Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc(Cl)c3)nc2n(CCC)c1=O
Yield: 68 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.95 g (17.5 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.51 g (19.2 mmol) of 3-chlorocinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 4.44 g (yield 67%) of Compound 39 as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].Cl>C1C=CC=CC=1.O1CCOCC1>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[Cl:14])[C:4]([CH2:8][CH2:9][CH3:10])=[N:3]1
Reactant: CCCc1cc(=O)n(C)[nH]1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCCc1nn(C)c(O)c1C(=O)c1ccccc1Cl
Temperature: 50 °C
Yield: 9.2 %

Procedure:
1.4 g. of 1-methyl-3-n-propyl-5-pyrazolone is dissolved in 10 ml. of dioxane with heating and then 1.5 g. of calcium hydroxide is added to the resulting solution. 1.75 g. of 2-chlorobenzoyl chloride is added dropwise with stirring at 50° C. After completion of the dropwise addition, the mixture is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is allowed to cool and 100 ml. of a 2N hydrochloric acid solution is added thereto. the mixture is extracted with 70 ml. of chloroform and an organic layer is separated. The layer is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off from the layer to give 2 g. of brown oily residue. the residue thus obtained is dissolved in a small amount of benzene and adsorbed on a silica gel column, which is then eluted with benzene:ethanol (50:1) to give 0.6 g. of crystals. The crystals are recrystallized from methanol-water (7:3) to give 0.25 g. of the desired product as colorless columns having a melting point of 125°-126° C. Yield 9.2%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:24])[C:15]([CH3:23])([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)C.[CH2:60]([SH:64])[CH2:61][CH2:62][SH:63].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[SH:63][CH2:62][CH2:61][CH2:60][S:64][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:24])[C:15]([CH3:23])([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)c1ccc(-c2ccc(Br)cc2)cc1)N1CCOCC1
Reactant: SCCCS
Agent: C=CC(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C=C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C(=O)c1ccc(-c2ccc(SCCCS)cc2)cc1)N1CCOCC1
Temperature: 25 °C

Procedure:
3.5 g (9.0 mmol) of 1-(4'-Bromo-biphenyl-4-yl)-2-methyl-2-morpholin-4-yl-propan-1-one (prepared by the method described in EP-A-3002) and 5.4 ml (54 mmol) of 1,3-propanedithiol are dissolved in 50 ml of dimethylacetamide, and the solution is stirred at around 140° C. together with 2.5 g of potassium carbonate for 2.5 h. Then the solution is cooled to room temperature and poured into water. The crude product is extracted with methylene chloride, washed with saturated sodium chloride solution, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.35 (s, 6H), 1.38 (t, 1H), 1.98 (tt, 2H), 2.61 (t, 4H), 2.69 (dt, 2H), 3.11 (t, 2H), 3.72 (t, 4H), 7.42 (d, 2H), 7.51 (d, 2H), 7.62 (d, 2H), 8.63 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)=[CH:20][CH:21]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
