Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-:4])C.[K+].O.CN(OC)[C:10](=[O:18])[C@@H:11]([OH:17])[CH2:12][CH:13]1[CH2:16][CH2:15][CH2:14]1>C1COCC1>[OH:17][C@@H:11]([CH2:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:10]([OH:18])=[O:4]
Reactant: CON(C)C(=O)[C@@H](O)CC1CCC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](O)CC1CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.3 %

Procedure:
A suspension of 33.66 g (0.3 mol) of potassium t-butoxide in 50 mL of THF was treated with 5.40 mL (0.3 mol) of H2O. The resulting mixture was treated with a solution of 11.48 g (0.061 mol) of N-methyl-N-methoxy 2-(S)-hydroxy-3-cyclobutyl propanamide (from Step C) in 20 mL of THF and stirred at rt for 20 h. The mixture was concentrated and the residue was partitioned between 300 mL of ether and 200 mL of H2O and the layers were separated. The pH of the aqueous layer was adjusted to 2 with concentrated HCl and extracted with 300 mL of EtOAc. The extract was washed with 100 mL of sat'd NaCl, dried over MgSO4 and concentrated to afford 7.50 g (85%) of the title compound: 1H NMR (500 MHz) δ 1.66-1.76 (m, 2H), 1.78-1.98 (4H), 2.06-2.16 (m, 2H), 2.51-2.61 (m, 1H), 4.20 (dd, J=8.0, 4.0, 1H).
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2>ClCCl>[CH:1]1([C:4]([C:29]2[C:28]3[C:32](=[C:24]([CH2:23][S:22][CH3:21])[CH:25]=[CH:26][CH:27]=3)[NH:31][CH:30]=2)([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(F)cc1)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
559 mg (3.10 mmol) of the compound from Example 77A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 12 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min and then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 361 mg (38% of theory) of the title compound.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[C:10]([NH:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:26][CH:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:14][C:12]1[CH:11]=[C:10]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[N:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:26][CH:27]3[CH2:31][CH2:30][NH:29][C:28]3=[O:32])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: Nc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(F)nc2)c1
Reactant: NC1CCNC1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCNC3=O)nc2)c1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
6′-Fluoro-N6-[4-(trifluoromethyl)pyridin-2-yl]-2,3′-bipyridine-4,6-diamine (50 mg, 0.143 mmol), 3-aminopyrrolidin-2-one (39.1 mg, 0.286 mmol), tribasic potassium phosphate (60.8 mg, 0.286 mmol), and N,N-diisopropylethylamine (0.050 ml, 0.286 mmol) were dissolved in dimethylsulfoxide (0.5 mL). The mixture was heated to 130° C. with stirring for three days. After allowing to cool to room temperature, the reaction mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated, and the organic layer was washed with water (3×5 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified using reverse phase HPLC (15 to 85% acetonitrile/water with 0.1% TFA gradient). The fractions containing the product were partitioned between 10% isopropanol/chloroform and 1:1 saturated aqueous sodium bicarbonate solution:brine. The layers were separated, and the aqueous layer was extracted with additional 10% isopropanol/chloroform. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-[(4-amino-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)amino]pyrrolidin-2-one. MS ESI calcd. for C20H19F3N7O [M+H]+ 430. found 430. 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.62 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.88 (dd, J=2.4, 8.8 Hz, 1H), 7.83 (s, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.94 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 6.53 (d, J=1.6 Hz, 1H), 6.46 (s, 1H), 5.97 (s, 2H), 4.60-4.52 (m, 1H), 3.25-3.20 (m, 2H), 2.52-2.46 (m, 1H), 1.87-1.79 (m, 1H). rhSyk IC50=4 nM.
Reaction SMILES: S(=O)(=O)(O)O.Cl[CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:29][CH2:30][NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([C:24](=[O:28])[CH2:25][CH2:26]Cl)=[CH:18][CH:17]=3)=[O:10]>C(Cl)Cl.C(OCC)(=O)C>[O:10]=[C:9]1[C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH2:29][CH2:30][NH:31][S:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[O:28])[CH2:25][CH2:26][C:20]=5[C:21]=4[C:22]=3[C:23]=2[CH2:7][CH2:8]1
Reactant: O=C(CCCl)c1ccc2c(c1)c1cc(C(=O)CCCl)ccc1n2CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CCc2c1ccc1c2c2c3c(ccc2n1CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)CC3
Temperature: 90 °C
Reaction time: 1.75 h

