Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:33])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:33][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]1
Reactant: CC1CCN(CCc2ccc(N)cc2Cl)CC1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Solvent: CN(C)C=O
Product: CC1CCN(CCc2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared in DMF analogously to Example 143 starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethyl]-phenylamine (Z46c). The crude product was purified by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether/EtOAc 3:1→2:1) and then triturated with petroleum ether.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: O=C1NCCc2ccc(Br)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)ccc2CCN1c1ccc(F)cc1
Temperature: 130 °C
Yield: 47.1 %

Procedure:
A mixture of 7-bromo-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 23-1, 60 mg, 0.265 mmol), 1-fluoro-4-iodobenzene (118 mg, 0.531 mmol), potassium carbonate (36.7 mg, 0.265 mmol) and copper (I) iodide (10.11 mg, 0.053 mmol) in DMF (1.000 mL) was heated at 130° C. for 5 h. The mixture was cooled to rt and filtered through a Celite pad, and the solids were washed with EtOAc. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 60:40 hexane-EtOAc) to give 7-bromo-2-(4-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one (40 mg, 47%). 1H NMR (400 MHz, chloroform-d) δ 7.15-7.27 (4 H, m), 7.04-7.13 (2 H, m), 6.48 (1 H, d, J=1.94 Hz), 2.96-3.08 (2 H, m), 2.73-2.84 (2 H, m). Mass spectrum m/z 320, 322 (M+H)+.
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[C:22]([CH2:28]O)[CH:21]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:44]1([CH2:50][CH2:51][CH2:52][NH2:53])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[O:1]([CH2:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[CH2:26][N:53]([CH2:52][CH2:51][CH2:50][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:28]2)[Si:2]([C:15]([CH3:18])([CH3:16])[CH3:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCCc1ccccc1
Reactant: CC(C)(C)[Si](OCc1ccc(CO)c(CO)c1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OCc1ccc2c(c1)CN(CCCc1ccccc1)C2)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.867 g (14.429 mM) of [4-(tert-butyldiphenylsiloxymethyl)-2-hydroxymethylphenyl]methanol and 12.6 ml (72.1 mM) of N,N-diisopropylethylamine in 100 ml of acetonitrile was added a solution of 3.47 g (30.3 mM) of methanesulfonyl chloride in 10 ml of acetonitrile dropwise with ice-cooling and the mixture was stirred at 0° C. for 0.5 hour. To this reaction mixture was added 2.15 g (15.9 mM) of 3-phenylpropylamine and the mixture was stirred at 80° C. overnight. The solvent was then distilled off under reduced pressure and the residue was diluted with aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to provide the title compound.
Reaction SMILES: [CH2:1]([C:3](O)([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:4]#[CH:5])[CH3:2].C[O:14][C:15]([CH3:17])=[CH2:16]>>[CH2:1]([C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:4][CH:5]=[CH:16][C:15](=[O:14])[CH3:17])[CH3:2]
Reactant: C#CC(O)(CC)CCC=C(C)C
Reactant: C=C(C)OC
Product: CCC(=CC=CC(C)=O)CCC=C(C)C

