Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CC(O)C>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]([CH3:13])[CH2:9][C:10](=[O:11])[NH:17][N:18]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A 1 l three-necked round-bottomed flask equipped with a condenser connected to a gas inlet, a glass rod air driven stirrer and a thermometer was charged with 63.8 g, (306 mmol) of (±)-3-(4'-hydroxybenzoyl)-3-methylpropanoic acid from Example H and 2-propanol (400 ml) at 40° C. The solution was placed under an atmosphere of nitrogen and heated to 65° C. Then hydrazine monohydrate (45 ml, 2.2 mol) was added dropwise over 10 min. The reaction mixture was heated to 80°-81° C. (reflux), stirred for 1 hour then slowly cooled to 3° C. over 1 hour with gentle stirring. The formed precipitate was collected by suction filtration, triturated in a 1 L beaker with deionized water (300 ml) at 23° C. for 2 hrs and collected by suction filtration. The solids were dried to constant weight in an air oven (90° C.) to provide 51.9 g (83.5%) of pure (±)-4,5-dihydro-6-(4'-hydroxyphenyl)-5-methyl-3(2H)-pyridazinone, m.p 268°-273° C.
Reaction SMILES: [CH3:1][Mg]Br.[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15].[Cl-].[NH4+]>O1CCCC1>[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]([OH:15])[CH3:1]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc2ccccc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methylmagnesium bromide (17.6 mL of 1.4 M in toluene, 24.7 mmol) was added at <10° C. to a solution of quinoline-2-carboxaldehyde (3.0 g, 19 mmol) in anhydrous tetrahydrofuran (50 mL). The mixture was stirred at RT for 1 h and poured into saturated aqueous ammonium chloride (100 mL), and the resulting mixture was extracted with ethyl acetate (3×150 mL). The extracts were dried, concentrated, and the residue chromatographed on silica eluted with 30% and 40% ethyl acetate-hexanes giving a yellow solid. Yield 2.46 g, 75%. 1H NMR (CDCl3, 400 mHz) δ 8.15 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.7 Hz), 7.81 (dd, 1H, J=1, 8 Hz), 7.71 (ddd, 1H, J=1, 7, 8.5 Hz), 7.51 (ddd, 1H, J=1, 7, 8.3 Hz), 7.33 (d, 1H, J=8.3 Hz), 5.07-4.99 (m, 2H), 1.56 (d, 3H, J=6.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1Br)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Yield: 93 %

Procedure:
To a closed glass vessel equipped with a thermometer and a stirrer, there are charged 105.3 g (0.3 moles) of 3,3'-dinitro-4-bromo benzophenone, 5 g of 5% palladium/active carbon catalyst (available from Nihon-Engelhardt Co.) and 300 ml of dioxane. With the mixture being stirred at 70°-80° C., hydrogen is introduced into the vessel so that 40.5 l (1.81 moles) of hydrogen is absorbed in the mixture over about 8 hours. Then, after 33 g (0.33 moles) of 40% aqueous solution of caustic soda is added, hydrogen is further introduced at 70°-80° C. with the mixture being stirred so that an additional 7.2 l (0.32 moles) is absorbed during three hours. The reaction liquid is filtered at 70°-80° C. so as to remove the catalyst and then allowed to cool giving yellow needle-like crystals of 3,3'-diamino benzophenone. The crystals is filtered, washed with 30 ml of 50% aqueous solution of dioxane, and dried. Yield 93% (59.2 g). M.P. 149°-150° C.
Reaction SMILES: [CH2:1]([C:4]12[CH2:19][C:18](=O)[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].C(S)(S)C.[H][H]>[Ni]>[CH2:1]([C:4]12[CH2:19][CH2:18][CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCC12CC(=O)C(c3ccccc31)c1ccccc12
Reactant: [H][H]
Agent: [Ni]
Agent: CC(S)S
Product: C=CCC12CCC(c3ccccc31)c1ccccc12

Procedure:
9-β-Propenyl-9,10-dihydro-9,10-ethanoanthracene (xi) is prepared from 9-β-propenyl-9,10-dihydro-9,10-ethanoanthracen-11-one (x) by a Wolff-Kishner reduction or treatment with ethanedithiol and then with hydrogen in the presence of Raney nickel.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[CH:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]Br)=[CH:14][CH:13]=1>>[CH2:19]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)[CH2:18][C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: BrCCc1ccccc1
Product: O=Cc1cn(CCc2ccccc2)c2ccccc12
Yield: 105.5 %

