOCCOCCOCCOCCOC1.[C-:43]#[N:44].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][C:43]#[N:44])([CH2:19][CH2:20]2)[CH2:17][O:16]3)[CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1
Reactant: Fc1cc(OC2CCCCO2)cc(C23CCC(CI)(CC2)CO3)c1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 40 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
A mixture of 1-(3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)phenyl)-4-(iodomethyl)-2-oxabicyclo[2.2.2]octane (732 mg, 1.640 mmol), 18-crown-6 (43 mg, 0.164 mmol), and NaCN (88 mg, 1.80 mmol) in DMF (1 mL) was stirred at 40° C. under N2 for 18 h. The reaction was cooled to rt and filtered. The filtrate was concentrated in vacuo. The residue was taken up in DCM (50 mL) and filtered. The residual solid was washed with DCM (10 mL×2). The combined organic filtrates were concentrated in vacuo. The crude oil was purified by flash chromatography (SiO2) using a 0% to 30% EtOAc/hexane gradient (15 min) to give the title compound (560 mg, 1.62 mmol, 99% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[Si]([O:39][CH2:40][CH2:41][C:42]#[C:43][B-](F)(F)F)(C(C)(C)C)(C)C.[K+].COC(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:43]#[C:42][CH2:41][CH2:40][OH:39])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: CC(C)(C)[Si](C)(C)OCCC#C[B-](F)(F)F
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2C#CCCO)CC1
Temperature: 135 °C
Yield: 23.9 %

Procedure:
2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (95 mg, 0.17 mmol, Example 69), potassium (4-(tert-butyldimethylsilyloxy)but-1-ynyl)trifluoroborate (75 mg, 0.26 mmol, ASDI, Newark, Del.), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (14 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), and cesium carbonate (182 mg, 0.56 mmol) were combined in toluene (1.5 mL) and water (0.2 mL). The reaction mixture was purged with nitrogen gas for several minutes and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 135° C. for 30 min. The reaction mixture was filtered through a pad of Celite® (diatomaceous earth) eluting with CH2Cl2 and the filtrate was concentrated in vacuo. The residue was suspended in 1N HCl (5 mL) and stirred at room temperature for 30 min. The mixture was partitioned between CH2Cl2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the organic material was dried (Na2SO4), filtered, and concentrated. This crude material was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (30% to 100% over 10 min) to provide 4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-1-ol (22 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.11 (dd, J=1.27, 4.99 Hz, 1H), 7.71 (dd, J=1.37, 3.72 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J=8.61 Hz, 1H), 7.35 (dd, J=3.81, 4.99 Hz, 1H), 7.08 (d, J=8.80 Hz, 1H), 4.88 (t, J=5.38 Hz, 1H), 3.50-3.59 (m, 2H), 3.27-3.32 (m, 4H), 3.08-3.15 (m, 4H) 2.56 (t, J=6.70 Hz, 2H); m/z (ESI, +ve ion) 543.1 (M+H)+. GK-GKRP IC50 (Binding)=0.656 μM. GK-GKRP EC50 (LC MS/MS-2)=0.895 μM.