215 mg of the target compound (0.55 mmol, 42.4%) was obtained using 1-(2-methoxyphenyl)piperazine (497 mg, 2.58 mmol), 4′-chlorobiphenyl-2-carbaldehyde (280 mg, 1.29 mmol) and NaBH(OAc)3 (832 mg, 3.87 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C@:8]([CH2:29][O:30][P:31]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH3:28])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[C:13]([N+:25]([O-])=O)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:43])[NH:7][C@:8]([CH2:29][O:30][P:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:32])([CH3:28])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:25])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@](C)(CCc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@](C)(CCc1ccc(O)c(N)c1)COP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an atmosphere of argon, a solution of [(R)-3-(4-Benzyloxy-3-nitro-phenyl)-1-(di-tert-butoxy-phosphoryloxymethyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (5.36 g, 8.6 mmol) in ethanol (250 mL) was treated with 10% palladium on charcoal (1.22 g). Argon was replaced by hydrogen and the reaction was stirred for 16 hours at RT. After filtration and removal of the solvent in vacuum, the residue was purified by silica gel column chromatography (dichloromethane/methanol 10/1) yielding the title compound as a colorless solid. 1H-NMR (CD3OD): δ=6.61-6.57 (m; 2H), 6.41 (dd; 1H), 6.22 (s; 1H), 4.55 (s; 1H), 4.41/3.93 (2m; 2H), 2.43 (m; 1H), 2.05 (m; 1H), 1.70 (m; 1H), 1.48 (s; 18H), 1.44 (s; 9H), 1.28 (s; 3H); MS (ESI+): 503.4 [M+H]+
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH:7]=[CH:6][CH:5]([OH:10])[O:4]1)[CH3:2].[CH:11]([O-])([O-])OC.S([O-])([O-])(=O)=O.[Mg+2]>>[CH2:1]([CH:3]1[C:8](=[O:9])[CH:7]=[CH:6][CH:5]([O:10][CH3:11])[O:4]1)[CH3:2]
Reactant: COC([O-])[O-]
Reactant: CCC1OC(O)C=CC1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCC1OC(OC)C=CC1=O
Yield: 86 %

Procedure:
A 14.2 g quantity of 2-ethyl-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran and 50 g of methyl orthoformate are reacted in the presence of 10 g of magnesium sulfate under reflux for 24 hours. After the reaction, the mixture is filtered to remove the magnesium sulfate, and the filtrate is concentrated in vacuum to remove the excess methyl orthoformate. The residue is poured into 50 ml of water, the mixture is extracted with ether, and the ethereal layer is washed with a sodium carbonate solution and dried over magnesium sulfate. The dried mass is distilled to remove the ether, and the residue is further distilled at a reduced pressure of 12 mm Hg to give 13.4 g of 2-ethyl-6-methoxy-3-oxo-3,6-dihydro-2H-pyran as a yellow liquid fraction at 85° to 90° C in a yield of 86%.
Reaction SMILES: C1N=CN(C(N2C=N[CH:10]=[CH:9]2)=O)C=1.CC(OC)(C)C.[C:19]([C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C@@:32]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)([OH:37])[CH2:33]C(O)=O)=[CH:26][C:25]=1[F:43])([CH3:23])[CH3:22])#[N:20].[C:44]([O-])(=[O:49])[CH2:45][C:46]([O-:48])=[O:47].C([Mg+2])C>CN(C1C=CN=CC=1)C.C1COCC1>[C:19]([C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C@@:32]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)([OH:37])[CH2:33][C:44](=[O:49])[CH2:45][C:46]([O:48][CH2:9][CH3:10])=[O:47])=[CH:26][C:25]=1[F:43])([CH3:23])[CH3:22])#[N:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C#N)c1ccc(CC[C@@](O)(CC(=O)O)C2CCCC2)cc1F
Reactant: O=C([O-])CC(=O)[O-]
Agent: CC[Mg+2]
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C[C@](O)(CCc1ccc(C(C)(C)C#N)c(F)c1)C1CCCC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A 1-L, 3-neck flask was charged with CDI (29.00 g, 0.179 moles), DMAP (733 mg, 0.006 moles), and MTBE (70 mL) (notes 1, 2). An MTBE solution of (3R)-5-[4-(1-cyano-1-methylethyl)-3-fluorophenyl]-3-cyclopentyl-3-hydroxypentanoic acid (41.28 g, 0.119 moles, 170 mL) was added to the stirred mixture over a 30 minute period. The addition funnel was rinsed with THF (5 mL) and the rinse was added to the reaction mixture. The mixture was stirred for 30 min and an aliquot was removed and analyzed by HPLC. Once acyl-imidazole formation was complete, the solution was added to a 500 mL addition