Procedure:
The same procedures used in Example 7 were repeated except for using 2.00 g of indole-3-carbaldehyde instead of the indole-4-carbaldehyde used in Example 7 and 2.35 g of 2-phenethyl bromide to give 3.34 g of 1-phenethylindole-3-carbaldehyde as a brown oily substance. The yield thereof was found to be 97%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]O.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][Br:12]
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(CCBr)c1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of 3-(fluoro)phenethyl alcohol (3.8 g, 27.0 mmol), in anhydrous dichloromethane (100 ml), cooled to 0° C., was added carbon tetrabromide (11.25 g, 34.0 mmol) and triphenylphosphine (10.62 g, 41.0 mmol). After stirring for 0.5 h the solvent was removed in vacuo and diethyl ether (100 ml) was added to the residue. The resultant precipitate was removed by filtration, the filtrate evaporated under reduced pressure and the crude product chromatographed on silica-gel eluting with ethyl acetate/hexane (1:1) to give 3-(fluoro)phenethyl bromide (5.51 g, 100%), δ (250 MHz, CDCl3) 3.16 (2H, t, J=7.4 Hz, CH2), 3.57 (2H, t, J=7.4 Hz, CH2), 6.91-7.01 (3H, m, Ar--H), 7.24-7.33 (1H, m, Ar--H).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[NH:28]1[CH2:31][CH:30]([CH2:32][OH:33])[CH2:29]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:28]3[CH2:31][CH:30]([CH2:32][OH:33])[CH2:29]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: OCC1CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 63 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1) and 3-azetidinemethanol hydrochloride to afford a yellow foam. HPLC (Condition 7) tR=5.51 min, UPLC-MS (Condition 3) tR=0.89 min, m/z=450.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.55-2.68 (m, 1H) 3.43-3.49 (m, 2H) 3.49-3.56 (m, 2H) 3.73-3.82 (m, 2H) 4.66-4.73 (m, 1H) 6.42 (br.s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.79-7.91 (m, 3H) 8.04 (d, J=2.35 Hz, 1H) 8.75 (br.s, 1H) 10.21 (s, 1H) 13.02 (s, 1H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([NH:19][C:20]1[CH:30]=[C:29]2[C:23]([C:24]([Cl:35])=[C:25]([O:31][CH2:32][CH2:33][CH3:34])[O:26][C:27]2=[O:28])=[CH:22][CH:21]=1)=[O:18])CC1C=CC=CC=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:36](N[C@H](C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCCC)OC2=O)=CC=1)=O)C)=O)C)(=O)[C:37]1C=CC=C[CH:38]=1.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCC)OC2=O)=CC=1)=O)C(C)C)(OC(C)(C)C)=O.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCC)OC2=O)=CC=1)=O)C)(OC(C)(C)C)=O.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCCC3C=CC=CC=3)OC2=O)=CC=1)=O)C)(OC(C)(C)C)=O>>[C:1]([NH:8][C@H:9]([C:17]([NH:19][C:20]1[CH:30]=[C:29]2[C:23]([C:24]([Cl:35])=[C:25]([O:31][CH2:32][CH2:33][CH3:34])[O:26][C:27]2=[O:28])=[CH:22][CH:21]=1)=[O:18])[CH:37]([CH3:38])[CH3:36])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCCOc1oc(=O)c2cc(NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)c3ccccc3)ccc2c1Cl
Reactant: CCCOc1oc(=O)c2cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)ccc2c1Cl
Agent: CCOc1oc(=O)c2cc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc2c1Cl
Agent: CCOc1oc(=O)c2cc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)ccc2c1Cl
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2c(Cl)c(OCCc3ccccc3)oc(=O)c2c1
Product: CCCOc1oc(=O)c2cc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc2c1Cl

