Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]1[C:12]2[C:11]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[N:10][N:9]([CH3:19])[C:8]=2[C:7](=O)/[C:6](=[CH:21]/N(C)C)/[CH2:5][CH2:4]1)C.S(O)(O)(=O)=O.[CH3:30][O:31][C:32](=[NH:34])[NH2:33].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:18][O:17][N:15]([CH3:16])[C:13]([C:11]1[C:12]2[CH2:3][CH2:4][CH2:5][C:6]3[C:7](=[N:34][C:32]([O:31][CH3:30])=[N:33][CH:21]=3)[C:8]=2[N:9]([CH3:19])[N:10]=1)=[O:14]
Reactant: COC(=N)N
Reactant: CCC1CC/C(=C\N(C)C)C(=O)c2c1c(C(=O)N(C)OC)nn2C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: COc1ncc2c(n1)-c1c(c(C(=O)N(C)OC)nn1C)CCC2
Yield: 59.5 %

Procedure:
To a solution of ethyl (7E)-7-[(dimethylamino)methylidene]-N-methoxy-N,1-dimethyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide (1.62 g, 5.3 mmol) in CH3CN (130 ml), O-methylisourea sulphate (5.22 g, 21.2 mmol) and K2CO3 (3 g, 22.2 mmol) were added. The reaction mixture was stirred at reflux for 16 h, then it was filtered to remove salts and the solvent was evaporated. The residue was suspended in DCM and washed with water; the organic phase was dried on Na2SO4, filtered and concentrated. The crude was purified by flash-chromatography in silica gel (hexane/AcOEt:1/1) to afford 1 g (62% yield) of the title compound as a white solid.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:3][C:4]2[C:5]3[C:10]([N:11]=[C:12]4[C:17]=2[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]4)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3ccccc3c(NCc3ccc(C(F)(F)F)cc3)c21
Temperature: 0 °C
Yield: 27.7 %

Procedure:
In 300 ml of toluene and 200 ml of 30% potassium hydroxide were combined 8.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one and 3.20 g of tetrabutylammonium hydrogen sulfate catalyst. The mechanically stirred mixture was warmed to reflux and 3090 g of 4-trifluoromethylbenzyl bromide in 50 ml of toluene was added dropwise over 1 hour. After stirring at reflux for 4 hours the reaction was complete by TLC. It was poured into 50 ml of ice and the aqueous layer was separated and extracted with DCM. The organics were combined, washed with saturated NaCl solution, dried over anhydrous magnesium sulfate and evaporated to an oil. The oil was purified by preparative HPLC (ethyl acetate) and the isolated product was recrystallized from dichloromethane/pentane (1:1 ) to yield 3.87 g of solid, mp 174°-176° C.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[ClH:23]>>[ClH:23].[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: COc1ccc(C(O)CCCCCn2ccnc2)c(OC)c1
Agent: Cl
Product: COc1ccc(C=CCCCCn2ccnc2)c(OC)c1

Procedure:
Treat 0.266 gm of the compound prepared in Example 68 with 11 ml of 0.1N HCl to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[N:39]1([CH2:45][CH2:46][O:47][C:48]2[CH:49]=[C:50]([NH2:54])[CH:51]=[CH:52][CH:53]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:54][C:50]1[CH:51]=[CH:52][CH:53]=[C:48]([O:47][CH2:46][CH2:45][N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:49]=1)=[N:6]2
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n2nc(Nc3cccc(OCCN4CCOCC4)c3)ncc12
Yield: 24.6 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), (3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)amine (38 mg, 0.17 mmol) and ethanol (2.5 mL) to afford 5-methyl-N-(3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (18 mg) as a yellow solid. MS m/z 431 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[CH2:7][C:6]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8](=[O:16])[CH2:7][C:6]3=[O:17])[CH2:30][CH2:31]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C1CC(=O)N(CCCBr)c2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(CCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)c2ccccc2N1
Temperature: 100 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Twenty five milliliters of dimethylformamide is added to 2.3 g of the compound of Example 209, 2.6 g of 1-[(4-chlorophenyl)phenylmethyl]piperazine and 2.2g of potassium carbonate and the resulting mixture is stirred at 100° C. for 4 hours. To the mixture, 0.35 g of 1-[(4-chlorophenyl)phenylmethyl]piperazine is added and the resulting mixture is stirred at 100° C. for 2.5 hours. The precipitate is removed by filtration and the filtrate is condensed, followed by purification by silica gel column chromatography (ethyl acetate:methanol=9:1-8:1) to obtain 3.7 g of (210).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[CH3:6][O:7][C:8](=[O:21])[C:9]1[C:10](=[C:15]([CH2:19][NH2:20])[CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12]>O>[CH3:6][O:7][C:8](=[O:21])[C:9]1[C:10](=[C:15]([CH2:19][NH:20][C:2]([NH2:3])=[O:1])[CH:16]=[CH:17][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(CNC(N)=O)c1C(=O)OC
Reaction time: 2 h
Yield: 68.3 %

