Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:10]([C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=3[C:14](OCC)=[O:15])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:24][NH2:25]>C(O)C>[C:1]1([C:7]2([C:10]3[C:12]4[C:13](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:14](=[O:15])[NH:25][N:24]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccccc1C(=O)C1(c2ccccc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(C2(c3ccccc3)CC2)c2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A solution of (2-(ethoxycarbonyl)phenyl)zinc(II) bromide (2.2 mL, 1.1 mmol) was added to a mixture of 1-phenylcyclopropanecarbonyl chloride (0.200 g, 1.1 mmol) and Pd(PPh3)4 (0.0644 g, 0.056 mmol) in THF (1.1 mL), stirred for 2 hours, diluted with EtOAc, washed with 1N HCl and brine, dried (Na2SO4), filtered, and chromatographed (20% Et2O/hexanes) to give 216.2 mg of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate. A mixture of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate (0.216 g, 0.735 mmol) and hydrazine hydrate (0.13 mL, 2.298 mmol) in ethanol (3 mL) was stirred at 75° C. overnight, and concentrated to give 179.7 mg of impure 4-(1-phenylcyclopropyl)phthalazin-1(2H)-one, which was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give impure 2-amino-4-(1-phenylcyclopropyl)phthalazin-1(2H)-one.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][C:16]1([CH3:32])[O:31][C@H:19]2[O:20][CH:21]([CH2:29][OH:30])[C@@H:22]3[O:26][C:25]([CH3:28])([CH3:27])[O:24][C@@H:23]3[C@@H:18]2[O:17]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:30][CH2:29][CH:21]2[O:20][C@@H:19]3[O:31][C:16]([CH3:32])([CH3:15])[O:17][C@H:18]3[C@H:23]3[O:24][C:25]([CH3:28])([CH3:27])[O:26][C@@H:22]23)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC1(C)O[C@H]2OC(CO)[C@@H]3OC(C)(C)O[C@@H]3[C@@H]2O1
Product: CC1(C)O[C@H]2OC(COc3cccc([N+](=O)[O-])c3C#N)[C@@H]3OC(C)(C)O[C@@H]3[C@@H]2O1
Yield: 59 %

Procedure:
Prepared as in Example 111c from 2,6 dinitrobenzonitrile and ((3aR,5aS,8as,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methanol in 59% yield as white sticky material. MS 408 (MH+), 424 (MH2O+).
Reaction SMILES: [CH2:1]([N:8]([CH3:21])[C:9](=[O:20])[C@@H:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][C@@H:10]([CH3:11])[C:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:21])=[O:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 85 %

