Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:26]3[CH:30]=[CH:29][N:28]=[C:27]3[C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (1.00 g), ethyl 2-imidazolecarboxylate (990 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the resulting solid precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give ethyl 1-[4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-oxazolyl]imidazole-2-carboxylate as pale yellow prisms (290 mg, 23%). Melting point 90-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[H-].[Na+].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19].O>C(OCC)C>[F:16][C:17]([F:23])([F:22])[S:18]([O:13][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([F:11])([F:12])[F:10])(=[O:20])=[O:19]
Reactant: OC(c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(OC(c1ccc(Cl)cc1)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (1.20 g, 5.70 mmol) was dissolved in diethyl ether (80 mL), and the resulting solution was cooled to 0° C. Then, 63% sodium hydride (217 mg, 5.70 mmol) was added thereto, and the resulting mixture was stirred for 1 hour. Thereafter, trifluoromethanesulfonyl chloride (0.910 mL, 8.55 mmol) was added dropwise thereto. Then, the temperature of the reaction solution was raised to room temperature, and the reaction solution was stirred for 2 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 93:7 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (495 mg, yield: 25%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[CH2:15][C:16]([CH2:18]Cl)=[CH2:17]>CN(C=O)C>[C:7]([O:6][C:5]([N:4]1[CH2:18][C:16](=[CH2:15])[CH2:17][O:1][CH2:2][CH2:3]1)=[O:11])([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C1COCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
A solution of tert-butyl 2-hydroxyethylcarbamate 38.1 (9.00 mL, 58.2 mmol) in DMF (50.0 mL) was cooled in a ice bath and treated portion wise with sodium hydride (60% in mineral, 5.12 g, 128 mmol). The mixture was stirred in ice bath for 15 minutes and then treated with 3-chloro-2-(chloromethyl)prop-1-ene (7.07 mL, 61.1 mmol). After addition was complete, the ice bath was removed and the reaction mixture was stirred was stirred at room temperature overnight. The mixture was diluted with water and extracted with ether. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford an oil which purified by flash chromatography (gradient EtAOAc/hexane 5%-40%) to afford the desired product (4.6, 37% yield) clear oil. LCMS 114.10 [M-tBuCO2]+.
Reaction SMILES: C1(=O)N([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)C(=O)C=C1.[NH2:15][CH2:16][CH2:17]C[Si](OCC)(OCC)OCC.C=O>C1(C)C=CC=CC=1>[O:12]1[C:9]2[CH:10]=[CH:11][CH:6]=[CH:7][C:8]=2[CH:17]=[CH:16][NH:15]1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=C1C=CC(=O)N1c1ccc(O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 37 %

Procedure:
This compound was prepared according to the method used for the previous examples by combining 4-maleimidophenol (18.9 g, 100 mmol), 3-aminopropyltriethoxysilane (22.1 g, 100 mmol), paraformaldehyde (6.3 g, 210 mmol), and toluene (150 mL). The final product was a highly viscous red liquid. The yield was 37%.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH2:22])[C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:13][CH:14]=1.[C:23](Cl)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]([CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[N:22][C:11]=2[CH:10]=1
Reactant: CN(C)CCCNc1ccc(Cl)cc1N
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCc1nc2cc(Cl)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Triethylamine (1.75 ml) was added to a solution containing 4-chloro-N1-[3-(dimethylamino)propyl]-1,2-benzenediamine (2.60 g) in chloroform (25 ml), and then a solution containing stearoyl chloride (3.46 g) in chloroform (5 ml) was added thereto while being cooled with ice. After being stirred for 3 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (9.00 ml) was added to a solution containing the residue (5.94 g) in ethanol (50 ml). After being stirred for 2 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (5.61 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-20:1), thereby yielding the entitled compound (4.90 g) as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]2)=[C:18]([C:32]([F:35])([F:34])[F:33])[CH:17]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][CH2:27]3)=[C:18]([C:32]([F:33])([F:35])[F:34])[CH:17]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: COC(=O)C1CCN(c2ccc(Nc3c([N+](=O)[O-])cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1CCN(c2ccc(Nc3c(N)cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 73.2 %