Procedure:
Potassium cyanate (1.9 g, 22.93 mmol) was added portionwise over 2 hours to a stirred solution of 3-aminomethyl-phthalic acid dimethyl ester hydrochloride (2.0 g, 7.7 mmol) in water (60 mL). After stirred for another 2 hours, the mixture was acidified to pH 4. The mixture was filtered to give 3-ureidomethyl-phthalic acid dimethyl ester (1.4 g, 70%): 1H NMR (DMSO-d6) δ 3.82 (s, 6H), 4.19 d, J=6.0 Hz, 2H), 5.63 (s, 2H), 6.38 (t, J=5.8 Hz, 1H), 7.54-7.62 (m, 2H), 7.78-7.81 (dd, J=2.2 and 6.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][S:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:5][CH:4]=1.C=O.[C:19]([BH3-])#N.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:19])=[CH:15][CH:16]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(CSC[C@@H]2CCCN2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CSC[C@@H]2CCCN2C)cc1
Yield: 41.7 %

Procedure:
The procedure described in Preparation 5-(4) was repeated, but using 2 g of (2S)-2-(4-methoxybenzylthiomethyl)pyrrolidine, 35% formalin and 848 mg of sodium cyanoborohydride in the presence of 44 ml of acetonitrile, to afford 883 mg of the title compound as an oil.
Reaction SMILES: ClC(C1C=C(CC(C)C)C=CC=1C(C1C=CC(CC(C)C)=CC=1C(Cl)C)=O)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[CH:36][CH:35]=[CH:34]2.C(C1C=CC=CC=1)C(C)C.[Cl:51][CH:52]([CH3:56])[C:53](Cl)=[O:54]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([C:53]([CH:52]([Cl:51])[CH3:56])=[O:54])[CH:35]=[CH:34]2
Reactant: CC(Cl)C(=O)Cl
Reactant: COc1ccc2ccccc2c1
Agent: CC(C)Cc1ccc(C(=O)c2ccc(CC(C)C)cc2C(C)Cl)c(C(C)Cl)c1
Solvent: CC(C)Cc1ccccc1
Product: COc1ccc2cc(C(=O)C(C)Cl)ccc2c1

Procedure:
Following the procedure of Example 1, but substituting in part (a) thereof 6-methoxynaphthalene for isobutylbenzene in the reaction with the alpha-chloropropionyl chloride, there is formed 1-chloroethyl 6-methoxy-2-naphthyl ketone. Then, as in part (b) of Example 1, the 1-chloroethyl 6-methoxy-2-naphthyl ketone, in heptane, is reacted with neopentyl glycol to form the neopentyl ketal of the ketone (also named 2-(1-chloroethyl)-2-(6'-methoxynaphthyl)-5,5-dimethyl-1,3-dioxane). In step (c) this alpha-chloroketal is mixed with a solution of zinc 2-ethylhexanoate in heptane, at a temperature of from about 135° to 150° C. to distill the heptane away and to cause the rearrangement of the α-chloroketal to the 3-chloro-2,2-dimethylpropyl ester of 2-(6-methoxy-2-naphthyl)propionic acid. The resulting oil can be cooled, treated with filter aid to adsorb zinc compounds, and diluted with heptane, stirred and filtered. The filtrate can be treated with carbon and filter aid material to remove colored impurities. The chloro-ester solution, so clarified, can be mixed with aqueous base as in part (d) of Example 1 to hydrolyze the ester and to form the sodium 2-(6'-methoxy-2-naphthyl)propionate salt. Then the sodium salt intermediate product can be precipitated from the mixture by dilution with water, cooling, seeding with sodium naproxen [sodium 2-(6'-methoxy-2-naphthyl)propionate] crystals and cooled to 0° to crystallize the sodium naproxen salt from the mixture, which solid salt is filtered and washed with heptane and dried, if desired. Then, as in step (c) of Example 1, the sodium naproxen crystals can be converted to the free naproxen acid [2-(6'-methoxy-2-naphthyl)propionic acid] by dilution with water and heptane, acidified as in part (e) of Example 1, separate the aqueous and organic liquid phases and washing the organic liquid phase with an aqueous buffer solution, and the organic solvent can be distilled to leave as residue the substantially pure naproxen acid, which can be further washed and dried with nitrogen to obtain drug-quality naproxen acid for use in preparing pharmaceutical formulations thereof.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH:9]1([NH:12][C:2]2[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:11][CH2:10]1
Reactant: Clc1ncncc1I
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Ic1cncnc1NC1CC1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
To a vial containing a solution of 4-chloro-5-iodopyrimidine (0.400 g, 1.664 mmol) in DMF (Volume: 2.67 ml) was added cyclopropanamine (0.461 ml, 6.65 mmol) followed by cesium carbonate (1.084 g, 3.33 mmol). The vial was sealed with a Teflon cap and heated at 90° C. for 3 hr, then allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with EtOAc. The filtrate was diluted with H2O and the layers were separated. The organic phase was washed with H2O (2×). The combined aqueous phases were back-extracted with EtOAc (3×). All organics were combined, dried over Na2SO4, filtered, and concentrated to afford an orange residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 20-70% EtOAc in hexanes over 19 min, tr=13.5 min) gave the title compound (348 mg, 1.320 mmol, 79% yield) as a yellow solid. ESI MS (M+H)+=262.0.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[CH:19][S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:21]([OH:23])=O.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:27]1([CH2:26][CH2:25][NH:24][C:21]([C:3]2[C:4]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]5[CH:18]=[CH:19][S:20][C:13]=45)=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])=[O:23])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: NCCN1CCOCC1
Reactant: Cc1sc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)NCCN1CCOCC1
Yield: 28.6 %

