Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]2[CH2:9][C:6]([CH3:10])([CH2:7][CH:8]=1)[CH2:5][CH2:4]2.C(OO)(=[O:13])C.C([O-])(=O)C.[Na+]>>[CH3:1][C:2]12[O:13][CH:8]1[CH2:7][C:6]1([CH3:10])[CH2:9][CH:3]2[CH2:4][CH2:5]1
Reactant: CC(=O)OO
Reactant: CC1=CCC2(C)CCC1C2
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC12CCC(C1)C1(C)OC1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
2,5-Dimethyl-bicyclo[3.2.1]oct-2-ene (800 g, 5.88 mol, obtained as above in EXAMPLE I) was fed into a solution of peracetic acid (CH3CO3H, 32%, 1.466 Kg, 6.18 mol) and sodium acetate (CH3CO2Na, 72 g, 0.882 mol), and cooled to 0° C. The reaction mixture was aged for 6 hours, and subsequently quenched with water and toluene. The reaction mixture was shaken and split. The organic layer was first washed with a solution of sodium carbonate (Na2CO3), and then with a solution of sodium sulfite (Na2SO3). Fractional distillation of the organic layer provided 2,6-dimethyl-3-oxa-tricyclo[4.2.1.0*2,4*]nonane (734 g) having a boiling point of 31° C. at a pressure of 18 mmHg
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=1)=[O:7].Cl>C(OCC)C.O1CCCC1>[OH:7][CH:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
A 1.0M solution (200 ml, 200 ml) of allyl-magnesium bromide in diethyl ether was dropped into a solution of t-butyl 4-formylbenzoate (30.9 g, 150 mmol) in anhydrous tetrahydrofuran, while stirring the latter under cooling with ice in a nitrogen stream. After the completion of the dropping, the obtained mixture was further stirred for 30 minutes, followed by the addition of 220 ml of 1N hydrochloric acid cooled with ice. The obtained mixture was vigorously stirred. The aqueous layer was further extracted with diethyl ether. The organic layers were combined, washed with an aqueous solution of common salt, dried and concentrated. The residue was purified by silica gel column chromatography to give t-butyl 4-(1-hydroxy-3-butenyl)benzoate. Yield: 8.2 g.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[C:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl.[CH3:21]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:13]([Cl:14])=[C:12]([C:15](=[O:19])[C:16](=[CH2:21])[CH2:17][CH3:18])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCC(=O)c1ccc(OCCC(=O)O)c(Cl)c1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(CC)C(=O)c1ccc(OCCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-(2,3-Dichloro-4-butyrylphenoxy)propionic acid (6.65 g, 0.022 mole), dimethylamine hydrochloride (12 g, 0.15 mole), paraformaldehyde (2.3 g, 0.077 equiv.) and acetic acid (1 ml) were mixed and stirred while heating on a steam bath for 2.5 hours. N,N-dimethylformamide (25 ml) was added to the mixture and stirring and heating continued for another 1.5 hours. The mixture was poured into ice water (600 ml) and the precipitate that formed removed by filtration, washed with water and dried. After recrystallization from butyl chloride, 58 g 3-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]-propionic acid remained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][CH2:18][CH:19]=[CH2:20]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:20][CH2:19][CH:18]=[CH2:17])[CH:7]=1
Reactant: C=CCCBr
Reactant: Oc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCOc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-fluorophenol (19.63 g, 102.8 mmol) in DMF (410 mL) was added Cs2CO3 (40.19 g, 123.36 mmol, 1.2 eq.) followed by 4-bromo-1-butene (15.26 g, 11.48 mL, 113.06 mmol, 1.1 eq.). The mixture was stirred overnight at a temperature between 50 and 60° C. Then additional amounts of Cs2CO3 and the bromoalkene (20.1 g, 0.6 eq.) and (7.53 g, 5.74 mL, 0.55 eq.) respectively were added to the reaction mixture and heating was continued overnight. The mixture was cooled to room temperature and diluted with water. The aqueous mixture was extracted with EtOAc and the aqueous layer was separated and extracted once with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated onto 50 g Celite. Flash chromatography (SiO2, Hexanes to 30% EtOAc 70% Hexanes) provided 11.87 g, 47%, of the title compound as a colorless to light yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(N(C)C(C)C)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (40 mg, 0.14 mmol, 1.00 equiv), 4-methoxyphenylboronic acid (62.6 mg, 0.41 mmol, 3.00 equiv), Pd(PPh3)4 (31.4 mg, 0.03 mmol, 0.20 equiv), K3PO4 (116 mg, 0.55 mmol, 4.00 equiv), 1,4-dioxane (3 mL). The resulting solution was stirred for overnight at 110° C. in an oil bath. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by prep-TLC with ethyl acetate/petroleum ether (1:8). This resulted in 40 mg (80%) of methyl 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.O>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCN(CC)C(=O)c1ccc(CBr)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(CN2CCC3(CC2)OCCO3)cc1
Reaction time: 16 h
Yield: 96 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]-decane (200 mmol, 28.6 g, 25.6 mL) is dissolved in 160 ml of dry acetonitrile under nitrogen and treated with K2CO3 (220 mmol, 30.3 g) followed by dropwise addition over 1.5 hours of 4-(bromomethyl)-N,N-diethylbenzamide (200 mmol, 54.01 g) as a solution in 81 mL of acetonitrile. After 16 hours, the reaction mixture is poured into 250 mL of water and extracted twice with 150 mL of methylene chloride. The pooled extracts were washed with 250 mL of brine, dried over Na2SO4 and concentrated in vacuo affording 63.9 g (192 mmol, 96% yield) of the product as a yellow-orange oil.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:16][C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:3][C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Yield: 90.1 %