Procedure:
To an ice-cold solution of (S)-tert-butyl 1-(benzyl(methyl)amino)-1-oxopropan-2-ylcarbamate (26.3 g, 0.090 mol) in CH2Cl2 (100 mL) was added TFA(100 mL) drop wise. The reaction mixture was warmed to ambient temperature. After 18.5 h, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between CH2Cl2 (250 mL) and saturated NaHCO3 (250 mL). The aqueous layer was separated and basified to pH=9-10 with 1 N NaOH and extracted again with CH2Cl2 (100 mL). The combined organic layers were washed with saturated NaHCO3 (100 mL), H2O (100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give (S)-2-amino-N-benzyl-N-methylpropanamide (14.7 g, 85%) as an amber oil. 1H NMR consistent.
Reaction SMILES: [CH2:1]([S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])CCCCC.C(S(C1C=C(S(CC(C)C)(=O)=O)C=CC=1[N+]([O-])=O)(=O)=O)C(C)C>>[CH3:1][S:7]([C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)(=[O:9])=[O:8]
Reactant: CCCCCCS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)CS(=O)(=O)c1ccc([N+](=O)[O-])c(S(=O)(=O)CC(C)C)c1
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
The following are obtained analogously: 4-hexylsulfonyl-nitrobenzene, melting point 44°-46° C.; 2-methylsulfonyl-nibrobenzene, melting point 104°-106° C., boiling point 215°-218° C. (0.25 mm Hg); 2,4-bis-isobutylsulfonylnitrobenzene, melting point 165°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[NH2:5].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[NH:5][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H](N)Cc1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cccc(O)c1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-hydroxyphenylalanine methyl ester (1 g) in CH2Cl2 (20 mL) at 0° C. was added triethylamine (2 mL) followed by DMAP (527 mg) and benzoyl chloride (1.1 mL). When addition was complete, the mixture was stirred for 17 hr at r.t. and then NH4OAc buffer was added. The aqueous phase was extracted with CH2Cl2 (3×) and the combined organics were washed with buffer, brine, dried (MgSO4) and concentrated. The residue was dissolved in MeOH (15 mL) and THF (1.5 mL) and NaOMe (1M in MeOH; 2.4 mL) was added at 0° C. After 2.5 hr, saturated aq. NH4Cl was added and the aqueous phase extracted with EtOAc (3×). The combined organics were washed with NH4OAc buffer (2×), H2O, brine, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc (1:1)) provided N-benzoyl-3-hydroxyphenylalanine methyl ester as a foam. A portion of this material (1.25 g), K2CO3 (866 mg) and methyl iodide (312 μL) in DMF (12 mL) were stirred at r.t. for 18 hr and then H2O (150 mL) was added. The mixture was extracted with EtOAc (3×) and the combined organics washed with NH4OAc buffer, H2O (2×) and brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc (55:45)) provided N-benzoyl-3-methoxyphenylalanine methyl ester as a gum. A portion of this material (950 mg) was dissolved in refluxing xylene (25 mL) and P2O5 (10.9 g) was added periodically over 5 hr. After refluxing for 5.5 hr, the mixture was cooled to r.t. and the xylene was decanted. The residual solid was dissolved in cold H2O (600 mL) and neutralized with solid NaHCO3. The aqueous mixture was extracted with EtOAc (3×) and the combined organics were washed with NH4OAc buffer (2×), brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc (3:2)) provided the title compound as a gum.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@@H:51]([C:53]([F:56])([F:55])[F:54])[CH2:52][N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@@H:51]([C:53]([F:54])([F:56])[F:55])[CH2:52][N:44]2[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CC[C@@H](C(F)(F)F)CN3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,8R,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (12 mg, 0.022 mmol) and Intermediate 61 (5.0 mg, 0.019 mmol) to give a white solid (6.5 mg, 43% yield). Anal. Calcd. for C43H51F3N4O5S m/z 792.7. found: 793.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.04 (m, 11H), 6.96 (dd, J=17.4, 10.3 Hz, 3H), 5.34-5.13 (m, 2H), 4.89 (d, J=63.4 Hz, 3H), 4.47 (dd, J=13.3, 4.2 Hz, 2H), 3.95 (s, 2H), 3.79 (s, 3H), 3.46 (d, J=42.0 Hz, 2H), 3.05 (s, 2H), 2.98-2.66 (m, 5H), 2.64-2.21 (m, 4H), 2.19-1.87 (m, 4H), 1.87-1.37 (m, 8H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7](=[CH2:11])[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:12]([OH:15])(=[S:14])[CH3:13].C(O)(C)C>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([CH2:11][S:14][C:12](=[O:15])[CH3:13])[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: C=C(C(=O)O)C1CCNCC1
Reactant: CC(O)=S
Solvent: CC(C)O
Product: CC(=O)SCC(C(=O)O)C1CCNCC1

