Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:8]([F:21])=[C:7]([NH:22]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1)C.OS(O)(=O)=O.CC#N>O>[NH2:22][C:7]1[CH:6]=[C:5]([CH:4]=[O:3])[N:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[C:8]=1[F:21]
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(-c2ccc(C(F)(F)F)nc2)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: Nc1cc(C=O)nc(-c2ccc(C(F)(F)F)nc2)c1F
Yield: 43.1 %

Procedure:
Following the procedure of Example 12, 6-(diethoxymethyl)-3-fluoro-6′-(trifluoromethyl)-N-trityl-[2,3′-bipyridin]-4-amine (1203 mg, 2 mmol), conc H2SO4 (0.5 mL), CH3CN (25 mL) and H2O (25 mL) gave 4-amino-3-fluoro-6′-(trifluoromethyl)-[2,3′-bipyridine]-6-carbaldehyde (248 mg, 0.861 mmol, 43.0%) as a white solid: mp 166-167° C.; 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 9.35 (s, 1H), 8.54 (d, J=8.2 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.40 (d, J=6.5 Hz, 1H), 4.67 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 192.35, 149.96 (d, J=8.9 Hz), 149.50 (d, J=5.2 Hz), 149.03 (d, J=260.1 Hz), 145.2, 143.03 (d, J=12.4 Hz), 140.95, 137.48 (d, J=5.3 Hz), 133.55, 122.83, 120.25 (d, J=2.7 Hz), 108.70 (d, J=4.3 Hz); 19F NMR (376 MHz, CDCl3) δ −67.98, −142.26; HRMS-ESI (m/z) [M+H]+ calcd for C12H7F4N3O, 285.0525. found, 285.0525.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[CH:4]=1.[ClH:12].[N:13]([O-])=O.[Na+]>O.C(OCC)C.C(O)C.[Fe]>[ClH:12].[ClH:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:13])=[C:5]([CH2:9][CH3:10])[CH:4]=1
Reactant: CCc1cccc(N(C)C)c1
Reactant: O=N[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCc1cc(N(C)C)ccc1N
Temperature: 5 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a 250 cm3 round bottom flask was added N,N-dimethyl-m-ethylaniline ((CH3)2NC6H4CH2CH3, MW 149.23, 4.68 g, 31.3 mmol), water (100 cm3), and hydrochloric acid (HCl, 8.5 cm3, 37%). The solution was cooled to 5° C. A solution of sodium nitrite (NaNO2, MW 69.0, 2.46 g, 35.7 mmol) in water (80 cm3) was then added dropwise. The mixture was stirred for 3 hours at room temperature. Iron fillings (Fe, MW 55.85, 5.24 g, 94 mmol) and hydrochloric acid (HCl, 8.5 cm3, 37%) were added. The mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate collected. The pH of the filtrate was adjusted to pH 7 using sodium bicarbonate (NaHCO3) solution, and extracted into ethyl acetate (3×50 cm3). The combined extracts were dried over magnesium sulfate (MgSO4). The mixture was filtered and the filtrate concentrated to yield a brown oil. The oil was dissolved in diethyl ether/ethanol (1:1) (175 cm3). Hydrochloric acid (HCl, 5 cm3, 37%) was added. The solution was filtered to give the product, N,N-dimethyl-m-ethyl-p-phenylenediamine dihydrochloride ((CH3)2NC6H4(CH2CH3)NH2.2HCl, MW 237.17, 4.44 g, 1.87 mmol, 60%) as a light brown solid. δH (250 MHz; D2O): 7.66 (1H, s, ArH), 7.56 (2H, s, ArH), 3.29 (6H, s, NCH3), 2.74 (2H, q, 7.5, CH2), 1.25 (3H, t, 7.5, CH3); δc (62.9 MHz; CDCl3): 15.5 (CH3) 25.6 (NCH2), 48.9 (NCH3), 122.1 (ArC), 124.6 (ArC), 128.1 (ArC), 132.6 (ArC), 143.3 (ArC), 144.9 (ArC).
Reaction SMILES: Br[C:2]1[C:3]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:13][N:14]([CH3:19])[C:15](=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([CH:17]=[CH:16][C:15]([N:14]([CH3:19])[CH3:13])=[O:18])=[C:3]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1
Reactant: CC(C)(C)c1cc(N)ncc1Br
Reactant: C=CC(=O)N(C)C
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C=Cc1cnc(N)cc1C(C)(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
De-gas a mixture of 5-bromo-4-tert-butyl-pyridin-2-ylamine (330 mg, 1.4 mol), N,N-dimethylacrylamide (0.22 mL, 2.1 mmol), triethylamine (0.4 mL, 2.1 mmol) in toluene (4 mL) while purging with nitrogen for 3 minutes. Add palladium(II)acetate (60 mg, 0.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (690 mg, 0.6 mmol) under nitrogen. Heat the reaction overnight in sealed vessel at 120° C. Cool the mixture to room temperature, filter through Celite® and concentrate. Purification by silica gel column chromatography (100% DCM to 3% MeOH in DCM) to yield the title compound (81% yield). LCMS (ES), m/z 248 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][NH:9][N:10]=1)[CH3:2].I[CH:13]([CH3:15])[CH3:14].[OH-].[Na+].C(OC(=O)CC1N=NN(C(C)C)N=1)C>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:10]([CH:13]([CH3:15])[CH3:14])[N:9]=[N:8][N:7]=1)[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)Cc1nn[nH]n1
Agent: CCOC(=O)Cc1nnn(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nnnn1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of (2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 13 mmol) in dimethylformamide (5 mL) was added 2-iodo-propane (11 g, 64 mmol) and sodium hydroxide (2.6 g, 64 mmol) and the solution was stirred at room temperature for 2 h. Ice water was added and the solution was extracted several times with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography to provide a mixture of (2-isopropyl-2H-tetrazol-5-yl)-acetic acid ethyl ester and (1-isopropyl-1H-tetrazol-5-yl)-acetic acid ethyl ester (2 g, 79% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2].[Br:17]N1C(=O)CCC1=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Br:17][C:5]1[CH:6]=[C:7]([CH:10]([CH:14]([CH3:15])[CH3:16])[C:11]([OH:13])=[O:12])[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(C(C(=O)O)C(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(C(=O)O)C(C)C)cc1Br
Yield: 59 %

