Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(C)=CC(C)=CC=1C.C([Li])CCC.Br[C:17]1[CH:18]=[C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:20][CH:21]=1.[Cl-].[NH4+].[O:32]1CCC[CH2:33]1>CCCCCC.C(OCC)(=O)C.CN(C)C=O>[CH:33]([C:17]1[CH:18]=[C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:20][CH:21]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)Cc1cc(Br)cs1
Reactant: C1CCOC1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Cc1cc(C=O)cs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-1,3,5-trimethylbenzene (1.22 g) in tetrahydrofuran (20.0 mL) was added a 1.59 M solution of n-butyllithium in n-hexane (3.86 mL) at −78° C., followed by stirring at −78° C. for 30 minutes. Subsequently, a solution of tert-butyl (4-bromo-2-thienyl)acetate (1.55 g) in tetrahydrofuran (15.0 mL) was added thereto, followed by stirring at −78° C. for 30 minutes. Subsequently, a 1.59 M solution of n-butyllithium in n-hexane (3.51 mL) was added thereto at −78° C., followed by stirring at −78° C. for 30 minutes. Further, N,N-dimethylformamide (0.451 mL) was added thereto, followed by stirring at −78° C. for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl (4-formyl-2-thienyl)acetate (355 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.[OH-].[Na+].CCOC(C)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CCCCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:13][CH:15]2[CH2:16][O:17]2)[C:3]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1c(C)cccc1O
Reactant: ClCC1CO1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)Nc1c(C)cccc1OCC1CO1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-methyl-2-acetamidophenol (0.165 g, 1 mmol), and epichlorohydrin (1.84 g, 20 mmol) was stirred at 70° C. to afford a clear solution. Triethylbenzylammonium chloride (0.15 g, 1 mmol) was then added and stirring was continued at 125° C. for 15 minutes. After cooling to room temperature 1M NaOH solution was added and the solution was extracted with dichloromethane. The organic extract was washed with water and dried. After evaporation of the dichloromethane the resulting brownish oil was purified through silica chromatography 50-70% EtOAc in heptane yielding the product as a colourless oil (0.12 g, 0.54 mmol).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1([N:12]2[C:16]([NH2:17])=[C:15]([C:18]#[N:19])[C:14]([CH3:20])=[N:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(O)(=O)C>[CH:6]1([N:12]2[C:16]([NH2:17])=[C:15]([C:18]([NH2:19])=[O:2])[C:14]([CH3:20])=[N:13]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Cc1nn(C2CCCCC2)c(N)c1C#N
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nn(C2CCCCC2)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To concentrated sulfuric acid (50 ml) at 0° C. was added 1-cyclohexyl-3-methyl-4-cyano-5-amino-1H-pyrazole (2.2 g, 10.8 mmol). The reaction mixture was warmed to room temperature and stirred for 24 hours. The solution was poured into ice/concentrated ammonium hydroxide, the solution was then neutralized with acetic acid and extracted with dichloromethane (2×400 ml). The solvent was removed in vacuo, the residue was extracted with ethyl acetate (75 ml) and treated with DARCO. The solution was filtered, the solvent was removed in vacuo and the residue was dissolved in ether and cooled. A precipitate was obtained which was collected by filtration, washed with ether and dried at 50° C. in high vacuum for 60 hours to afford 1.83 g (76%) of 1-cyclohexyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide as yellow needles, m.p. 181°-182° C.
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12](O)=[C:11]([Cl:16])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:6][CH3:7])=[C:11]([Cl:16])[CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Under nitrogen, 7.3 mL (77 mmol) of dimethylsulfate was added to a stirred suspension of 10 g (48 mmol) of 4-bromo-2-chlorophenol and 5.4 g (38 mmol) of powered K2CO3 in 75 mL of fresh acetone. After 2 hours at reflux, the reaction was cooled to ambient temperature, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate; the resulting solution was washed with water and dried over MgSO4. Concentration in vacuo gave 10.2 g (96%) of 4-bromo-2-chloroanisole as a colorless solid: mp 68.5-70.5° C.; NMR (CDCl3) δ 3.88 (s, 3H), 6.80 (d, J=9 Hz, 1H), 7.33 (dd, J=2, 9 Hz, 1H), 7.50 (d, J=2 Hz, 1H).
Reaction SMILES: C[Mg]Br.[C:4]([NH:7][C:8]1[CH:13]=[C:12]([C:14]2[O:15][C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[C:17]([C:19](N(OC)C)=[O:20])[N:18]=2)[C:11]([CH3:32])=[CH:10][N:9]=1)(=[O:6])[CH3:5].Cl.[C:34]([O-])(O)=O.[Na+]>>[C:19]([C:17]1[N:18]=[C:14]([C:12]2[C:11]([CH3:32])=[CH:10][N:9]=[C:8]([NH:7][C:4](=[O:6])[CH3:5])[CH:13]=2)[O:15][C:16]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])(=[O:20])[CH3:34]
Reactant: O=C([O-])O
Reactant: CON(C)C(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl
Agent: C[Mg]Br
Agent: Cl
Agent: [Na+]
Product: CC(=O)Nc1cc(-c2nc(C(C)=O)c(-c3ccccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Methylmagnesium bromide (3.0 M in diethyl ether, 0.18 mL, 0.53 mmol) was added to 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-N-methoxy-N-methyl-1,3-oxazole-4-carboxamide (0.19 g. 0.45 mmol) in THY (1 mL) under an atmosphere of argon at 0° C. The reaction mixture was allowed to warm to rt and stir overnight and then additional methylmagnesium bromide (3.0 M in diethyl ether, 0.30 mL, 0.90 mmol) was added. The reaction mixture was then allowed to stir for 24 hr. Aqueous HCl was added and then the mixture was basified with NaHCO3 and washed with EtOAc. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-{4-[4-acetyl-5-(2-chlorophenyl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.12 g, 54%). LCMS (FA): m/z=370.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=457.0, tR (minutes, Method G)=3.02
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH3:13])[C:3]1=[O:14].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.ClCCl>[C:22]([O:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH3:13])[C:3]1=[O:14])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCN1C(=O)C(O)c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C