Procedure:
A solution of 2-(piperidin-4-yl)prop-2-enoic acid (0.30 g, 1.64 mmol) in 6 mL of 1:1 thioacetic acid/isopropanol was stirred for 24 hours. The reaction mixture was concentrated in vacuo to afford the crude product, 2-(piperidin-4-yl)-3-(acetylthio)propanoic acid. The product was dissolved in 2 mL of water, cooled to 0° C., degassed with nitrogen, and 2 mL of ammonium hydroxide was added. The reaction mixture was stirred for 1 hour, concentrated in vacuo and the residue was dissolved in 10% HCl and purified by preparative HPLC to afford 73 mg of pure 2-(piperidin-4-yl)-3-mercaptopropanoic acid, as a trifluoroacetic acid salt, NMR (D2O) 1.30-1.43 (m,2), 1.70-1.90 (m,3), 2.32-2.42 (m,1), 2.50-2.60 (m,1) 2.63-2.72 (m,1), 2.79-2.90 (m,2), 3.22-3.34 (m,2) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)#[N:2].[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1F.[H-].[Na+]>CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1[N:5]1[CH:6]=[CH:7][C:3]([C:1]#[N:2])=[CH:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: N#Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccn(-c2ccc([N+](=O)[O-])cc2F)c1
Yield: 41.5 %

Procedure:
3-Cyanopyrrole (3.6 g, 39.1 mmol , CE Loader et al, Can. J. Chem., 1981, 59, 2673) and 3,4-difluoronitrobenzene (6.5 g, 40.9 mmol) were dissolved in DMF (50 ml) and cooled in an ice-bath. The mixture was stirred and sodium hydride (60% in oil, 1.6 g, 40 mmol) added over 20 minutes. After allowing the mixture to come to ambient temperature, it was heated to 650 for 1 hour. Solvent was evaporated, the residue triturated with water, and filtered. The crude solide was purified by flash chromatography on silica, eluting with dichloromethane. Relevant fractions were combined to give the title product (3.75 g), mp 117-119°.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-])=O)[CH2:3][CH2:2]1.[H][H]>[Pd].C(O)C>[CH:1]1([NH:4][C:5]2[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1NC1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NC1CC1

Procedure:
Title compound 380 (3.1 g, 17.4 mmol) and palladium on charcoal 10% (0.3 g, 10% w/w) were mixed in ethanol (100 mL) and the reaction mixture was stirred under 45 PSI of hydrogen for 4 hours. The mixture was filtered to remove the catalyst and the filtrate was evaporated to afford title compound 381 as black oil that was used without further purification. MS (m/z): 148.9 (M+H).
Reaction SMILES: C([CH:3]([O-])[CH:4]=[CH:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C[OH:25]>C1COCC1.CCOC(C)=O.[Pd]>[OH:25][CH:4]([CH3:3])[CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2
Reactant: CO
Reactant: CCC([O-])C=Cc1cc2cc(OC)ccc2[nH]1
Agent: [Pd]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(CC(C)O)cc2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
Compound 429 (631 mg, 2.57 mmol) was dissolved in THF (20 mL) and stirred at 0° C. under Argon. 2 M LAH in THF (3 eq, 15 mL) was added dropwise. The resulting mixture was warmed to rt for 1 h and volatiles were evaporated in vacuo. The residue was carefully quenched with ice-cold 0.5 N HCl (200 mL) and then extracted with EtOAc (200 mL). The organic layer was separated and dried over Na2SO4. The resulting crude oil was purified by chromatography (30% to 70% EtOAc/hexanes) to provide a crude yellow solid, which demonstrated ˜85% purity based on 1H NMR. The impurity was determined to be a partially reduced alkene intermediate. The yellow solid was further reacted by dissolving in EtOAc (10 mL) and MeOH (10 mL) in a glass hydrogenation flask. 10% Pd/C (58 mg, 10% w/w) was added and the sample was hydrogenated for 4 h at 35 psi of H2 to ensure complete reduction. The mixture was filtered over Celite and purified by chromatography (20% to 70% EtOAc/hexanes) to yield a light-yellow solid (216 mg, 41%): mp 85-88° C. (lit.19 62-65° C.). TLC Rf 0.22 (50% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.07 (s, 1H), 7.18-7.17 (d, 1H, J=8.7 Hz), 7.01 (d, 1H, J=2.4 Hz), 6.78-6.77 (dd, 1H, J1=8.7 Hz, J2=2.46 Hz), 6.19-6.18 (d, 1H, J=1.98 Hz), 3.84 (s, 3H), 3.75-3.73 (t, 2H, J=6.06 Hz), 2.87-2.85 (t, 2H, J=7.2 Hz), 1.97-1.94 (quin, 2H, J=6.12 Hz). 13C NMR (150 MHz, CDCl3) δ 154.2, 140.0, 131.2, 129.3, 111.16, 111.04, 102.1, 99.7, 62.3, 56.0, 31.9, 24.9. Elemental analysis for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.10; H, 7.23; N, 6.74.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH2:35][CH3:36]>>[NH2:32][C:23]1[C:22]2[N:21]=[C:20]([CH2:33][CH2:34][CH2:35][CH3:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][S:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
According to the general method of Example 5, 4-nitrobenzenesulfonyl chloride and 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine were combined. N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-nitro-1-benzenesulfonamide was isolated as the hydrochloride salt (white solid), m.p. 96.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.70 (very broad s, 2H), 8.38-8.34 (m, 2H), 8.19 (d, J=8.2 Hz, 1H), 8.09 (t, J=5.6 Hz, 1H), 8.03-7.99 (m, 2H), 7.80 (d, J=7.4 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 4.55 (t, J=7.4 Hz, 2H), 2.94 (t, J=7.7 Hz, 2H), 2.86 (q, J=6.2 Hz, 2H), 1.80 (m, 4H), 1.58 (m, 2H), 1.45 (q, J=7.5 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H); IR (KBr) 3283, 3100, 2957, 2870, 2782, 1670, 1606, 1528, 1347, 1311, 1162, 1092, 854, 746, 737, 686 cm−1; MS (EI) m/e 496.1902 (496.1893 calcd for C24H28N6O4S). Anal calcd for C24H28N6O4S*HCl*0.85H2O: C, 52.57; H, 5.64; N, 15.33. Found: C, 52.57; H, 5.46; N, 15.33.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[C:27]1([CH:33]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:34]([OH:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:42]12[CH2:49][CH2:48][CH:45]([CH2:46][CH2:47]1)[C@@H:44](O)[CH2:43]2>C1COCC1>[C:27]1([CH:33]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:34]([O:36][C@@H:44]2[CH:45]3[CH2:48][CH2:49][N:42]([CH2:47][CH2:46]3)[CH2:43]2)=[O:35])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccccc1)N1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCC1
Reaction time: 8 h
Yield: 27.2 %

