Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27]2[S:28][CH:29]([CH2:32][C:33]([OH:35])=O)[CH2:30][N:31]=2)=[CH:14]3)=[CH:6][CH:5]=1.Cl.[CH3:37][N:38](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.CN>CCCCCC.C(OCC)(=O)C.CO.O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27]2[S:28][CH:29]([CH2:32][C:33]([NH:38][CH3:37])=[O:35])[CH2:30][N:31]=2)=[CH:14]3)=[CH:6][CH:5]=1
Reactant: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
A mixture of {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (300 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (231 mg), 1-hydroxybenzotriazole (162 mg), methylamine hydrochloride (81 mg), triethylamine (0.2 mL), and N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:50:50 to 10:90:0, volume ratio) to give an orange oil. The obtained orange oil was purified by preparative HPLC to give the title compound (150 mg, yield 49%) as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14]>>[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:18][CH:17]=1)[CH3:14]
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(Nc2nc(C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloro-2-methylquinazoline and 4-ethoxyaniline by a procedure similar to Example 28 (93%). 1H NMR (CDCl3): 7.83 (m, 1H), 7.81 (m, 1H), 7.42 (m, 1H), 7.65-7.71 (m, 2H), 7.46 (ddd, J=8.4, 6.9, 1.5, 1H), 7.37 (s, broad, 1H), 6.92-6.97 (m, 2H), 4.06 (q, J=6.9, 2H), 2.68 (s, 3H), 1.43 (t, J=6.9, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([C:5]2[CH:6]=[N:7][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:3][C:4]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH3:28])=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccccc1-c1cc(NS(C)(=O)=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
To a solution of 100 mg (0.2 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide i (Example 73) in 2 ml pyridine were added 27 μl (0.35 mmol) methanesulfonyl chloride and the mixture was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in ethyl acetate, washed twice with saturated aqueous sodium hydrogencarbonate solution, brine and dried (magnesium sulfate). Chromatography of the residue afforded 24 mg (42%) of the title compound as a white foam.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH2:15]([O:17][C:18]1[C:23]2[CH:24]([NH2:27])[CH2:25][O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1)C.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:15][O:17][C:18]1[C:23]2[CH:24]([NH:27][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)[CH2:25][O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: CCOc1cccc2c1C(N)CO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cccc2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CO2
Temperature: 140 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (2.0 g, 9.6 mmol) in 1-methyl-2-pyrrolidone (5 mL) with the above described rac-4-ethoxy-2,3-dihydro-benzofuran-3-ylamine (3.78 g, ca. 10 mmol, max. 50% purity) and N-ethyldiisopropylamine (2.45 mL, 14.4 mmol) was stirred at 140° C. for 2 h. Cooled to 23° C., poured onto water and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as a yellow solid (0.60 g, 18%); MS: m/e=352.4 (M+H+).