Procedure:
To a solution of compound 8.2 methyl 1-(4-(6-bromo-3-nitroquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.26 g, 0.47 mmol, 1 equiv.) in dioxane (3 mL) at room temperature was added Tin(II) chloride dihydrate (0.53 g, 2.35 mmol, 5 equiv.). The resulting mixture was heated to 80° C. under argon for 5 hours. Upon cooling to room temperature, the mixture was neutralized with aqueous NaHCO3 and filtered. The flitrate was extrated with EtOAc (30 mL×2) and the combined organic layer was washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (hexanes:EtOAc 1:1) to afford desired product 8.3 methyl 1-(4-(3-amino-6-bromoquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.18 g; 73%). LC-MS (M+H): 523.10
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([NH2:24])=O)[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]#[N:24])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: NC(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 98.1 %

Procedure:
To a suspension of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (280 mg, 0.775 mmol) in N,N-dimethylformamide (3.0 mL) was added thionyl chloride (0.17 mL, 2.33 mmol), and the mixture was stirred at 50° C. for 40 min. The mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (261 mg, 0.760 mmol, 98%).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:29])[CH3:28]>O>[CH2:27]([O:29][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)[CH3:28]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 25 °C

Procedure:
A mixture of 0.29 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine, 0.15 g of potassium carbonate and 6 ml of ethanol was refluxed with heating for 8 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 2-(3-ethoxypyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 11).
Reaction SMILES: Cl[CH:2](Cl)[C:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.[CH:29](O)(C)C>>[CH:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])([CH3:29])[CH3:2]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Reactant: CC(C)O
Product: CC(C)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)-ceph-3-em-4-carboxylic acid (12.0 g., 25.8 m.mole.) was refluxed in isopropanol (100 ml.) for 45 minutes. After filtration through a pad of Kieselguhr, the isopropanol solution was poured into water (1000 ml.) and the pH adjusted to 8.5. The solution was extracted with ethyl acetate (2 × 100 ml.) and the extracts discarded. The solution was then acidified to pH 1.5 with 2N-hydrochloric acid and extracted with ethyl acetate (3 × 100 ml.). The ethyl acetate extracts were dried over magnesium sulphate and evaporated. The residue (8.5 g.) was dissolved in a mimimum of hot ethanol, from which the title compound separated on cooling (1.5 g., 15%). This material recrystallised from ethanol as colourless prisms, m.p. 169°-171° (d), [α]D28 + 87° (c 1.0, tetrahydrofuran), λλmax (ethanol) 237 nm (ε 14,500), 260 nm (ε 7,900), νmax (Nujol) 1775 (β-lactam), 1728 (COOH), 1668 and 1535 cm.-1 (CONH), N.M.R. (D2O, with sodium bicarbonate) 5.64 and 5.95 (quartet: J = 16 Hz, -CH2OCH(CH3)2), 6.31, 8.87τ )-CH2 -OCH (CH3)2 respectively). (Found: C, 51.6; H, 5.1; N, 6.7; S, 16.3. C17H20N2O5S2 requires C, 51.5; H, 5.1; N, 6.1; S, 16.2%). Rf 0.32 (system B), 0.65 (system C).
Reaction SMILES: COC(=O)CN[C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH2:39]([O:41][C:42]([C:44]1[S:45][C:46]([NH2:49])=[N:47][N:48]=1)=[O:43])[CH3:40]>CCCCCCC.C(OCC)(=O)C>[CH2:39]([O:41][C:42]([C:44]1[S:45][C:46]([NH:49][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])=[N:47][N:48]=1)=[O:43])[CH3:40]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: CCOC(=O)c1nnc(N)s1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)c1nnc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)s1

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 5-amino-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (commercially available, CAS RN 64837-53-2) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Yellow solid (67%). MS (ESI): m/z=652.12 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[NH:10][N:9]=1.[CH2:31]=[O:32]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][OH:32])[N:9]=1
Reactant: C[C@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12
Reactant: C=O
Solvent: CO
Product: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2CO

