Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][O:65][CH2:66][C:67](O)=[O:68]>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][N:51]([C:67](=[O:68])[CH2:66][O:65][CH3:64])[CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCC(Oc2cc3ncnc(Nc4cccc(Cl)c4F)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
HATU (0.24 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (250 mg), diisopropylethylamine (0.37 ml) and methoxyacetic acid (0.054 g) in methylene chloride (9 ml) and the mixture was stirred at room temperature for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.200 g); 1H N Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.37 (s, 3H), 3.41 (m, 2H), 3.77 (m, 2H), 3.98 (s, 3H), 4.09 (s, 2H), 4.85 (m, 1H), 7.26 (m, 1H), 7.30 (s, 1H), 7.39 (m, 1H), 7.59 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.34 (br s, 1H); Mass Spectrum: (M+H)+ 475.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:37])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[CH2:20][N:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1)=[O:16]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:37])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:36]=[CH:35][CH:34]=[C:19]([CH2:20][N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(CN2CCNCC2)c1
Yield: 69.4 %

Procedure:
The solution of tert-butyl 4-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)benzyl)piperazine-1-carboxylate (160 mg, 0.314 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at 27° C. for 16 h. The solution was concentrated and the residue was purified by prep-HPLC to give the title product (89 mg, Yield 69.0%). 1H NMR (D2O, 400 MHz): δ 7.66-7.56 (m, 2H), 7.51-7.44 (m, 1H), 7.44-7.37 (m, 1H), 7.16-7.06 (m, 3H), 7.02 (d, J=7.3 Hz, 1H), 4.11 (quin, J=5.9 Hz, 1H), 3.73-3.60 (m, 2H), 3.56-3.49 (m, 2H), 3.49-3.42 (m, 1H), 3.41-3.32 (m, 1H), 2.86-2.75 (m, 8H), 2.68-2.58 (m, 2H), 2.56-2.32 (m, 4H). LCMS (m/z): 409.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine (202 mg, 0.688 mM), then morpholine (120 μL, 1.38 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 extracts thus obtained were combined together and then dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to give the title compound (235 mg, yield: 99%).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C(O)C>[Pd].C1C2C(CCCC2)CCC1.C=CCCCCCCCCCC>[O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([OH:10])=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C1CCCc2occc21
Agent: [Pd]
Agent: C=CCCCCCCCCCC
Solvent: C1CCC2CCCCC2C1
Solvent: CCO
Product: Oc1cccc2occc12
Temperature: 80 °C

Procedure:
3.76 g (27.6 mmol) of 6,7-dihydro-1-benzofuran-4(5H)-one (prepared according to Tetrahedron Lett. 1994, 35, 6231) and 10% of palladium on activated carbon in 34 ml of decalin and 6 ml of dodecene are heated in a metal bath at 200° C. overnight. The mixture is cooled to 80° C., ethanol is added and the mixture is filtered off through CELITE (diatomaceous earth). The CELITE (diatomaceous earth) is washed twice with ethanol and the filtrate is concentrated. The residue, which still contains decalin and dodecene, is mixed with petroleum ether and cooled in an ice bath. An oily precipitate forms. The solvent is decanted off and the oil is purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].ClC(Cl)C.[Br:14]Br.Br>[Fe]>[Cl:8][C:5]1[C:6]([Br:14])=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: BrBr
Agent: [Fe]
Agent: Br
Solvent: CC(Cl)Cl
Product: Cc1cc(Cl)c(Br)cc1Br
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
51.4 g (0.25 mol) of 2-bromo-5-chlorotoluene, 25 ml of dichloroethane and 1.5 g of iron powder are introduced into a round-bottomed flask. 40 g (0.25 mol) of bromine are added dropwise at 38°-40° C. with stirring, hydrogen bromide being evolved. The product precipitates out during the addition. The suspension is maintained by adding a further 35 ml of dichloromethane with vigorous agitation. Stirring is continued for 30 minutes after addition of the bromine. The crystal slurry is taken intosolution at room temperature using 20 ml of dichloromethane and the iron powder is filtered off. The organic phase is concentrated by evaporation in a Rotavapor.58 g of 5-chloro-2,4-dibromotoluene is obtained, corresponding to 81.6% of theory relative to 2-bromo-5-chlorotoluene, purity (from gas chromatography): 91%, melting range 91°-95°C.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[Br:7][C:8]1[S:12][C:11]([C:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=O)=[N:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.[Cl-].[NH4+]>[Br:7][C:8]1[S:12][C:11]([CH:13]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:3][CH:2]=[CH2:1])=[N:10][CH:9]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=CCC(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)OCC)CC1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
Methyltriphenylphosphonium bromide (2.58 g, 7.22 mmol), potassium tert-butoxide (0.8248 g, 7.35 mmol) and toluene (24 ml) were combined and heated under reflux for 1 h. Then, the mixture was cooled to −10° C. and ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl) carbonyl]cyclohexane-carboxylate (1.022 g, 2.95 mmol) in 2 ml of toluene was added dropwise. The mixture was stirred between 2° C. to 3° C. for 1.5 h. The reaction was diluted with aqueous saturated ammonium chloride, extracted with EtOAc (2×) and the combined organic phases were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (0-8% EtOAc in hexane) to afford ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)but-3-en-1-yl]cyclohexanecarboxylate. MS ESI calc'd. for C16H22BrNO2S [M+H]+ 372, 374. found 372, 374. 1H NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 5.65 (dd, J=6.9, 10.2, 1H), 5.13-4.79 (m, 2H), 4.10 (q, J=7.1, 2H), 2.97-2.89 (m, 1H), 2.62-2.38 (m, 2H), 2.23-1.86 (m, 4H), 1.70-1.60 (m, 2H), 1.50-1.28 (m, 2H), 1.23 (t, J=7.0, 3H), 1.12-0.92 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:14]2[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]3[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: COc1ncccc1Nc1ncnc(Cl)n1
Reactant: Brc1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1Nc1ncnc(-n2ncc3ccc(Br)cc32)n1
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-1H-indazole (172 mg, 0.87 mmol) in DMF (8 mL) was added NaH (60% in oil, 69.8 mg, 1.75 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes before the addition of 4-chloro-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (311.18 mg, 1.31 mmol). Stirring was continued at RT for 2 hr. The reaction mixture was quenched with water and EtOAc added. The resultant precipitate was collected and further drying under vacuum gave the title compound as a beige solid; 1H NMR (250 MHz, CDCl3) δ 4.09 (3H, s), 7.05 (1H, d, J=2.28 Hz), 7.50 (1H, dd, J=8.53, 1.68 Hz), 7.62-7.70 (1H, m), 7.88-8.09 (2H, m), 8.30 (1H, d, J=0.76 Hz), 8.74 (1H, dd, J=7.77, 1.68 Hz), 8.83 (1H, s), 9.01 (1H, s); LC-MS: m/z=+397.9/399.8 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:19][C:20]1[C:21](Cl)=[N:22][CH:23]=[C:24]([CH:36]=1)[C:25]([N:27]([CH3:35])[CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26]>>[Cl:19][C:20]1[C:21]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[N:22][CH:23]=[C:24]([CH:36]=1)[C:25]([N:27]([CH3:35])[CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26]
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CN(CCN1CCCC1)C(=O)c1cnc(Cl)c(Cl)c1
Product: CN(CCN1CCCC1)C(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1

