Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=1.CC(C)([O-])C.[K+].O>CN1C(=O)N(C)CCC1>[CH3:16][C:12]1[CH:11]=[C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: Cc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 10.7 %

Procedure:
To a solution of 4-aminophenol (3.6 g, 32.8 mmol) and 4-chloropicoline (5.0 g, 39.3 mmol) in anh DMPU (50 mL) was added potassium tert-butoxide (7.4 g, 65.6 mmol) in one portion. The reaction mixture was heated at 100° C. with stirring for 18 h, then was allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3×150 mL). The combined extracts were sequentially washed with water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried (Na2SO4), and concentrated in vacuo. The resulting oil was purified by flash chromatography (50% EtOAc/50% hexane) to afford the desired product as a yellow oil (0.7 g, 9%): CI-MS m/z 201 ((M+H)+). A4c. General Method for Substituted Aniline Synthesis Via Nucleophilic Aromatic Substitution Using a Halopyridine
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O-:21][Mn](=O)(=O)=O.[K+].[O-]S([O-])=O.[Na+].[Na+].Cl>CC(C)=O.O>[CH3:1][C@H:2]([O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]([OH:21])=[O:15])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCC[C@H](C)Oc1ccc(C=O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCC[C@H](C)Oc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1.086 g (3.89 mmol) of (S)-4-(1-methylheptyloxy)-2-nitrobenzaldehyde in 40 ml of acetone was added a solution of KMnO4 (0.984 g, 6.23 mmol) in 47 ml of water dropwise. The reaction mixture was stirred at room temperature for 6 h and then treated with 5% Na2SO3 (100 ml), acidified with conc. HCl (pH: 4-5), and the resulting solution was extracted with ethyl ether several times. The organic extract was concentrated and extracted with 10% NaOH solution. The alkaline extract was washed with ether, acidified with conc. HCl/ice, and the resulting solution extracted with ethyl ether. The organic layer was washed with water, dried, and the solvent evaporated. (S)-4-(1-Methylheptyloxy)-2-nitrobenzoic acid (Compound 37, Scheme VI, R1 =(S)--OCH(CH3)C6H13) was obtained as a dark orange liquid (0.8 g, 70%) which was used in the next step without further purification; Rf [hexanes/ethyl acetate 70/30+1 drop of acetic acid]: 0.16; 1H NMR (300 MHz, CDCl3): δ0.86(t, 3H, J=6.8 Hz), 1.16-1.48(m, 8H), 1.32(d, 3H, J-=5.(Hz), 1.60(m, 1H), 1.72(m, 1H), 4.45(m, 1H), 7.02(dd, 1H, J=2.4 Hz J=8.8 Hz), 7.09(d, 1H, J=2.4 Hz), 7.90(d, 1H, J=8.8 Hz); 13C NMR (300 MHz, CDCl3): δ13.98, 19.22, 22.51, 25.24, 29.14, 31.68, 36.14, 79.94, 110.26, 117.84, 118.98, 132.97, 150.69, 160.61, 170.81; Mass spectrum, m/z(rel.intensity): 295(M+ 1), 265(9), 166(8), 135(36), 112(14), 71(66), 57(100), 55(27), 43(94), 41(69).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][OH:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:19]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][O:15][CH3:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn(Cc2ccccc2)nc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nn(Cc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
Into a 250-mL 3-neck round-bottom flask, was placed a solution of (1-benzyl-4-methyl-1H-pyrazol-3-yl)methanol (compound 268.2, 1.7 g, 8.4 mmol) in THF (50 mL). The solution was cooled to 0° C., then sodium hydride (470 mg, 11.8 mmol, 60% dispersion in mineral oil) was added in portions at 0° C., and then the mixture was stirred for 20 min. Iodomethane (750 μL, 12 mmol) was added at 0° C., then the resulting mixture was stirred for 2 h at room temperature. The reaction was carefully quenched by drop-wise addition of water (30 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to obtain the title compound as a yellow oil (1.5 g, 83%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].O.O.P([O-])(O)(O)=[O:25].[Na+].Cl([O-])=O.[Na+].C(OCC)(=O)C>C(#N)C.O.OO>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:25])=[O:12])[CH:9]=2)[N:4]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=P([O-])(O)O
