Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[C:11](=[O:24])[C:10](NC3C=CC(OC(F)(F)F)=CC=3)=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(=[O:39])C.COC1CCC(OC)O1.C(O)(C(F)(F)F)=O>O.C1COCC1>[OH:39][C:10]1[C:11](=[O:24])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:15][CH:14]=2)[CH:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)[CH:9]=1
Reactant: Cc1cccc(C2C=C(Nc3ccc(OC(F)(F)F)cc3)C(=O)N2c2ccc(OC(F)(F)F)cc2)c1
Reactant: CC(=O)O
Agent: COC1CCC(OC)O1
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C2C=C(O)C(=O)N2c2ccc(OC(F)(F)F)cc2)c1
Temperature: 40 °C

Procedure:
Charge THF (20 mL, 5 vols) to a flask containing (±)-5-(3-methyl-phenyl)-1-(4-trifluoromethoxy-phenyl)-3-(4-trifluoromethoxy-phenylamino)-1,5-dihydro-pyrrol-2-one (4.18 g, 8.22 mmol). Add acetic acid (1.88 mL, 32.89 mmol,) to the above clear solution to afford a yellow solution. Add 2,5-dimethoxytetrahydrofuran (1.28 mL, 9.87 mmol,), then add water (0.2 mL, 9.87 mmol). Add TFA (1.25 mL, 16.44 mmol,) to the reaction mixture and observe a slight exotherm (23 to 30° C.). Heat the reaction mixture to 40° C. for 22 hours. Pour the brown solution into water (50 mL) and extract with ethyl acetate (50 mL×2). Wash the organic phase with saturated sodium bicarbonate solution (20 mL×2), brine (50 mL), dry over magnesium sulfate and evaporate to afford the titled compound. MS (m/z): 350.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1.ClCCl>[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](=[O:19])(=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5 g (27.64 mmol) of 4-fluoro-2-(trifluoromethyl)-aniline is dissolved in 25 ml of dry pyridine and the solution is cooled to 0° C. A solution of 4.82 g (27.4 mmol) of chlorosulfonyl acetic acid methyl ester in 20 ml of dichloromethane is instilled in the cooled solution in the course of about 10 minutes with the temperature being maintained. Then it is stirred for 6 hours at room temperature. The reaction solution is then diluted with 100 ml of dichloromethane, the pyridine is shaken out with 2N hydrochloric acid, the organic phase is dried on magnesium sulfate, filtered and evaporated to dryness. The residue is crystallized from diethyl ether/hexane yield is obtained as a crystallizate. Melting point 84°-86° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C:13]([OH:15])=O)=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:11]3[C:6]=2[CH:7]=[CH:8][N:9]=[CH:10]3)[S:20][CH:21]=1
Reactant: O=C(O)Cc1ccc(F)c2cnccc12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cc1ccc(F)c2cnccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(8-fluoroisoquinolin-5-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine using protocol B. Retention time (min)=1.987, method [7], MS (ESI) 432.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 9.74 (s, 1H), 8.66 (d, J=6.6 Hz, 1H), 8.30 (d, J=6.1 Hz, 1H), 8.20 (b s, 1H), 8.1 (dd, J=8.24, 5.5 Hz, 1H), 7.67 (dd, J=9.9, 7.7 Hz, 1H), 7.1 (s, 1H), 4.46 (s, 2H).
