Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]2[NH:5]1.I[CH3:29]>C1COCC1>[CH3:29][N:5]1[C@@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N[C@@H]2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a suspension of NaH (17 mg of 60% in mineral oil, hexane-washed, 0.42 mmol) in 2 mL of THF at ambient temperature was added (±)-cis-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 1, Part H (75 mg, 0.21 mmol) as a solution in 2 mL of THF. The reaction was stirred for 20 min, at which time gas evolution had ceased and the reaction mixture was homogeneous. Then there was added iodomethane (0.039 mL, 0.63 mmol) and the reaction was allowed to stir at ambient temperature for 1 h. The reaction was quenched with water, diluted with EtOAc and washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 2:1 hexane/EtOAc) to afford 30 mg (39%) of the title compound. LRMS (ESI): 315.22 (M+H—C4H8)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:4]2[CH:3]=[C:2]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:7]=[CH:6][CH:5]=2)=[CH:11][CH:12]=1
Reactant: Brc1cccc(C#Cc2ccncc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C(#Cc1cccc(-c2cnccn2)c1)c1ccncc1
Yield: 39.6 %

Procedure:
To a solution of 4-[(3-bromophenyl)ethynyl]pyridine (387 mg, 1.50 mmol) in toluene (10 mL) is added tetrakis(triphenylphosphine)palladium (87 mg, 0.075 mmol) and 2-(tributylstannyl)pyrazine (1.45 g, 3.75 mmol) at room temperature. After refluxing for 24 h, the reaction mixture is cooled and diluted with EtOAc (100 mL), washed with saturated NaHCO3 (2×30 mL), brine (30 mL), dried over MgSO4 and concentrated on a rotary evaporator. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 40/60 to give the title compound (153 mg, 40%) as solid. mp: 94-95° C. MS(+) ES: 258 (M+OH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].O[CH2:9][C:10](CO)(C)[C:11](=[O:13])[CH3:12]>ClCCl>[C:11]([C:10]1([CH3:9])[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2][CH2:1]1)(=[O:13])[CH3:12]
Reactant: CC(=O)C(C)(CO)CO
Reactant: COC(C)(C)OC
Solvent: ClCCl
Product: CC(=O)C1(C)COC(C)(C)OC1
Reaction time: 1 h

Procedure:
2,2-Dimethoxypropane (418.0 g, 4.0 mol) and The 3,3-Bis(hydroxymethyl)-2-butanone (264.32 g, 2.0 mol) were mixed together in 1 liter of dichloromethane. Amberlyst-15 ion exchange resin (strongly acidic; 40.0 g) was added to the solution and the resultant suspension stirred vigorously at room temperature. After 1 hr TLC indicated no starting material and complete conversion to the desired product. The spent resin was separated from the solution by filtration through a thick pad of anhydrous potassium carbonate. Subsequently, the residual dimethoxypropane and dichloromethane were removed in vactio to give a pale straw-colored liquid. The liquid solidified upon standing as large clear, colorless crystals, m.p. 48-50° C.; 300 g, 87.1% of theoretical yield; H-NMR spectra were consistent. Elemental Analysis calculated for C9H16O3: C, 62.77; H, 9.36. Found: C, 62.00; H. 9.01.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([CH:11]([S:13][CH3:14])[CH3:12])[CH:8]=[N:7][C:6]=1[C:15]([F:18])([F:17])[F:16])C.[OH-].[Li+].Cl>O1CCCC1>[CH3:14][S:13][CH:11]([C:9]1[CH:8]=[N:7][C:6]([C:15]([F:18])([F:17])[F:16])=[C:5]([CH:10]=1)[C:4]([OH:19])=[O:3])[CH3:12]
Reactant: CCOC(=O)c1cc(C(C)SC)cnc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSC(C)c1cnc(C(F)(F)F)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a dry 50 mL glass vial equipped with magnetic stirrer, and nitrogen inlet, was charged 0.5 g (0.00170 moles) of 5-(1-methylthioethyl)-2-trifluoromethylnicotinic acid ethyl ester, and 10 mL of tetrahydrofuran (THF). The solution was cooled to about 0° C. and 5.1 mL of 1N aqueous lithium hydroxide solution (0.00511 moles) was added slowly via syringe. The reaction was stirred at 0° C. for 1 hour, then overnight at ambient temperature. An aliquot was analyzed by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), which indicated that the reaction was essentially complete. The mixture was acidified to pH=2 with 1M aqueous hydrochloric acid, and extracted with 3 aliquots of 50 mL of ethyl acetate. The extract was dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under vacuum on a rotary evaporator to afford 0.410 g of the title compound as a tan solid. 1H NMR (CDCl3): δ 1.66 (d, 3H), 1.96 (s, 3H), 3.98 (q, 1H), 8.01 (bs, 1H), 8.30 (s, 1H), and 8.80 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](OCC)=[O:23])[CH:19]=[C:18]([CH2:27][O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[BH4-].[Na+].CC(C)=O>C(O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][OH:23])[CH:19]=[C:18]([CH2:27][O:28][CH2:29][C:30]([F:32])([F:33])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CCOC(=O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc(CO)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reaction time: 3 h