funnel. A separate 1-L, 3-neck flask was charged with ethyl magnesium malonate (51.30 g, 0.179 moles) and THF (100 mL) (the solids did not dissolve in THF, even after warming to 40° C.). The stirred mixture was heated to 40° C. and the acyl-imidazole solution was slowly added to the mixture. Stirring was continued at 40° C., and aliquots were periodically removed and analyzed by HPLC for completion. After the reaction was complete, heating was discontinued and the solution allowed to cool to rt. The solution was diluted with IPE (200 mL) and 1 N HCl (360 mL), the mixture was stirred for 15 minutes, and the phases were separated. The organic phase was extracted with H2O (10 mL), the phases separated, and the organic layer was added to a 1-L, 3-neck flask. The solution was distilled to a minimum of −3.3 volumes to remove H2O (the distillate temperature was 48° C. during azeotrope distillation and the distillation was ended after the distillate temperature was steady at ˜50° C.). The solution was used directly in the next step.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:19]([O:18][C:16]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:17])([CH3:21])[CH3:20]
Reactant: OC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-hydroxyl-piperidine (8.1 g, 80 mmol) and triethylamine (11.2 mL, 1 eq) in 200 mL of DCM, was added isopropyl chloroformate (80 mL of a 1 M solution in toluene, 1 eq). The reaction mixture was stirred at room temperature for 3 h, quenched with a saturated solution of bicarbonate and extracted with DCM twice. The combined extracts were washed with a saturated solution of bicarbonate, dried over magnesium sulfate and evaporated to give 2a.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:21]2[C:4](=[CH:5][C:6]3[C@@H:7]([S:36][CH2:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:8]4[C:17]([C@H:18]([S:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:19]=3[CH:20]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([Cl:34])[CH:14]=2)[CH:9]=4)[CH:3]=1.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Cl:24][C:23]1[C:2]([Cl:1])=[CH:3][C:4]2[C:21](=[CH:20][C:19]3[C:6]([CH:5]=2)=[C:7]([S:36][CH2:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:8]2[C:17](=[CH:16][C:15]4[C:10]([CH:9]=2)=[CH:11][C:12]([Cl:35])=[C:13]([Cl:34])[CH:14]=4)[C:18]=3[S:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1
Reactant: Clc1cc2cc3c(cc2cc1Cl)[C@H](SCCc1ccccc1)c1cc2cc(Cl)c(Cl)cc2cc1[C@H]3SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: [K+]
Solvent: c1ccccc1
Product: Clc1cc2cc3c(SCCc4ccccc4)c4cc5cc(Cl)c(Cl)cc5cc4c(SCCc4ccccc4)c3cc2cc1Cl
Temperature: 60 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
A mixture of 2,3,9,10-tetrachloro-trans-6,13-bis(phenylethylthio)-6,13-dihydropentacene (0.3 g, 0.44 mmol), tetrachloro-1,4-benzoquinone (0.22 g, 0.89 mmol) and potassium carbonate (0.61 g, 4.45 mmol) in dry benzene (50 mL) was stirred at 60° C. for 48 h under an argon atmosphere in the dark. After cooling to RT, the reaction mixture was filtered and washed with CH2Cl2. After evaporation of the filtrate, the solid residue was passed through short column of n-Al2O3 eluted with CH2Cl2 and the deep blue band was collected. The solvent was evaporated to give pure 2,3,9,10-tetrachloro-6,13-bis(phenethylthio)pentacene as deep blue solids in 17% yield (0.05 g). 1H NMR (500 MHz, CDCl3): δ 9.48 (s, 4H), 8.11 (s, 4H), 7.24 (m, 6H), 7.06 (m, 4H), 3.27 (t, 4H, J=7.32 Hz), 2.85 (t, 4H, J=7.32 Hz). 13C NMR (125.68 MHz, CDCl3): δ 132.89, 132.44, 132.25, 128.95, 128.73, 128.59, 127.07, 126.56, 126.14, 38.04, 36.53. LDI-MS m/z: 688 [M+], UV-vis λmax(nm): 628, 577, 537.