Procedure:
This material was prepared from the reaction of 2-methyl-6-(thieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carboxylic acid 133a (93 mg, 0.27 mmole) with 4-(2-aminoethyl)morpholine (0.12 mL, 0.82 mmole), diisopropylethylamine (0.10 mL, 0.55 mmole), and HBTU (155 mg, 0.41 mmole) in a manner similar to that previously described for example 117 to give a white crystalline solid (35 mg, 28%). 1H NMR (DMSO-d6, 300 MHz) δ 8.51 (1H, d, J=5.27 Hz), 8.28 (1H, t, J=5.37 Hz), 8.15 (1H, d, J=5.46 Hz), 7.94 (1H, dd, J=2.26 Hz), 7.94 (1H, d, J=8.48 Hz), 7.59 (1H, d, J=5.46 Hz), 7.33 (1H, dd, J=2.26, 8.85 Hz), 6.64 (1H, d, J=5.27 Hz), 3.58 (4H, t, J=4.33 Hz), 3.43 (2H, q, J=6.09 Hz), 3.32 (2H, m), 2.63 (3H, s), 2.52–2.39 (4H, m).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:24]([OH:26])=O)=[N:7][N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[F:45][C:46]([F:53])([CH3:52])[CH2:47][NH:48][CH2:49][CH2:50][OH:51].C(OC(C)C)(C)C>C(Cl)Cl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:8]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([C:24](=[O:26])[N:48]([CH2:47][C:46]([F:53])([F:45])[CH3:52])[CH2:49][CH2:50][OH:51])=[N:7]1
Reactant: CC(=O)Oc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(F)(F)CNCCO
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CC(=O)Oc1c(C(=O)N(CCO)CC(C)(F)F)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
4-Acetoxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6d (581.0 g, 1.48 mol) was dissolved in 10 liters of methylene chloride to give a pale yellow, slightly opaque solution. The solution was filtered through Celite® to give a clear green colored solution. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (296.8 g, 1.64 mol) was added in one portion as a solid at room temperature to give an opaque suspension (addition is slightly endothermic). 4-Methylmorpholine (182.9 g, 1.80 mol) was added over 15 minutes while keeping the temperature between 18–22° C. (reaction returned to being yellow in color). Reaction stirred for 3 hours at room temperature, then 2-(2,2-difluoropropylamino)-ethanol (228.3 g, 1.64 mol) was added neat over 10 minutes while keeping the temperature between 20–25° C. The reaction was stirred for 15 hours, then washed twice with 6 liter portions of 10% citric acid and once with 5 liters of brine. The crude product solution was concentrated in vacuo to a thick orange oil, then reconstituted in 4 liters of isopropyl ether. After removing 1 liter of distillates precipitate began to form. To the crude product suspension was added 1.5 liters of isopropyl ether and then the mixture was stirred at room temperature for 1 hour. The precipitated solids were collected by filtration and the resulting filtercake was rinsed with 2 liters of room temperature isopropyl ether, followed by air-drying for 16 hours. Acetic acid 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[(2,2-difluoro-propyl)-(2-hydroxyethyl)-carbamoyl]-1H-pyrazol-4-yl ester I-6e (603.0 g, 78%) was isolated as a granular off-white solid.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2C=[CH:35][CH:36]=[CH:37][C:32]=2N=N1.N1CCCCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:2]([N:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21]([N:29]4[CH2:35][CH2:36][CH2:37][CH2:32][CH2:33]4)=[O:23])[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:9][CH2:10]1)([CH3:4])[CH3:3]
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCCCC4)cc3c2)CC1
Yield: 51 %