Procedure:
To a flame dried flask cooled under argon was added the crude 3-hydroxy-1-propylindolin-2-one (0.1 grams, 0.52 mmol) and DMAP (0.007 grams, 0.057 mmol). This was taken up in 5.0 mL of dichloromethane. While stirring at room temperature triethyl amine (78 μL, 0.57 mmol) was added followed by benzoyl chloride (67 μL, 0.57 mmol). The reaction stirred at room temperature until all of the starting material had been consumed. Once complete, the reaction was diluted with water, and the two layers separated. The aqueous layer was washed with dichloromethane twice. The combined organic solution was dried with sodium sulfate, filtered, and concentrated. Chromatography on silica gel using Hexanes/Ethyl acetate (8:2) afforded the desired compound. Yield, 67% for the two steps. 1H-NMR δ 8.11 (d, 2H), 7.58 (dd, 1H), 7.44 (m, 3H), 7.36 (t, 1H), 7.05 (t, 1H), 6.89 (d, 1H), 6.19 (s, 1H), 3.72 (m, 2H), 1.77 (m, 2H), 1.03 (t, 3H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:18]1([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: OCCO
Solvent: CCCCCC
Product: c1ccc(CNc2ccccc2)cc1
Yield: 90.6 %

Procedure:
The general procedure under argon or air was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.6) afforded N-(phenyl)benzylamine (166 mg, 91% isolated yield) as colorless liquid. Spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745-1748.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([Cl:37])[CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([Cl:37])[CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccccc3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(3-chloro-4-Methylphenyl)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 14 mg of 2-(benzamido)-4-(3-chloro-4-methylphenyl)benzoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-methoxyphenyl)benzoate (472 mg, 1.0128 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10 ml) and 1,4-dioxane (20 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (100 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (440 mg, 0.9734 mmol, 96%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=[CH:3][C:2]([O:1][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:11][CH:10]=2)=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.7 g, 6.3 mmol), ethyl 5-bromopentanoate (1.4 g, 7.0 mmol), potassium carbonate (0.97 g, 7.0 mmol) and N,N-dimethylformamide (30 ml) was stirred at 50° C. for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 5-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}pentanoate (2.2 g, yield 67%) as crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[NH3:25]>CN(C=O)C>[NH2:25][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: N
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N
Yield: 85.2 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28 in 30 ml of DMF was stirred at room temperature while NH3 was bubbled in. Reaction was monitored by GC. The residue was kugelrohr distilled at 80 Pa, pot temperature 106° C., giving 4.17 g (85.2%) of product as a yellow solid; mp 69°-70° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: Cc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 4 h
