Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH2:1].[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([CH3:11])[N:4]=1.C(N(CC)CC)C.CN(C)C=O>N1C=CC=CC=1>[NH2:2][C:3]1[C:8]([C:9](=[S:1])[NH2:10])=[CH:7][N:6]=[C:5]([CH3:11])[N:4]=1
Reactant: S
Reactant: Cc1ncc(C#N)c(N)n1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(C(N)=S)c(N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrogen sulfide is passed through a mixture of 4-amino-2-methyl-5-pyrimidinecarbonitrile (6.707 g., 0.050 m.), triethylamine (7.0 ml., 0.050 m.), dimethylformamide (25 ml.) and pyridine (100 ml.) with stirring for 3 hours at ambient temperature. The mixture is poured into ice water (500 ml.) and the cream-colored solid which separates is collected by filtration, washed with water, dried at 110° C./0.1 mm. The yield of product melting at 260° C. dec. (uncorr.) is 7.663 g. (91.1%). This material is recrystallized from dimethylformamide-water (Darco G-60) affording colorless crystals melting at 264° C. dec. (uncorr.) in a yield of 5.110 g. (60.8%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([S:27][CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([S:27][CH2:28][CH2:29][C:30]2[O:31][C:1](=[O:2])[NH:33][N:32]=2)[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(SCCc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A 12.5% solution of phosgene in toluene (5.5 mL, 6.2 mmol) is added dropwise to a -78° C. solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (1.0 g, 2.94 mmol) in tetrahydrofuran (100 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a heavy oil which is chromatographed on a 100 g column of silica with methanol/chloroform (3/97). After coevaporation with dichloromethane the product solidifies affording 0.64 g (63%) of 5-[2-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]thio]ethyl]-1,3,4-oxadiazol-2(3H)-one, mp 86.0°-87.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([N:14]2[CH2:18][C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C@@H:16]([C@@H:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=3)[CH3:28])[CH2:15]2)=[O:13])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([C:12]([N:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[CH:16]([CH:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=3)[CH3:28])[CH2:15]2)=[O:13])[CH2:11]1
Reactant: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(C(=O)C2CN(C(=O)OC(C)(C)C)C2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CNC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a stirred solution of 3-[(3R,4S)-3-[(S)-1-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester (0.14 g, 0.25 mmol) in 4 mL of CH2Cl2 was added 1 mL of TFA. After one hour at RT, the reaction was quenched by addition of aq. NaOH 1M (until ph=10) and the product was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo to yield 0.106 g (92%) of the title compound as a white foam. ES-MS m/e: 445.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[CH2:29](Br)[C:30]#[CH:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)=[CH:10][C:11]([O:18][CH2:31][C:30]#[CH:29])=[N:12][C:13]=2[C:14]([F:15])([F:17])[F:16])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(=O)[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c(C(F)(F)F)n1
Reaction time: 60 h
Yield: 46.6 %

Procedure:
A mixture of 0.11 g of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-oxo-pyridine (step 5 of Example 1), 2.5 g of propargyl bromide, 0.3 g of potassium carbonate, and 5 mL of DMF was stirred for 60 hours and concentrated in vacuo. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO4 and filtered through silica gel. The filtrate was reconcentrated in vacuo and the residue was crystallized from ether/hexane to give 56 mg of white solid: mp 138°-139° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:4][O:5][C:6]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]([CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]2[CH:23]=[CH:24][S:25][C:7]=12)[CH3:2].C([Li])CCC.[Br:35]C(Br)(F)C(F)(F)F>C1COCC1>[Br:35][C:13]1[S:14][C:10]2[C:9]([CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]3[CH:23]=[CH:24][S:25][C:7]3=[C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:26][CH2:27][CH2:28][CH3:29])[C:11]=2[CH:12]=1
Reactant: FC(F)(F)C(F)(Br)Br