Reactant: CCOC(=O)c1c(Br)c2cc(C=O)ccc2n1CC(C)C
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Br)c2cc(C(=O)O)ccc2n1CC(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
In 7 ml of acetonitrile is dissolved 0.65 g of ethyl 3-bromo-5-formyl-1-isobutyl-1H-indole-2-carboxylate. To the solution are successively added at ambient temperature 1.56 g of sodium dihydrogen-phosphate dihydrate dissolved in 22 ml of water and 0.64 ml of 30% aqueous hydrogen peroxide. Then, 0.68 g of sodium chlorite dissolved in 20 ml of water is dropwise added thereto at 5-10° C. The mixture thus obtained is stirred at 60° C. for one hour. Ethyl acetate and water are added to the reaction mixture, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 0.37 g of 3-bromo-2-(ethoxycarbonyl)-1-isobutyl-1H-indole-5-carboxylic acid is obtained as a yellow solid product.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]=3[CH:22]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1>[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:9]([CH2:8][CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[O:19])[O:17][C:16]([CH3:20])([CH3:21])[O:15][C:14]=3[CH:22]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: CC1(C)OC(=O)c2ccc(NCCCC3CCCC3)cc2O1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: CC1(C)OC(=O)c2ccc(N(CCCC3CCCC3)C(=O)c3ccc(Br)cc3)cc2O1
Temperature: 60 °C
Reaction time: 7 h
Yield: 58.7 %

Procedure:
To a cold (0° C.) solution of 7-[(3-cyclopentylpropyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (1.70 g, 5.60 mmol) in pyridine (10 mL) was added 4-bromobenzoyl-chloride (Aldrich, 1.47 g, 6.72 mmol) and the resulting reaction mixture was stirred 10 min at 0° C., 30 min at rt and 7 hrs at 60° C. The solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (15/85)) gave 1.6 g (59%) of the title compound as a white solid. HPLC, Rt: 5.2 min (purity: 99.5%). 1H NMR (CDCl3) δ: 7.81 (d, J=7.3 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.7 Hz, 2H), 6.76 (dd, J=1.9 Hz, J=8.3 Hz, 1H), 6.56 (d, J=1.9 Hz, 1H), 3.91 (t, J=7.9 Hz, 2H), 1.80-1.25 (m, 17H), 1.12-0.95 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:14]3[C:15]([C:20](=[O:30])[N:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[N:22]=3)=[CH:16][NH:17][C:18]=2[CH3:19])[CH:8]=1)CCC>[OH-].[Na+]>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]2[C:20](=[O:30])[C:15]3=[CH:16][NH:17][C:18]([CH3:19])=[C:13]([C:9]4[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=4)[C:6]([OH:31])=[O:5])[C:14]3=[N:22]2)=[CH:24][CH:25]=1
Reactant: CCCCOC(=O)c1cccc(-c2c3nn(-c4ccc(Cl)cc4)c(=O)c-3c[nH]c2C)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 3-[2-(4-chlorophenyl)-3,5-dihydro-6-methyl-3-oxo-2H-pyrazolo[4,3-c]pyridin-7-yl]benzoic acid butyl ester (from Example 25, Step a) (0.350 g, 0.803 mmol) in 1M aqueous NaOH (3.9 ml) was stirred at room temperature overnight. The mixture was then filtered from a little dark orange solid, which was washed with water, and the combined filtrates were neutralised to pH 5 by the addition of 5M aqueous HCl. The resulting yellow solid was collected by filtration, washed with water, then hexane, and dried at 70° C. under vacuum to afford 0.223 g (73%) of the title compound; 1H NMR (250 MHz, DMSO-d6) δ2.25 (3H, s), 7.43 (2H, d, J 9.0 Hz), 7.65 (1H, t, J 7.7 Hz), 7.77 (1H, dt, J 7.8, J′1.5 Hz), 8.01 (1H, dt, J 7.7, J′1.4 Hz), 8.07 (1H, t, J 1.4 Hz), 8.12 (2H, d, J 9.0 Hz), 8.60 (1H, d), 12.57 (1H, d, J 6.3 Hz), 13.09 (1H, br s); MS (ES+) m/z 380/382 [MH]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[C:4](=[CH2:11])/[C:3]/1=[C:12](/[O:15][Si](C)(C)C)\[CH:13]=[CH2:14].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.C1COCC1.O>[CH3:9][C:5]1([CH3:10])[C:6]([CH3:8])=[CH:7][C:2]([CH3:20])([CH3:1])[C:3]2[C:12](=[O:15])[CH2:13][CH2:14][CH2:11][C:4]1=2