Yield: 18.6 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (200 mg), piperazine (250 mg) in anhydrous DMSO (2 ml) was stirred at 70° to 80° C. for 4 hours. After the reacting mixture was concentrated under reduced pressure, to the resulting residue was added methanol and the resulting precipitate was filtered off. After the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography eluting chloroform-methanol (20:1) chloroform-methanol-concentrated aqueous ammonia (10:10:1) and further purified by preparative thin layer chromatography eluting chloroform-methanol (20:1)→chloroform methanol-concentrated aqueous ammonia (10:10:1→10:10:3) to give the title compound (46 mg) as redish powder, mp 300° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH:16]=[C:15]2[C@@H:5]([CH2:6][C:7]3[C:17]4[C:10](=[CH:11][CH:12]=[CH:13][C:14]2=4)[NH:9][CH:8]=3)[N:4]([CH3:18])[CH2:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[CH3:18][N:4]1[C@H:5]2[C:15]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:17]=3[C:7]([CH2:6]2)=[CH:8][NH:9]4)=[CH:16][C@H:2]([NH:1][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1C[C@@H](N)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C[C@@H](NC(=O)C(C)(C)C)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5.5 g 8α-amino-6-methyl-9,10-didehydro-ergoline in 200 ml CH2Cl2 is cooled to 0° and treated with 6.44 ml triethylamine followed by dropwise addition of 2.97 ml pivaloyl chloride. The mixture is stirred for 2 hours at room temperature and washed with water. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on 200 g silica gel using 98:2 CH2Cl2 /CH3OH and then crystallized from ether to yield 6-methyl-8α-pivaloylamino-9,10-didehydro-ergoline, m.p. 158°-159°.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[C:13](=[O:26])[CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[N:27]1([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[N:28]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:20]1([CH2:19][CH2:18][CH2:17][N:14]2[CH:15]=[CH:16][C:11]([C:9]3[CH:8]=[N:7][N:6]4[C:2]([C:36]5[CH:35]=[CH:34][CH:33]=[C:32]([N:27]6[CH:31]=[CH:30][CH:29]=[N:28]6)[CH:37]=5)=[CH:3][N:4]=[C:5]4[CH:10]=3)=[CH:12][C:13]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: O=c1cc(-c2cnn3c(Br)cnc3c2)ccn1CCCN1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=c1cc(-c2cnn3c(-c4cccc(-n5cccn5)c4)cnc3c2)ccn1CCCN1CCCCC1
Temperature: 120 °C

Procedure:
4-(3-Bromo-imidazo[1,2-b]pyridazin-7-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (1.0 eq, 0.096 mmol, 40 mg), [3-(1H-pyrazol-1-yl)phenyl]boronic acid (1.50 eq, 0.144 mmol, 28.5 mg) and Na2CO3 (2.0 eq, 0.192 mmol, 20.4 mg) are dissolved in DME/H2O (3/1 ml) and PdCl2(PPh3)2 (0.1 eq, 0.0096 mmol, 6.74 mg) is added. The reaction mixture is then heated in a microwave at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the product is purified by flash column chromatography eluting with CH2Cl2/MeOH (80:20) to give 1-(3-piperidin-1-yl-propyl)-4-[3-(3-pyrazol-1-yl-phenyl)imidazo[1,2-b]pyridazin-7-yl]-1H-pyridin-2-one as a yellow solid; [M+H]+=480
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.CC([O-])=O.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CCCCCCC>[C:1]([O:10][C:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: c1ccc2ccccc2c1
Reactant: CCCCCCCC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCCCC
Product: CCCCCCCC(=O)Oc1cccc2ccccc12
Reaction time: 5 h
Yield: 73 %