Procedure:
PS-DCC (loading: 1.25 mmol/g; 0.99 g, 1.24 mmol) was suspended in dry THF (12 ml). HOBT (0.19 g, 1.24 mmol), 2-phenyl-2-(pyrrolidin-1-yl)acetic acid hydrochloride (0.15 g, 0.62 mmol) and (R)-quinuclidin-3-ol (0.24 g, 1.86 mmol) were sequentially added. The mixture was shaken overnight and then PS-DCC was filtered washing with EtOAc and THF. The solution was evaporated and the residue was dissolved in EtOAc (30 ml) and washed with water (15 ml) and with a sat. NaHCO3 (20 ml). The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=92/8 to 85/15) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(pyrrolidin-1-yl)acetate (53 mg, 27.2% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[N:10][S:11][CH:12]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[S:11]1[CH:12]=[C:8]([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH:9]=[N:10]1
Reactant: Brc1cccc(-c2cnsc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4cnsc4)n3)cnc2n1
Yield: 33.1 %

Procedure:
2-Bromo-6-(isothiazol-4-yl)pyridine (0.27 g, 1.13 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-80%) and trituration with isohexane gave 3-[6-(isothiazol-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (130 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.41 (1H, d, J 7), 7.62 (1H, d, J 8), 7.78 (1H, d, J 8), 7.92 (1H, dd, J 8 and 8), 8.56 (1H, s), 9.12 (1H, s), 9.13 (1H, s), 10.45 (1H, d, J 7); m/z (ES+) 347 (M++H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[C:32]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2)(=[O:34])[CH3:33]
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1c(C)c2c(c(OC(C)=O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (10.0 g) was dissolved in pyridine (50.0 ml) followed by the addition of acetic anhydride (10.0 ml). The mixture was stirred at room temperature for 90 minutes, then poured into water and extracted with ethyl acetate. The organic solution was dried and evaporated to give morpholinoethyl E-6-(1,3-dihydro-4-acetoxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1(Br)[CH2:11][CH2:10][O:9][CH:8]1[O:12][CH2:13][CH3:14])=[O:6])[CH3:2].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:16])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:12][CH2:13][CH3:14])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)C1(Br)CCOC1OCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)C1CCOC1OCC
Reaction time: 8 h
Yield: 91.4 %