Reactant: C=C/C(O[Si](C)(C)C)=C1\C(=C)C(C)(C)C(C)=CC1(C)C
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=CC(C)(C)C2=C(CCCC2=O)C1(C)C
Temperature: 410 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution containing (5a) (2.5 mmol) in toluene (15 ml) was injected over 1 hour through a 20 cm column packed with quartz tubes heated at 410° C. using argon as carrier. The column was washed with 5 ml of pure toluene and the collected mixture was evaporated to dryness. The concentrate was added to a solution of oxalic acid (1.12 mmol) in THF (10 ml) and water (1 ml) and the mixture was stirred at room temperature for 1 hour then quenched with a saturated bicarbonate solution and extracted with diethylether. The organic layer was washed with water and brine, then dried with MgSO4, and evaporated to dryness. The crude was purified by bulb-to-bulb distillation and column chromatography (Silicagel, Cyclohexane/EtOAc 99/1). Yield: 62%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][C@H:14]([CH2:16]O)[C@@H:13]([OH:18])[C@H:12]1[OH:19].S(Cl)([Cl:22])=O.[OH-].[NH4+]>CN(C)P(N(C)C)(N(C)C)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][C@H:14]([CH2:16][Cl:22])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: O=S(Cl)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](CCl)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
(±)-(1R*,2S*,3R*,5R*)-3-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)-1,2-cyclopentanediol (J. Am. Chem. Soc. 1969, 91, 3075) (0.94 g, 3.54 mmol) was stirred in hexamethylphosphoramide (13 ml) with cooling (ice bath) while thionyl chloride was added. The mixture was stirred under nitrogen at 25° C. for 18 hours. Ice water (50 ml) was added to the cooled mixture. The resulting solution was neutralized with concentrated ammonium hydroxide. The white precepitate was filtered off and dissolved in refluxing methanol (125 ml). Concentrated ammonium hydroxide (10 ml) was added and the solution allowed to cool slowly to 25° C. over 1 hour. The methanol was evaporated and the residual solid slurried in cold water and filtered to give title compound as an off-white powder (0.92 g, 92%); mp 188°-189° C. dec.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[CH2:38]([NH2:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>O1CCCC1.C(OCC)(=O)C>[CH2:38]([NH:50][C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3](=[O:17])[C:2]([F:1])([F:19])[F:18])=[CH:16][CH:15]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCCCCN
Reactant: O=C(O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A solution of (E)-4-(4,4,4-trifluoro-3-oxo-1-butenyl)phenoxyacetic acid (0.810 g, 2.95 mmol) in tetrahydrofuran (20 ml) was treated with EEDQ (0.767 g, 3.10 mmol) and dodecylamine (0.575 g, 3.10 mmol). After 2 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed with water, 0.1N hydrochloric acid, saturated sodium bicarbonate, brine and dried. Evaporation of the solvent under reduced pressure gave a solid which was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (8:12) gave 0.750 g (58%) of the title material as white needles after recrystallization from ethyl acetate-hexane: mp 78.5-79° C.
