Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=[O:4])CC.[OH:6][C:7]([CH2:41]Br)=[C:8]([N:12]1[C:15](=[O:16])[CH:14]([NH:17][C:18](=[O:37])[CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:13]1[S:38]C=O)[C:9]([O-:11])=[O:10].[C:43]1([CH3:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:24]([O:23][C:21]([NH:20][CH:19]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:18]([NH:17][CH:14]1[C:15](=[O:16])[N:12]2[C:8]([C:9]([O:11][CH2:49][C:43]3[CH:48]=[CH:47][C:46]([O:4][CH3:1])=[CH:45][CH:44]=3)=[O:10])=[C:7]([OH:6])[CH2:41][S:38][C@H:13]12)=[O:37])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccccc1
Reactant: O=CSC1C(NC(=O)C(NC(=O)OCc2ccccc2)c2ccccc2)C(=O)N1C(C(=O)[O-])=C(O)CBr
Reactant: CCC(=O)O
Product: COc1ccc(COC(=O)C2=C(O)CS[C@@H]3C(NC(=O)C(NC(=O)OCc4ccccc4)c4ccccc4)C(=O)N23)cc1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To 0.430 g. (1.1 mmol.) of mercuric acetate in a mixture of 20 ml. of toluene and 10 ml. of propionic acid are added 0.632 g. (1 mmol.) of 3-hydroxy-4-bromo-2-[2-formylthio-4-oxo-3-(α-benzyloxycarbonylaminophenylacetamido)-1-azetidinyl]-2-butenoate, p-methoxybenzyl ester, in 20 ml. of toluene. The mixture is stirred for 30 minutes at 15° C., after which time the solution becomes cloudy. Hydrogen sulfide is bubbled into the mixture, and the mixture then is filtered through activated charcoal and a filter aide. The resulting filtrate is evaporated, and a residue comprising p-methoxybenzyl 7-(α-benzyloxycarbonylaminophenylacetamido)-3-hydroxy-3-cephem-4-carboxylate is obtained.
Reaction SMILES: O=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([O:14][CH:15]=[CH2:16])(=[O:13])[CH3:12]>>[CH3:7][C:6]1([CH3:9])[CH2:5][C:4]2([CH3:10])[CH:14]([CH2:2][CH2:3]2)[C:15](=[O:16])[CH2:8]1.[C:11]([O-:14])(=[O:13])[CH3:12]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: C=COC(C)=O
Product: CC(=O)[O-]
Product: CC1(C)CC(=O)C2CCC2(C)C1

Procedure:
The photochemical reaction system of this invention is illustrated by another dual irradiation in which the inner flask reaction is the same as in Example 1, but in which the photochemical reaction in the outer flask consists in reacting isophorone with vinyl acetate to yield 4,4,6-trimethyl bicyclo[4.2.0]octane-2-one (7 or 8) acetate: ##STR3##
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=C)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.C[N+]1([O-])CC[O:28]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=[O:28])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: C=Cc1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Reactant: C[N+]1([O-])CCOCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: Cn1ncc2cc(Cc3cnc4ccc(C=O)nn34)c(F)cc21
Temperature: 46 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
To a mixture of 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)-6-vinylimidazo[1,2-b]pyridazine (50 mg, 0.163 mmol) osmium(VIII) oxide (103 mg, 8.13 μmol), was added a solution of NMO (29.5 mg, 0.252 mmol) in acetone (2 ml) and H2O (0.16 ml). The reaction mixture was heated to 46° C. After stirring for 4 h, the solvent was removed and a mixture of THF (6 ml) and H2O (1.5 ml) was added to dissolve the residue, then sodium periodate (69.6 mg, 0.325 mmol) was added and the resulting mixture was stirred at 46° C. for 12 h. The reaction mixture was then quenched with Na2SO3(aq), extracted with DCM, dried over Na2SO4, filtered through Celite and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with gradient Hex:EA to give 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine-6-carbaldehyde (20 mg), yield 38%. 1H-NMR (400 MHz, CDCl3) δ ppm 10.09 (s, 1H), 8.07 (dd, 1H), 7.89 (d, 1H), 7.74 (s, 1H), 7.63 (m, 2H), 7.10 (d, 1H), 4.54 (s, 2H), 4.03 (s, 3H). LCMS (method A): [MH]+=310, tR=3.95 min.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([CH3:20])[CH:9]=2)=[C:5]([O:23][CH3:24])[CH:4]=1)#[N:2].[N-:25]=[N+:26]=[N-:27].[Na+].Cl.C([N:32]([CH2:35]C)CC)C.Cl>CN1CCCC1=O>[CH3:24][O:23][C:5]1[CH:4]=[C:3]([C:1]2[NH:27][N:26]=[N:25][N:2]=2)[CH:22]=[CH:21][C:6]=1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[N:10]([CH3:20])[CH:9]=1.[N+:17]([C:35]1[NH:32][N:27]=[N:26][N:25]=1)([O-:19])=[O:18]
Reactant: CCN(CC)CC
Reactant: COc1cc(C#N)ccc1Cc1cn(C)c2ccc([N+](=O)[O-])cc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(-c2nnn[nH]2)ccc1Cc1cn(C)c2ccc([N+](=O)[O-])cc12
Product: O=[N+]([O-])c1nnn[nH]1
Temperature: 150 °C
Yield: 590.3 %