Procedure:
Ethyl-2-(3-bromo-2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (100 g) dissolved in dichloromethane (500 ml). Sodium sulphite solution (15%, 1000 ml) was added to it. Reaction mass was stirred for 8 hrs. Organic and aqueous layer separated dichloromethane layer was washed with water (2×200 ml). Dichloromethane layer was then concentrated to residue to get Ethyl-2-(2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (Yield 67 g)
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:21]=[C:20]2[N:8]([CH2:9][C:10]3[C:11]2=[N:12][C:13]2[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:22])[C:6]=1[CH3:23])[CH2:3][CH3:4].[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39]([NH:41][CH2:42][P:43](=O)([OH:45])[OH:44])=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1>O>[CH:33]1[C:34]2[CH:35]([CH2:37][O:38][C:39]([NH:41][CH2:42][P:43]([OH:45])([O:1][CH:2]([C:5]3[CH:21]=[C:20]4[N:8]([CH2:9][C:10]5[C:11]4=[N:12][C:13]4[C:18]([CH:19]=5)=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:7](=[O:22])[C:6]=3[CH3:23])[CH2:3][CH3:4])=[O:44])=[O:40])[C:36]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(NCP(=O)(O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Solvent: O
Product: CCC(OP(=O)(O)CNC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 21 except using (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one and [[[(9-fluorenylmethoxy)carbonyl]amino]methyl]phosphonic acid. Anal. Calcd for C35H32N3O6P.9/8 H2O: C, 65.49; H, 5.38; N, 6.55. Found: C, 65.83; H, 5.28; N, 6.14.
Reaction SMILES: BrC1N(CC=C(C)C)[C:4]([C:11](OC)=O)=[C:5]([C:7](OC)=O)N=1.[Br:20][C:21]1[NH:22][C:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=1.BrCC#CC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:20][C:21]1[N:25]([CH2:11][C:4]#[C:5][CH3:7])[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]=1
Reactant: COC(=O)c1nc(Br)n(CC=C(C)C)c1C(=O)OC
Reactant: CCOC(=O)c1nc(Br)[nH]c1C(=O)OCC
Agent: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc(C(=O)OCC)c1C(=O)OCC

Procedure:
Prepared analogously to 1b from 3.50 g (12.02 mmol) diethyl 2-bromo-imidazole-4,5-dicarboxylate with 1.09 ml (12.1 mmol) 1-bromo-2-butyne and 2.07 g (15.00 mmol) potassium carbonate in 15 ml of dimethylformamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1([C@@H:29]2[CH2:33][O:32][C:31](=[O:34])[NH:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:30]1[C@H:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:33][O:32][C:31]1=[O:34])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Br
Reactant: O=C1N[C@H](C2CCCCC2)CO1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)OC[C@H]1C1CCCCC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A heavy wall flask was charged with trans-cyclohexane diamine (18.9 mg, 0.17 mmol, 0.5 equiv), 3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (100 mg, 0.332 mmol, 1.0 equiv), K2CO3 (92 mg, 0.664 mmol, 2.0 equiv), CuI (31.6 mg, 0.166 mmol, 0.5 equiv), (R)-4-cyclohexyl-oxazolidin-2-one (56.2 mg, 0.332 mmol, 1.0 equiv) and 1,4-dioxane (0.5 mL). The mixture was flushed with N2 and stirred at 110° C. for 18 hours, after which the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel, EtOAc/heptane 30% to give product 54 mg (yield 42%).