Procedure:
Using 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol and 5,6-dichloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)nicotinamide, and in the same manner as in Example 65 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (99 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[N:15]#[C:16]Br.CC(C)=O.C(N(CC)CC)C>O>[O:13]=[C:12]1[CH:11]=[CH:10][C:9](=[O:14])[N:8]1[C:4]1[CH:3]=[C:2]([O:1][C:16]#[N:15])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CC(=O)N1c1cccc(O)c1
Reactant: N#CBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#COc1cccc(N2C(=O)C=CC2=O)c1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
A 34.05 gram portion of N-(3-hydroxyphenyl)maleimide (0.18 mole), 20.02 grams of cyanogen bromide (0.189 mole) and 300 milliliters of acetone were added to a reactor and maintained under a nitrogen atmosphere with stirring. The stirred solution was cooled to -10° C. then 18.31 grams of triethylamine (0.1809 mole) was added to the reactor over a fifteen minute (900 s) period and so as to maintain the reaction temperature at -5° to -4° C. After completion of the triethylamine addition, the reactor was maintained at -5° to -3° C. for an additional thirty minutes (1800 s), followed by addition of the reactor contents to 1500 milliliters of deionized water. After five minutes (300 s), the water and product mixture was multiply extracted with three 100 milliliter volumes of methylene chloride. The combined methylene chloride extract was washed with 500 milliliters of 0.05 percent aqueous hydrochloric acid followed by washing with 500 milliliters of deionized water then drying over anhydrous sodium sulfate. The dry methylene chloride extract was filtered and solvent removed by rotary evaporation under vacuum for 60 minutes at 60° C. 3-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)phenyl cyanate (34.25 grams) was recovered in 88.9 percent yield as a light tan colored powder. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure (disappearance of phenolic hydroxyl absorbance, appearance of cyanate absorbance at 2232 and 2274 cm-1, maintenance of maleimide carbonyl absorbance at 1714 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Clc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1
Yield: 57.1 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.354 g), 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.475 g), triethylamine (0.552 g), and ethylene glycol (2 mL) give 0.363 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 145-146° C.; MS m/z 360; IR (mineral oil) 823, 1500, 1496, 1225, 814 cm-1. 1H NMR (CDCl3) δ2.72, 3.19, 3.76, 6.83, 7.13, 7.19, 7.52, 7.53, 8.14.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]([Cl:20])[C:14]([NH2:19])=[CH:15][C:16]=1[O:17][CH3:18])=[O:10])[CH2:4][CH3:5].C(N(CC)CC)C.[Cl:28][C:29]1[CH:41]=[CH:40][C:32]([O:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36])=[CH:31][CH:30]=1.[OH-].[Na+]>O.C(Cl)(Cl)Cl>[Cl:28][C:29]1[CH:41]=[CH:40][C:32]([O:33][C:34]([CH3:38])([CH3:39])[C:35]([NH:19][C:14]2[C:13]([Cl:20])=[CH:12][C:11]([C:9]([NH:8][CH2:7][CH2:6][N:3]([CH2:2][CH3:1])[CH2:4][CH3:5])=[O:10])=[C:16]([O:17][CH3:18])[CH:15]=2)=[O:36])=[CH:31][CH:30]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(NC(=O)C(C)(C)Oc2ccc(Cl)cc2)cc1OC
Yield: 73.7 %

