Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH2:31][CH2:32][CH:33]1[CH2:35][CH2:34]1>>[CH:33]1([CH2:32][NH:31][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=4[Cl:28])[C:15]=3[O:14]2)[CH2:35][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: NCC1CC1
Product: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)OC(CNCC1CC1)C2

Procedure:
The title compound was prepared (0.066 g, 54%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.30 mmol) and (aminomethyl)cyclopropane (0.21 g, 3.0 mmol). mp 130-133° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[I:15](O)(O)(O)(O)(O)=O.II.S(=O)(=O)(O)O>O.C(O)(=O)C>[I:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CCc1ccc(-c2ccccc2)cc1
Reactant: [O-][I+](O)(O)(O)(O)O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(-c2ccc(I)cc2)cc1
Temperature: 70 °C

Procedure:
25.0 g (137 mmol) of 4-ethylbiphenyl, 7.23 g (27.4 mmol) of orthoperiodic acid, 13.9 g (54.9 mmol) of iodine, 133 ml of acetic acid, 27 ml of water and 4.1 ml of sulfuric acid were placed in a 500 ml three-necked flask with a mechanical stirrer and bulb-shaped cooler. This was heated to 70° C. in a water bath, and subjected to the reaction for 2 hours. The product was cooled down to the ambient temperature. To this was added 300 ml of water, which was subjected to the extraction with chloroform. The resultant chloroform phase was washed with sodium thiosulfate and water in this order. To this was added sodium sulfate, and the dehydration was carried out. After the filtration was carried out, the chloroform was distilled away in an evaporator to obtain a light yellow solid. The resultant solid was recrystallized in the presence of ethanol to obtain a white crystal. The yield of the compound was 71%. Its melting point was 145-149° C. The IR chart is shown in FIG. 24.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[CH:7](O)[CH2:6][CH2:5]2.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[CH2:7][CH:6]=[CH:5]2
Reactant: Cc1cc2c(cc1C)C(O)CC2
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C)CC=C2
Yield: 82.2 %

Procedure:
A 1 L three-neck round bottom flask equipped with a condenser, mechanical stirrer, nitrogen inlet and a thermometer was charged with 5,6-dimethyl-1-indanol (41.25 g, 0.254 mol), toluene (250 mL), pyridine (250 mL, 3.1 mol), and p-toluenesulfonyl chloride (52.0 g, 0.273 mol). The mixture was heated to reflux and dehydration was monitored by GC. After 2.5 hours at reflux the reaction mixture was cooled, quenched in 5% HCl (1.2 L ice-water), and extracted with diethyl ether (500 mL). The organic phase was washed with 5% aqueous sodium bicarbonate, water, and then dried over anhydrous magnesium sulfate. Rotary evaporation followed by vacuum distillation (79° C./0.5 mm Hg) yielded 5,6-dimethylindene (30.1 g, 98+% purity by GC) as white crystalline solid (mp 34-35° C.). 1HNMR (CD2Cl2, 500 MHz) δ7.24 (s, 1H); 7.16 (s, 1H); 6.80 (m, 1H); 6.45 (m, 1H); 3.32 (s, 2H); 2.28 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C@@H:20]([O:36][CH:37]2[CH2:41][CH2:40][CH:39]=[CH:38]2)[C@H:19]([CH3:42])[O:18][C:17]1=[O:43])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:11]([O:10][C:9]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C@@H:20]([O:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C@H:19]([CH3:42])[O:18][C:17]1=[O:43])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2cccc3ccccc23)[C@H]1OC1C=CCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2cccc3ccccc23)[C@H]1OC1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-cyclopent-2-en-1-yloxy-9-methyl-7-(1-naphthylmethyl)-2-oxo-1,5-dioxonan-3-yl]carbamate (210 mg, 0.353 mmol) in EtOAc (3.5 mL) was added 10% Pd/C (37.5 mg, 0.035 mmol). The reaction was put under a H2 atmosphere (balloon) and stirred at room temperature for 5 h, whereupon the H2 was purged from system and the reaction was filtered through a pad of Celite®. The pad was washed with EtOAc (2×6 mL) and the organics were combined and concentrated to dryness to afford tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-(cyclopentoxy)-9-methyl-7-(1-naphthyl-methyl)-2-oxo-1,5-dioxonan-3-yl]carbamate (193 mg, 92%) as a white powder: mp 49-55° C.; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.3 Hz, 1H), 7.82 (dd, J=8.1, 1.5 Hz, 1H), 7.74-7.67 (m, 1H), 7.54-7.41 (m, 2H), 7.40-7.31 (m, 2H), 5.05 (app t, J=7.7 Hz, 1H), 4.90-4.79 (m, 1H), 4.21-4.12 (m, 1H), 3.94 (dd, J=11.7, 7.5 Hz, 1H), 3.88 (dd, J=11.7, 8.0 Hz, 1H), 3.73 (dd, J=13.6, 2.9 Hz, 1H), 3.53-3.35 (m, 3H), 2.71 (app t, J=12.8 Hz, 1H), 2.07-1.96 (m, 1H), 1.90-1.70 (m, 6H), 1.63-1.49 (m, 5H), 1.38 (s, 18H); ESIMS m/z 620 ([M+Na]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=2)[O:3]1.Cl>[OH-].[Na+]>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:23])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[O:5]1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)OB(c2ccc([C@@H]3C[C@H]3C(=O)O)cc2)OC1(C)C
Temperature: 100 °C

