Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:19]1[S:23][C:22]([C:24]2[CH2:28][CH:27]([CH2:29][OH:30])[O:26][N:25]=2)=[CH:21][CH:20]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[C:19]1[S:23][C:22]([C:24]2[CH2:28][CH:27]([CH2:29][OH:30])[O:26][N:25]=2)=[CH:21][CH:20]=1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](CO)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)s2)c(F)c1
Temperature: 90 °C
Yield: 26.5 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (195 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (60 mg).
Reaction SMILES: [CH2:1]([C:3]1[S:21][C:6]2[NH:7][C:8](=[O:20])[N:9]([C:12]3[N:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-:46].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:21][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:46])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:20])[N:9]([C:12]3[N:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(-c3ccc(OC)nn3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(-c3ccc(OC)nn3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
A mixture of 6-ethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.86 g), potassium carbonate (0.27 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and acetone (5 mL). 1N Aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.17 g, 30%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)#[N:2].[CH3:14][CH2:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[C:1]([C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH3:14])=[O:7])#[N:2]
Reactant: CCCC(N)CCC
Reactant: COc1ccc(C(=O)O)c(C#N)c1
Product: CCCC(CCC)NC(=O)c1ccc(OC)cc1C#N
Yield: 73 %

Procedure:
Prepared in a similar manner to example 4 using 2-cyano-4-methoxybenzoic acid and 4-Heptylamine. Yield: 73%. 1H NMR (CD3OD): δ0.94 (t, 6H, J=7.3 Hz), 1.38 (m, 4H), 1.53 (m, 4H), 4.02 (s, 3H),4.12 (m, 1H), 7.27 (d, 1H, J=9.40 Hz), 8.11 (d, 2H, J=2.21 Hz). MS (M+H, 275).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+].[N+:14]([C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)([O-:16])=[O:15]>CN(C)C=O.C(OCC)C>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:18]1[CH:19]=[CH:20][N:21]=[C:17]1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-methyl-2-pentene (25 g, 0.154 mol) was dissolved in dry dimethylformamide (DMF) (200 mL). To the solution was added K2CO3 (21.3 g, 0.154 mol) and 2-nitroimidazole (17.4 g, 0.154 mol). The mixture was stirred under N2 atmosphere at 75° C. for 48 hours. DMF was evaporated on a rotary evaporator. The yellow gummy residue was stirred with water (150 mL) to give yellow solid, which was dissolved in diethyl ether (150 mL), dried over Na2SO4 and evaporated on a rotary evaporator to yield the title product. Yield 27.8 g (92%). mp: 49-51° C. MS: (M+H)+=196, M+=195. 1H NMR (CDCl3) δ 1.45 and 1.68 (s, 6H, gem-di-CH3), 2.52 (q, 2H, CH2CH=), 4.43 [t, 2H, CH2—(2-nitroimidazoly)], 5.08 (t, 1H, CH2CH=), 7.05 and 7.14 (s, 2H, 2-nitroimidazolyl-H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[C:36]([OH:38])=[O:37].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:41].Cl([O-])=O.[Na+].S(=O)(=O)(O)N>ClCCl.O>[C:2]([CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[C:36]([OH:38])=[O:37])([OH:41])=[O:1]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCCO)C(C(=O)O)C2c1ccc2c(c1)OCO2
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: ClCCl
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCC(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
(1RS, 2SR, 3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (0.07 g, 0.13 mmol) was dissolved in dry dichloromethane (0.5 ml) and Dess-Martin periodinane (0.07 g, 0.17 mmol) added in dry dichloromethane (1 ml). After 2h. the product was partitioned between ether and saturated aqueous sodium carbonate solution containing sodium thiosulfate. The ether extract was washed with water then brine, dried (MgSO4 anhydrous), filtered and evaporated to give an oil which was used without purification. The crude product was dissolved in t-butanol (5 ml) and to this was added a solution of sodium chlorite (1 8 mg, 0.2 mmol) and sulfamic acid (21 mg, 0.22 mmol) in water (1.5 ml). After 1 h. stirring at ambient temperature the product was extracted into ethyl acetate. The organic layer was washed with water then brine then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography on silica-gel (eluant: ethyl acetate/hexane/3% acetic acid) to give 12 mg of free acid which was converted to its bis-dicyclohexylamine salt.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=O)[C:3]=12.O.[NH2:24][NH2:25]>C(O)C>[CH2:11]([N:10]1[N:9]=[CH:8][C:7]2[C:2]3[NH:25][N:24]=[C:17]4[C:16]5[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=5[CH2:14][CH2:13][C:4]([C:3]=34)=[N:5][C:6]1=2)[CH3:12]
Reactant: CCn1ncc2c(Cl)c3c(nc21)CCc1ccccc1C3=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCn1ncc2c3[nH]nc4c3c(nc21)CCc1ccccc1-4
Yield: 97 %