Procedure:
The acid catalysed reaction of 3-ethyl-7-methyl-oct-1-yn-6-en-3-ol with isopropenyl methyl ether and subsequent base-catalysed isomerisation of the resulting β-ketoallene (G. Saucy, R. Marbet, Helv. 50, 1158, 1967) gave a good yield of 6-ethyl-10-methyl-undeca-3,5,9-trien-2-one which was cyclised with 85% phosphoric acid in a known manner [H. Rouve, M. Stoll, Helv. 30, 2216 (1947)]. The resulting product contained 90% 11-methyl-α-ionone and 11-methyl-γ-ionone (two isomers) in the ratio of 7:3. In a manner analogous to the epoxidation of α-ionone (Example 4), from 13.4 g (0.065 mol) of 11-methyl-α-ionone there were obtained 13.9 g of crude 11-methyl-α-ionone epoxide of which 13.4 g (~0.06 mol) were dissolved together with 6.1 g (0.03 mol) of aluminium isopropylate in 30 ml of isopropanol. By following the procedure described in Example 1 there were obtained 13.7 g of a crude product. From this crude product there were obtained by distillation over a 5 cm Widmer column 2.10 g (17%) of olfactorily good product of boiling point 73°-75° C./0.05 mmHg and which contained above 85% 17 and the corresponding 7-oxa-bicyclooctane 17a. A sample purified by means of preparative GC showed the following spectral data:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CCN(CC)CC.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([N:13]1[CH2:12][CH2:11][CH:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:17]=[CH:16][C:5]=3[N:6]=2)[CH2:15][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc2nc(OC3CCN(Cc4ccccc4)CC3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of Compound 1B (4.32 g, 13.79 mmol) in THF (100 mL) was added Et3N (3.84 mL, 27.6 mmol) followed by (bromomethyl)benzene (1.64 mL, 13.8 mmol). Upon completion of addition, the reaction mixture was stirred at rt overnight. After this time, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL), and then extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (40 mL) and dried (MgSO4). The solvent was removed and the resulting residue was recrystallized from MeOH to give Compound 14A as a white solid (2.12 g, 5.26 mmol, 38% yield). LC/MS (m/z)=404 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.Cl[S:13]([OH:16])(=[O:15])=[O:14].CO>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:6][C:7]=1[S:13]([OH:16])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)(C)c1cccc(Br)c1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a cooled (0° C.) solution of commercially available 1-bromo-3-tert-butylbenzene (42.6 g; 199 mmol) in anhydrous dichloromethane (800 mL) was added chlorosulfonic acid (15.9 mL; 239.0 mmol) dropwise. After addition was complete, the reaction was stirred at 0° C. for an additional 30 minutes, allowed to gradually warm to room temperature and further stirred overnight. The reaction mixture was concentrated under reduced pressure to about 500 mL and washed with aqueous hydrochloric acid (20 mL; 20N). The organic layer was separated and dried over magnesium sulfate which resulted in formation of a white precipitate. Methanol (200 mL) was added to dissolve the precipitate. The organic solution was filtered and concentrated under reduced pressure to yield the title product as a white solid (53.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11]Cl)[CH:7]=1.[OH-].[NH4+:14]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][NH2:14])[CH:5]=[N:4][CH:3]=1
Reactant: [NH4+]
Reactant: ClCCCOc1cncc(Cl)c1
Agent: [OH-]
Solvent: CO
Product: NCCCOc1cncc(Cl)c1
Temperature: 100 °C
Yield: 63.4 %

Procedure:
The 3-chloro-5-(3-chloropropoxy)pyridine (5.74 g, 28.0 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 55 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 3.30 g (63.4%) of an oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.Cl.CC1C=CN=C(N)C=1C.[CH2:40]([NH:44][C@H:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:46]=[CH2:47])[CH:41]([CH3:43])[CH3:42]>C(Cl)Cl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:16][CH:17]=[CH2:18])[C:13]([N:44]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:46]=[CH2:47])=[O:15]
Reactant: C=CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: C=C[C@H](NCC(C)C)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Product: C=CCC(C(=O)N(CC(C)C)[C@@H](C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pent-4-enoic acid (467 mg), EDAC.HCl (529 mg), and dimethyl aminopyridine (20 mg) in DCM (10 ml) at −20° C. under N2 was added a solution of (1S)-N-isobutyl-1-phenylprop-2-en-1-amine in DCM (6 ml). The mixture was allowed to stir at −20° C. for 1 hr then RT overnight. The next day the reaction was diluted with DCM and extracted with 0.1 N HCl. The aqueous layer was back extracted with DCM (×2). All organics were combined, dried (Na2SO4), filtered and evaporated. The resulting residue was purified by column chromatography (20% EtAOc/Hexane) to afford the title compound as a mixture of diastereomers in the form of a clear oil (628 mg, 82%). 1H NMR (300 MHz, d6-DMSO) δ 0.50-0.732 (m, 7H), 1.24-1.98 (m, 3H), 2.15-2.26 (m, 1H), 2.73-3.3 (m, 4H), 4.74-5.42 (m, 4H), 5.75-6.24 (m, 3H), 6.99-7.38 (m, 5H), 7.79-7.88 (m, 4H). MS APCI, m/z=417 (M+1), LC/MS, 2.93 min.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=O)[NH:18][N:17]=2)[CH:11]=1.[NH3:28]>>[F:27][C:2]([F:26])([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:20]=[C:19]([C:21]([NH2:28])=[O:23])[NH:18][N:17]=2)[CH:11]=1
Reactant: CCOC(=O)c1cc(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n[nH]1
Reactant: N
Product: NC(=O)c1cc(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n[nH]1
Yield: 74 %

Procedure:
The pyrazole ester (47 mg, 0.1 mmol) from Step 2 was treated with ammonia gas in a sealed tube as described in Step 2 of EXAMPLE 140 to provide the titled compound, after purification by reverse phase HPLC (acetonitrile/water system) (gradient: 40% to 100% acetonitrile over 11 minutes) in 74% yield (0.036 g, retention time 6.57 minutes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=2[CH:20]=[C:19]([CH3:28])[N:18]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:16][C:17]1[C:26]2[C:21](=[C:22]([NH:27][C:10]([NH:9][CH2:8][C:6]3[CH:5]=[CH:4][C:3]([C:12]([F:13])([F:14])[F:15])=[C:2]([F:1])[CH:7]=3)=[O:11])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([CH3:28])[N:18]=1
Reactant: Cc1cc2c(N)cccc2c(C)n1
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2c(C)n1
Temperature: 25 °C