Reactant: CCCCC(CC)COc1c2ccsc2c(CC(CC)CCCC)c2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(CC)COc1c2cc(Br)sc2c(CC(CC)CCCC)c2ccsc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A dry 500-mL three-neck flask was flushed with N2 and was charged with 8-(2-ethylhexoxy)-4-(2-ethylhexyl)thieno[2,3-f]benzothiophene (8.4 g, 0.020 mol) and THF (200 mL, 0.1 M) via deoxygenated syringe. The reaction flask was cooled to −78° C. and a 2.0 M solution of n-butyllithium in hexanes (10 mL, 0.020 mol) was added dropwise via deoxygenated syringe. After 30 minutes of stirring at −78° C., dibromotetrafluoroethane (7.8 g, 0.030 mol) was added to the reaction flask and stirring continued for 1 hour at −78° C. The cooling bath was removed and the reaction mixture was allowed to warm up to ambient temperature. As the reaction was completed, cool DI water (50 mL) was slowly added to the reaction flask. Then, the reaction mixture was poured into 150 mL of cool water and extracted with hexanes (200 mL) three times. The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The product was purified using column chromatography on silica gel with hexanes/chloroform (gradient) to yield colorless oil (4.2 g, 42%).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].O>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=1[C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)C(C)(C)C)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (compound 4) (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added thereto, and the mixture was stirred at −78° C. for 20 min. Pivaloyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (21 mg, yield 21%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:18]=[CH:17][O:16][N:15]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:14]3[CH:18]=[CH:17][O:16][N:15]=3)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)=[CH:27][CH:26]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CC(c1ccc(O)cc1)c1ccon1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CO/N=C(\COc1ccc(COc2ccc(C(CC(=O)OC)c3ccon3)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged dry THF (5.0 mL) and methyl 3-(4-hydroxyphenyl)-3-(1,2-oxazol-3-yl)propanoate (0.18 g, 0.74 mmol). To the above mixture (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.2 g, 0.74 mmol) was added and the resulting mixture stirred at 0° C. for 5 min. Triphenyl phosphine (0.25 g, 0.96 mmol) was added to the mixture and stirred at 0° C. for 15 min followed by the addition of diisopropylazadicarboxylate (0.19 g, 0.96 mmol). After stirring the resulting mixture at RT for 10 h, the RM was evaporated to remove the THF. The residue was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×2). The organic layer was washed with saturated brine solution (15 mL) and dried over anhydrous Na2SO4. Concentration of the solvent and purification of the resulting residue by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate (ratio) as eluant, gave the product (0.1 g, yield: 27.47%): MS (ESI, 120 eV): m/z=501.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 8.20 (d, 1H), 7.57-7.60 (t, 2H), 7.22-7.28 (m, 5H), 7.07-7.10 (d, 2H), 6.81-6.85 (m, 4H), 5.99-6.00 (d, 1H), 5.12 (s, 2H), 4.85 (s, 2H), 4.47-4.52 (t, 1H), 3.98 (s, 3H), 3.56 (s, 3H), 3.18-3.26 (q, 1H), 2.82-2.90 (q, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][OH:16])([O-:3])=[O:2].[H-].[Na+].[CH2:19](Br)[C:20]#[CH:21]>CN(C=O)C.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][O:16][CH2:21][C:20]#[CH:19])([O-:3])=[O:2]
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1ccc(NCCO)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
2-(2,4-dinitrophenylamino)ethanol (s-1a) (410 mg, 1.80 mmol, 1.0 equiv.) was dissolved in 3 mL of DMF and slowly added to a slurry of NaH (86.4 mg, 3.6 mmol, 2 equiv.) in 5 mL of DMF in a flame dried flask pre-cooled to 0° C. To the resulting slurry, 80% propargyl bromide (0.240 mL, 2.16 mmol, 1.2 equiv.) in toluene, cooled to 0° C., was added slowly. The ice bath was removed and the reaction was allowed to stir at room temperature for an additional 15 hours. The reaction was then re-cooled to 0° C., quenched with saturated NH4Cl, and extracted with diethyl ether (3×150 mL). The organic layers were combined, dried, concentrated under reduced pressure, and chromatographed (silica gel, 1×25 cm, 0% CH3OH in CHCl3, then 2.5% CH3OH in CHCl3) to yield 2,4-dinitro-N-(2-(prop-2-ynyloxy)ethyl)aniline (s-2a) as a dark yellow solid (310 mg, 64.8%). IR (thin film) 3356 (m), 3285 (m), 3105 (w), 2871 (w), 2117 (w), 1616 (s), 1584 (s), 1521 (s), 1499 (m), 1423 (m), 1274 (s), 1089 (s), 920 (m); 1H NMR (400 MHz, CDCl3) δ 9.16 (d, J=2.6 Hz, 1H), 8.76 (bs, 1H), 8.28 (dd, J=9.5, 2.7 Hz, 1H), 6.96 (d, J=9.5 Hz, 1H), 4.25 (d, J=2.4 Hz, 2H), 3.91-3.84 (m, 2H), 3.65 (d, J=5.3 Hz, 1H), 2.50 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 149.5, 136.3, 130.7, 130.4, 124.4, 114.1, 78.9, 75.5, 67.3, 58.7, 43.3. HRMS (ES+) calc'd for C11H11N3O5 (M+H) m/z 266.0732 Found 266.0771.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[C:5]=1[CH3:13].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CN(C=[O:24])C>O.CCOCC>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:24])=[C:5]([CH3:13])[C:6]=1[CH3:12]