Procedure:
Into a solution of 0.15 g (0.67 mM) of 2-(4-ethoxyphenyl)isovaleric acid in 3 ml of chloroform, 0.24 g (1.35 mM) of N-bromosuccinimide was added, and the mixture was heated for 3 hours in the presence of a catalytic amount of anhydrous aluminum chloride under a reflux condition. The oily substance obtained by condensing the reaction mixture was subjected to silica gel column chromatography while using a 1:3 mixture of ethyl acetate and n-hexane as an eluent, thereby 0.12 g of 2-(3-bromo-4-ethoxyphenyl)isovaleric acid was obtained as a colourless and oily substance (yield: 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cn1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Yield: 82.4 %

Procedure:
Using 5-bromo-2-picolinic acid (5.0 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (4.7 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (7.6 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([N:64]2[C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=3[N:66]=[CH:65]2)[CH:59]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([N:64]2[C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=3[N:66]=[CH:65]2)[CH:59]=1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc2c(c1)ncn2-c1cc([C@@H]2CCCN2)ccn1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-n2cnc3ccccc32)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (51 mg, 0.21 mmol), HOBt (31 mg, 0.23 mmol) and HBTU (88 mg, 0.23 mmol) in DMF (5 mL) is stirred at room temperature for 30 min. Then a solution of —((S)-4-pyrrolidin-2-yl-pyridine-2-yl)-1H-benzoimidazole (10) in DMF (5 mL) is added, followed by diisopropylethylamine (135 mg, 1.05 mmol). After stirring at room temperature for 2 h, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 5%˜40%) to give {(S)-2-[(S)-2-(2-benzoimidazol-1-yl-pyridin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamic acid tert-butyl ester (71 mg, 67%) as a white solid. M/Z=504.2 [M+1]
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1([C:27]#[CH:28])[OH:26]>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1([CH:27]=[CH2:28])[OH:26]
Reactant: C#CC1(O)c2cc(OC)ccc2CC(N(C)S(=O)(=O)c2ccc(C)cc2)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C=CC1(O)c2cc(OC)ccc2CC(N(C)S(=O)(=O)c2ccc(C)cc2)C1(C)C
Yield: 95 %

Procedure:
A mixture of 205 g of 2,2-dimethyl-1-ethinyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4-tetrahydro-1-naphthol, 0.8 g of 0,5% palladium on calcium carbonate, 0.8 g 5% palladium on charcoal and 1000 ml of ethyl acetate is submitted to hydrogenation at atmospheric pressure and room temperature. After the absorption of 1200 ml of hydrogen the catalysts are removed by filtration. The solution is concentrated by evaporation in vacuo of most of the solvent, whereafter the product crystallizes as white crystals melting at 152°-154° C. Yield 95%.
Reaction SMILES: O1CCCOB1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Br[C:16]1[CH:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([C:21]1[CH:22]=[CH:16][C:17]2[C:19](=[C:7]3[C:8](=[C:9]([NH2:10])[N:18]=2)[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:20]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ccc(N)c(Br)c1
Reactant: N#Cc1ccccc1B1OCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCc1ccc2nc(N)c3ccccc3c2c1
Reaction time: 18 h
Yield: 65.6 %