Procedure:
A mixture of 11.0 g. of 4-chloro-1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin5(1H)one (0.035 mol.), 4.5 g. of hydrazine hydrate 98% (0.09 mol.) and 125 ml. of abs. ethanol is refluxed for 3 hours with stirring. Then the reaction solution is filtered while hot and allowed to crystallize in a refrigerator. The crystallized 2,5,7,8-tetrahydro-5-ethyl-1,2,4,5,6-pentaazabenzo[6,7]cyclohepta[1,2,3-cd]-as-indacene which is filtered off, washed with alcohol and ether, melts at 229°-231°. Evaporation of the mother liquor to dryness and treatment with water yields a further crop of 1.9 g. of the product. Total yield 97%. Recrystallization from ethanol elevates the melting point to 230°-232°.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:3][CH:2]=1.Cl.O1CCOCC1.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>ClCCl>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:38](=[O:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Reaction time: 0.75 h
Yield: 36.1 %

Procedure:
To (R)-tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (26.4 mg, 0.064 mmol) is added 4M HCl in 1,4-dioxane (0.321 ml, 1.283 mmol) at room temperature. The reaction mixture is stirred for 45 minutes and concentrated under reduced pressure. To a solution of the obtained residue in dichloromethane (0.4 mL) is added succinic anhydride (7.70 mg, 0.077 mmol) and DIPEA (0.013 mL, 0.077 mmol). The reaction mixture is allowed to stir at room temperature for 14 hours and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C-18, H2O (0.1% TFA)/CH3CN) to give (R)-4-(1-(biphenyl-4-yl)-4-tert-butoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (9.5 mg). HPLC retention time=1.70 minutes (condition A); MS (ES+)=412.1 (m+1); 356.0 (m-tBu+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9 H) 2.36-2.51 (m, 4 H) 2.64-2.67 (m, 2 H) 2.87 (A of ABX, Jab=13.5 Hz, Jax=5.7 Hz, 1 H), 2.97 (Jab=13.5 Hz, Jbx=6.2 Hz, 1 H) 7.24-7.26 (m, 2 H) 7.31-7.35 (m, 1 hp 7.43 (t, J=7.75 Hz, 2 H) 7.53 (d, J=8.0 Hz, 2 H) 7.57 (d, J=7.6 HZ, 2 H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C>[CH2:18]([O:17][C:15]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A solution of tert-butyl 4-aminopiperidine-1-carboxylate (1.2 g, 6 mmol) in dichloromethane (20 mL) was cooled to 0° C. Carbobenzoxy chloride (1.03 mL, 7.2 mmol) and diisopropylethylamine (3.15 mL, 18 mmol) were added at the same temperature, and the solution was stirred at 0° C. for one hour. The reaction solution was neutralized with saturated aqueous potassium carbonate solution, diluted with ethyl acetate, washed with brine, and dried over magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1) to obtain 1.5 g of the title compound as a yellow oily substance (75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH:13]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14]2)[CH:6]=1.I[CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:13]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14]2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(CNC2CCN(c3nc4ccc(Cl)cc4s3)C2)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(Cc1cccc(CC(=O)OC)c1)C1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 36 %