Procedure:
A mixture of 3-(4-cyano-2-methoxybenzyl)-1-methyl-5-nitroindole (0.458 g.), sodium azide (0.741 g.), and triethylamine hydrochloride (0. 785 g.) in dry N-methyl-2-pyrrolidinone (6 ml.), under nitrogen, was stirred and heated at 150° C. for 1.5 hours. The mixture was cooled to ambient temperature, 1N hydrochloric acid (25 ml.) added cautiously, while stirring, the precipitated solid isolated by filtration, washed with water and dried in vacuo to give 3-[2-methoxy-4-(1-H-tetrazol-5-yl)benzyl]-1-methyl-5-nitroindole, (V) (0.484 g., 94%) as a yellow powder, m.p. 249°-250° C.; partial NMR (250 MHz, DMSO-d6): 3.82 (s,3H, NMe); 3.97(s,3H, OMe); 4.13(s,2H, ArCH2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O>[CH2:15]([O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14])[CH3:16]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc(O)ccc2c1
Reaction time: 16 h

Procedure:
A solution of 6-hydroxy-2-naphthoic acid (75.9 g, 0.40 mol) in ethanol (1.0 L) and sulfuric acid (5.0 mL) was heated to reflux under an atmosphere of nitrogen. After 16 hours, the volume was removed to approximately half via simple distillation and the resulting solution was diluted with water. The resulting cloudy mixture was extracted with EtOAc (4×) and the combined organics were successively washed with NaHCO3 (0.25 M, twice), water, brine and dried (MgSO4). The mixture was filtered and evaporated to give 6-hydroxy-naphthalene-2-carboxylic acid ethyl ester, 85.4 g (98%).
Reaction SMILES: [C:1]1(=[O:7])[CH:5]=[CH:4][C:3](=O)[CH2:2]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH:12]=O.[NH2:18][C:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH:20]=1>C(O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]2[C:20]3[C:21](=[O:25])[CH2:22][CH2:23][CH2:24][C:19]=3[NH:18][C:3]3[CH:4]=[CH:5][C:1](=[O:7])[C:2]2=3)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=C1C=CC(=O)C1
Reactant: NC1=CC(=O)CCC1
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CCO
Product: O=C1C=CC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCC1=O)N2