Procedure:
A solution of ethyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carboxylate (0.38 g, 0.82 mmol) in ethanol (20 mL), was heated to 45°. Citric acid (1.255 g, 6.53 mmol) and sodium borohydride (0.309 g, 8.16 mmol) were added in portions (of 5-10 mg each) keeping pH within a range of 5-7 over 3 h. Acetone (2 mL) was added and reaction mixture was stirred for 15 min. Chloroform (40 mL) was added. The mixture was filtered and concentrated. The residue was purified by column chromatography on silica column eluting with a gradient of MeOH and DCM to give the title compound as a solid, 0.24 g (69%).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[NH2:37][C:38]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:40][C:39]=1[C:49](=O)[CH3:50].[OH-].[K+]>C(O)C>[NH2:37][C:38]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:40][C:39]=1[C:49]1[CH:50]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[N:22]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=4[N:19]=3)[CH:14]=2)[N:9]=1
Reactant: CC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2ccccc2)sc1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 14 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3-amino-5-phenyl-thiophen-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (19 mg, 14% yield). MS: 545.24 (M+H+); HPLC Procedure B, retention time=8.25 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1Oc1nccs1
Temperature: 150 °C
Reaction time: 15 h
Yield: 92.1 %

Procedure:
To a solution of 4-bromo-2-ethyl-phenol (1.00 g, 4.97 mmol) in DMF (40 mL) was added 2-bromothiazole (0.341 mL, 3.82 mmol) and finely crushed K2CO3 (3.17 g, 22.9 mmol). The mixture was stirred at 150° C. for 15 hours, at which time the hot solution was filtered through filter paper. The filtrate was diluted with CH2Cl2 and H2O and then brought to pH 6.0 with 6.0N HCl. The aqueous layer was extracted with CH2Cl2 and the organic layer was washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated to yield a yellow oil (1.0 g, 92%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.6 Hz, 3 H), 2.62 (q, J=7.5 Hz, 2 H), 6.79 (d, J=3.8 Hz, 1 H), 7.10 (d, J=8.5 Hz, 1 H), 7.19 (d, J=3.8 Hz, 1 H), 7.35 (dd, J=8.7, 2.4 Hz, 1 H), 7.43 (d, J=2.4 Hz, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Yield: 41.7 %