Reaction SMILES: Cl.F[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14]N1CC2OC(CNC2)C1)[C:6]#[N:7].[Br:24]CCCBr.C([O-])([O-])=O.[K+].[K+].C[N:36]([CH:38]=O)C>>[Br:24][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:38]#[N:36]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(OCCCN2CC3CNCC(C2)O3)c(F)c1
Reactant: BrCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(OCCCBr)c(C#N)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
4-Hydroxyisophthalonitrile (4.4 g, 0.03 mol; see step (iii) above) was dissolved in dry DMF (100 mL). 1,3-Dibromopropane (36 g, 0.12 mol) and K2CO3 (8.2 g, 0.06 mol) were added. Then the reaction mixture was then stirred at 60° C. for 15 h before being cooled to RT and filtered through a Celite® bed. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, using 2% ethyl acetate in petroleum ether as eluent, to yield the title compound (5.1 g, 63%) as pale yellow solid.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]CC)=[O:12])=[CH:6][C:5]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][CH3:25])[CH2:20][CH2:19]1)=[O:17]>C1COCC1.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][C:5]=1[C:16]([N:18]1[CH2:19][CH2:20][CH:21]([O:24][CH3:25])[CH2:22][CH2:23]1)=[O:17]
Reactant: CCOC(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC1CCN(C(=O)c2cc(CC(=O)O)ccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Lithium hydroxide (0.752 g, 31.39 mmol) was added in one portion to ethyl 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetate (42) (2.03 g, 6.28 mmol) in THF (20 mL) and water (20 ml) at 25° C. under air. The resulting mixture was stirred at room temperature for 2 hours. The THF was evaporated and the mixture diluted with water (30 mL). The aqueous solution was acidified with 2N HCl and the product extracted into EtOAc (3×30 ml). The combined extracts were dried (MgSO4), filtered and evaporated to a give the desired material as a white solid (1.580 g, 85% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.54-1.84 (3H, m), 1.89-1.96 (1H, m), 3.12-3.20 (1H, m), 3.36 (3H, s), 3.45-3.53 (2H, m), 3.58 (2H, s), 3.60-3.66 (1H, m), 3.93-4.02 (1H, m), 7.01-7.06 (1H, m), 7.28-7.32 (2H, m); m/z (LC-MS, ESI+), RT=0.78 (M+H 296.3).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:36][C:37]1[N:45]=[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])[N:43]=[C:42]2[C:38]=1[NH:39][C:40](=[O:62])[N:41]2[CH2:51][CH2:52][CH2:53][NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.CCN(CC)CC.[CH3:70][O:71][C:72](=[O:78])[CH2:73][CH2:74][C:75](O)=[O:76]>CN(C=O)C.CO>[NH2:36][C:37]1[N:45]=[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])[N:43]=[C:42]2[C:38]=1[NH:39][C:40](=[O:62])[N:41]2[CH2:51][CH2:52][CH2:53][N:54]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:75](=[O:76])[CH2:74][CH2:73][C:72]([O:71][CH3:70])=[O:78]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccccc3)c2n1
Reactant: COC(=O)CCC(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccccc3)C(=O)CCC(=O)OC)c2n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
PyBop (0.47 g) was added to a mixture of the product from example 1 step (viii) (0.25 g), Et3N (0.7 ml) and succinic acid monomethyl ester (0.16 g) in DMF (8 ml) and stirred at rt for 4 days. MeOH (10 ml) was added, the solvent evaporated under reduced pressure and the residue purified by RPHPLC, yield 46 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:4]2[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccco3)cc2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccco3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
There was dissolved, in 1,4-dioxane (4 mL), 5,7-dichloro-2-furan-2-yl-pyrazolo[1,5-a]pyrimidine (167 mg, 0.657 mM), then morpholine (115 μL, 1.31 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the resulting residue was diluted with water and then extracted with methylene chloride. The extract thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (186 mg, yield: 93%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]=1[CH2:39][CH2:40][C:41](O)=[O:42])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]=1[CH2:39][CH2:40][C:41]([N:12]1[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)=[O:42])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Product: O=C(c1ccc(F)cc1)C1CCN(C(=O)CCc2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Yield: 77.7 %

Procedure:
Condensation between 4-(4-fluorobenzoyl) piperidine.hydrochloride (682 mg) and 3-(2,4-dibenzyloxyphenyl)propionic acid (1.04 g) is carried out in the same manner as in Example 1, (i) to yield 1-[3-(2,4-dibenzyloxyphenyl)propionyl]-4-(4-fluorobenzoyl)piperidine (1.20 g) in the colorless columnar crystal form.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35]Cl.[NH:37]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][N:37]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: ClCCCCBr
Reactant: C1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCN3CCCCCC3)c2n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 6.1 %