Reactant: C1CCNC1
Reactant: COc1ccc(C=C(Br)Br)c(C)c1C
Reactant: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COc1ccc(CC(=O)N2CCCC2)c(C)c1C
Temperature: 80 °C

Procedure:
Under an N2 atmosphere, 1-(2,2-dibromovinyl)-4-methoxy-2,3-dimethylbenzene was dissolved in a mixture of DMF (43 mL) and water (14 mL). Pyrrolidine (5.67 mL, 68 mmol) was added and the reaction was heated to 80° C. for 20 h. The reaction was diluted with Et2O and water. The layers were separated and the organic layer was washed with 0.25M HCl (aq) and brine. The organic extract was dried (Na2SO4), filtered, and concentrated in vacuo. Flash column chromatography of the residue, eluting with 0% to 100% ethyl acetate in hexanes, afforded the title compound. LC-MS ESI (pos.) m/z: 248.2 (M+H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[CH:6]([O:9][CH3:10])[O:7][CH3:8].[NH2:13][C:14]([NH2:16])=[S:15].C[O-].[K+]>CC(O)C>[CH3:8][O:7][CH:6]([O:9][CH3:10])[C:5]1[CH:4]=[CH:3][NH:16][C:14](=[S:15])[N:13]=1
Reactant: COC(OC)C(=O)C=CN(C)C
Reactant: NC(N)=S
Agent: C[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COC(OC)c1cc[nH]c(=S)n1
Yield: 73 %

Procedure:
The product from step 1 (4.8 g), thiourea (2.53 g) and potassium methylate (2.33 g) were heated together in boiling propan-2-ol (30 cm3) for 6 hours. The reaction mixture was allowed to cool overnight. The solvent was removed by evaporation under reduced pressure, the residue was dissolved in water and washed with ethyl acetate, the organic layer being discarded. The basic aqueous layer was acidified to pH 5 using glacial acetic acid and the product was extracted into ethyl acetate. Evaporation of the ethyl acetate under reduced pressure gave 3.769 g of an orange oil. 1H NMR (DMSO): δ3.46(6H,s); 5.14(1H,s); 6.94(1H,d); 7.18(1H,br s); 8.18(1H,d).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([O:22][CH3:23])[CH2:18][CH2:17]2)[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.P(=O)(O)(O)O>O>[Br:1][C:2]1[N:3]=[C:4]2[N:15]([C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Agent: O=P(O)(O)O
Solvent: O
Product: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(Br)nc32)CC1
Temperature: 80 °C

Procedure:
7-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (alternate approach). Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4-methoxycyclohexanamine.hydrochloride (1.5 equiv), NMP and DIEA were combined and heated to 127° C. and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to 35° C. over 4 h. The batch was transferred to a mixture of ethyl acetate and 5% brine. The aqueous layer was removed and the organic layer containing the batch was washed successively with 5% brine and water. The organic layer containing the batch was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected by vacuum filtration. The filter cake was washed with MTBE and the product was dried in a vacuum to give 41% yield of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate (1 equiv), water and 85% phosphoric acid (3:1) was heated to 80° C. over 1 h. Heating was maintained for 18 h to effect reaction completion. Upon reaction completion, the mixture was cooled to 25° C. and filtered to give a crude product as tan solid. The resulting solids were washed with water, slurried in water and filtered. The filter cake was washed with water until the pH of the filtrate was between 4 and 8. The resulting material was dried under vacuum to give 89% yield of 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyloxy)propan-2-yl)pyridine (1 equiv), sodium carbonate (3 equiv) and PdCl2(AmPhos)2 (0.003 equiv) were combined in isopropanol and heated at 70° C. for 1.5 h. Standard work-up and purification afforded the protected compound in 93% yield. Deprotection using standard conditions for removal of a trimethylsilyl-group and isolation gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][O:31][CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COCCOCOc1ccc(C=CC=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(C=CC=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)ccc1O

Procedure:
To a solution of 650 mg (2.1 mmol) of N-(3-benzhydroxypropyl)piperazine in dry tetrahydrofuran (5 ml) was added a solution of 818 mg (2.1 mmol) of N-[5-[3methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidihe-2-thione in dry tetrahydrofuran (6 ml) and the mixture was reacteed at room temperature for 14 hours. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was diluted with chloroform. The mixture was washed, in turn, with 2N aqueous solution of sodium hydroxide and water and the organic layer was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with 1% methanol in chloroform, to give 1.106 g (1.8 mmol) of N-[5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine. To a solution of 1.064 (2.1 mmol) of the amide compound in methanol (10 ml) was added 370 mg (1.95 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 1.5 hous under argon atmosphere. The mixture was concentrated by evaporation under reduced pressure, diluted with chloroform and washed, in turn, with a saturated aqueous solution of sodium hydrogencarbonate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a 1 to 2% methanol in chloroform, to give 730 mg (1.42 mmol) of N-[5-(3-methoxy-4-hydroxyphenyl)-2,4-pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)=O.O=[C:8]1[CH2:27][CH2:26][C:11]2[C:12]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:13]=3[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[CH2:9]1.O>CN(C)C=O>[CH3:1][N:2]([CH3:3])[CH:8]1[CH2:27][CH2:26][C:11]2[C:12]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:13]=3[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[CH2:9]1
Reactant: CNC
Reactant: O=C1CCC2=C(C1)c1ccccc1Oc1ccc(Cl)cc12
Solvent: O
Solvent: CN(C)C=O
Solvent: O=CO
Product: CN(C)C1CCC2=C(C1)c1ccccc1Oc1ccc(Cl)cc12

Procedure:
To a mixture of 10 ml of dimethylamine and 3.1 ml of 98% formic acid at -10° C. a solution of 11.5 g of 2-keto-6-chloro-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine in 30 ml of dimethylformamide are added dropwise. The mixture is refluxed for 10 hours. After cooling, the mixture is poured into water and extracted into ether. The ether layer is then washed with 300 ml of 2 N HCl. The acidic water layer is made alkaline with 2 N NaOH, after which the alkaline aqueous solution is extracted with ether once more. The ether layers are collected, dried and then evaporated. The oil obtained crystallizes as maleate: melting point 171° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([O:18]C)[C:7]([O:14]COC)=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])([CH3:3])[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl.CC(O)=O.Br>[OH:14][C:7]1[C:6]([OH:18])=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COCOc1c(OC)cc(C(C)C)cc1C(=O)OC
Agent: Br
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1cc(O)c(O)c(C(=O)O)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-Isopropyl-3-methoxy-2-methoxymethoxy-benzoate in 5 mL dry CH2Cl2 cooled to −80° C., BBr3 (3.4 mL of a 1 m solution in CH2Cl2) was added dropwise via a syringe. The mixture was then stirred 30 min. at −70° C., then the cooling bath was removed and the stirring continued at r.t. for 1 h. The reaction was the quenched by addition of H2O and the resulting mixture was extracted twice with 30 mL CH2Cl2. The combined organic fractions were dried over MgSO4 and evaporated in vacuo to yield a brown solid. This material was redissolved in 1 mL AcOH to which 2.5 mL HBr (33% in AcOH) was added The mixture was stirred at 120° C. for 5 h, then H2O was slowly added and the mixture was extracted with EtOAc. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo to yield the desired product as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-])=O)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd].[Br-].[Zn+2].[Br-]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[NH2:15])[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH3:2]
Reactant: CCOC(=O)CN(Cc1cc(Cl)ccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1cc(Cl)ccc1N)C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
To a solution of [tert-butoxycarbonyl-(5-chloro-2-nitro-benzyl)-amino]-acetic acid ethyl ester (69.0 g, 0.186 mol) in ethyl acetate (1200 ml) was added zinc bromide (8.5 g, 0.037 mol). The reaction mixture was purged with argon after 15 minutes. After addition of the palladium catalyst (10% on activated charcoal, 7.9 g, 0.0074 mol) the mixture was hydrogenated at ambient pressure during a period of ca. 48 h until ca. 13 l of hydrogen gas had been consumed. The catalyst was removed by filtration and the filtrate was washed with two portions of saturated aqueous sodium bicarbonate solution and brine, each. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (60.6 g, 95.5%) as yellow waxy solid. MS m/e: 343 (M+H+).