Procedure:
Using the procedure described in Example 161C, 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (2.00 g, 9.3 mmol) was reacted with phenyl chloroformate (1.6 g, 10.2 mmol) and K2CO3 (1.7 g, 12.1 mmol) in THF (20 mL), which was purified by silica gel chromatography (0-50% EtOAc/hexane) to afford phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate as solid (1.3 g, 42%). 1H NMR (300 MHz, DMSO-d6) δ 10.0 (s, 1H), 7.55 (m, 4H), 7.40 (m, 3H), 7.08-7.23 (m, 3H), 6.37 (s, 1H), 1.3 (s, 9H); LC-MS (ESI) m/z 336 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][C:4]([CH2:7][OH:8])([CH3:6])[CH2:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>C(Cl)Cl>[CH3:10][S:11]([O:8][CH2:7][C:4]1([CH3:6])[CH2:5][C:2]([F:9])([F:1])[CH2:3]1)(=[O:13])=[O:12]
Reactant: CC1(CO)CC(F)(F)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)CC(F)(F)C1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
To a solution of Intermediate 229A (100 mg, 0.735 mmol) and TEA (0.102 mL, 0.735 mmol) in DCM was added methanesulfonyl chloride (0.059 mL, 0.735 mmol) dropwise at 5° C. and the reaction mixture was stirred for 3 h. The reaction mass was diluted with DCM, washed with water and brine, dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 30% EtOAc in petroleum ether). Fractions containing the product were combined and evaporated to afford the Intermediate 229B as a yellow oil (100 mg, 63.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.27 (s, 2H), 3.01 (s, 3H), 2.55-2.69 (m, 2H), 2.06-2.37 (m, 2H), 1.15 (s, 3H).
Reaction SMILES: [H-].[Na+].C(C1OC2C=CC=CC=2C=1C(=O)C1C=CC(O)=CC=1)C.ClCC#N.[CH2:27]([C:29]1[O:30][C:31]2[CH:49]=[CH:48][CH:47]=[CH:46][C:32]=2[C:33]=1[C:34]([C:36]1[CH:45]=[CH:44][C:39]([O:40][CH2:41][C:42]#[N:43])=[CH:38][CH:37]=1)=[O:35])[CH3:28].[N-:50]=[N+:51]=[N-:52].[Na+].Cl>CN(C=O)C.C1COCC1>[CH2:27]([C:29]1[O:30][C:31]2[CH:49]=[CH:48][CH:47]=[CH:46][C:32]=2[C:33]=1[C:34]([C:36]1[CH:45]=[CH:44][C:39]([O:40][CH2:41][C:42]2[NH:52][N:51]=[N:50][N:43]=2)=[CH:38][CH:37]=1)=[O:35])[CH3:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1oc2ccccc2c1C(=O)c1ccc(OCC#N)cc1
Agent: CCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Agent: Cl
Agent: N#CCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1oc2ccccc2c1C(=O)c1ccc(OCc2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To an ice-water cooled suspension of NaH (0.18 g) in dry DMF (5 ml), is added a solution of a 2-ethyl-3-(4-hydroxybenzoyl)benzofuran, 1.00 g, in dry DMF 12 ml dropwise. After stirring for about 15 minutes running, chloroacetonitrile (0.24 ml) is added and heated up to 100° C. for 3 hours. After cooling to room temperature, the reaction mixture is poured over ice-water 100 ml and submitted to extraction by ethyl acetate. The solvent layer is washed by 10% NaOH solution and washed by NaCl solution and then dried by Na2CO3. Removing the solvent from the resulting solution gives a yellowish oily substance, that is 4-(2-ethyl-3-benzofuroyl)phenoxyacetonitrile. The obtained substance, in an amount of 1.05 g is dissolved in 15 ml of THF under an N2 gas stream. To this solution, aluminum chloride anhydride powder, 0.46 g, and then sodium azide, 0.98, are added and heated up to reflux for 24 hours. The reaction mixture is cooled by ice water and 10% HCl is added dropwise to make the solution acidic. After removal of THF, water is added and extracted by ethyl acetate (30 ml×2). The organic layer is washed by NaCl solution and dried over NaCO3. A solid substance obtained after removal of the organic solvent is recrystallized from CH2Cl2.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 25 °C