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (192 mg, 0.547 mmol) and potassium carbonate (189 mg, 1.368 mmol) were suspended in DMF (3 ml) and heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature, 1-bromo-4-chlorobutane (0.063 ml, 0.547 mmol) was added and the reaction stirred for a further 18 hours. Hexahydro-1H-azepine (54.2 mg, 0.547 mmol) and triethylamine (0.076 ml, 0.547 mmol) were added and the reaction mixture heated to 60° C. for 18 hours. The solvent was removed in vacuo and the residue was partitioned between DCM (5 ml) and water (5 ml). The aqueous phase was re-extracted with DCM (5 ml) and the combined organic extracts were concentrated in vacuo. The residue was dissolved in 1:1 MeOH:DMSO (2 ml) and purified in 2 injections by MDAP (Method B). This provided material (74 mg) that was still impure and which was repurified by MDAP (Method A). The product containing fractions were evaporated under a stream of nitrogen to give the title compound as a clear gum (13 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:51]2[CH:52]=[N:53][NH:54][CH:55]=2)O1>>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:5]2[C:4]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:3][C:2]([C:51]3[CH:52]=[N:53][NH:54][CH:55]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(-c3cn[nH]c3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Strem Chemicals), and was isolated as an orange amorphous solid (95%). m/z (ESI, +ve ion) 376.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.98 (1H, br. s.); 11.70 (1H, s); 8.89 (1H, br. s.); 8.59 (2H, br. s.); 8.17 (2H, br. s.); 7.87 (2H, br. s.); 7.74 (1H, br s.); 6.84 (1H, s); 3.85 (3H, s); 2.46 (3H, br. s.).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12](Br)[S:13][C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[CH2:22][N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[CH:24]2)[CH2:17][CH2:16]1.O1CCO[CH2:36][CH2:35]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]([CH2:35][CH3:36])[S:13][C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[CH2:22][N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[CH:24]2)[CH2:17][CH2:16]1
Reactant: O=C(Cn1ccc2cccnc21)N1CCN(c2sc(Br)nc2-c2nc3ccccc3[nH]2)CC1
Reactant: C1COCCO1
Product: CCc1nc(-c2nc3ccccc3[nH]2)c(N2CCN(C(=O)Cn3ccc4cccnc43)CC2)s1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A vial was charged with Example 38 (50 mg), 1,1′-bis(diphenylphosphin)ferrocen dichloropalladium-(II)-chlorid complex (in DCM 1/1, 3.91 mg) and dioxane (1.5 mL) at RT under argon, sealed and evacuated and backfilled with argon three times. Diethylzinc (1.5M in toluene) was added. The resulting orange suspension was shaken at 100° C. for 1.5 h. The reaction mixture was allowed to cool down, was quenched with water (0.5 mL) dropwise and evaporated to dryness. The resulting brown solid was purified by preparative LC-MS (I) to afford 17 mg of beige solid. LC-MS (A): tR=0.65 min; [M+H]+: 472.3.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:10]1([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:22]([O-])(=O)C.[Na+].C=O>>[C:10]1([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:2]3[NH:1][C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:4]4[CH:3]=3)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)[O-]
Reactant: c1ccc(N2CCNCC2)cc1
Agent: C=O
Agent: [Na+]
Product: c1ccc(N2CCN(Cc3cc4cccnc4[nH]3)CC2)cc1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol),1-phenylpiperazine (64.9 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H) 3.14 (m, 4H) 4.03 (s, 2H) 5.60 (s, 1H) 7.09 (m, 3H) 7.84 (m, 3H) 8.06 (dd, J=8.31, 1.53 Hz, 1H) 8.20 (dd, J=4.75, 1.70 Hz, 1H). (ESI) m/z 293 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1[nH]c2cnc3ccc(Br)cc3c2n1-c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccccc2)c2cnc3ccc(Br)cc3c2n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.13 mmol) of 8-bromo-1-(2-chloro-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one [see under B)], 48.8 mg (0.40 mmol) of phenylboronic acid (Fluka, Buchs, Switzerland), 53 mg (0.27 mmol) of cupric acetate anhydrous (Fluka, Buchs, Switzerland) and 56 μl (0.4 mmol) of triethylamine are dissolved in 1 ml of anhydrous dichloromethane and the suspension is stirred for 16 h at room temperature. After this time, additional phenylboronic acid (24 mg), cupric acetate anhydrous (27 mg) and triethylamine (28 μl) are added and the suspension is stirred at room temperature for 24 h. The suspension is evaporated to dryness and the crude compound is purified by clash chromatography (dichloromethan with 0.5% of methanol) to obtain the title compound: Analytical HPLC: tret=8.22 min (Grad. 2); ES-MS: m/e0=449.9. 451.9.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)C(OCC)=O>Cl>[ClH:14].[Br:15][C:11]1[CH:12]=[C:13]([Cl:14])[C:8]([CH2:2][NH2:1])=[N:9][CH:10]=1
Reactant: CCOC(=O)C(N)c1ncc(Br)cc1Cl
Agent: Cl
Product: NCc1ncc(Br)cc1Cl
Yield: 182.4 %

Procedure:
A stirred solution of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (0.5 g, 1.7 mmol) in 3 N HCl (25 mL) was heated at reflux for 4 h. The reaction mixture was washed with diethyl ether and water. The combined ether layer was concentrated under reduced pressure to afford the title compound as an off-white solid (400 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m/z 221.15 ([M+H]+).