Procedure:
Sulfuric acid (200 mL) was heated to 40° C. Then, compound 57 (18.47 g, 32.12 mmol) was added in portions. The mixture was heated to 90° C. and kept at this temperature for 1.5-2 h (TLC monitoring, eluent: CH2Cl2-ethyl acetate, 4:1). The resulting mixture was poured onto ice. The grey precipitate was filtered off, washed on a filter with a mixture of CHCl3-MeOH (4:1). The remaining precipitate (on a filter) was recrystallized with DMF, washed with CH3CN and ether. Yield of pure 58: 2.2 g (14%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>CC(OC)(C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C@H:6]2[CH2:7][C@@H:12]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(Br)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a 1-neck, 1-L round bottom flask equipped with a magnetic stirrer was added 265 mL methyl tert-butyl ether. The flask was evacuated and flushed with nitrogen three times. 2,2′-Isopropylidenebis[(4R)-4-tert-butyl-2-oxazolidine] (2.39 g, 8.03 mmol) was added, followed by copper(I) tridluoromethanesulfonate benzene complex (4.49 g, 8.03 mmol). The green suspension was stirred at room temperature for about 2 hours and was then filtered. The filtrate was added to a 4-neck, 5-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and addition funnel. Then, 4-bromostyrene (150 g, 0.803 mol) was added to this solution and the reaction was cooled to 0° C. via an ice/water bath. Ethyl diazoacetate (167 mL, 1.606 mol) was dissolved in 1675 mL of MTBE and the solution was evacuated/flushed with nitrogen three times. This solution was then added to an addition funnel and added dropwise to the reaction mixture. A slight exotherm was observed. The ethyl diazoacetate was allowed to add slowly over the weekend and the reaction slowly warmed to room temperature. The reaction was poured into a large extractor and diluted with 4 L MTBE. The organics were washed with 2×1 L 3% aq. ammonium hydroxide and 2 L brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dissolved in heptane and a small amount of dichloromethane, injected onto an ISCO 1500 g column prepacked in heptane. The column was eluted with 100% heptane over 1 column volume, 0-20% ethyl acetate/heptane over 6.5 column volumes, and held at 20% ethyl acetate/heptane over 8 column volumes. The product containing fractions were collected and concentrated to give 191 g (yield 88%) of the title compound. 1H NMR (500 MHz, (CDCl3): 7.42 (d, 2H), 7.01 (d, 2H), 4.21 (q, 2H), 2.49 (m, 1H), 1.88 (m, 1H), 1.62 (m, 2H), 1.25 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[C:48]([CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([C:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)=[O:49])[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(C)c(C)c3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(C)c(C)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dimethyl-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]3)O1.Br[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][N:29]=[CH:30]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH:30]1[C:31]2[C:26](=[C:25]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]4)[CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: Brc1cccc2cnccc12
Reactant: COC(=O)c1cccc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Yield: 70.9 %