Procedure:
7-(Boc-phenylalanyl)amino-4-chloro-3-propyloxyisocoumarin, 7-(benzoylalanylalanyl)amino-4-chloro-3-propyloxyisocoumarin, 7-(Boc-valyl)amino-4-chloro-3-ethoxyisocoumarin, 7-(Boc-alanyl)amino-4-chloro-3-ethoxyisocoumarin and 7-(Boc-alanyl)amino-4-chloro-3-(2-phenylethoxy)isocoumarin can be prepared by the same procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:41])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[O:15])[S:10][C:11]=1[CH2:12][CH3:13].NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:17]([NH:16][C:14]([C:9]1[S:10][C:11]([CH2:12][CH3:13])=[C:7]([C:6]2[N:5]([CH3:41])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:15])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38]
Reactant: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CCc1sc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (316 mg, 0.53 mmol) in tetrahydrofuran (1.314 ml) and methanol (1.3 ml) at 25° C. was added hydrazine (0.16 ml, 5.26 mmol) dropwise. After 12 h, the solution was concentrated, purified via column chromatography (silica, 5% MeOH in DCM (1% NH4OH)) and converted to the HCl salt by adding excess 2M HCl in Et2O (2 ml) to the residue in MeOH (5 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxamide (163 mg, 0.30 mmol, 57% yield) as a white solid: LCMS (ES) m/z=471, 473 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (br. s., 1H) 8.04 (bs, 3H) 7.85 (s, 1H) 7.65-7.72 (m, 2H) 7.52-7.59 (m, 2H) 7.39-7.46 (m, 1H) 4.41-4.47 (m, 1H) 3.71 (s, 3H) 2.98-3.07 (m, 4H) 2.67 (q, J=7.58 Hz, 2H) 1.16 (t, J=7.58 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH:18]=[C:17]([C:20]#[C:21][Si](C)(C)C)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16]=[C:17]([C:20]#[CH:21])[CH2:18][CH2:19]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC=C(C#C[Si](C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (1.0 g, 7.2 mmol) was added to a solution of 1-tert-butoxycarbonyl-4-trimethylsilylethynyl- 1,2,3,6-tetrahydropyridine (44.9 g, 16 lmmol) in methanol (250 ml) under a nitrogen atmosphere and the mixture was stirred at room temperature for 3 hours. The solution was evaporated in vacuo without heating. The residue was dissolved in ether (250 ml), washed with sodium carbonate (sat., 100 ml), water (50 ml) and brine (50 ml) before drying (MgSO4) and evaporation in vacuo to give the title compound as a white waxy solid (30.0 g, 90%); δH (CDCl3) 1.46 (9H, s, OC(CH3)3), 2.24-2.26 (2H, m, tetrahydropyridinyl CH2), 2.89 (1H, s, ethynyl CH), 3.49 (2H, t, J 5.7 Hz, tetrahydropyridinyl CH2), 3.95-3.97 (2H, m, tetrahydropyridinyl CH2) and 6.10 (1H, s, tetrahydropyridinyl CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:11]([S:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)(CCCCCN2C(=O)c3ccccc3C2=O)Sc2ccc(C)cc2)cc1OC
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C#N)(CCCCCN)Sc2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 112.6 %

Procedure:
A mixture of 4.72 g of α-(3,4-dimethoxyphenyl)-1,3-dihydro-α-[(4-methylphenyl)thio]-1,3-dioxo-2H-isoindole-2-heptanenitrile, 100 mL of ethyl alcohol, and 7.0 mL of hydrazine hydrate is heated under reflux. In about a 30 minutes, a heavy precipitate forms. After 1.33 hours, the reaction is cooled to room temperature and concentrated in vacuo. The residue is warmed on a steam bath with 2N hydrochloric acid for 10 minutes. Diatomaceous silica and chloroform are added, the mixture is shaken thoroughly and then filtered through more diatomaceous silica. The organic phase is washed first with aqueous ammonia, then brine, and, after drying (sodium sulfate), it is concentrated in vacuo to give 3.97 g of the desired product as a yellow oil. MS(CI): m/z 385(M+H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:12]1[N:17]=[C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]([CH3:37])([O:29][Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:28])=[N:26][C:21]3=[N:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=1.[F:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([B:47]2[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:55])([CH3:54])[O:48]2)[CH:40]=1>>[F:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[C:41]([B:47]2[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:55])([CH3:54])[O:48]2)[CH:40]=1.[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([CH3:28])([O:29][Si:30]([CH2:31][CH3:32])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:37])=[N:26][C:21]4=[N:20][CH:19]=3)[N:17]=2)[CH:9]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(Br)n3)cnc2n1
Agent: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(-c4cc(F)ccc4C#N)n3)cnc2n1