Procedure:
(S)-1-[3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]propan-2-ol (2.4 g, 5.5 mmol) was suspended in 50 mL MeOH and stirred. Formaldehyde (3.3 mL, excess) was added and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 2.0 g of 1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-hydroxymethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol, MS (M+H)=462.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][O:36][CH3:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][CH2:35][O:36][CH3:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: COCCN(c1ccc(I)cc1)c1ncccn1
Product: COCCN(c1ccc(/C=C/CC(NC(=O)c2c(Cl)cccc2Cl)C(=O)OC)cc1)c1ncccn1
Yield: 77 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (89 mg) was reacted with N-(4-iodophenyl)-N-(2-methoxyethyl)pyrimidin-2-amine (116 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((2-methoxyethyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (120 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→cyclohexane/chloroform=1/1→cyclohexane/chloroform=1/2) was used for purification.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17]>O1CCCC1>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([O:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])=[N:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride and oil bath heating. To a mixture of sodium hydride (189 mg, 4.73 mmol) in anhydrous tetrahydrofuran (2 mL) at 0° C. a solution of 2-chloro-5-nitropyridine (500 mg, 3.16 mmol) and 2-(dimethylamino)ethanol (353 mg, 3.96 mmol) in anhydrous tetrahydrofuran (4 mL) was added dropwise. The reaction was warmed to room temperature and stirred for 16 h. The THF was evaporated, and water (100 mL) and EtOAc (200 mL) were added. The aqueous layer was extracted with EtOAc (200 mL), and the organic layers combined, washed with brine, dried over sodium sulfate and concentrated to give a brown oil. Purification column chromatography on silica gel using 5% methanol/methylene chloride yielded 2-(5-nitropyridin-2-yloxy)-N,N-dimethylethanamine as a light yellow solid (233=mg, 35%). LC/MS (m/z): 212.2 (MH+), Rt 1.28 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]([C:9]2[CH:10]=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2cc(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
66 mg (0.33 mol) of 5-fluoro-1H-indol-7-carboxylic acid, 80 mg (0.30 mmol) of (4-tert-butyl-benzyl)-2-phenyl-ethyl-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 7:3) to yield 85 mg (66%) product as a light yellow viscous oil. MS (ISP) 429.4 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH:8]=[O:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CCOCC>[CH2:10]1[CH2:11][O:12][CH:8]([CH:2]([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:9]1
Reactant: OCCO
Reactant: COC(=O)CC(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)CC(C)C1OCCO1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-methyl-4-oxo-butanoate (86.3 g), ethylene glycol (61.75 l g, 0.996 m), p-toluenesulfonic acid (1 g) and benzene (700 ml) is refluxed under nitrogen for 16 hr. The resulting mixture is allowed to cool to room temperature and treated with ether (300 ml). The organic phase is washed with 5% sodium bicarbonate solution (100 ml), dried (Na2SO4) and evaporated in vacuo to give methyl 4,4-ethylenedioxy-3-methylbutanoate as a crude product (63.2 g). This material is used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[N:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:27]=[N:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (390 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg), potassium carbonate (414 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (649 mg, yield 80%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[O:26]1[CH2:30][CH2:29]OC1=O>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:29][CH2:30][OH:26]
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCCOc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 81 %

Procedure:
3-(2-Quinolinyl-methoxy)phenol (12.5 g), potassium carbonate (10.4 g) and 1,3-dioxolan-2-one (44 g) were stirred on an oil bath at 100° C. for 2 hours. The mixture was cooled, poured into water and extracted with DCM. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and evaporated. The residue was stirred up in DIPE. The precipitate was filtered off and dried, yielding 11.9 g (80.6%) of 2-[3-(2-quinolinyl-methoxy)phenoxy]ethanol (intermediate 5).
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([CH3:5])=O.[C:10]([CH2:12][C:13]([NH2:15])=O)#[N:11]>>[C:10]([CH:12]1[C:3]([CH3:5])=[CH:2][CH2:1][NH:15][CH2:13]1)#[N:11]
Reactant: N#CCC(N)=O
Reactant: CCOC(=O)CC(C)=O
Product: CC1=CCNCC1C#N
Reaction time: 2.5 h

Procedure:
reacting ethyl acetoacetate with cyanoacetamide and a base, in the presence of an organic solvent, at a temperature of from 60° C. to 80° C., for 1 to 4 hours, to produce 3-cyano-2,6-dihydro-4-methylpyridine;
Reaction SMILES: [CH:1]1([S:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Cl:27]>>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:8]([S:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:9]#[N:10]
Reactant: ClCCCCCBr
Reactant: COc1ccc(C(C#N)SC2CCCCC2)cc1OC
Product: COc1ccc(C(C#N)(CCCCCCl)SC2CCCCC2)cc1OC

Procedure:
The procedure of Example 2 is repeated using 3.0 g of α-(cyclohexylthio)-3,4-dimethoxy benzeneacetonitrile and 2.0 mL of bromo-5-chloropentane. This affords 3.1 g of the desired product as a colorless oil.