Procedure:
The product from Example 205A (4.4 mmol) in toluene (10 mL) was treated with 1,3-dimethyl-5-isoquinolinamine (375 mg, 2.18 mmol) and DIEA (3.5 mL). The mixture was heated at 80° overnight. After cooling to room temperature, the precipitated solids were collected by filtration and chromatographed on silica gel (98:2 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.13 (d, 1H, J=7.8 Hz), 7.75-7.83 (m, 2H), 7.61 (s, 1H), 7.38-7.51 (m, 3H), 7.18 (t, 1H, J=6.1 Hz), 4.46 (d, 2H, J=5.8 Hz), 2.84 (s, 3H), 2.59 (s, 3H); MS (ESI+) m/z 392 (M+H).
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].C1(C)C=CC=CC=1.[OH-].[Na+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CN(C)C=O>[CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([O:7][CH2:20][CH:22]1[O:24][CH2:23]1)=[O:6])[CH2:2][CH3:3]
Reactant: ClCC1CO1
Reactant: CCCC(CCC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCC(CCC)C(=O)OCC1CO1
Reaction time: 6 h

Procedure:
Into a flask were introduced 70 g (0.48 mol) of di-n-propylacetic acid, 250 ml of toluene and 30 ml of N,N-dimethylformamide. After this operation, 40 g of 50%-aqueous solution of sodium hydroxide were added. This mixture was heated to 60°-80° C. and 138.7 g (1.5 mol) of epichlorhydrine were introduced. The reaction medium was maintained under stirring for 6 hours at 70°-80° C. and then concentrated in a rotary evaporator. After extraction with ethyl ether, the organic fractions were collected and distilled under 1 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH:7]=[C:8]([O:9][CH3:10])[C:4]=2[CH:3]=1.[H-].[Na+].[C:15]([O:18][CH2:19][CH2:20]Br)(=[O:17])[CH3:16]>CN(C=O)C>[CH3:10][O:9][C:8]1[C:4]2[CH:3]=[C:2]([O:1][CH2:20][CH2:19][O:18][C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][C:5]=2[O:6][CH:7]=1
Reactant: CC(=O)OCCBr
Reactant: COc1coc2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1coc2ccc(OCCOC(C)=O)cc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
164 mg (1.0 mmol) XXI and 48 mg (1.2 mmol, 60%) NaH were stirred for 30 mins. in 20 ml DMF at 0° C. 227 μl (2.0 mmol, 97%) 2-bromoethyl acetate were added to the resulting suspension which was then stirred for 72 h at room temperature. The reaction was quenched by addition of 3 ml saturated NH4Cl solution and the solvents were removed in vacuo. The residue was taken up in ethyl acetate and water, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over Na2SO4. After column filtration (40 g SiO2, n-hexane:ethyl acetate=2:1, applied with ethyl acetate), XXII was obtained in a yield of 220 mg (0.88 mmol, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C1CCNC1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol) Pyrrolidine (85 mg, 1.2 mmol) DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 294 (31.3 mg, yield: 5.9%). 1HNMR (DMSO-d6, 400 MHz): δ8.81 (s, 1H), 8.38 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.98-7.97 (m, 1H), 7.78-7.77 (m, 1H), 7.76-7.78 (m, 2H), 7.46-7.40 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.48 (t, J=4.4 Hz, 1H), 7.26 (s, 1H), 6.60 (d, J=8.8 Hz, 1H), 4.38 (s, 2H), 3.54 (s, 3H), 3.22 (s, 2H), 2.07 (s, 4H). ESI-MS: m/z=529 [M+H+]
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1([C:11](=[O:13])[CH3:12])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1([C:11](=[O:13])[CH2:12][Br:36])[CH2:9][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C1(C(C)=O)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)C1(C(=O)CBr)CC1
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a stirred solution of 15 (3.30 g, 17.9 mmol) in methylene chloride (150 mL) and triethylamine (5.01 mL, 3.61 g, 35.7 mmol), was added dropwise triethylsilyl trifluoromethanesulphonate (4.07 mL, 4.72 g 17.9 mmol) at 0° C. After 20 minutes, N-bromosuccinimide (3.53 g, 19.8 mmol) was added, and the cooling bath was removed. Water (50 mL) was then added, and the mixture was extracted with methylene chloride (3×100 mL). The organic phase was dried over anhydrous MgSO4, concentrated under reduced pressure, and the residue was purified by column chromatography (3-10% ethyl acetate/hexane) to give 3.42 g (13.0 mmol; 73% yield) of 16. 1H NMR MHz, CDCl3) δ 0.96 (3H, t, J=7.4 Hz), 1.47 (2H, m), 1.60-1.66 (6H, m), 4.16 (2H, t, J=6.7 Hz), 4.50 (2H, s). 13C NMR (100 MHz, CDCl3) δ 13.7, 19.2, 21.2, 30.5, 33.2, 35.1, 65.5, 170.4, 197.6. MS (EI) m/z 264 (40, M+), 262 (39, M+), 208 (20), 206 (20), 190 (56), 188 (54), 183 (71), 169 (100); exact mass (ESI) calculated for C10H15O3BrNa ([M+Na]+) 285.0102, found 285.0114.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH:13]1[CH2:18][N:17]2[C:19](=[O:29])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=[C:16]2[N:15]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:31]=2)[CH2:14]1)C1C=CC=CC=1.ClCCl.[H][H]>[Pd].CO>[NH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][N:17]2[C:19](=[O:29])[CH:20]=[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:22]=[C:16]2[N:15]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:31]=2)[CH2:14]1
Reactant: O=C(NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1