Procedure:
The title compound was synthesized in analogy to example 9, intermediate a), from 5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, piperidine and N,N-diisopropylethylamine (7 eq.) in DMF to give the desired product as a light brown foam (51%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=2[CH3:42])[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=2[CH3:42])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1C
Product: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)c1C

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K18) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow oil (310 mg, 78%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:29][O:28][C:5]1[CH:4]=[CH:3][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=2)=[CH:7][C:6]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2cccc(C(F)(F)F)c2)cc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 120 °C
Yield: 43.7 %

Procedure:
A vial was charged with 1-(5-CHLORO-2-METHOXYPHENYL)-N-(PYRIMIDIN-4-YL)ISOQUINOLINE-6-SULFONAMIDE (Example 146; 64.66 mg, 0.151 mmol) (3-(trifluoromethyl)phenyl)boronic acid (57.5 mg, 0.303 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (3.11 mg, 7.57 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (11.47 mg, 0.015 mmol), and potassium phosphate (96 mg, 0.454 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (689 μl) and water (68.9 μl) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 120° C. The mixture was extracted with EtOAc (4×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 3.5% MeOH/DCM) to give 1-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (35.6 mg, 0.066 mmol, 43.8% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.02 (br. s., 1H), 8.76-8.64 (m, 2H), 8.57 (s, 1H), 8.25 (d, J=5.8 Hz, 1H), 8.12 (d, J=5.7 Hz, 1H), 8.04-7.90 (m, 4H), 7.83-7.72 (m, 2H), 7.70-7.62 (m, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.03 (d, J=6.0 Hz, 1H), 3.71 (s, 3H). m/z (ESI) 537.2 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][CH2:27][NH:28][C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[CH:15]3[CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:10].[CH2:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][CH2:27][N:28]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]3[CH2:14]1
Reactant: Cc1cccc(NCCCN2CCc3cccc4c3C2CC4)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(N(CCCN2CCc3cccc4c3C2CC4)S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
Benzenesulfonyl chloride (48.6 mg, 0.28 mmol) was added to a solution of [3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-m-tolyl-amine dihydro-chloride (43.0 mg, 0.11 mmol) and N,N′-diisopropylethylamine (2 ml) in CH2Cl2 (2 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 ml), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (20.0 mg, 36% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=O)[CH:2]=1.S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[CH3:18][CH:14]1[CH2:13][C:12]2[C:19](=[CH:20][CH:21]=[CH:22][C:11]=2[C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:15]1=[O:17]
Reactant: CC(Cc1ccccc1-c1cnc2ccccc2c1)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1Cc2c(cccc2-c2cnc3ccccc3c2)C1=O
Temperature: 80 °C

Procedure:
A solution of 145 g (0.5 mol) of 2-(2-(3-quinolyl)benzyl)propionic acid in 119 g (1.0 mol) of thionyl chloride was stirred at room temperature for 18 hours. Excess thionyl chloride was removed at 10 mbar and the acid chloride was taken up in 400 cm3 of toluene. The solution was added dropwise at 10° C. to a suspension of 73 g (0.55 mol) of AlCl3 in 1000 cm3 of toluene and heated at 80° C. for 1 hour. The reaction mixture was poured onto 1000 g of ice and acidified with concentrated aqueous HCl to a pH of 1. The organic phase was separated off and the aqueous phase was further extracted 3 times with 200 cm3 each time of Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution and subsequently dried (MgSO4). This gave 64 g (47%) of 2-methyl-4-(3-quinolyl)-1-indanone which was further reacted without further purification.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:17](Cl)=[O:18])([CH3:13])([CH3:12])[CH3:11]>>[CH2:1]([NH:9][C:17](=[O:18])[C:16]1[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]([OH:23])=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In the manner of Example 1, n-octylamine was reacted with 3,5-di-t-butyl-4hydroxybenzoyl chloride to produce N-n-octyl-3,5-di-t-butyl-4-hydroxybenzamide; melting point 133°-135°C. When tested by the procedure of Example 2, the sample containing this compound lasted 1000 hours, about 3.3 times as long as the control.