Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1>ClCCl>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:22])/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Aminobenzophenone (10.00 g, 0.0507 mol) was added to a stirred solution of maleic anhydride (4.98 g, 0.0508 mol) in dichloromethane (200 ml). After 10 minutes of stirring at room temperature, yellow precipitate was formed. Stirring was continued for a further 3 hours, following which the solid was collected, washed with dichloromethane (3×30 ml) and diethyl ether (2×30 ml) and finally air dried to yield the maleanmic acid. (Found: C, 68.74; H, 4.57; N, 4.41%. C17H13NO4 requires C, 69.15; H, 4.44; N, 4.74%). H.p.l.c (Kromazil C18, 49.95% MeOH, 49.95% H2O, 0.1% CF3CO2H): 99.7% λmax 306 nm; ε 20560. 1H-n.m.r (DMSO): δ 10.62 (1H, s, NH); 7.8-7.5 (9H, m, phenyl); 6.45 (1H, d; CH=CH); 6.31 (1M, d, CH=CH); 3.38 (1H, S, CO2H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH:21]3[CH2:22][CH2:23][CH:17]2[CH2:18][CH:19]([OH:24])[CH2:20]3)[CH2:10][CH2:9]1)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[ClH:26].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH:17]3[CH2:23][CH2:22][CH:21]2[CH2:20][CH:19]([OH:24])[CH2:18]3)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C3CCC2CC(O)C3)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CCN2C3CCC2CC(O)C3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ester 26 (4.5 g, 12.73 mmol) is dissolved in 4M HCl in dioxane at 0° C. and stirred at room temperature for 3 hours. After evaporation of the solvent the product is dried at high vacuum.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(O)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>O>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 65 %

Procedure:
A solution of 71 g potassium hydroxide in 300 ml water is dripped under reflux, into a mixture of 215 g 4-hydroxy-4'-nitrobiphenyl (see Example 3) and 4000 ml ethanol. Then, 217 g 6-bromohexanol is added, subsequently, the mixture is heated under reflux for 15 h. After cooling, the solvent is removed in a vacuum and the residue is slurried up with water dried. The raw product is filtered off, washed neutral with water and recrystallized from ethanol (melting point: 119° C.); yield: 65%.
Reaction SMILES: C([O:9][CH:10]1[CH:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][CH2:13][CH:12]([CH3:19])[CH2:11]1)(=O)C1C=CC=CC=1>[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH:12]1([CH3:19])[CH2:13][CH2:14][CH:15]([CH:16]([CH3:17])[CH3:18])[CH:10]([OH:9])[CH2:11]1
Reactant: CC1CCC(C(C)C)C(OC(=O)c2ccccc2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Product: CC1CCC(C(C)C)C(O)C1

Procedure:
Benzoylation reaction was conducted to a menthol wherein the scandium (III) pentafluorophenylbis(triflyl)methide obtained from Examples 13 and 14 was used as a Lewis acid catalyst (Chemical formula 38). 1-menthol (0.18 g, 1 mmol) and benzoic anhydride (0.34 g, 1.5 mmol) were reacted while stirring in acetonitrile (4.8 mL) at 26° C. for 1 day, under the presence of the scandium (III) pentafluorophenylbis(triflyl)methide as 1 mol % of Lewis acid catalyst. Two to 3 drops of triethylamine was added to stop the reaction, the solution was added with 5 mL water, then concentrated and dried, and the menthyl benzoate produced was extracted with diethylether. The organic phase was analyzed with 1HNMR and it was found that the menthyl benzoate showed a high yield of 79%. The same reaction as mentioned above was conducted, except for the use of scandium (III) triflate [Sc(OTf)3] as a conventionally known Lewis acid catalyst, instead of the scandium (III) pentafluorophenylbis(triflyl)methide mentioned above. The yield of menthyl benzoate was only 48%. Based on these results, it was found out that the catalytic activity of the scandium (III) pentafluorophenylbis(triflyl)methide of the present invention is much more higher compared to that of the existing Lewis acid catalysts.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24]>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])=[CH:15][CH:14]=1)[CH3:24]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1ccc(C(=O)O)cc1
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)cc1
Yield: 46 %