Procedure:
A mixture of ester from step 2 and NaOH (20%, 30 mL) was heated to 100° C. for 1.5 h, cooled to rt, acidified with HCl 10% and extracted with EtOAc. The organic extract was dried over Na2SO4 and the solvent evaporated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21)c1ccccn1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with commercially available 2-bromo-1-pyridin-2-ylethanone gave the title compound.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(NCC)C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1>C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([OH:17])[CH2:4][N+:1]([O-:3])=[O:2])[CH:11]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccnc1
Solvent: CCNCC
Solvent: CCO
Product: O=[N+]([O-])CC(O)c1cccnc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled stirring solution of 15 grams (0.25 mol) nitromethane and 0.35 gram (0.005 mol) diethylamine in 26 milliliters of ethanol was added dropwise 10 grams (0.093 mol) 3-pyridine carboxaldehyde. The reaction was stirred for 3 hours at 0° C. then warmed to ambient temperature. Concentration yielded crude 1-(3-pyridyl)-2-nitroethanol.
Reaction SMILES: C[C:2]1([C:22]([O-:24])=[O:23])[CH2:6][CH:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[N:3]1C(OC(C)(C)C)=O.O1CCOC[CH2:26]1>Cl>[CH3:26][O:24][C:22](=[O:23])[C@@H:2]1[CH2:6][CH:5]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:4](=[O:14])[NH:3]1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(Cc2ccccc2)CC1(C)C(=O)[O-]
Agent: Cl
Product: COC(=O)[C@@H]1CC(Cc2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(1,1-Dimethylethyl) 2-methyl-5-oxo-4-(phenylmethyl)-1,2-pyrrolidinedicarboxylate (0.415 g, 1.24 mmol) was dissolved in 4M hydrogen chloride in dioxane (2 ml) and stirred at room temperature for 2 hrs. The solvent was evaporated to give a colourless oil which crystallized on standing to give methyl-5-oxo-4-(phenylmethyl)-prolinate as a creamy/white solid (0.205 g). This was used without further purification in the next step.
Reaction SMILES: [C:1]12[C:6](=O)[CH:5]=[C:4]([CH:8]=1)[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]2=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]12[CH2:8][C:4](=[CH:5][C:6]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]2=1
Reactant: C1CCNCC1
Reactant: O=C1C=C2C=C1c1ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C2CC(=C1N1CCCCC1)c1ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Benzobicyclo[2.2.1]hepteneone (0.5 g) was combined with piperidine (1 ml), p-toluenesulfonic acid (0.1 g), and toluene (25 ml) and heated to reflux for 20 hours. The solution was concentrated on a rotary evaporator and the residue was distilled on a Kugelrohr apparatus (120° C. at 0.05 mm Hg). The distillate was combined with glacial acetic acid (10 ml) and sodium cyanoborohydride (0.5 g) and stirred at room temperature for 12 hours. The solution was made basic by the addition of 10% sodium hydroxide in water. The resulting mixture was extracted with ether (3×50 ml) and the combined ether layers were dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was distilled on a Kugelrohr apparatus (120° C. at 0.05 mm Hg) to provide the product as a colorless oil. Analytical data are reported in Table I.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]([CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([NH:7][C@@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])=[O:6].I[CH3:20]>C1COCC1>[CH3:20][N:7]([C@@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])[C:5](=[O:6])[C@H:4]([CH3:3])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CI
Reactant: C=CC[C@H](NC(=O)[C@@H](C)CCCC)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)O)N(C)C(=O)[C@H](C)CCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Step D (3): General procedure: Sodium hydride (60% dispersion in mineral oil, 231 mg, 5.79 mmol) was carefully added portionwise to a solution of (S)-2-((S)-2-methylhexanamido)pent-4-enoic acid (diastereomer A from Step D (2), 440 mg, 1.93 mmol) and iodomethane (961 μL, 15.4 mmol) in THF (25 mL) at 0° C. The resulting mixture was allowed to warm to rt and stirred overnight (18 h). The reaction was chilled to 0° C. and quenched with EtOAc. The mixture was diluted with water and poured into 1 N NaOH. The aqueous layer was extracted with diethyl ether. The aqueous layer was then acidified with 1 N HCl and extracted with EtOAc. The second organic extract was sequentially washed with aqueous sodium bisulfite solution and brine solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 370 mg (80% yield) of the title compound (diastereomer A) as a clear viscous oil. Diastereomer B from Step D (2) was subject to the same procedure to afford 580 mg (97% yield) of the title compound (diastereomer B) as a clear viscous oil. Data for diastereomer A: LRMS (M−H)−=240.1 1H NMR (500 MHz, CDCl3) δ ppm 0.82-0.90 (m, 3H) 1.05-1.13 (m, 3H) 1.17-1.42 (m, 5H) 1.62-1.73 (m, 1H) 2.52-2.61 (m, 1H) 2.63-2.87 (m, 2H) 2.99 (d, J=3.36 Hz, 3H) 5.00-5.16 (m, 3H) 5.64-5.76 (m, 1H). Data for diastereomer B: LRMS (M−H)−=240.2; 1H NMR (500 MHz, CDCl3) δ ppm 0.82-0.90 (m, 3H) 1.10 (dd, J=11.29, 6.71 Hz, 3H) 1.17-1.43 (m, 5H) 1.60-1.75 (m, 1H) 2.52-2.83 (m, 3H) 2.99 (d, J=3.05 Hz, 3H) 5.01-5.16 (m, 3H) 5.63-5.77 (m, 1H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[CH:16]=[C:11]3[C:10]([CH3:30])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:30][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)=[CH:21][CH:22]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4ccc(N5CCN(C)CC5)cc4)cnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ncc(-c3ccc(N4CCN(C)CC4)cc3)cc12
Temperature: 50 °C