Procedure:
A solution of 4-cyclopentene-1,3-dione (1.14 g, 10.2 mmol), 3-bromo-4-fluorobenzaldehyde (2.05 g, 10.1 mmol), and 3-amino-2-cyclohexenone (1.14 g, 10.2 mmol) in absolute ethanol (50 mL) were magnetically stirred and heated at reflux for 36 hours. The mixture was vacuum filtered and the solid was washed with ethyl acetate-hexane. The filtrate was concentrated and the residue was chromatographed on silica gel (100 g) using EtOAc-hexane (75:25), then EtOAc, finally EtOAc—EtOH (95:5). The product was obtained as a tan crystalline solid, (720 mg, 1.92 mmol).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:38]=[CH:37][C:15]([CH2:16][C:17]2[CH:18]=[C:19]([C@@:24]34[O:31][C@@:28]([CH2:32][OH:33])([CH2:29][O:30]3)[C@@H:27]([OH:34])[C@H:26]([OH:35])[C@H:25]4[OH:36])[CH:20]=[CH:21][C:22]=2[Cl:23])=[CH:14][CH:13]=1)C1C=CC=CC=1.C(O)=O>C(O)C.O1CCCC1.[Pd]>[Cl:23][C:22]1[CH:21]=[CH:20][C:19]([C@@:24]23[O:31][C@@:28]([CH2:32][OH:33])([CH2:29][O:30]2)[C@@H:27]([OH:34])[C@H:26]([OH:35])[C@H:25]3[OH:36])=[CH:18][C:17]=1[CH2:16][C:15]1[CH:37]=[CH:38][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCCOCc5ccccc5)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Solvent: C1CCOC1
Product: OCCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of intermediate (1S,2S,3S,4R,5S)-5-(3-(4-(2-(Benzyloxy)ethoxy)benzyl)-4-chlorophenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (4 mg, 0.007 mmol) in a mixture of ethanol and tetrahydrofurane (1 mL, 4 to 1 in volume) was successively added formic acid (12 microL, 0.30 mmol) and palladium black (7.5 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 2 hours, the palladium was filtered through a pad of Celite®, the filtrate was evaporated and the residue was dried under high vacuum to afford 2.6 mg (80% yield) of the desired product. LCMS 453.5 (M+H+; positive mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 3.56 (d, J=7.8 Hz, 1 H), 3.58-3.72 (m, 4 H), 3.79 (d, J=7.8 Hz, 1 H), 3.82-3.88 (m, 2 H), 4.02 (t, J=4.9 Hz, 2 H), 4.05 (s, 2 H), 4.16 (d, J=7.6 Hz, 1 H), 6.84-6.89 (m, 2H), 7.11 (d, J=8.5 Hz, 2 H), 7.35-7.42 (m, 2 H), 7.47 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9](O)=[C:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][C:12]=3[OH:21])[C:4]2=[CH:3][CH:2]=1.[NH3:23]>>[NH2:23][C:9]1[CH:8]=[CH:7][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]=1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[OH:21]
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: N
Product: Nc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 200 °C
Yield: 91 %

Procedure:
To a 125 mL Teflon lined autoclave was added 5 g (17.5 mmol) of 1,1′-bi-2-naphthol, 23.47 g (175 mmol) of (NH4)2SO3H2O and 65 mL of concentrated aqueous ammonia. The mixture was heated in an oil-bath to 200° C. for 5 days, then cooled down to ambient temperature and filtered. The resulting solid was washed with water followed by recrystallization from benzene to afford 4.52 g (15.8 mmol, 91%) of pure 2-amino-2′-hydroxy-1,1′-binaphthyl. Enantiomerically pure NOBIN can be obtained by the resolution methods reported in the literature (Ding, K.; Wang, Y.; Yun, H.; Lin, J.; Wu, Y.; Terada, M.; Okubs, Y.; Mikami, K.; Chem. Eur. J. 1999, 5, 1734-1737).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: OCCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCOCc1ccccc1

Procedure:
The 3-benzyloxypropanol (Aldrich, 0.28 g, 1.7 mmol), triethylamine (0.67 mL, 5.0 mmol), and methanesulfonyl chloride (0.19 mL, 2.5 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:18][CH:19]=O>CCO>[N:1]1[CH:18]=[CH:19][N:3]2[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=12
Reactant: O=CCCl
Reactant: COC(=O)c1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccn2ccnc2c1
Yield: 72.2 %