Reaction SMILES: [O-2:1].[Ca+2:2].C(=O)=[O:4].[C:6]([O-:9])([O-:8])=[O:7].[Ca+2]>O>[OH-:4].[Ca+2:2].[OH-:7].[OH2:1].[C:6]([O-:9])([O-:8])=[O:7].[Ca+2:2]
Reactant: O=C=O
Reactant: [O-2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: [OH-]
Reaction time: 0.25 h

Procedure:
To prepare the aragonitic precipitated calcium carbonate of the invention, a milk of lime (Ca(OH)2) slurry or slake is prepared by adding water to calcium oxide (CaO) with agitation. Preferably, about ten parts water having a temperature of at least about 40° C. (Centigrade) is added to one part CaO to produce a slake having a solids content of about 11 percent, based on the weight of Ca(OH)2 in the solution. The slake is screened to remove grit, typically with a screen that will remove grit of about +60 mesh, and the slake temperature is adjusted to about 50° C. Dry aragonite, such as M60 Aragonite from the Mississippi Lime Company, located in St. Genevieve, Mo., is added, and the slake is agitated for about 15 minutes. Preferably, the amount of aragonite added is equivalent to about five percent of the total amount of precipitated calcium carbonate that will be produced from the slake. Carbon dioxide gas is then added with vigorous agitation. The gas stream rate should be sufficient to convert substantially all of the Ca(OH)2 to CaCO3 in about three hours, forming a precipitated calcium carbonate slurry of about 14 percent solids. Carbonation is complete when the pH falls to 7, at which time the carbon dioxide (CO2) stream is terminated. Typically, between about 9 ft3 and 10 ft3 of CO2 are required for each kilogram of precipitated calcium carbonate produced. The product can then be dewatered to a concentration of about 70 percent solids to produce a cake that can be treated with a typical dispersant, e.g., sodium polyacrylate, and dispersed on a flat-blade or similar dispersion unit.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:42]=[CH:41][C:8]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH:20]=[C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=5)[NH:23][C:22]4=[O:32])=[CH:17][CH:18]=3)[N:13](COCC[Si](C)(C)C)[N:12]=2)=[CH:7][CH:6]=1)[CH3:3].B(F)(F)F.CCOCC.Cl>>[CH3:1][N:2]([CH2:4][C:5]1[CH:42]=[CH:41][C:8]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH:20]=[C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=5)[NH:23][C:22]4=[O:32])=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: COc1ccc2c(c1)C(=Cc1ccc3c(C=Cc4ccc(CN(C)C)cc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=Cc1ccc3c(C=Cc4ccc(CN(C)C)cc4)n[nH]c3c1)C(=O)N2

Procedure:
According to the method of Example A22B, 3-((3-(4-((dimethylamino)methyl)styryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one (19 mg, 0.033 mmol) was treated with boron trifluoride etherate, followed by 2 N HCl (water/EtOH) treatment. The solvents were removed in vacuo using additional EtOH to azeotropically remove water. The residue was dissolved in MeOH/EtOAc and filtered to remove solid, then the solvent was evaporated in vacuo. Purification by prep-HPLC gave the title compound (E isomer, first eluting fraction, 94% by HPLC) as an orange solid (11 mg, 60%,). 1H NMR (400 MHz, CD3OD) δ ppm 8.26 (d, J=8.5 Hz, 1 H), 7.88 (d, J=9.3 Hz, 2 H), 7.80 (d, J=8.3 Hz, 2 H), 7.61 (s, 2 H), 7.51-7.58 (m, 3 H), 7.26 (s, 1 H), 6.84 (s, 2 H), 4.34 (s, 2 H), 3.63 (s, 3 H), 2.89 (s, 6 H); MS ESI 451.2 [M+H]+, calcd for [C28H26N4O2+H]+ 451.22. The second eluting fraction was the Z-isomer (5 mg, 30%). 1H NMR (400 MHz, CD3OD) δ ppm 8.89 (s, 1 H), 8.15 (d, J=9.0 Hz, 1 H), 7.99 (dd, J=9.0, 1.3 Hz, 1 H), 7.90 (s, 1H), 7.81 (d, J=8.3 Hz, 2 H), 7.57-7.61 (m, 2 H), 7.53 (d, J=8.3 Hz, 2 H), 7.33 (d, J=2.0 Hz, 1H), 6.85 (dd, J=8.4, 2.4 Hz, 1 H), 6.80 (d, J=8.4 Hz, 1 H), 4.34 (s, 2 H), 3.84 (s, 3 H), 2.89 (s, 6 H); MS ESI 451.2 [M+H]+, calcd for [C28H26N4O2+H]+ 451.22.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.N[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>C(O)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH:32]2[CH2:31][CH2:30][O:29][CH2:28][CH2:33]2)=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=1
Reactant: NC1CCCCO1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