Procedure:
In a manner identical to Example 15, 4-prenyloxybenzoic acid (1.44 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (1.0 ml), thereby yielding 1.02 g (46%) of the aimed compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[N:7][C:6]([C:14]([NH2:16])=O)=[C:5]2[Cl:17].O=P(Cl)(Cl)Cl.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[N:7][C:6]([C:14]#[N:16])=[C:5]2[Cl:17]
Reactant: COc1cc2nnc(C(N)=O)c(Cl)c2cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nnc(C#N)c(Cl)c2cc1Br
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a suspension of 6-bromo-4-chloro-7-methoxycinnoline-3-carboxamide (Method 21) (12 g, 37.9 mmol) in DCM (400 ml) was added POCl3 (200 ml). Triethylamine (15 ml) was then added carefully to the mixture which was stirred at reflux for 7 h. The reaction was then allowed to cool to rt and conc. in vacuo. The crude residue was then carefully treated with sat'd aqueous NaHCO3 at 0° C. A precipitate formed which was collected via vacuum filtration. The filter cake washed with water (˜100 mL), collected, and dried in vacuo to provide the title compound as a grey solid (9.80 g, 87%) which was used without further purification. 1H NMR: 8.71 (s, 1H), 8.29 (s, 1H), 4.30 (s, 3H); m/z: 299.
Reaction SMILES: [CH2:1]([C:3]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=[CH:14][C:4]=1[O:5]/[C:6](=[CH:10]\[C:11](O)=[O:12])/[C:7]([OH:9])=[O:8])[CH3:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([C:3]1[C:4]2[O:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][C:11](=[O:12])[C:14]=2[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH3:31])[CH3:2]
Reactant: CCCc1ccccc1OCCCOc1cccc(O/C(=C\C(=O)O)C(=O)O)c1CC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1CC
Temperature: 25 °C

Procedure:
A mixture of 1.07 parts of 2-ethyl-3-(3-[2-propylphenoxy] propoxy)phenoxyfumaric acid and 1 part of concentrated sulphuric acid was shaken at room temperature for seventeen hours, then 25 parts of water were added. The resulting solution was made basic by addition of excess sodium carbonate, then re-acidified with 2N hydrochloric acid and extracted with ethyl acetate. Evaporation of the ethyl acetate under reduced pressure gave an oil which on trituration with acetone gave 0.674 parts of 8-ethyl-4-oxo-7-(3-[2-propylphenoxyl]propoxy)-4H-1-benzopyran-2-carboxylic acid, m.pt. 198°-199°.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3]>C1COCC1.C(O)C.[C].[Rh]>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: [Rh]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 108.6 %

Procedure:
A mixture of 5% rhodium-carbon (50% wet, 10 mg) and 9-[4-(1-methylethoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (110 mg) in THF (30 mL) and ethanol (30 mL) was stirred under a hydrogen atmosphere (3 atm) at room temperature for 7 hr. The reaction mixture was filtered, the filtrate was concentrated to give the title compound (121 mg) as a white solid. The obtained solid was crystallized from THF and diisopropyl ether to give a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][CH3:14].[CH3:15][C:16]([CH3:18])=O>>[CH:16]([NH:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:12][CH2:13][CH3:14])=[C:3]([CH3:2])[CH:8]=1)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: CCCc1ccc([N+](=O)[O-])cc1CCl
Product: CCCc1ccc(NC(C)C)cc1C

Procedure:
By the procedure of Example 1, α-chloro-2-propyl-5-nitrotoluene is reacted with acetone to afford the desired title product.
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[C:3](=[O:8])C(OC)=O.[OH:19]O.Cl>[OH-].[Na+]>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:2]([CH3:1])[C:3]([OH:8])=[O:19])=[CH:10][CH:11]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: OO
Reactant: COC(=O)C(=O)C(C)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 0 °C
Yield: 79 %