Procedure:
20.0 g (87.7 mmol)2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 13.7 g (73.1 mmol) 2-bromo-4-butylaniline, 1.70 g (1.46 mmol) tetrakis(triphenylphosphine)palladium(0), and 27.2 g (198 mmol) potassium carbonate where refluxed in 400 mL toluene and 200 mL ethanol under N2 atmosphere for 20 h. HPLC and TLC revealed almost complete consumption of the aniline. An additional 1.8 g 2-(1,3,2-dioxaborinan-2-yl)benzonitrile was added and refluxed continued for an additional 18 h. The reaction mixture was cooled and passed through a filter. The solids were washed with ethyl acetate to remove organics from the collected base. The filtrate was then evaporated down and dried on silica. The sample was purified using silica gel chromatography with 100% ethyl acetate as the eluent. The product fractions were then evaporated down to a minimal amount and the product recrystallized from EtOAc/hexanes to give 12.0 g of the title compound as light yellow solids (65.9% yield, GC-MS confirmed).
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][CH:5]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1)[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:4][CH:5]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][CH:24]=1)[CH2:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[CH2:1][CH3:2]
Reactant: CCI
Reactant: Cc1cccc(CCNCCCC(O)c2ccc(NS(C)(=O)=O)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)CCc1cccc(C)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
0.24 ml 3.04 mmol) of ethyl iodide was added to a suspension of 1.0 g (2.77 mmol) of N-[4-[1-hydroxy- 4-[2-(6-methyl-2-pyridyl)ethylamino]butyl]phenyl]methanesulfonamide prepared in Example 3-(4) and 0.70 g (8.31 mmol) of sodium hydrogencarbonate in 15 ml of dimethylformamide. The mixture was stirred at 50° C. for 2 h and then filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3). 0.96 g (yield: 89%) of the intended compound was obtained in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([C:9]([CH3:19])=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:1][C:2]1[C:3]([F:20])=[C:4]([C:9]([CH3:19])=[C:10]([N:12]([CH2:21][CH3:22])[CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)c(NC2CCOCC2)cc(Br)c1F
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CCN(c1cc(Br)c(F)c(C(=O)OC)c1C)C1CCOCC1
Yield: 96.3 %

Procedure:
To a solution of methyl 3-bromo-2-fluoro-6-methyl-5-[(oxan-4-yl)amino]benzoate (500 mg, 1.44 mmol) in 1,2-Dichloroethane (15 ml) at room temperature and under nitrogen was added acetaldehyde (0.81 ml, 14.44 mmol) followed by acetic acid (0.5 ml, 8.67 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (3.06 g, 14.44 mmol) at room temperature. After stirring for 2 hours deionized water (20 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 85:15 Heptane:EtOAc) to give 519 mg (96%) of methyl 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoate as a pale yellow oil that solidified upon standing. LC-MS 94%, 2.45 min (3 minute LC-MS method), m/z=373.9/375.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.33 (d, J=6.6 Hz, 1H), 3.95 (s, 5H), 3.32 (td, J=11.7, 2.1 Hz, 2H), 3.00 (q, J=7.1 Hz, 2H), 2.88 (tt, J=10.9, 4.0 Hz, 1H), 2.25 (s, 3H), 1.73-1.54 (m, 4H), 0.85 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]([F:24])([F:23])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH2:22].[OH-].[Na+]>>[N+:1]([C:14]1[C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:23])[F:24])[C:13]=1[NH2:22])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(F)(F)F)ccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Nitric acid (7 mL) was added to sulfuric acid (10 mL) cautiously at 0° C. 2,5-Bis(trifluoromethyl)benzenamine (2 g, 8.7 mmol) was added in small portions at 0° C. over 20 minutes and the resulting slurry was stirred at 0° C. to room temperature for 3 hours. The mixture was poured into ice water (100 mL) and basified with sodium hydroxide solution, and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to give a crude product of 2-nitro-3,6-bis(trifluoromethyl)benzenamine (containing isomers) which was used in the next step without further purification (2.3 g). MS (ESI): m/z 275 [M+H]+
Reaction SMILES: C(O[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])C.[H][H].[CH2:19]([OH:21])[CH3:20]>[Pd]>[CH2:19]([O:21][CH:7]([CH2:6][C:5]1[CH:4]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:20]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccccc1OCC
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccccc1)OCC
Yield: 97 %