Procedure:
Using tert-butyl {{5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate (1 g), (4-fluorophenyl)boronic acid (628 mg), sodium carbonate (708 mg) and tetrakis(triphenylphosphine)palladium (388 mg), a procedure as in Reference Example 56 was performed to give the title compound as a pale-yellow oil (yield 930 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.Br[C:29]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2.C([O-])([O-])=O.[Cs+].[Cs+]>ICCC.COCCOC.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16]([C:29]3[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:36]=[C:35]4[C:30]=3[CH:31]=[CH:32][CH:33]=[N:34]4)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: FC(F)(F)c1ccc2ncccc2c1Br
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCCI
Product: Cc1noc(C)c1-c1cc(-c2c(C(F)(F)F)ccc3ncccc23)c2c(c1)[nH]c(=O)n2C
Temperature: 120 °C

Procedure:
To a microwave vial containing 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (30 mg, 0.08 mmol, 1 equiv.) was added 5-bromo-6-(trifluoromethyl)quinoline (68 mg, 0.24 mmol, 3 equiv.), Cs2CO3 (105 mg, 0.33 mmol, 4 equiv.) and PEPPSI™-IPr catalyst (11 mg, 0.016 mmol, 0.2 equiv.) and dissolved in DME-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120° C. for 30 min in microwave. The reaction was concentrated in vacuo and purification was then carried out by reverse phase HPLC.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:20])=O.[NH2:21][C:22]([NH2:24])=[S:23]>CCO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:21]=[C:22]([NH2:24])[S:23][CH:2]=3)=[C:6]([CH3:20])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ccc(F)cc2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ccc(F)cc2)cc(C)c1-c1csc(N)n1
Yield: 84.2 %

Procedure:
A mixture of 2-bromo-1-(4-(4-fluorophenoxy)-2,6-dimethylphenyl)ethanone (5.74 g, 17.0 mmol) and thiourea (1.30 g, 17.1 mmol) in 95% EtOH (24.3 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-fluorophenoxy)-2,6-dimethylphenyl)thiazol-2-amine (4.50 g) as yellow solids in 84% yield: 1H NMR (500 MHz, CDCl3) δ 7.05-6.97 (m, 4 H), 6.66 (s, 2 H), 6.28 (s, 1H), 5.95 (s, 2 H), 2.14 (s, 6H).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C:23](=[O:24])[N:5]2[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]3[N:12]([CH3:19])[C:13]([NH:16]C=O)=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12.C(OCC)(=O)C>O1CCCC1.CO>[ClH:1].[ClH:1].[ClH:1].[NH2:2][C@@H:3]1[C:23](=[O:24])[N:5]2[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]3[N:12]([CH3:19])[C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12
Reactant: Cn1c(NC=O)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1c(N)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 12 h