Procedure:
4-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl }benzonitrile was synthesised from 2-bromo-4-fluorobenzonitrile following the procedure in Example 22. 3-(6-Bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine was coupled to 4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl }benzonitrile following the procedure in Example 2 to give 4-fluoro-2-{6-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl }benzonitrile as an orange oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A solution of 6-chloro-1-hexanol (100 g) in dry pyridine (500 ml) was treated with p-toluenesulfonyl chloride (227 g) at 5°-10° C. After stirring 2 h at 10° C., the mixture was poured into ice water (2 L), followed by extraction with ethyl ether. The organic extract was washed with ice water and brine, dried, filtered and evaporated to give a syrup, which was further dried at high vacuum. The crude product was overlayered with pentane and cooled in dry ice/acetone to give a solid (210 g, 99%), mp 36°-37° C.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:41])=[C:12]([CH2:14][O:15][C:16]2[CH:40]=[CH:39][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:18][CH:17]=2)[N:13]=1.O.Cl>O1CCCC1>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:41])=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:39][CH:40]=2)[N:13]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
Lithium hydroxide monohydrate (163 mg) was added to a solution of ethyl E-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate (670 mg) in tetrahydrofuran (6 ml)-water (4 ml)-etbanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.9 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoic acid (625 mg, yield 98%) as colorless crystals. m.p. 112-113° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(c) from 5-bromoindole-2-carboxylic acid ethyl ester and 4-isopropoxyphenylboronic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
Under the presence of nitrogen, 5-nitroindolin (50 mg, 0.30 mmol) was dissolved in dimethylformamide (2 ml) at room temperature and benzyl bromide (0.04 ml. 0.34 mmol) and potassium carbonate (0.126 ml, 3.0 equivalent) were added and stirred at room temperature for 48 hours. After completing the reaction, water and ethyl acetate (respectively 5 ml) were added to separate layers, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. Finally, the residue was purified through flash column chromatography (an eluent:ethyl acetate/n-hexane=1/4, v/v). As a result, the present compound (45 mg, productive yield 58%) was obtained.
Reaction SMILES: Cl[CH:2]([C:14](=[O:16])[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>CO>[C:17]([O:20][CH:2]([C:14](=[O:16])[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10])(=[O:19])[CH3:18]
Reactant: CN=C(NC#N)NCCSCC(Cl)C(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CN=C(NC#N)NCCSCC(OC(C)=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A 50 ml two-necked flask was charged with 0.64 g of the same N-{2-(2-chloro-3-oxobutylthio)ethyl}-N'-cyano-N"-methylguanidine as used in Example 1, 10 ml of methanol, and 0.31 g of anhydrous sodium acetate, and the mixture was stirred at room temperature for 8 hours. Methanol was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and then dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure to give 0.57 g (yield 82%) of the desired product as a brown liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]/[C:7](O)=[O:8])[CH3:2].[C:11]([OH:15])([CH3:14])([CH3:13])[CH3:12].C1CCC(N=C=NC2CCCCC2)CC1.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:15][C:7](=[O:8])/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of fumaric acid mono-ethyl ester (721 mg, 5 mmol) and tert-butanol (0.938 mL, 10 mmol) in 10 mL of DCM was added DMAP (122 mg, 1 mmol) followed by DCC (2.06 g, 10 mmol). The resulting mixture was stirred at rt for 16 h, taken to dryness under reduced pressure, stirred overnight with 50 mL acetone and filtered to remove DCU. The resulting filtrate was concentrated under reduced pressure, and the residue taken up in EtOAc. The EtOAc was washed twice with 30 mL 0.1 M KHSO4, and once with 30 mL saturated NaHCO3 and once with 30 mL of brine. The resulting EtOAc solution was treated with charcoal and dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel flash chromatography using a gradient of 0–15% EtOAc in hexanes as eluent to give essentially pure (one peak on HPLC) 4-1 (350 mg, 35% yield).
Reaction SMILES: [H-].[Na+].F[C:4]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].O>O1CCOCC1>[CH:16]1([N:15]2[C:4]3[C:5](=[CH:19][C:20]([F:25])=[C:21]([F:24])[C:22]=3[CH3:23])[C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(C)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)cc2c1=O
Yield: 78.1 %

Procedure:
To the cooled mixture of 55% sodium hydride (50 mg) in anhydrous dioxane (2 ml) was added ethyl 2-(2,4,5-trifluoro-3-methylbenzoyl)-3-cyclopropylaminoacrylate (300 mg) slowly with stirring. After stirring for 30 minutes at room temperature, to the reacting mixture was added water (5 ml), the resulting precipitate was collected by filtration, washed with water and recrystallized from methanol to give the title compound (220 mg) as white needles.