5-(Benzoxazol-2-yl)-2-fluoronitrobenzene (see Working Example 15-2) (0.55 g, 2.13 mmol), triethylamine (0.26 g, 2.57 mmol), and aminotetrahydropyran (0.24 g, 2.34 mmol) were added to ethanol (10 mL), and this reaction mixture liquid was heated to reflux with stirring for 2 hours. The reaction mixture was cooled to room temperature and was concentrated under reduced pressure, and 0.1N aqueous hydrochloric acid solution (50 mL) was added to the residue obtained, this was successively extracted with ethyl acetate (approx. 50 mL, 4 times), washed with water (30 mL), and dried over anhydrous sodium sulfate, and the solvent was distilled off at reduced pressure. The residue obtained was purified by silica gel column chromatography to yield the title compound (440 mg, 60.9% yield) as light brown crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:42](O)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)/[C:42]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
A solution of triphenylphosphine (165 mg, 0.63 inmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (112 mg, 0.63 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylic acid (123 mg, 0.37 mmol) in methylene chloride (3 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (92.5 mg, 0.93 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide (36 mg, 23%) as an amorphous solid: EI-HRMS m/e calcd for C19H19ClN6OS (M+) 414.1029, found 414.1029.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:28]4[CH:29]=[N:24][CH:25]=[N:26][CH:27]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4cncnc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and pyrimidine-5-boronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.38 min; Mass spectrum (ESI+): m/z=383 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[ClH:9].[NH2:10][OH:11]>CO>[ClH:9].[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:10][OH:11])=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON=Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A solution of 4-pyridine carboxaldehyde (25.0 g, 233 mmol) in 100 ml of methanol was treated with hydroxylamine hydrochloride (17.84 g, 250 mmol) and stirred 15 minutes at room temperature. The resulting white solid was collected by filtration and dried in vacuo to provide 27.0 g of 4-pyridine carboxaldehyde oxime, hydrochloride, mp 246°-247° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=2)[CH2:11][NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][CH2:11][C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)[N:7]=3)[CH:21]=[CH:20][CH:19]=2)[CH:14]=1
Reactant: Clc1nccc(-c2cccc(CNc3cccnc3)c2)n1
Reactant: NCCc1ccc(O)cc1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CNc4cccnc4)c3)n2)cc1

Procedure:
Intermediate 63 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 398. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.2 (m, 1H), 8.3 (s, 1H), 8.2 (m, 2H), 8.1 (m, 2H), 8.0 (m, 3H), 7.7 (s, 1H), 7.5 (d, 2H), 7.1 (m, 4H), 6.6 (m, 2H), 4.2 (m, 1H), 3.2 (m, 2H), 2.7 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClCCl.C(OCC)C>[C:18]([Si:15]([O:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=1)([CH3:17])[CH3:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,5-Dibromophenol (59.6 mmol; 15 g) and imidazole (65.5 mmol; 4.5 g) were dissolved in dichloromethane (150 mL) and tert-butyl-dimethylsilylchloride (65.5 mmol; 9.9 g) was added. The reaction mixture was stirred at room temperature for 16 hours, diluted with diethyl ether, and filtered. The organic solution was washed with saturated ammonium chloride, saturated sodium hydrogen carbonate, and water and dried and evaporated to dryness. Yield: 22 g. HPLC-MS: m/z: 366.9 (M+); Rt: 3.09 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(Cl)cc21
Yield: 66.9 %

Procedure:
1,1-Dimethylethyl N-((7-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (1.21 g, 3 mmol) was stirred in TFA (5 mL, 67 mmol) at room temperature for 20 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (650 mg). MS (m/e)=324.1 (M+H)+. Calculated for C15H14ClNO5 323.06.