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-3-methyl-5-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine (160) in CHCl3 (20 mL) was added trifluoroacetic acid (5 mL) and heated at 50° C. for 12 hours. After completion of the reaction the solvents were removed, diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform twice. The organic layer was washed with brine solution and dried over sodium sulphate and the solvent completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound in 10% MeOH/CHCl3 as pale yellow solid compound 161 (8 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.O>[CH2:12]([O:19][C:20]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCNC(=O)OCc1ccccc1
Temperature: 2.5 °C

Procedure:
Ethyl 3-aminopropionate hydrochloride (10 g) was dissolved in a mixture of tetrahydrofuran (100 ml) and water, which was cooled at 0 to 5° C. in an ice bath and adjusted to pH 8.2 with 30% aqueous sodium hydroxide solution. To a resulting solution was added with care benzyloxycarbonyl chloride (10.3 ml), with maintaining the pH from pH 8.0 to 9.0 with 30% aqueous sodium hydroxide solution at 0 to 5° C. The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated, which was washed two times with saturated sodium chloride in water and dried over magnesium sulfate. Solvent was removed under reduced pressure to give ethyl 3-(benzyloxycarbonylamino)-propionate (15.3 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl.Cl[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1.C(OCC)C>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(O)cc1
Reactant: ClCCc1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(OCCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
240 mg (60% in oil, 6 mmol) of sodium hydride are slowly added to a solution of 1.48 g (12 mmol) of 4-methoxyphenol in 7 ml of dimethylformamide and the mixture is stirred at room temperature for 1 hour. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalyst) are added and the mixture is stirred at 80° C. for 2 days. The reaction mixture is cooled and 150 ml of diethyl ether are added. The precipitate is separated by filtration and the filtrate is evaporated under reduced pressure to give a residue which is purified by preparative high performance chromatography. The title compound is converted to the oxalate and recrystallized from ethanol, M.p.: 178°-181° C. Elemental analysis: calculated: C 55.8 H 5.37 N 9.5 found: C 55.9 H 5.40 N 9.6
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[CH:4][C:3]=1[F:12].Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(F)c(Br)cc1N
Temperature: 25 °C