Procedure:
To a solution of Methyl 2-aminopyridine-4-carboxylate (10.0 g, 66 mmol, 1.0 equiv) in EtOH (150 ml) was added NaHCO3 (11.1 g, 132 mmol, 2.0 equiv) followed by chloroacetaldehyde (50% by weight in water, 13.0 ml, 99 mmol, 1.5 equiv). The mixture was refluxed for 2 h. Solvents were removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The resulting precipitate was washed with Et2O and recrystallised from MeOH/Et2O to afford 8.4 g of product. 1H NMR (400 MHz, DMSO-d6): 8.66 (1H, d), 8.16 (2H, s), 7.80 (1H, s), 7.33 (1H, d), 3.90 (3H, s). MS: [M+H]+ 177.
Reaction SMILES: [K].[CH2:2]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(N(C)C)=O>O>[CH2:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Brc1ccccc1
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCc1cccc(Oc2ccccc2)c1
Temperature: 150 °C

Procedure:
Into the round bottom flask containing potassium salt of 3-pentadecyl phenol is added bromobenzene followed by Cu powder and in a solvent, DMAc (dimethyl acetamide). The reaction mixture is heated at 150° C. for 6 h. After completion of the reaction, the obtained dark colored reaction mixture is poured into water and the Cu salts are removed by filtration. The filtrate is extracted in a solvent, washed with water and dried, purified to obtain arylated product, 1-pentadecyl-3-phenoxybenzene.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[CH:15](=O)[CH2:16][CH2:17]C.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O.O1CCCC1>[CH3:14][N:13]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[N:2]([CH3:20])[CH:1]1[CH2:15][CH2:16][CH3:17]
Reactant: CCCC=O
Reactant: CNc1cccc2cccc(NC)c12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1N(C)c2cccc3cccc(c23)N1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of N,N'-dimethyl-1,8-naphthalene diamine (prepared in Example 1) (0.93 g, 5 mmol), distilled butyraldehyde (0.43 g, 6 mmol), p-toluene sulfonic acid (5 mg), and tetrahydrofuran (5 ml), was stirred at room temperature for 15 minutes. The mixture was basified with 25% sodium hydroxide (1.0 ml), diluted with water (20 ml) and extracted with ethyl ether (100 ml). The extract was dried over potassium carbonate and concentrated to an oil which was recrystallized from ether-hexane to give crystals of 2,3-dihydro-1,3-dimethyl-2-propyl perimidine: mp 70°-71° C.; NMR (CDCl3) 7.08(m, 4H), 6.29(m, 2H), 4.22(t, 1H), 3.03(s, 6H), 1.4(m, 4H), 0.8(t, 3H); IR (KBr) 1592, 1582 cm-1.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:9][C:10](=O)[NH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[N:11]=[N:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[CH:9]=1
Reactant: O=c1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCCCC2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCCCC2)nn1
Temperature: 80 °C
Yield: 44.4 %