Procedure:
Metoclopramide (59.8 g.; 0.2 mole) and triethylamine (30.0 g; 0.3 mole) are dissolved in 400 ml. of chloroform. To this mixture there is added dropwise 2-(4-chlorphenoxy)-2-methylpropionic acid chloride (72.0 g.; 0.3 mole). The mixture is heated under reflux for two hours and is subsequently mixed with 100 ml. of 20% caustic soda solution and with water. After evaporation, the distillation residue is recrystallized from methanol whereby 73.2 g. (73.7% of theory) of 4-[2-(4-chlorphenoxy)isobutyroylamino]-5-chloro-2-methoxy-N-[2-(diethylamino)-ethyl]benzamide having a melting point of 120°-121° C. is obtained.
Reaction SMILES: [H][H].[F:3][C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(OCC)(=O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:3])[CH:14]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAc was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 h to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The PH of the solution was adjusted to 4 with NaOH (aq.). The mixture was extracted with more ethyl acetate. The organic layer was washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 h. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 h and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation with a hydrogen balloon converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]([C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1)=[O:4].Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][CH:2]([F:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CC1(C)OB(c2ccc(C(=O)C(F)F)cc2)OC1(C)C
Reactant: Fc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(F)cn2)cc1)C(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Pd(dppf)Cl2 (3.06 g, 4.2 mmol) was added to a degassed, ambient temperature solution of 2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (30 g, 84 mmol), 2-bromo-5-fluoropyridine (15 g, 84 mmol) and sodium carbonate (20 g, 189 mmol) in N,N-dimethylformamide (400 mL) and H2O (100 mL). After stirring at 90° C. overnight, the reaction mixture was poured into ice and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with petroleum ether/ethyl acetate (20:1) afforded the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.[Cl:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27](Cl)=[O:28]>C(OCC)(=O)C>[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([NH:8][C:27](=[O:28])[CH:26]([Cl:25])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A toluene [350 milliliters (mL)] solution of 3-aminobenzotrifluoride [35.5 grams (g) 0.22 mol] and pyridine (19.1 grams, 0.24 mol) was cooled in an ice bath. 2-Chloro-2-phenylacetyl chloride (45.8 grams, 0.24 mol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 ×200 mL) and dried with magnesium sulfate. The solvent was removed in a rotary evaporator to provide the desired N-(3-trifluoromethylphenyl)-2-chloro-2-phenylacetamide (61.6 grams, 89% yield) whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[CH:44][C:45]([S:48](F)(=[O:50])=[O:49])=[N:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:45]2[CH:44]=[CH:43][C:42]([F:41])=[CH:47][N:46]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(F)c1ccc(F)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccc(F)cn2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 28 h
Yield: 28.5 %

Procedure:
To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran (2.5 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg), 15-crown-5 (220 mg) and 5-fluoropyridine-2-sulfonyl fluoride (120 mg) at room temperature, and the mixture was stirred at room temperature for 28 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:3) to give the title compound as a pale-yellow oil (yield 69 mg, 29%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([OH:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[F:14][C@@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[C:10]([O:13][CH2:16][CH:15]([F:14])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCC[C@H](F)CO
Reactant: COC(=O)c1ccc(O)c(F)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCC(F)COc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C

Procedure:
0.05 mol of methyl 2,3-difluoro-4-hydroxybenzoate, 0.05 mol of (S)-2-fluorooctan-1-ol and 0.06 mol of triphenylphosphine are dissolved in 125 ml of tetrahydrofuran, and 0.06 mol of diethyl azodicarboxylate is added dropwise with stirring and ice cooling. The mixture is allowed to warm to room temperature and is stirred for a further 8 hours. The solvent is then removed by distillation, and the methyl 2,3-difluoro-4-(2-fluorooctyloxy)benzoate is purified by column chromatography. 2,3-Difluoro-4-(2-fluorooctyloxy)benzoic acid is obtained therefrom by hydrolysis using aqueous/alcoholic potassium hydroxide solution.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([OH:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:21][C:22]1[C:27]([CH2:28][CH2:29]O)=[CH:26][CH:25]=[C:24]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:23]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:29][CH2:28][C:27]2[C:22]([CH3:21])=[N:23][C:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=3)=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)c2ccccc2c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Product: CCOC(=O)C(C)(C)Oc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc2c1

Procedure:
In analogy to the procedures described in example 4D] and 4E], 2-(4-hydroxy-naphthalen-2-yloxy)-2-methyl-propionic acid ethyl ester (example 17D]) was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 4K]) to give 2-methyl-2-(4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-naphthalen-2-yloxy)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as orange solid.