Procedure:
A mixture of [3-[[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamino]methyl]phenyl]acetic acid methyl ester (68 mg), 1-iodobutane (37 μL), potassium carbonate (45 mg) and dimethylformamide (1 mL) was stirred at 80° C. for 3.5 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The residue was purified by column chromatograph on silica gel to give the title compound (28 mg). Yield: 36%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[OH-].[K+].Br[CH2:13][CH2:14][CH3:15]>CS(C)=O.O>[CH2:15]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH:14]=[CH2:13]
Reactant: Cc1cccc(C)c1O
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOc1c(C)cccc1C
Reaction time: 0.5 h

Procedure:
2,6-Dimethylphenol (1.22 g) is added to a mixture of powdered potassium hydroxide (2.24 g) in dimethylsulfoxide (20 ml). Then 3-bromopropane (2.42 g) is added at 20°-25° and stirred for 0.5 hr. The mixture is diluted with water (100 ml) and extracted with methylene chloride (3×). The organic extracts are washed with water (2×) and then with saline, dried over sodium sulfate and concentrated under reduced pressure to give 1-allyloxy-2,6-dimethylbenzene.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([O:12][C:13]1[CH:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47]>C1COCC1.C(O)C>[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47].[NH2:1][CH2:4][C@@H:5]([O:12][C:13]1[CH:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CN=[N+]=[N-])c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CN)c1ccccc1
Temperature: 60 °C

Procedure:
The product from step (b) (2.79 g) in dry THF (80 ml) was treated with triphenylphosphine (3.47 g) and water (12 ml) and the mixture heated at 60° C. for 2 h. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate which was washed with water and dried (MgSO4). The solvent was evaporated and the residue purified by chromatography (silica, ethyl acetate and then 10% 7M ammonia in methanol/dichloromethane as eluent) to give an oil. This was dissolved in ethanol (10 ml), treated with fumaric acid (70.3 mg) and heated until a clear solution was obtained. The mixture was evaporated and the residue triturated with ether to give after filtration and drying in vacuo the final compound (222 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=O)[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=[S:30])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Solvent: c1ccncc1
Product: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Temperature: 25 °C
Yield: 38.6 %

Procedure:
3-[4-(2,6-Dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester (250 mg, 0.64 mmol) was dissolved in 8 mL of pyridine. P4S10 (430 mg, 1.5 eq) was added and the reaction mixture was stirred under reflux for 3 h. It was then cooled to rt and quenched with 3 mL of H2O and then with enough 6 N HCl to bring the pH to 3. The resulting reaction mixture was extracted with CHCl3. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford 100 mg of the desired product.
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[NH:9][C:7](=[O:8])[CH2:6]2)[CH2:3][CH2:2]1.[Br-].[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N+:23]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][N:9]2[C:7](=[O:8])[CH2:6][C:4]3([CH2:5][CH2:1][CH2:2][CH2:3]3)[CH2:12][C:10]2=[O:11])[CH2:22][CH2:21]1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Reactant: O=C1CC2(CCCC2)CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCO
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 66.5 %

Procedure:
A mixture of 3,3-tetramethyleneglutarimide (7.5 g., 0.045 mole), 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane bromide (15.4 g., 0.045 mole), potassium carbonate (6.2 g., 0.045 mole) in 250 ml. of n-butanol is refluxed for a 21 hour period, filtered and evaporated to dryness. Residual material is warmed 45 minutes with acetic anhydride and evaporated to dryness. Water is added to the residue and the mixture basified with aqueous sodium hydroxide. Insolubles are collected and washed with water to provide 11.5 g. (66.5% yield) of 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl]-8-azaspiro[4.5]decane-7,9-dione as the free base, m.p. 90°-98° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][C:14]#[CH:15])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O1[CH2:21][CH2:20]COO1.C=O.[CH2:24]([NH:26][CH2:27]C)[CH3:25]>O1CCOCC1.C(O)(=O)C>[CH2:24]([N:26]([CH2:20][CH3:21])[CH2:27][C:15]#[C:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)[CH3:25]
Reactant: C#CCCCc1cccc(OC(C)=O)c1
Reactant: C1COOOC1
Reactant: CCNCC
Agent: C=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCN(CC)CC#CCCCc1cccc(OC(C)=O)c1