Procedure:
A suspension of 6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-2H-pyridazin-3-one (0.62 mmol, 0.22 g) in phosphorous oxychloride (6.7 mmol, 0.60 mL) was heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (25 mL), washed with water (25 mL), saturated NaHCO3 (2×10 mL) and dried (Na2SO4). The residue was purified on a 12 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to give 6-chloro-3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.102 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[CH:41][CH:40]=[CH:39]2)(=[O:33])=[O:32])[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[C:13]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[NH:27])=[CH:24][CH:23]=1)=[N:12]2)=[O:6])[CH3:3].[C:44](=[O:47])([O-])[O-:45].[K+].[K+].C(=O)([O-])OC1C=CC([N+]([O-])=O)=CC=1[CH2:61][CH2:62][S:63]([CH3:66])(=[O:65])=[O:64]>O1CCCC1>[CH2:2]([O:4][C:5]([CH2:7][N:8]([S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[CH:41][CH:40]=[CH:39]2)(=[O:32])=[O:33])[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[C:13]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH2:28])=[N:27][C:44]([O:45][CH2:61][CH2:62][S:63]([CH3:66])(=[O:65])=[O:64])=[O:47])=[CH:29][CH:30]=1)=[N:12]2)=[O:6])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)c(=O)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: CS(=O)(=O)CCc1cc([N+](=O)[O-])ccc1OC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OCCS(C)(=O)=O)cc1)c(=O)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
0.5 g (0.77 mmol) of 4-{[6-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}-benzamidine-hydrochloride, 0.32 g (2.3 mmol) of potassium carbonate and 0.39 g (1.4 mmol) of 2-(methylsulphonyl)-ethyl-4-nitrophenyl carbonate are stirred in 40 ml tetrahydrofuran for 54 hours at ambient temperature. The solvent is distilled off and the residue is taken up in methylene chloride and sodium hydrogen carbonate solution. The combined organic extracts are dried and evaporated down. The residue is chromatographed on aluminium oxide and eluted with methylene chloride+1-5% ethanol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH:10]=[CH:11][C:12]=1[Cl:13].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:29](O)=[O:30].N1C=CC=CC=1>O>[Cl:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[NH:6][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:34]([N:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)=[C:26]([F:25])[CH:27]=1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2F)CC1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CN1CCN(c2ccc(C(=O)Nc3cc(NC(=O)c4ccc(C#N)cc4)ccc3Cl)cc2F)CC1
Temperature: -10 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
Phosphoryl chloride (0.1 I ml) was added dropwise to a stirred mixture of N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.2 g), 3-fluoro-4-(4-methylpiperazin-1-yl)benzoic acid (0.26 g) and pyridine (2 ml) which had been cooled to −10° C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was diluted with water and was stirred overnight. The precipitate was isolated, washed with diethyl ether and dried under vacuum at 55° C. There was thus obtained the title compound as a solid (0.212 g);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Sc2ncc(Br)cn2)cc1
Yield: 74 %

Procedure:
A solution of 5-bromo-2-chloropyrimidine (5 g, 0.026 mol), 4-aminothiophenol (3.24 g, 0.026 mol), and K2CO3 (7.14 g, 0.052 mol) in dry DMSO (50 mL) was stirred at 120 ° C. for 2.5 hours under N2. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried. The solvent was evaporated to give a residue that was purified by silica gel flash column chromatography (ethyl acetate-hexane 1:3) to give 4-(5-bromopyrimidin-2-ylsulfanyl)phenylamine (4n), yield 74%. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 7.37 (d, J) 8.0 Hz, 2H), 6.72 (d, J) 8.0 Hz, 2H), 2.63 (s, 2H); EI-MS m/z 281 [M]+, 283 [M+2]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH2:40])=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH:40][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][CH2:10][C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Reactant: O=C(O)c1ccccc1NCc1c[nH]c2ncccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3c[nH]c4ncccc34)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-benzoic acid (Step A, 516 mg, 2.0 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol), TBTU (0.706 g, 2.2 mmol), and DIEA (0.7 mL) in 30 mL of CH2Cl2 was stirred at RT for 2 h, then diluted with more CH2Cl2. The organic layer was washed with water, brine, dried with MgSO4, filtered, and condensed. The residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2), to obtain the titled compound as oil. MS (ES+): 526 (M+H)+. Calc'd for C31H35N5O3-525.27.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH3:16][O:17][CH2:18]Cl>O1CCCC1>[CH3:16][O:17][CH2:18][C:4]1([C:6]#[N:7])[CH2:5][C:2](=[CH2:1])[CH2:3]1
Reactant: COCCl
Reactant: C=C1CC(C#N)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1CC(C#N)(COC)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-methylenecyclobutanecarbonitrile (1.00 g, 0.0107 mol) in tetrahydrofuran (40 mL, 0.5 mol) was added 2.00 M of lithium diisopropylamide in tetrahydrofuran (6.44 mL) at −78° C. After stirred at −78° C. for 30 min, to the resulting mixture was added chloromethyl methyl ether (1.02 mL, 0.0134 mol). The reaction was stirred at −78° C. for 30 min, then allowed to warm up to rt, quenched with ammonium chloride, then extracted with ether. The combined organic layers were washed with water, brine, dried, and evaporated to dryness. The crude residue was used directly in next step.