Procedure:
Ethyl 4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoate (E167a) (1.5 g, 4.5 mmol) was diluted in ethanol (30 ml) and treated with 2N sodium hydroxide (7.9 ml). After stirring at reflux for 24 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude mixture was applied to a SCX ion exchange cartridge (Varian bond-elute) and washed with water, methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were reduced in vacuo to afford the title compound (E167b) as the ammonium salt. MS (ES+) m/e 303 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[CH:16]=[N:17][CH:18]=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:39]=[C:33]7[CH2:34][N:35]([CH3:38])[CH2:36][CH2:37][N:32]7[N:31]=6)[C:26](=[O:40])[N:25]([CH3:41])[CH:24]=5)[C:20]=4[CH:21]=[O:22])[C:9]3=[O:14])[C:4]=2[CH2:3]1.[BH4-].[Na+]>CO>[OH:22][CH2:21][C:20]1[C:15]([N:8]2[CH2:7][CH2:6][N:5]3[C:4]4[CH2:3][C:2]([CH3:1])([CH3:42])[CH2:13][C:12]=4[CH:11]=[C:10]3[C:9]2=[O:14])=[CH:16][N:17]=[CH:18][C:19]=1[C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:39]=[C:33]3[CH2:34][N:35]([CH3:38])[CH2:36][CH2:37][N:32]3[N:31]=2)[C:26](=[O:40])[N:25]([CH3:41])[CH:24]=1
Reactant: CN1CCn2nc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a solution of 150a (170 mg, 0.30 mmol) in methanol (10 mL) was added sodium borohydride (68 mg, 1.8 mmol) at 0° C. The mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was quenched with water (2 mL) and concentrated. The residue was purified with reverse-phase prep-HPLC to afford 150 (42 mg, 25%) as a pale yellow solid. MS-ESI: [M+H]+ 569. 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.48 (s, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J=2.5 Hz, 1H), 6.82 (s, 1H), 5.67 (s, 1H), 4.63-4.55 (m, 2H), 4.37-4.35 (m 1H), 4.22-4.18 (m, 3H), 4.05-3.97 (m, 3H), 3.69 (s, 3H), 3.59-3.57 (m, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.56 (s, 2H), 2.50 (s, 2H), 2.46 (s, 3H), 1.26 (s, 6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:11][N:10]=[C:9]2[CH3:18])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:45][C:46]([F:58])([F:57])[C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54](O)=[O:55])=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:9]([CH3:18])=[N:10][N:11]=[C:12]2[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:54](=[O:55])[CH2:53][C:50]2[CH:49]=[CH:48][C:47]([C:46]([F:57])([F:45])[F:58])=[CH:52][CH:51]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nnc([C@H]2CCCN2)n1Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc([C@H]2CCCN2C(=O)Cc2ccc(C(F)(F)F)cc2)n1Cc1ccc(Cl)cc1
Yield: 91.6 %

Procedure:
(R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole hydrochloride (50 mg, 0.8 mmol) was dissolved in dichloromethane (2 ml). HATU (75 mg, 0.19 mmol), (α,α,α-trifluoro-p-tolyl)acetic acid (37 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.078 ml, 0.45 mmol) were added while stirring. The reaction mixture was stirred for 12 h then evaporated to dryness. Residue was taken up in EtOAc (20 ml) and washed with saturated solutions of NaHCO3 and NaCl. Organics were dried (NaSO4), filtered and concentrated. Purification by HPLC (water/acetonitrile gradient, 20% to 100% acetonitrile with 0.1% TFA) afforded the desired product as a white amorphous solid (76.3 mg, 91%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](O)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16]>>[C:4]1([C:1](=[O:3])[CH2:2][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)CCCCC(=O)O
Reactant: CC(=O)c1ccccc1
Product: CC(C)CCCCC(=O)CC(=O)c1ccccc1

Procedure:
In the preferred embodiment of this invention, acetophenone is reacted with the methyl ester of isooctanoic acid, which results in the 1-phenyl isodecane-1,3-dione product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH:15]=O)=[C:10]([Cl:17])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([N:22](C(C)C)CC)(C)C.Cl.NO.ClC(Cl)(Cl)C#N>C1COCC1.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]#[N:22])=[C:10]([Cl:17])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C=O)c(Cl)n1
Agent: Cl
Agent: NO
Solvent: N#CC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of compound tert-butyl(4,6-dichloro-5-formylpyridin-2-yl)carbamate (3.0 g, 10.3 mmol) in THF (30.0 mL) was added diisopropylethylamine (2.76 mL, 15.4 mmol) followed by hydroxylamine hydrochloride (0.78 g, 11.3 mmol) at 0° C. and was stirred at room temperature for 3 h. After confirming the completion of starting material by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to get crude product. To the crude product was added trichloroacetonitrile (30.0 mL) and was heated at 85° C. for 2 h. After confirming the completion of starting material by TLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes:ethyl acetate=9:1) to afford product. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.02 (s, 1H), 1.46 (s, 9H), MS ES calc'd. for C11K11C12N3O2 [M+H]+ 288. Found 288.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1.[NH:14]1CC[CH2:16][CH2:15]1.C1C=CC=CC=1.ClCC#N>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH:10]2[CH2:16][C:15]#[N:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: C1CCNC1
Agent: N#CCCl
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(CC#N)C(=O)CC2
Reaction time: 8 h