Reaction SMILES: O.NN.[CH2:4]([N:11]([C:15]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])C(=O)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C.[Cl-].[Na+]>C(OCC)(=O)C>[CH2:4]([NH:11][C:15]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)N(Cc1ccccc1)c1cc(Oc2ccccc2)ccc1C(=O)O
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1NCc1ccccc1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A suspension of hydrazine monohydrate 2.0 mL of 2-(N-benzylacetamido)-4-phenoxybenzoic acid 0.10 g was heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, acetic acid 5.0 mL was added to it, and ethyl acetate and saturated sodium chloride aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate:acetic acid=80:20:1] to give 2-(benzylamino)-4-phenoxybenzoic acid 20 mg of white solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:24]1([C:35](O)=[O:36])[CH:25]=[CH:26][CH:27]=[C:28]2[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=23)=[O:36])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)thio]phenyl}propan-1-ol (450 mg, 1.51 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (284 mg, 1.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435 mg, 2.27 mmol) and 1-hydroxybenzotriazole hydrate (231 mg, 1.51 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (396 mg, 51%).
Reaction SMILES: B(Br)(Br)Br.ClCCl.C([O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:28]([CH3:39])[N:29]=[C:30]([C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[C:19]=3[C:18]=2[CH:17]=1)C1C=CC=CC=1.O>FC(F)(F)C(O)=O>[OH:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:28]([CH3:39])[N:29]=[C:30]([C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[C:19]=3[C:18]=2[CH:17]=1
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1O
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
A 1.0 M boron tribromide solution in dichloromethane (38.2 ml, 38.2 mmol) is slowly added dropwise to a solution of 4-(8-benzyloxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (3.82 g, 9.09 mmol) in trifluoroacetic acid (38 ml) under a dry nitrogen atmosphere with ice-bath cooling. When the addition is complete, the mixture is subsequently stirred for a further 30 min. When the reaction is complete (HPLC-MS check), the reaction mixture is carefully added to water (800 ml) and extracted twice with ethyl acetate (200 ml each time). The combined organic phases are washed with water (150 ml) and semi-saturated NaHCO3 solution (200 ml), subsequently dried using Na2SO4 and filtered with suction. The filtrate is evaporated in vacuo, suspended in a little ethanol, filtered off with suction and dried in a high vacuum, giving the title compound 4-(8-hydroxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (2.86 g, 8.66 mmol) as a solid having a melting point of 288.9° C. MS: 331.1 (M+H+), TLC (HPTLC): Rf=0.34 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=C[C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].S(Cl)([Cl:22])(=O)=O.[CH:24]([Cl:27])(Cl)Cl>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[C:13]([Cl:22])[CH:12]=[C:24]([Cl:27])[C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: O=S(=O)(Cl)Cl
Product: CCOC(=O)c1cnc2c(OC)c(Cl)cc(Cl)c2c1Cl
Temperature: 65 °C
Yield: 29 %

Procedure:
To a stirred solution of 4-chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (1.00 g, 3.76 mmol) in chloroform (50 mL) was added, dropwise over 1 h, a solution of sulfuryl chloride (15 mL) in chloroform (15 mL) whilst maintaining the temperature at 25-30° C. The solution was then heated at 60-70° C. for 48 h. During this time, further sulfuryl chloride (2 mL) was added at regular intervals (2, 24 and 30 h). The solution was allowed to cool to RT and added to ice-aqueous ammonia, adjusting the pH to 8. The mixture was then extracted with dichloromethane (20 mL×3), the extracts combined and concentrated. Column chromatography (silica gel, dichloromethane/methanol (100:1)) gave the title compound 26 as a cream solid (0.36 g, 29%). 1H-NMR (CDCl3, 400 MHz): δ 9.04 (s, 1H), 7.78 (s, 1H), 4.51 (q, J=7.1, 2 H), 4.14 (s, 3H), 1.46 (t, J=7.1, 3 H).