Procedure:
Concentrated hydrochloric acid (0.353 ml) was added to a mixture of bis(trifluoroacetic acid) salt of 7β-amino-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (0.565 g) in tetrahydrofuran (3 ml) and methanol (3 ml) at ambient temperature. After being stirred at the same temperature for 12 hours, the mixture was added dropwise to ethyl acetate (100 ml). The resulting precipitate was collected by filtration to give 7β-amino-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate trihydrochloride (292 mg).
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:16]=1[NH:25][C:26]([CH:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:27].O[NH:39][C:40](=[NH:53])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>C1COCC1>[CH2:41]([C:40]1[N:39]=[C:29]([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]([NH:25][C:16]2[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=2[O:14][CH3:13])=[O:27])[O:30][N:53]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCCCCCC(=N)NO
Reactant: COc1cc(OC)c(NC(=O)C(C(=O)O)c2ccccc2)c(OC)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1noc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
Carbonyl dimidazole (0.28 g, 1.71 mmol) was added to a solution of α-[[(2,4,6-trimethoxyphenyl)amino]carbonyl]-benzene acetic acid (0.56 g, 1.63 mmol) in dry THF (20 mL), and the resulting mixture was stirred at room temperature for 1 hour, then N-hydroxy-tridecane imidamide (0.37 g, 1.63 mmol) was added, and the mixture stirred for 1.5 hours, concentrated in vacuo, dissolved in glacial acetic acid, and refluxed for 1.5 hours. The solution was concentrated and azeotroped with benzene (2×25 mL), dissolved in ethyl acetate, and washed with NaHCO3, water, brine, dried with MgSO4, and recrystallized from ethanol/water to yield a white solid (0.093 g, 11%). (found): C, 69.25; H, 8.08; N, 7.68. ##STR13##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][OH:14])[O:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:14][CH2:13][CH:10]2[O:9][C:8]3[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[O:12][CH2:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])cc3O2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A 500 mL round bottomed flask equipped with a magnetic stir bar is charged with [7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (37.3 g, 177 mmol) and anhydrous pyridine (150 mL). The solution is cooled to 5° C. and p-toluenesulfonyl chloride (42.1 g, 221 mmol) is added in one portion. After 1 h, the cooling bath is removed, and the solution is stirred for another 3 h. The reaction mixture is poured into a rapidly stirred flack containing water (750 mL). The precipitate is collected by vacuum filtration, and the filter cake is rinsed with water and suction dried to give the title compound (63.8 g, 99%) as yellow granules. LCMS (Standard Method): 2.81 min, 388 (M+Na)+. 1H NMR (300 MHz, DMSO-d6) δ7.79-7.72 (m, 3H), 7.49-7.42 (m, 3H), 7.06 (d, J=8.8 Hz, 1H), 4.59-4.55 (m, 1H), 4.41 (dd, J=2.6, 11.6 Hz, 2H), 4.22 (dd, J=6.3, 11.5 Hz, 1H), 4.12 (dd, J=6.8, 11.7 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][OH:15])=[CH:8][CH:7]=2)=[CH:3][N:4]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cncc2ccccc12
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: OCc1ccc(-c2cncc3ccccc23)cc1

Procedure:
Under an argon atmosphere, a mixture of 1.09 g (7.2 mmol) of (4-hydroxymethyl)phenylboronic acid, 1.24 g (6 mmol) of 4-bromoisoquinoline and 0.28 g (0.24 mmol) of palladium tetrakis(triphenylphosphine) in 50 ml of toluene and 10 ml of aqueous sodium carbonate solution (2M) is heated at reflux overnight. The filtrate is concentrated under reduced pressure and the residue is taken up in 150 ml of ethyl acetate and 40 ml of water. After the phases have settled and been separated, the organic phase is washed in succession with 20 ml of water and 20 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a 60/40 then 40/60 mixture of cyclohexane and ethyl acetate. This gives 1.12 g of a white solid.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:80])[C@@H:76]([NH2:79])[CH2:77][F:78])[CH2:71][CH2:70]1)=[O:68])[CH3:65].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:80])[C@@H:76]([NH:79][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:77][F:78])[CH2:71][CH2:70]1)=[O:68])[CH3:65]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 164 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 2 ml DMF were added 152 mg HATU, 0.20 ml DIPEA and 144 mg 4-((R)-2-Amino-3-fluoro-propionyl)-piperazine-1-carboxylic acid ethyl ester. After stirring for 3 h saturated NaHCO3 solution (1.5 ml) was added and the mixture passed through a Chem Elute® cartridge eluting with DCM. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:7](=[O:19])[C:6]=2[CH:5]=[C:4]2[NH:20][C:21]([C:23]3[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=3[NH:29][CH:30]([CH3:42])[CH2:31][C:32]3[C:37]([F:38])=[C:36]([F:39])[CH:35]=[C:34]([F:40])[C:33]=3[F:41])=[N:22][C:3]=12>[Zn].C(O)(=O)C>[CH3:1][C:2]1[C:10]2[CH2:9][N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[C:7](=[O:19])[C:6]=2[CH:5]=[C:4]2[NH:20][C:21]([C:23]3[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=3[NH:29][CH:30]([CH3:42])[CH2:31][C:32]3[C:33]([F:41])=[C:34]([F:40])[CH:35]=[C:36]([F:39])[C:37]=3[F:38])=[N:22][C:3]=12
Reactant: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2
Yield: 10.4 %