Reaction SMILES: C([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6][CH:5]=1)(=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+:25].[C:26]([O:33][CH2:34][CH3:35])(=[O:32])[C:27]([O:29]CC)=O.[CH2:36]([O:38]CC)[CH3:37]>>[CH2:9]([N:8]1[CH:4]=[C:5]([C:36](=[O:38])/[CH:37]=[C:27](\[O-:29])/[C:26]([O:33][CH2:34][CH3:35])=[O:32])[N:6]=[CH:7]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1.[Li+:25]
Reactant: CC(=O)c1cncn1Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)/C([O-])=C/C(=O)c1cn(Cc2ccccc2)cn1
Temperature: -75 °C

Procedure:
5-Acetyl-1-benzylimidazole (24.97 mmol, 5 g) was dissolved in dry diethyl ether (100 ml) under nitrogen atmosphere. The mixture was cooled to −75° C. and lithium bis(trimethylsilyl)amide (27.5 mmol, 27.5 ml) was added dropwise. The resulting mixture was stirred at −75° C. for an hour. Diethyl oxalate (32.5 mmol, 4.74 g) was added and the mixture was allowed to warm to ambient temperature after which the mixture was stirred for a day at RT. The formed precipitate was removed by filtration and the precipitate was washed with diethyl ether. The precipitate was dried under vacuum. 7.38 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.22 (t, 3H), 4.11 (q, 2H), 5.61 (s, 2H), 6.17 (s, 1H), 7.15-7.31 (m, 5H), 7.48 (d, 1H), 7.88 (d, 1H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.Cl.N1C=CC=CC=1>C1COCC1>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13].[C:9]([O:16][CH:29]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13]
Reactant: O=C(O)/C=C\C(=O)OCc1ccccc1
Reactant: C1=COCCC1
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C([O-])/C=C\C(=O)OC1CCCCO1
Product: O=C([O-])/C=C\C(=O)OCc1ccccc1

Procedure:
Poly(styrene [50 mol %], benzyl hydrogen maleate [50 mol %]) was prepared by stirring at reflux for 25 hours a mixture of poly(styrene [50 mol %], maleic anhydride [50 mol %]), 200 mL of benzyl alcohol and 400 mL of THF. The THF was removed on a rotary evaporator, and the product was precipitated in hexane followed by precipitation from THF with diethyl ether to give 46 g of poly(styrene, benzyl hydrogen maleate). A mixture of 25 g of poly(styrene, benzyl hydrogen maleate), 150 mL of 3,4-dihydro-2H-pyran, and 0.5 g of pyridine hydrochloride was stirred at reflux 18 hours. THF was added to reduce the viscosity, and the mixture was stirred 1 hour with crosslinked poly(dimethylaminomethylstyrene). After filtration, the product was precipitated from the filtrate in methanol to give 29 g of poly(styrene, benzyl maleate, tetrahydropyranyl maleate). 1H HMR (360 MHz) shows the molar ratio of tetrahydropyranyl groups (δ 5.8 ppm) to benzyloxy groups (δ 5.0 ppm) to be about 4.4:1. Titration with 0.1N sodium hydroxide shows 0.09 meq/g of COOH groups. DSC: decomposition endotherm 140.75° C. TGA: 24.7% weight loss at 147.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([O:8][CH3:13])[CH:7]=1
Reactant: COC(=O)c1ncc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ncc(OC)cc1Cl
Temperature: 55 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
In a 1-L round bottom flask, the methyl 3-chloro-5-hydroxypicolinate (25.00 g, 133 mmol) and cesium carbonate (87 g, 267 mmol) were taken up in DMF (200 ml), and iodomethane (41.7 ml, 666 mmol) was added. A water-cooled condenser was attached, and the reaction vessel was heated in a 55° C. oil bath. After 3 h, the reaction was concentrated. The residue was taken up in 1.2 L of 80% EtOAc-hexane and 500 ml of brine. Not all the solids went in, so the mixture was filtered through Celite. The resulting filtrate's organic layer was separated, washed with brine (100 ml), dried over MgSO4 and concentrated. The residue was purified through silica gel using 30% to 40% EtOAc in hexane, affording 19.1 g (95 mmol) of a tan solid (71% yield). MS m/z=202 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.[NH:19]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC(OC)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: c1ccc(NCCc2ccccn2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CCc2ccccn2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a 25 ml round bottom flask, 0.21 g 4-methoxybenzenesulfonyl chloride and 0.08 mL of pyridine were dissolved in 10 ml of MTBE. To this solution was added 0.2 g of 2-(2-anilinoethyl)pyridine. The reaction was heated at reflux for one hour and then let cool down to room temperature. To the reaction was added 10 mL of water. The organic layer was separated and washed with 10 mL of water. The organic layer was dried over MgSO4, filtered, and concentrated to yield a brown oil. The oil was purified on silica gel to recover 0.3 g of a tanned solid with the following spectroscopic properties:
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:25])=[C:12]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22]([O-:24])=[O:23])[C:13]=1[Cl:14].[Na+].CN(C)C=O.CO>C(Cl)Cl>[Cl:14][C:13]1[C:8]([CH3:7])=[CH:9][CH:10]=[C:11]([Cl:25])[C:12]=1[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:1])=[O:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)[O-])c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
Oxalyl chloride (9.50 g, 74.8 mmol) in 20 ml of methylene chloride is added dropwise to a 0° C. suspension of meclomen (10.20 g, 34.4 mmol) and dimethylformamide (2.70 ml, 34.7 mmol) in 50 ml of methylene chloride. The clear yellow solution is stirred at 0° C. for 90 minutes then added by cannula to 110 ml of methanol at room temperature. The white suspension is stirred at room temperature overnight. The white solid is collected providing 7.52 g of product. The filtrate is concentrated and the residue partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over magnesium sulfate and concentrated, providing an additional 2.45 g of product (94% total), mp 130°-131° C.