Procedure:
Methyl 3-methyl-3-(4-isobutylphenyl)pyruvate (1.19 g, 4.8 mmol) was dissolved in a 1N sodium hydroxide aqueous solution (15 ml), and a 35% hydrogen peroxide aqueous solution (5.0 ml) was dropwise added under cooling (0° C.) and stirring. The temperature of the mixture was returned to room temperature, and the mixture was stirred overnight. Then, mixture was acidified with hydrochloric acid and extracted with ether, whereby 2-(4-isobutylphenyl)propionic acid (0.78 g, yield: 79%) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:10][C:9]([CH2:33][C:34]#[N:35])([N:11]3[CH:15]=[C:14]([C:16]4[C:17]5[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[C:18]=5[N:19]=[CH:20][N:21]=4)[CH:13]=[N:12]3)[CH2:8]2)[CH2:3][CH2:2]1.[CH2:36]([N:38]([CH2:41][C:42]1[N:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[N:45]=[C:44]([C:52](O)=[O:53])[CH:43]=1)[CH2:39][CH3:40])[CH3:37].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>O1CCCC1>[CH2:36]([N:38]([CH2:41][C:42]1[N:47]=[C:46]([C:48]([F:50])([F:51])[F:49])[N:45]=[C:44]([C:52]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:10][C:9]([CH2:33][C:34]#[N:35])([N:11]4[CH:15]=[C:14]([C:16]5[C:17]6[CH:24]=[CH:23][NH:22][C:18]=6[N:19]=[CH:20][N:21]=5)[CH:13]=[N:12]4)[CH2:8]3)[CH2:3][CH2:2]2)=[O:53])[CH:43]=1)[CH2:39][CH3:40])[CH3:37]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: CCN(CC)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
{1-Piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (30.0 mg, 0.0609 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added to a mixture of 6-[(diethylamino)methyl]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (22.8 mg, 0.0822 mmol, from Step A), triethylamine (33.9 μL, 0.244 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (28.9 mg, 0.0761 mmol) in tetrahydrofuran (0.67 mL), that was prestirred for 30 minutes. After stirring overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate, filtered and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, and solvents were removed in vacuo. The residue was then stirred with ethylenediamine (0.2 mL) in methanol (1 mL) until deprotection was complete. Purification via preparative HPLC-MS (MeCN/H2O containing 0.15% NH4OH) afforded product. Yield: 0.0156 g (41%); LC-MS: 622.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.61 (d, 1H), 7.06 (d, 1H), 4.06 (ddd, 1H), 3.82 (s, 2H), 3.75 (d, 2H), 3.62-3.46 (m, 5H), 3.31-3.21 (m, 1H), 3.16-3.06 (m, 1H), 2.55 (q, 4H), 1.85-1.74 (m, 1H), 1.70-1.60 (m, 1H), 1.37-1.18 (m, 2H), 0.98 (t, 6H). 19F NMR (400 MHz, DMSO-d6): δ −69.46 (s, 3F).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([CH3:30])[C:12](=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[CH:5][CH:4]=1)#[N:2].[S].[CH3:32][NH:33][CH2:34][CH2:35]N>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([CH2:17][NH:16][CH2:15][CH2:14][CH2:13][C:12]([N:11]([CH3:30])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[N:33]([CH3:32])[CH2:34][CH2:35][N:2]=2)=[CH:8][CH:7]=1)=[O:29])(=[O:20])=[O:19]
Reactant: CNCCN
Reactant: CN(CCc1ccc(C#N)cc1)C(=O)CCCNCS(=O)(=O)c1cccc(Cl)c1Cl
Agent: [S]
Product: CN(CCc1ccc(C2=NCCN2C)cc1)C(=O)CCCNCS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Analogously to 13b), 4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-methyl-N-{2-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}butyramide was prepared from 0.62 g (1.32 mmol) of N-[2-(4-cyanophenyl)ethyl]-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-methylbutyramide, 48 mg (1.49 mmol) of sulphur and 3 ml of N-methylethylenediamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([CH:35]2[O:39][C:38](=[O:40])[NH:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:37]4[CH2:36][CH:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:39][C:38]4=[O:40])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: O=C1NCC(c2ccccc2)O1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4CC(c5ccccc5)OC4=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-oxazolidin-2-one.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][OH:20]>CN(C)C=O>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH2:18][CH2:19][OH:20])[CH:5]=1)[CH3:14]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C=O)c(OCCO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a solution of 4-diethylamino-2-hydroxybenzaldehyde (1.00 g, 5.17 mmol) in 10 mL of dry N,N-dimethylformamide was added sodium hydride (250 mg, 55%, 5.7 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, 2-bromoethanol (1.1 mL, 15 mmol) was added with additional stirring at 50° C. overnight. After quench with NH4Cl aqueous solution at 0° C., the solution was extracted with ethyl acetate three times. The extracts were washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 25/75) to obtain the title compound as a brown gum (566 mg, 46%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:27]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:28]>C1COCC1.O.C(O)(C)C>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)=[O:28])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: CON(C)C(=O)c1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: O
Solvent: CCCCCC
Product: CCOc1cc(C(=O)c2ccc3ncccc3c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.8 %