Procedure:
A mixture of 4-methyl-6-(1-methylpiperidin-4-yl)-2-(2-oxo-4-(1-(2,3,5,6-tetrafluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.93 g, 1.65 mmol), zinc dust (1.02 g, 15.6 mmol), and 30 mL of acetic acid was heated at reflux for 14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 0.10 g (11.0%) of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 12.93 (s, 1H, NH), 11.28 (d, J=8.5 Hz, 1H, NH), 11.23 (d, J=4.1 Hz, 1H, NH), 7.75 (m, 1H, ArH), 7.60 (s, 1H, ArH), 7.36 (m, 1H, ArH), 6.19 (d, J=8.0 Hz, 1H, ArH), 4.40 (s, 2H, CH2), 4.28 (m, 1H, CH), 3.99 (m, 1H, CH), 3.07 (m, 2H, CH2), 2.88-2.84 (m, 2H, CH2), 2.74 (s, 3H, CH3), 2.20 (s, 3H, CH3), 2.02-1.98 (m, 2H, CH2), 1.82-1.80 (m, 2H, CH2), 1.67 (m, 2H, CH2), 1.36 (d, J=6.0 Hz, 3H, CH3); Mass (ESI, positive) m/z 583.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][N:3]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[O:26])=[CH:4][N:3]=1
Reactant: COc1ccc(CNc2nc(Cl)ncc2C(O)c2ccccn2)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(Cl)ncc2C(=O)c2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-[(hydroxy)(2-pyridyl)methyl]pyrimidine (prepared in the above (2)) 46 mg, manganese dioxide 230 mg and chloroform 2.3 ml is stirred at room temperature for 3 hours. After removal of insoluble substances by filtration, the filtrate is concentrated in vacuo to give 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylcarbonyl)pyrimidine 39 mg. mp 117-119° C. (recrystalization from diethyl ether), MS(m/z): 389(M+H)+
Reaction SMILES: CC(=CCCC(=CC=O)C)C.C#CC.[CH3:15][C:16]1[CH:21]=[CH:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]=1[CH:24]([OH:28])[C:25]#[C:26][CH3:27].CC1C=CCC(C)(C)C=1C(=O)C#CC>O=[Mn]=O>[CH3:15][C:16]1[CH:21]=[CH:20][CH2:19][C:18]([CH3:22])([CH3:23])[C:17]=1[C:24](=[O:28])/[CH:25]=[CH:26]\[CH3:27]
Reactant: CC#CC(O)C1=C(C)C=CCC1(C)C
Agent: O=[Mn]=O
Agent: C#CC
Agent: CC#CC(=O)C1=C(C)C=CCC1(C)C
Product: C/C=C\C(=O)C1=C(C)C=CCC1(C)C

Procedure:
Safranal, prepared according to Compt. rend. 262, 1725 (1966), was reacted with propyne to give 2,6,6-trimethyl-1-[1-hydroxy-2-butynyl]-1,3-cyclohexadiene, following the procedure outlined in Example 18, paragraph b, for the reaction of citral with propyne. The above carbinol was oxidised with MnO2 to 2,6,6-trimethyl-1-tetrolyl-1,3-cyclohexadiene, following the procedure described in Example 18, paragraph c), for the oxidation of the dihydro analogue. The above acetylenic ketone was then partially reduced to the title compound following the method described in Example 18, paragraph a). Cis-2,6,6-trimethyl-1-crotonoyl-1,3-cyclohexadiene gave the following NMR data (CCl4): 1.06 (6 H, s), 1.69 (3 H, s), 2.09 (2 H, d, J = 2.3 cps), 2.14 (3 H, d, J = 5.5 cps), 5.81 (2 H, t + s, J = 2.3 cps), 6.2 (2 H, complex band) ppm (δ).