Reaction SMILES: [H-].[Na+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[OH:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[N:23]([CH2:39][CH2:40][N:41]=3)[C:24]([NH:30][C:31]([C:33]3[CH:34]=[N:35][CH:36]=[N:37][CH:38]=3)=[O:32])=[N:25][C:26]=2[C:27]=1[O:28][CH3:29].Cl.Cl[CH2:44][CH2:45][N:46]([CH3:48])[CH3:47]>CN(C=O)C>[CH3:47][N:46]([CH3:48])[CH2:45][CH2:44][O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[N:23]([CH2:39][CH2:40][N:41]=3)[C:24]([NH:30][C:31]([C:33]3[CH:34]=[N:35][CH:36]=[N:37][CH:38]=3)=[O:32])=[N:25][C:26]=2[C:27]=1[O:28][CH3:29]
Reactant: COc1c(O)ccc2c1N=C(NC(=O)c1cncnc1)N1CCN=C21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OCCN(C)C)ccc2c1N=C(NC(=O)c1cncnc1)N1CCN=C21
Temperature: 25 °C
Yield: 55.9 %

Procedure:
Sodium hydride (865 mg, 22 mmol, 60% dispersion in mineral oil) was diluted in DMF (35 mL). N-(8-Hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide bis(trifluoroacetate) (1.75 g, 3.1 mmol) was added, followed by 2-chloro-N,N-dimethylethanamine hydrochloride (890 mg, 6.2 mmol). The reaction mixture was stirred at rt until gas evolution ceased and then was heated to 50° C. for 2 h. At this time, the mixture was cooled to rt, and an additional equivalent of 2-chloro-N,N-dimethylethanamine hydrochloride (445 mg, 3.1 mmol) was added. The resulting reaction mixture was stirred at 50° C. overnight. After cooling to rt, the excess sodium hydride was carefully quenched by the addition of water and the mixture was extracted several times with DCM. The combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure. The resultant solid was triturated with EtOAc and hexanes to afford the title compound as a solid (710 mg, 56%): HPLC MS RT=1.09 min, MH+=410.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.47 (2H, s), 9.39 (1H, s), 8.12 (1H, d), 7.52 (1H, d), 4.61 (4H, m), 4.26 (2H, m), 4.03 (3H, s), 3.67 (2H, br t), 2.93 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27](F)[CH:26]=2)=[N:4][C:5]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)C(=O)OC(C)(C)C)=[CH:6][CH:7]=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]3)[CH:26]=2)=[N:4][C:5]([NH:8][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:23])([CH3:24])[CH2:18]2)=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1ccc(Cl)c(-c2cc(F)ncc2Cl)n1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(N[C@H]4CC[C@H](O)CC4)ncc3Cl)n2)CCO1
Temperature: 135 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3,5′-dichloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (30 mg, 0.062 mmol) in DMSO (0.4 mL) was added trans-4-aminocyclohexanol (36 mg, 0.31 mmol) and DIEA (0.022 mL, 0.12 mmol). The mixture was stirred at 135° C. for 3 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The resulting residue was re-dissolved in trifluoroacetic acid (1 mL), stirred for 15 min at ambient temperature, and then concentrated under reduced pressure. The crude resulting residue was purified by reverse phase HPLC and lyophilized to give 23 mg of trans-4-(3,5′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexanol as its TFA salt. LCMS (m/z): 479.3 (MH+), retention time=0.72 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (d, J=12.91 Hz, 2H) 1.08 (s, 6 H) 1.15-1.35 (m, 4 H) 1.54 (d, J=12.91 Hz, 2 H) 1.71-2.10 (m, 5 H) 3.00 (d, J=6.65 Hz, 2 H) 3.31-3.63 (m, 5 H) 6.47 (s, 1 H) 6.58 (d, 1 H) 7.50 (d, J=9.00 Hz, 1 H) 8.05 (s, 1 H)