Procedure:
To a solution of 4-bromo-2-ethoxy-1-methoxy-benzene (1.74 g, 7.5 mmol) in THF (15 mL) was added a solution of n-butyllitium in hexane (3.0 mL, 2.5 N, 7.5 mmol) at −78° C. and kept for 20 min. To the mixture was added a solution of quinoline-6-carboxylic acid methoxy-methyl-amide (1.55 g, 7.2 mmol) in THF (10 mL) at −78° C. After 2 h, isopropanol (2 mL) and water (50 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The solvent was removed and the residue was stirred with ether (20 mL). Filtration gave (3-ethoxy-4-methoxy-phenyl)-quinolin-6-yl-methanone as a yellow solid (1.5 g). The solid was used in the next step without further purification.
Reaction SMILES: BrCC1CC1(F)F.Br[CH2:9][CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][N:29]([CH2:9][CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: FC(F)(F)CCCBr
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC1(F)CC1CBr
Product: CCOC(=O)c1sc(N2CCN(CCCC(F)(F)F)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as described in Preparation 13, making variations to replace bromomethyl-2,2-difluorocyclopropane with 4-bromo-1,1,1-trifluorobutane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 98% yield: MS (ES+) m/z 366.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.[Pd]>[CH3:11][N:12]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:5]=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)[CH:14]=[N:13]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 120 °C

Procedure:
8.1 A suspension of 1.00 g (5.0 mmol) of 5-bromo-7-azaindole, 2.00 g (9.1 mmol) of 1-methylpyrazole-4-boronic acid pinacol ester, 300 mg (0.26 mmol) of Pd[(PPh3]4 and 9 ml of Na2CO3 (addition as 2 M solution) in 12 ml of DMF is heated at 120° C. under microwave conditions for 30 min. The reaction mixture is filtered, and the filtrate is evaporated. The residue is purified on a silica-gel column with dichloromethane/methanol as eluent, giving 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine as yellow solid, ESI 199
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:21]I.CO>C1COCC1>[CH3:21][N:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:20][CH:19]=1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:12]
Reactant: CI
Reactant: Cc1ccc(CNS(=O)(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CN(C)S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Sodium hydride (80% dispersion in oil) (0.24 g, 10 mmol) was added to a stirred solution of N-4-methylbenzyl phenylsulphonamide (2.47 g, 10 mmol) in dry THF (50 mi) under argon. After 1.5 h the grey solid of sodium hydride disappeared and a white precipitate formed. The mixture was cooled to 0° C. and treated with methyl iodide (0.62 ml, 10 mmol). The reaction was allowed to warm to ambient temperature and stirred or 16 h. Methanol (1 ml) was added and the reaction mixture evaporated to dryness. The residue was partitioned between ethyl acetate (80 ml) and water (80 ml). The organic layer was separated, washed with water (2×50 ml), dried over MgSO4, filtered and the solvent removed to give the crude product. Flash chromatography (flash silica, gradient elution 0-10% ethyl acetate in hexane) gave, after crystallisation from ethyl acetate/hexane, N-methyl N-4-methylbenzyl phenylsulphonamide (0.89 g, 34%) as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1CNCCN1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCNCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and piperazine. LCMS (Method C): 539 (M+H)+, Retention time 7.4 minutes.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cu][C:15]#[N:16].C(N)CN>CN1CCCC1=O>[C:15]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH:8]=[CH:9]2)=[CH:4][CH:3]=1)#[N:16]
Reactant: CC1(C)C=Cc2cc(Br)ccc2C1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: CC1(C)C=Cc2cc(C#N)ccc2C1
Yield: 96 %

Procedure:
A solution of 7-bromo-3,3-dimethyl-3,4-dihydronaphthalene (6.2 g) and copper (1) cyanide (3.5 g) in N-methylpyrrolidone (60 ml) was heated under reflux for 2 hours. After cooling, the mixture was poured into 10% aqueous ethylenediamine (200 ml) and extracted into ethyl acetate. The combined extracts were washed with water, and dried over magnesium sulphate. Solvent and drying agent were removed and the residue chromatographed on silica gel using ether-pentane (1:10) as eluant gave the dihydronaphthalene as a white crystalline solid (4.6 g), having mp 50°-52° C.;