Procedure:
A mixture of 7-methoxy-2-tetralone (472 g., 2.68 mole), pyrrolidine (241 g., 3.40 mole) and benzene (2.5l) was refluxed under nitrogen with water separation (Dean-Stark trap) for 2 hrs. and then distilled for a further 1 hr. (1.2l) of distillate). Chloroacetonitrile (324 g., 4.30 mole) was added during 15 mins. and the mixture was refluxed for 4 hrs. and then left at room temperature overnight. Water (1.5l) was added and the mixture was refluxed for 3 hrs. The organic layer was separated while still hot, washed with 3N sulphuric acid (500 ml.) and filtered with suction through a pad of magnesium sulphate. The product crystallized from benzene and from benzene-ether (two crops) as yellow prisms (484 g., 84%); m.p. 97°-99° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.COC(=O)C=CC1C=CC(O)=CC=1.[CH2:27](Cl)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34]>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CC(C)CCCCCCCl
Agent: COC(=O)C=Cc1ccc(O)cc1
Product: COC(=O)CCc1ccc(OCCCCCCC(C)C)cc1

Procedure:
1.4 3-(4-isononyloxyphenyl)-propionic acid methyl ester (refractive index at 20° C. : 1.4904) was prepared from 3-(4-hydroxyphenyl)-propionic acid methyl ester, substituted on an equimolar basis for 4-hydroxycinnamic acid methyl ester, and isononyl chloride by the method described in 1.1.
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH2:6]1.C(O[C:16]([C:18]1[N:22]2[CH2:23][CH2:24][N:25]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:21]2=[N:20][C:19]=1[CH3:35])=[O:17])C.[OH-].[Na+]>C1C=CC=CC=1>[CH:5]1([CH2:8][N:9]([CH2:10][CH2:11][CH3:12])[C:16]([C:18]2[N:22]3[CH2:23][CH2:24][N:25]([C:26]4[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])[C:21]3=[N:20][C:19]=2[CH3:35])=[O:17])[CH2:7][CH2:6]1
Reactant: CCCNCC1CC1
Reactant: CCOC(=O)c1c(C)nc2n1CCN2c1c(C)cc(C)cc1C
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCN(CC1CC1)C(=O)c1c(C)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of trimethyl aluminum (2.0 M in heptane, 2.2 mL, 4.4 mmol) was added to a solution of N-cyclopropylmethyl-N-propylamine (0.63 mL, 4.4 mmol) in benzene (3 mL) at 0° C. The mixture was warmed up to room temperature and stirred at this temperature for 1.5 h, and then added to a stirred solution of 2-methyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylic acid ethyl ester (0.172 g, 0.55 mmol) in benzene (8.0 mL). The mixture was refluxed for 12 h. Upon cooling at 0° C., 1 N sodium hydroxide (25 mL) was added dropwise to the above mixture. The mixture was extracted with dicholoromethane (40 mL), and the organic layer was dried over anhydrous sodium sulfate. Solvents were removed in vacuo and the residue was subjected to chromatography using ethyl acetate/hexanes (1:1) as eluent to afford the title compound as a light yellow oil which solidified upon cooling (0.209 g, 100% yield). 1H NMR (CDCl3, 300 MHz) δ; 13C NMR (CDCl3, 75 MHz) δ 163.1, 156.0, 141.0, 136.5, 136.1, 132.7, 128.7, 115.8, 52.6, 50.3, 47.1, 42.1, 20.1, 19.9, 17.3, 14.6, 10.3, 9.2, 2.8. Mass spec.: 381.26 (MH+).