Procedure:
The reaction was carried out in a glass reactor furnished with a thermometer, mechanical stirrer, Dean Stark type collector equipped with a reflux condenser and gas and liquid tubes. The reactor was charged with 40 g. of octanoic acid, 10 g. (78 m mols) of naphthalene, 8 g. of heptane, 0.34 g. (1.5 millimols) of Pd(OAc)2 0.45 g (1.5 m mols of Sb(OAc)3 and 0.15 g (1.5 m mols) of KOAc. Dean Stark Collector was filled with heptane. The reaction was carried out at 170° C. with vigorous stirring for 5 hours. GLC analysis showed that 57 m mols (73% yield) of naphthyl octanoate were produced.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[C:5]([O:9][CH3:10])=[CH:6][C:7]=1[F:8].OS(O)(=O)=O.[CH3:20]O>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:20])=[O:13])[C:5]([O:9][CH3:10])=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(F)c(F)cc1CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1cc(F)c(F)cc1OC

Procedure:
4.04 g of 2-(3,4-difluoro-6-methoxyphenyl)acetic acid (D3) are dissolved in 34 ml of methanol. 1.54 ml of H2SO4 (95-98%, extra pure) are subsequently added, and the reaction solution is heated under reflux for 3 h. For work-up, the mixture is diluted with 100 ml of water and extracted twice with 150 ml of ethyl acetate each time. The combined organic phases are washed with 50 ml of saturated NaHCO3 solution, dried over Na2SO4, filtered off with suction and evaporated to dryness in vacuo. The residue is recrystallised from cyclohexane, giving 4.0 g of the title compound as a colourless solid having a melting point of 48.3° C.; MS: 216.1 (M+); TLC: Rf=0.60 (cyclohexane/diethyl ether 1:1 parts by volume).
Reaction SMILES: [CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[C:13]([CH2:15][C:16](O)=[O:17])#[N:14]>C(OC(=O)C)(=O)C>[C:1]1([C:16](=[O:17])[CH2:15][C:13]#[N:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: c1cc2c3c(c1)ccn3CCC2
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)c1cn2c3c(cccc13)CCC2
Temperature: 25 °C

Procedure:
5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (3.0 g, 19.1 mmol) and cyanoacetic acid (1.7 g, 20.0 mmol) in acetic anhydride (50 ml) were heated to 90° C. for 1.5 hours. After cooling to room temperature the product precipitated out, was filtered off, washed with cold methanol and dried under reduced pressure to obtain 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-oxo-propionitrile as cream colored crystals (3.457 g). 400 MHz 1H NMR (CDCl3) δ: 7.99 (d, J=7.6 Hz 1H), 7.83 (s, 1H), 7.25 (s, 1H), 7.07 (d, J=6.4 Hz, 1H), 4.23 (m, 2H), 3.88 (s, 2H), 3.01 (m, 2H), 2.28 (m, 2H); LCMS: 225 [M+H]
Reaction SMILES: [N+]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:23][O:24][C:25]1[C:26]([NH2:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>COCCO>[CH3:23][O:24][C:25]1[C:26]([NH:31][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=4)[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: COc1ccccc1N
Solvent: COCCO
Product: COc1ccccc1Nc1cccc2c1C(=O)c1cc([N+](=O)[O-])ccc1C2=O

Procedure:
50 g of 1,7-dinitro-anthraquinone and 150 ml of o-anisidine are stirred for 9 hours at 120° - 125° C and then diluted with 150 ml of ethylene glycol monomethyl ether, the mixture is stirred until cold and stirred for several hours longer in an ice bath, and the product is filtered off and successively washed with a little ethylene glycol monomethyl ether, methanol and water. 40.4 g of 1-o-anisidino-7-nitro-anthraquinone are obtained.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].C([O-])(O)=O.[Na+].[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>CO>[CH2:12]([S:14]([NH:1][NH:2][C:3]([NH:5][NH:6][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])=[O:4])(=[O:16])=[O:15])[CH3:13]
Reactant: CCS(=O)(=O)Cl
Reactant: NNC(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)NNC(=O)NNS(=O)(=O)CC
Reaction time: 1 h

Procedure:
A mixture of 45 g (0.5 mole) carbohydrazide, 85 g NaHCO3 (1.0 mole) and 250 ml methanol was stirred and 128.5 g (1.0 mole) ethane sulfonyl chloride was dropped in. The temperature rose from 25° C to 45° C during the reaction which took 1 hour. Stirring was continued for two hours. The produce was filtered, washed and dried. Yield: 145.9 g m.p. 195° C.