Procedure:
4-Bromo-5-fluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 4-bromo-3-fluoro-6-nitroaniline (320 mg, 1.36 mmol) and SnCl2 °2H2O (1.53 g, 6.81 mmol) dissolved in 7 mL ethyl acetate and 3 mL absolute ethanol under N2 was heated at 75° C. for 8 h. Some starting material had remained (by TLC) after only 1 h heating. All the starting material had reacted after 8 h as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 50 mL H2O. Sufficient sat'd NaHCO3 solution was added (foaming ) to bring the pH to 5. The resulting mixture was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with 20 mL sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a white powder 277 mg (99%). 1H NMR (CDCl3) δ3.22 (br s, 2H, NH2); 3.60 (br s, 2H, NH2); 6.50 (d, 1H, JHF =9.6 Hz, H-6); 6.83 (d, 1H, JHF =6.6 Hz, H-3).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][C:24]1[O:25][CH:26]=[CH:27][N:28]=1.C(N(CC)CC)C>C(OCC)(=O)C>[F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13]([NH:23][C:24]2[O:25][CH:26]=[CH:27][N:28]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Nc1ncco1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ncco1)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A solution of 15.9 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride in 210 ml of ethyl acetate was added with stirring at 5°-8° C. under nitrogen to a solution of 3.57 g of 2-amino-oxazole and 4.3 g of triethylamine in 50 ml of ethyl acetate and after the temperature returned to room temperature, it stood overnight at that temperature. The mixture was vacuum filtered and the filtrate was washed and evaporated to dryness under reduced pressure. The 14.23 g of residue was triturated with 100 ml of N sodium hydroxide solution for 3 hours and was then diluted with 200 ml of water. The mixture was vacuum filtered and the filtrate was treated with activated carbon. The pH was adjusted to 1 by addition of N hydrochloric acid and the mixture was vacuum filtered. The recovered product was washed with water and dissolved in ethyl acetate. The solution was evaporated to dryness and the 8.77 g of product were crystallized twice from acetic acid to obtain 5.73 g (30.8% yield) of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(oxazol-2-yl)-3-quinoline-carboxamide melting at 258° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1O
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1Oc1cccc([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 3-fluoronitrobenzene (3.53 g, 25 mmol) and 2-methoxyphenol (3.72 g, 30 mmol) in anhydrous N,N-dimethylformamide (25 mL) under nitrogen was treated with anhydrous potassium carbonate (7.6 g, 55 mmol) and heated to 110° C. for 65 h, then cooled to room temperature. The solution was diluted with dichloromethane (50 ml) and treated with DOWEX® 550A OH anion exchange resin (log) which had been washed dry with methanol. Stirring was continued for one hour, the mixture was filtered, and the filtrate concentrated in vacuo (exhaustively at end to remove DMF) to give 3-(2-methoxyphenoxy)nitrobenzene as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH3:11])=O)=[C:6]([CH:8]=1)[NH2:7].[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:7][C:6]2[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:11])(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)c1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Yield: 21.4 %

Procedure:
Following General Procedure B, the title compound (52 mg, 21%) was prepared from 5-chloro-2-(methylsulfinyl)aniline (Intermediate 2) (120 mg, 0.635 mmol) and 3,4-dichlorobenzene-1-sulfonyl chloride (156 mg, 0.635 mmol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:29](O)(=[O:31])[CH3:30]>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:29](=[O:31])[CH3:30])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol -3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.08 g, 0.2 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.2 mmol) in mixture of THF-DCM (1:1, 3 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.045 g, 50%). 1H NMR (400 MHz, CD3OD) δ 7.34-7.33 (m, 2H), 7.11 (d, J=10.7 Hz, 1H), 7.01-6.97 (m, 2H), 5.14-5.04 (m, 1H), 4.30-4.17 (m, 2H), 1.99 (s, 3H), 1.88-1.81 (m, 1H), 1.50 (d, J=6.8 Hz, 3H), 0.94-0.92 (m, 2H), 0.67-0.63 (m, 2H). MS: Calcd.: 426. Found: [M+H]+ 427.