Procedure:
Methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthoate (2.2 g, 7.0 mmol), 5-Bromoisoquinoline (1.33 g, 6.3 mmol), a 2M solution of sodium carbonate (9.6 mL) and palladium tetrakistriphenylphospine (0.37 g, 0.32 mmol) were heated in Toluene-EtOH (105 mL-21 mL) at 80° C. overnight. Solvent was evaporated and mixture was extracted with ethyl acetate. Organic phase was washed with brine, dried, filtered and evaporated. Residue was purified by chromatography (ethyl acetate-hexane 10:90->20:80->30:70->40:60->60-40. to give 1.4 g of the title compound as an off-white solid
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)Cl.C(N(CC)CC)C.[C:37](Br)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[N:19]([C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)c1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(c1ccccc1)n1c(=O)c(F)cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a solution of 0.50 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 20 ml of dioxane were added 0.75 ml of trimethylchlorosilane and 2.00 ml of triethylamine, and the mixture was stirred at room temperature for 2 hours. Then, the resulting mixture was left to stand at 60° C. for 30 minutes. To the reaction mixture were added 0.42 g of benzoyl bromide and 1.00 ml of triethylamine, and the mixture was left to stand at 60° C. for 1 hour. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate. Then, the solution was washed with saturated aqueous solution of sodium chloride. The ethyl acetate layer was separated and concentrated. The residue was dissolved in 30 ml of methanol and 0.5 ml of acetic acid was added thereto. The mixture was left to stand overnight. The solvent was distilled off and the residue was applied to a silica gel column to conduct gradient elution using chloroform and mixtures of methanol (up to 2%) and chloroform, giving 0.35 g of the title compound as a powder in a yield of 54%.
Reaction SMILES: [Cl-].[Na+].[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:6]([NH2:8])=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>ClCCCl>[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:6]#[N:8]
Reactant: COC(C(N)=O)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 20 ml. of dry 1,2-dichloroethane containing 2.0 g. of sodium chloride is added 3.32 g. of 2-methoxy-2-(2-pyridyl)acetamide. After stirring at room temperature for 15 minutes, 1.7 ml. of phosphorus oxychloride is added. The solution is refluxed for 18 hours. The solution is then cooled and made basic with 10% aqueous sodium hydroxide solution. The aqueous phase is extracted three times with chloroform and the combined chloroform extracts are washed three times with water and once with brine and dried over magnesium sulfate. Filtration, removal of solvent and distillation in vacuo gives 2-methoxy-2-(2-pyridyl)acetonitrile, b.p. 72°-76°C./0.2 mm.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH2:9][CH2:8][C:7]3[S:10][C:11]([NH:13][C:14]([CH:16]4[C:18]([CH3:20])([CH3:19])[C:17]4([CH3:22])[CH3:21])=[O:15])=[N:12][C:6]=3[C:5]=12.CC(C)([O-])C.[K+].[CH3:29][O:30][CH2:31][CH2:32]Br>CN(C=O)C.CCOC(C)=O>[CH3:29][O:30][CH2:31][CH2:32][N:12]1[C:6]2[C:5]3=[N:1][O:2][N:3]=[C:4]3[CH2:9][CH2:8][C:7]=2[S:10]/[C:11]/1=[N:13]\[C:14]([CH:16]1[C:18]([CH3:20])([CH3:19])[C:17]1([CH3:22])[CH3:21])=[O:15]
Reactant: COCCBr
Reactant: CC1(C)C(C(=O)Nc2nc3c(s2)CCc2nonc2-3)C1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1c2c(s/c1=N\C(=O)C1C(C)(C)C1(C)C)CCc1nonc1-2
Temperature: 250 °C

Procedure:
The product of Example 123B (1 equiv), potassium tert-butoxide (1.1 equiv) and 2-bromoethyl methyl ether (1 equiv) were combined in DMF (0.1 M) and heated in a SmithSynthesizer™ microwave at 250° C. for 15 minutes. The mixture was diluted with EtOAc and washed with 1 M aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography afforded the title compound and the product of Example 124. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 6H), 1.26 (s, 6H), 1.57 (s, 1H), 3.10 (t, J=7.5 Hz, 2H), 3.23 (s, 3H), 3.26 (t, J=7.4 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 4.67 (t, J=5.8 Hz, 2H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9](Cl)[N:8]=[C:7]([Cl:14])[N:6]=1)=[O:4].[NH3:15]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:15])[N:8]=[C:7]([Cl:14])[N:6]=1)=[O:4]
Reactant: N
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1nc(Cl)nc(N)c1OC
Reaction time: 0.5 h
Yield: 29 %

Procedure:
2,6-Dichloro-5-methoxypyrimidine-4-carboxylic acid methyl ester (750 mg, 3.16 mmol; see J. Med. Chem. 49(5), 1693-1705; 2006 for preparation) was dissolved in chloroform and 2N ammonia in methanol (2 eq) was added dropwise while in a cooling bath. The reaction mixture was stirred for 30 min, after which an additional 2 eq of 2N ammonia in methanol was added. The reaction was stirred at ambient temperature for 16 h. Additional 2N ammonia in methanol (2 eq) was added. The reaction was stirred for 2 h during which time a solid precipitated. The solid was filtered off and water was added to the filtrate. The crude material was extracted from the filtrate with dichloromethane three times and the combined organic phases were washed with brine, dried and concentrated under vacuum. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to provide the title compound (202 mg, 29% yield): mp 162-167° C.; 1HNMR (CDCl3): δ 5.75 (br s, 2H), 3.97 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:17](=[O:19])[CH3:18])=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(Br)cn1
Temperature: 25 °C