Procedure:
A solution of ethyl 2-ethoxycinnamate (53.9 g, 0.267 mol; prepared as described in Justus Liebigs Ann. Chem. 699, 53 (1966) ) in ethanol (500 ml) was hydrogenated in the presence of 5% palladium on activated charcoal (5.0 g) at ambient temperature under pressure 10 atm until absorption of hydrogen ceased. The catalyst was filtered off and the filtrate was evaporated to give 52.8 g (97%) of ethyl 2-ethoxy-3-phenylpropionate as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)[CH:8]=1
Reactant: CSc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 66.7 %

Procedure:
2-Cyano-4-methylthiopyridine (2.36 g, 15.7 mmol) and methyl thiosalicylate (5.28 g, 31.4 mmol) were dissolved in toluene (100 ml), and triethylamine (9.9 ml, 70.7 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (3.00 g, 68%) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:24])[O:21][C@@H:20]([CH2:22][NH2:23])[CH2:19][O:18]1.C(O)C>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][C@H:20]3[CH2:19][O:18][C:17]([CH3:24])([CH3:16])[O:21]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CN)O1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)OC[C@H](CNc2c([N+](=O)[O-])cnc3cc(Br)ccc23)O1
Yield: 96.1 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (11.00 g, 38.26 mmol) was reacted with (S)-2,2-dimethyl-[1,3]dioxolane-4-methanamine (5.81 g, 57.4 mmol) according to the method described in Part A of Examples 125-135. When the reaction was complete, it was concentrated under reduced pressure, and the residue was stirred with water (100 mL). The resulting solid was isolated by filtration, mixed twice with ethanol and concentrated under reduced pressure. The solid was then triturated with diethyl ether, isolated by filtration, and dissolved in dichloromethane. An insoluble impurity was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 14.05 g of (S)-(7-bromo-3-nitroquinolin-4-yl)-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].Cl>CCOCC>[CH2:13]([N:16]([CH2:17][CH2:18][CH3:19])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:14][CH3:15]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCNCCC
Agent: Cl
Solvent: CCOCC
Product: CCCN(CCC)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
An amount of 37.1 gm (0.2 mol) of p-nitrobenzoyl chloride in 300 ml of ether were added dropwise, with agitation and at room temperature, into a solution of 50.6 gm (0.5 mol) of dipropylamine in 400 of ether. Then, the mixture was agitated for one hour at room temperature and one hour at boiling temperature, the reaction mixture was treated with dilute hydrochloric acid, and the ether phase washed with water and evaporated. An amount of 44.3 gm of p-nitrobenzoic acid dipropylamide in the form of a light-yellow, oily residue was obtained.
Reaction SMILES: CC1C=C([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]=2)C=CC=1C(O)=O.Cl.[NH2:32][OH:33].[C:34](Cl)(=[O:38])[C:35](Cl)=O>N1C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:12]2[C:13]([CH3:14])=[C:35]([CH:15]=[CH:16][CH:11]=2)[C:34]([NH:32][OH:33])=[O:38])=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)c(C)c2)cc1OCCCCCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cccc(C(=O)NO)c2C)cc1OCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-methyl-4-[4-methoxy-3-(5-phenylpentyloxy)phenyl]benzoic acid (0.13 g, 0.32 mmoles) in oxalyl chloride (5 ml) was heated to reflux under nitrogen for about 10 minutes. The solution was concentrated under reduced pressure and the residue dried at about 25° C. (0.05 mm pressure). The residue was then dissolved in dry THF (5 ml) and added slowly to a solution of hydroxylamine hydrochloride (0.022 g, 0.32 mmoles) in pyridine at about 0° C. After stirring at about 25° C. for about 16 hours the volatiles were removed under reduced pressure and the residue was slurried in 1NHCl. The mixture was then extracted with ethyl acetate and the combined organics were washed with water and brine, and dried over MgSO4. Filtration followed by concentration under reduced pressure yielded a beige solid. Recrystallization from isopropyl ether (10 ml) gave 0.055 grams of the title compound as an off-white solid. M.P. 125°-126°C.; analysis calc'd. for C26 H2 gNO4 : C,74.43; H, 6.97; N, 3.34. Found: C, 73.85; H, 6.78; N, 3.34.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][NH:27][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCCNCc4ccc(F)c(F)c4)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, 3,4-difluorobenzylamine, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 13. Purity by LC/MS=96%, [M+H]+=413.