Procedure:
Add 5-m-acetoxyphenylpent-1-yne (9.5 g) to a mixture of trioxan (0.5 g), 40% formalin (5.5g), diethylamine (4g), acetic acid (2.75 g), dioxan (25 cc), and cuprous chloride (0.13 g) at room temperature. Heat the mixture thus obtained to 70°, to obtain a clear green solution, and maintain under nitrogen at that temperature for 12 hours. Cool and add ice, pour the product into ice-cold saturated potassium bicarbonate and extract the mixture with ether. Wash and dry, evaporate the extracts under reduced pressure and distil to obtain 1-diethylamino-6-m-acetoxyphenylhex-2-yne (9.9 g), b.p. 152°-154°/0.1 mm, as a pale yellow mobile liquid.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]([C:10](O)=O)[CH2:6]2)OCC1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26]1[C:27](=[O:40])[N:28]([CH2:37][CH2:38][CH3:39])[C:29](=[O:36])[N:30]([CH2:33][CH2:34][CH3:35])[C:31]=1[NH2:32]>C(Cl)Cl>[CH2:37]([N:28]1[C:27](=[O:40])[C:26]2[NH:25][C:10]([CH:7]3[CH2:8][CH2:9][C:5](=[O:1])[CH2:6]3)=[N:32][C:31]=2[N:30]([CH2:33][CH2:34][CH3:35])[C:29]1=[O:36])[CH2:38][CH3:39]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C1CCC2(C1)OCCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C3CCC(=O)C3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
2.4 g (0.014 mol) of 1,4-dioxaspiro[4,4]nonan-7-carboxylic acid are dissolved in 56 ml of methylene chloride and after the addition of 2.2 g (0.014 mol) of carbonyldiimidazole stirred for 1 hour at ambient temperature. Then 3.2 g (0.014 mol) of 5,6-diamino-1,3-dipropyluracil are added and the mixture is stirred for a further 4 hours at ambient temperature. The solution is evaporated down in vacuo, the oily residue is mixed with 70 ml of water and 4.5 g of Ca(OH)2 and stirred for 1 hour at 70° C. 100 ml of 50% NaOH are added, the mixture is stirred for a further hour at 70° C. and for 16 hours at ambient temperature. Whilst being cooled with ice, the solution is adjusted to pH 6 with HCl and extracted with methylene chloride. After drying and evaporation in vacuo the combined organic phases yield a crystalline residue which is recrystallised from ethanol using activated charcoal. 0.8 g (16%) of white crystals are obtained, m.p. 147°-148° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C:15]2[N:26]([CH3:29])[N:27]=[CH:28][C:14]1=2.C(Cl)Cl.O.NN>C(O)C>[NH2:3][O:12][CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][C:15]2[N:26]([CH3:29])[N:27]=[CH:28][C:14]1=2
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ON
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a mixture of tert-butyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate 136 (2.50 g, 6.27 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.360 mL, 6.27 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was washed with ether and methanol to give 137 (1.06 g, 62%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:16][CH:17]=1)#[CH:11]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:11]#[C:10][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH:15]=[CH:16][CH:17]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C#Cc1cccc(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C#Cc2nc(Cl)ncc2F)c1)C(F)(F)F
Yield: 77.6 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloro-5-fluoropyrimidine (1.56 g, 9.4 mmol), anhydrous, degassed THF (100 mL), dichlorobis(triphenyl-phosphine)palladium(II) (62 mg, 0.09 mmol), copper(I) iodide (10 mg, 0.05 mmol), and TEA (0.164 g, 0.23 mmol). After heating the reaction at 60° C. for 30 min. N-(3-ethynylphenyl)-2,2,2-trifluoroacetamide (1.0, 4.69 mmol) was added dropwise as a solution in THF (25 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed onto silica gel and purified by column chromatography (2-10% EtOAc in hexanes) to afford the desired product (1.25 g, 78%) as an off white solid. ES-LC/MS m/z=344 [M+H]+.