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.C(Cl)(Cl)Cl>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)Cc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a suspension of 5-amino-2-cyanopyridine (0.500 g, 4.2 mmol) in dry dichloromethane (20 mL) was added triethylamine (0.637 g, 6.3 mmol) and the mixture was stirred at 0° C. To the reaction mixture phenylacetyl chloride (0.973 g, 6.3 mmol) was added dropwise and stirred at 0° C. for 1 hour and then at room temperature for 24 hours. The reaction mixture was diluted with chloroform (100 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified using column chromatography (silica gel, 20% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-methoxyaniline (38 mg, 0.193 mmol) similar to Example 13 and isolated as a pink solid (18 mg, 25%). 1H NMR (CDCl3): 8.82 (dd, J=1.4, 4.7 Hz, 2H), 8.32 (dd, J=1.7, 4.4 Hz, 2H), 7.84 (d, J=2.1 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.02 (s, 1H), 6.77 (dd, J=3.3, 9.3 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].CO[CH:11](OC)[CH2:12][NH2:13].[ClH:16]>CO>[ClH:16].[NH:2]1[CH:11]=[CH:12][N:13]=[C:1]1[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1ncccn1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CO
Product: c1cnc(-c2ncc[nH]2)nc1
Temperature: 100 °C
Reaction time: 30 h

Procedure:
A mixture of 2-Cyanopyrimidine (8.0 g, 76 mmol, prepared according to Liebigs Ann. Chem. 2, 1981, 333-341) and Aminoacetaldehyde dimethyl acetal (8 g, 76 mmol) is heated at 100° C. for 4 hours, cooled, and 100 mL of MeOH and 5 mL of concentrated HCl are added. The mixture is heated at reflux with stirring for 30 hours, cooled and evaporated to dryness in vacuo. 50 mL of i-ProH is added to the residue and the mixture is heated at reflux with stirring for 30 minutes and cooled. The crystals are collected by filtration, washed with ether, and dried to give the title compound. 1H NMR (DMSO): δ 9.08 (d, 2H), 7.87 (s, 2H), 7.75 (t, 1H). LRMS calcd 146. found 147 (MH+).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:18][NH:19][C:20](=[O:21])[C:10]3=[CH:9]2)=[CH:3][CH:2]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:18][N:19]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:20](=[O:21])[C:10]3=[CH:9]2)=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-c4ccccc4)cc3)cc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cn(Cc3ccc(-c4ccccc4)cc3)c3ccccc3c-2nn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Biphenyl-4-ylmethyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one [(Example 8, Step 3), 110 mg, 0.313 mmol] was dissolved in N,N-dimethylformamide (5 mL), cooled to 0° C. and treated with sodium hydride (37.6 mg, 0.939 mmol, 3 equiv). After stirring for 15 minutes, the mixture was warmed to ambient temperature and stirred for an additional 15 minutes. The mixture was cooled to 0° C., treated with benzyl bromide (0.112 mL, 0.939 mmol, 3 equiv) and after 5 minutes, was warmed to ambient temperature over 2 hours and stirred for an additional 14 hours at ambient temperature. The mixture was poured into water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound: high resolution mass spectrometry (ES+) m/z 442.1922 [(M+H)+; calculated for C30H24N3O: 442.1914].
Reaction SMILES: [C:1]([C:4]1[CH:38]=[CH:37][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21]([C:23]3[N:27](CC4C=CC(OC)=CC=4)[N:26]=[N:25][N:24]=3)=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:6]([CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[C:5]=1[OH:45])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:38]=[CH:37][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[O:22])[C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:6]([CH2:39][CH2:40][C:41]([F:42])([F:44])[F:43])[C:5]=1[OH:45])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cc(OCCCOc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)ccc2C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(OCCCOc2ccc(C)c(NC(=O)c3nnn[nH]3)c2)c(CCC(F)(F)F)c1O

Procedure:
A solution of 2.84 g (4.5 mmol) of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methyl-phenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 90 ml of trifluoroacetic acid and 9 ml of anisole is refluxed for 60 minutes. The reaction mixture is concentrated under reduced pressure, about 150 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide thus obtained, of melting point 236°-238° C. (decomposition), is dissolved in 50 ml of tetrahydrofuran, and one equivalent of sodium, dissolved in 5 ml of methanol, is added. After addition of ether, crystallizations starts. The sodium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide of melting point 115°-125° C. (decomposition) is thus obtained.