Procedure:
A mixture of 200 mg (1.00 mmol) 2-(5-bromopyridin-2-yl)ethanamine, 86.6 μL (1.09 mmol) pyridine and 2 mL DCM is charged with 103 μL (1.09 mmol) acetic anhydride and stirred at r.t. over night. The mixture is treated with saturated aq. NaHCO3 solution and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is evaporated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:3]=2[O:2][CH3:1])=[O:7])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Product: COc1cc([N+](=O)[O-])ccc1C(=O)N1CCN(C)CC1

Procedure:
Prepared from 2-methoxy-4-nitrobenzoic acid and 1-methyl-piperazine (TPTU, CH2Cl2/CH3CN, Et3N): MS: [M+1]+=280; Anal.: CHN.
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[OH:38][Li].O>O.C1COCC1>[OH:1][C:2]1([C:29]2[S:33][C:32]([OH:38])=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[O:14])[CH2:11]2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reactant: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cnc(O)s3)CC2)C1

Procedure:
A solution of N-({1-[4-Hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a, 100 mg, 0.18 mmol) and LiOH hydrate (Aldrich, 15 mg, 0.36 mmol) in water (1 mL) and THF (1 mL) was heated to 60° C. in a sealed tube for 2 hours. The crude solution was directly purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].C(OCC)(=O)C>[N+](C)([O-])=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: N#CCOc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: C[N+](=O)[O-]
Product: N#CCOc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
A solution of 7.5 g of (4-hydroxy-phenoxy)-acetonitrile dissolved in 60 ml of nitromethane was cooled in an ice bath and 3.88 ml of 70% nitric acid was added dropwise. After 45 minutes, the reaction mixture was poured into ethyl acetate, washed with brine, dried (MgSO4), and evaporated to dryness. The crude product was purified by silica gel chromatography eluting with ethyl acetate/hexane (1:3), giving 5.45 g of (4-hydroxy-3-nitro-phenoxy)-acetonitrile as a yellow solid, mp 113.1-114.1° C.
Reaction SMILES: O.[C:2]1(=[O:8])O[C:5](=[O:6])[CH:4]=[CH:3]1.[CH2:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].P(=O)(O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:9]([N:21]1[C:5](=[O:6])[CH:4]=[CH:3][C:2]1=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCN
Agent: O=P(O)(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCN1C(=O)C=CC1=O
Temperature: 215 °C

Procedure:
A glass flask having an inner volume of 3 liters was fitted with a thermometer, a stirrer, and a water separator. In this reactor, 240 g of a solution containing 120 g of maleic anhydride in xylene was placed. Then, a solution containing 220 g of dodecylamine in 1880 g of xylene was added gradually and piecemeal over a period of 120 minutes at 40° C. to the reactor. After the addition was completed, the mixture in the reactor and 65.4 g of orthophosphoric acid (purity 89% by weight) added thereto were heated at 215° C. for 1 hour under 4.4 kg/cm2. G to effect reaction. The resultant reaction mixture was cooled to 30° C., washed with 400 ml of water, and separated into a water layer and a xylene layer. The xylene layer was separated by filtration to effect removal of insolubles. The xylene layer was distilled to expel xylene. Consequently, there was obtained 258 g of slightly impure N-dodecyl maleimide. This product was found to have purity of 85.3% by weight, indicating the yield to be 69.9 mol % based on dodecylamine.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:5][CH3:6].[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:3]([CH:7]1[N:15]([CH2:40][C:37]2[CH:36]=[CH:35][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[N:23]([C:22]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:24]=[N:25][N:26]=3)=[CH:39][CH:38]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[NH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc2ncccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC1Nc2cccnc2N1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
To a stirred suspension of NaH (102 mg of an 80% dispersion, 3.39 mmol) in dry dimethylformamide (6 mL) at rt was added 2-butylimidazo[4,5-b]pyridine (495 mg, 2.83 mmol) in one portion. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (1.50 g, 2.70 mmol) was added in one portion. The resulting dark colored mixture was warmed to rt and stirred for 15 hours. The excess NaH was quenched with water (1 mL) and the bulk of the DMF was removed in vacuo at 40°-50° C. Extraction with EtOAc (4×20 mL) from brine (60 mL), drying (K2CO3), and concentration gave a thick dark oil. Purification by flash chromatography (SiO2, solvent gradient: 80% EtOAc/hexanes, 100% EtOAc) gave 417 mg (23%) of 2-butyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-1H-imidazo[ 4,5-b]pyridine as a thick oil: Rf=0.75 (SiO2, 100% EtOAc).