Procedure:
A solution of {2-[6-Oxo-1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,3,4,6-tetrahydro-2H-pyrimido[1,2-a]pyrimidin-3-yl]-ethyl}-carbamic acid benzyl ester (100 mg, 0.17 mmol), dichloromethane (5 mL) and methanol (15 mL) was added 10% palladium on carbon (5 mg) and stirred at room temperature over an atmosphere of hydrogen overnight. Reaction filtered through a bed of Celite, and solvent removed under vacuum to afford a white solid. M+1=468.
Reaction SMILES: C(S[C:9]1[N:14]=[N:13][C:12]2[CH2:15][CH2:16][N:17]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][C:11]=2[CH:10]=1)C1C=CC=CC=1.O.[NH2:28][NH2:29]>C(O)C>[C:19]([N:17]1[CH2:16][CH2:15][C:12]2[N:13]=[N:14][C:9]([NH:28][NH2:29])=[CH:10][C:11]=2[CH2:18]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)N1CCc2nnc(SCc3ccccc3)cc2C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A solution of 4.0 g of 3-benzylmercapto-6-benzoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 1.5 g of hydrazine hydrate in 10 cc of 95% ethanol is heated in an autoclave at a bath temperature of 150° for 16 hours. The oil obtained after concentrating the reaction mixture in a vacuum, is divided between chloroform and a small amount of water, and the organic phase is concentrated to a red oil. The title compound is obtained by crystallization from dimethyl formamide. M.P. 220°-223° (decomp.).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]([CH:13](P(OC)(OC)=O)[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12].[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[N+:42]([O-:44])=[O:43])[CH:37]=O)([O-:33])=[O:32]>O1CCCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[CH:37][C:36]1[CH:39]=[CH:40][C:41]([N+:42]([O-:44])=[O:43])=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,1,3,3-Tetramethylguanidine (41.2 mL, 329 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-alpha-phophonoglycine trimethyl ester (114.1 g, 344 mmol) in tetrahydrofuran (800 mL). The mixture was stirred at room temperature for 15 min and cooled to −78° C. A solution 3,4-dinitro-benzaldehyde (61.4 g, 313 mmol) in tetrahydrofuran (200 mL) was slowly added via cannula. The resulting mixture was stirred at −78° C. for 2 h and then allowed to warm to room temperature overnight. Solvents were removed in vacuo, and the yellow residue was dissolved in 4.5 L of ethyl acetate. The solution was washed with 1.5 L of 1N sulfuric acid, water twice, brine and dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was crystallized from ethyl acetate (20 g crude product/100 mL of ethyl acetate). The yellow crystals were collected and further purified by chromatography on silica gel using methylene chloride as eluent. The title compound was obtained a s yellow crystals (77%). 1H-NMR (CDCl3, 500 MHz) δ 7.85 (d, J=1.5 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.5, 1.5 Hz, 1H), 7.35–7.34 (m, 3H), 7.34 (br s, 2H), 7.23 (s, 1H), 6.95 (br s, 1H), 5.07 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8](C)[C:9](=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][CH3:9]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
3.6 g (12.7 mmol) of tert-butyl (3-bromophenyl)-N-methylcarbamate, prepared in a manner analogous to Example 1b), are dissolved in 15 ml of dichloromethane. 5 ml of trifluoroacetic acid are added and the reaction mixture is stirred at ambient temperature for 1 hour. The reaction is halted by the addition of 50 ml of a saturated sodium hydrogencarbonate solution and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 50/50). 2.14 g of 3-bromo-N-methylaniline are obtained in the form of an oil. Yield=90%.