Reaction SMILES: OP(OP(O)O)O.C(C1C=C(C(C)(C)C)C=CC=1C(C1C=CC(C(C)(C)C)=CC=1C(C)(C)C)(C(CO)(CO)CO)[OH:23])(C)(C)C.P(O)(O)O.[C:49]([C:53]1[CH:58]=[C:57]([C:59]([CH3:62])([CH3:61])[CH3:60])[CH:56]=[C:55]([C:63]([CH3:66])([CH3:65])[CH3:64])[C:54]=1C(O)C(CCCC)(CC)CO)([CH3:52])([CH3:51])[CH3:50].OP(OP(O)O)O.C(C(CCCCCCCCCCCCCCCCCC)(C(CO)(CO)CO)O)CCCCCCCCCCCCCCCCC.C(C1C=CC=CC=1OP(OC1C=CC=CC=1CCCCCCCCC)OC1C=CC=CC=1CCCCCCCCC)CCCCCCCC>>[C:63]([C:55]1[CH:56]=[C:57]([C:59]([CH3:62])([CH3:60])[CH3:61])[CH:58]=[C:53]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:54]=1[OH:23])([CH3:66])([CH3:64])[CH3:65]
Reactant: CC(C)(C)c1ccc(C(O)(c2ccc(C(C)(C)C)cc2C(C)(C)C)C(CO)(CO)CO)c(C(C)(C)C)c1
Reactant: CCCCC(CC)(CO)C(O)c1c(C(C)(C)C)cc(C(C)(C)C)cc1C(C)(C)C
Agent: CCCCCCCCCCCCCCCCCCC(O)(CCCCCCCCCCCCCCCCCC)C(CO)(CO)CO
Agent: CCCCCCCCCc1ccccc1OP(Oc1ccccc1CCCCCCCCC)Oc1ccccc1CCCCCCCCC
Agent: OP(O)O
Product: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
Phosphites (Secondary Antioxidants) that can be used in the present invention include, but are not limited tris-(2,4-di-t-butylphenyl)phosphite,tetrakis(2,4-di-tert-butylphenyl)[1,1-biphenyl]-4,4′-diylbisphosphonite, bis(2,4-di-t-butylphenyl) pentaerythritol diphosphite, bis(2,4-di-t-cumylphenyl) pentaerythritol diphosphite, tetrakis(2,4-di-t-butylphenyl) 4,4′-biphenylene diphosphonite, 2,4,6 tri-t-butylphenyl 2 butyl 2 ethyl 1,3 propane diol phosphite, distearyl pentaerythritol diphosphite, tris(nonylphenyl)phosphite and trilauryl trithio phosphite, e.g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][C@@H:11]([NH:14][CH:15]3[CH2:18][O:17][CH2:16]3)[C@H:10]([OH:19])[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([NH:29][CH2:30][CH3:31])[C:26]2=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:25]2[N:24]=1.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>CN(C=O)C>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][C@H:11]3[N:14]([CH:15]4[CH2:16][O:17][CH2:18]4)[C:37](=[O:38])[O:19][C@@H:10]3[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([NH:29][CH2:30][CH3:31])[C:26]2=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:25]2[N:24]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC4COC4)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Solvent: CN(C)C=O
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OC(=O)N4C3COC3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.5 %

Procedure:
To (+/−)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(oxetan-3-ylamino)piperidin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (90 mg, 0.177 mmol) in DMF (5 mL) was added 1,1′-carbonyldiimidazole (200 mg, 1.233 mmol) and the reaction stirred at 25° C. 16 hr. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford rac-2-((2-chloro-5-cyano-3-((3aR,7aR)-1-(oxetan-3-yl)-2-oxohexahydrooxazolo[5,4-c]pyridin-5 (2H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (48.8 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([N+:19]([O-])=O)[C:10]([NH:17][CH3:18])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[C:5]([CH3:22])[O:4][N:3]=1.[OH-].[Na+]>C(O)C>[NH2:19][C:9]1[C:10]([NH:17][CH3:18])=[C:11]([CH:16]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:22])[CH:8]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: CNc1c(C(=O)OC)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1c(N)cc(-c2c(C)noc2C)cc1C(=O)OC
Temperature: 120 °C

Procedure:
To methyl 5-(3,5-dimethylisoxazol-4-yl)-2-(methylamino)-3-nitrobenzoate (2000 mg, 6.55 mmol) was added stannous chloride (3726.66 mg, 19.65 mmol) and Ethanol (100 ml) in a pressure tube. The suspension was then heated in sealed vessel to 120° C. for 90 minutes at which point the reaction was cooled then stirred in a mixture of EtAc/1N NaOH for 1 hour or until precipitates form. Precipitates were filtered and crude mixture was diluted in EtAc and water and extracted 3× with EtAc. Organics were washed with water then brine, dried over sodium sulfate and evaporated to dryness under reduced pressure. Residue was purified by silica gel chromatography using MeOH/DCM as the eluent to afford methyl 3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-(methylamino)benzoate as a dark form (1.1 g, 61%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:12][CH:13]([OH:16])[CH:14]=[CH2:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:15][CH2:14][C:13](=[O:16])[CH3:12])=[CH:6][CH:5]=1
Reactant: C=CC(C)O
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(C)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of methyl-4-bromobenzoate (1.0 g, 4.65 mmol) in triethylamine (13 mL) was added 3-buten-2-ol (1 mL, 11.63 mmol), palladium (II) acetate (0.104 g, 0.465 mmol), and then triphenylphosphine (0.244 g, 0.93 mmol). The reaction was stirred in a 75° C. oil bath overnight under nitrogen atmosphere. Monitoring by TLC (3:1 hexane:ethyl acetate) showed the product and aryl bromide. The reaction was cooled to room temperature and then concentrated. Water was then added followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (5:1 to 3:1 hexane:ethyl acetate) to obtain the product (250 mg, 26% yield). 1H NMR (600 MHz, CDCl3): δ 7.95 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.4 Hz), 3.90 (s, 3H), 2.95 (t, 2H, J=7.45 Hz), 2.77 (t, 2H, J=7.68 Hz), 2.14 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:15](=[O:18])[CH2:16]Br)[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[CH2:19]([NH:26][CH2:27][CH2:28][NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]([CH2:16][C:15]([C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12](=[O:14])[CH3:13])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)=[O:18])[CH2:27][CH2:28][NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)Oc1ccc(C(=O)CBr)cc1OC(C)=O
Reactant: O=C(Cc1ccccc1)NCCNCc1ccccc1
Product: CC(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(C)=O

Procedure:
3',4'-Bis(acetoxy)-2-bromoacetophenone was reacted with N-[2-(benzylamino)ethyl]-2-phenylacetamide using a similar procedure to that described in Example 1 for the analogous pivaloyloxy derivative to give 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(acetoxy)acetophenone, which was isolated as its free base and converted to its hydrochloride salt with ethereal hydrogen chloride to give a solid, m.p. 140°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[CH:4][C:3]=1[Br:12].C[Si]([CH:17]=[N+:18]=[N-])(C)C.C(OCC)C>CO.ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:18][CH3:17])=[O:10])=[CH:4][C:3]=1[Br:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ccc(CC(=O)O)cc1Br
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CNC(=O)Cc1ccc(N)c(Br)c1
Temperature: 25 °C

Procedure:
To 2-(4-amino-3-bromo-phenyl)acetic acid (5 g, 21.73 mmol) in methanol (50 mL) and dichlormethane (100 mL) is added at −5° C. trimethylsilyldiazomethane in diethylether 2 mol/L (31.51 mL, 63.03 mmol) dropwise over a period of 30 min. The reaction mixture is allowed to warm up to r.t. and concentrated. The crude product is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2c([n+]([O-])c1)CCCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[n+]([O-])c2c(c1[N+](=O)[O-])CCCC2

Procedure:
6.5 Grams of 3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide was added dropwise in a mixture consisting of 7 ml of fuming nitric acid and 7 ml of concentrated sulfuric acid under ice-cooled condition with stirring. The reaction mixture was stirred at 40° C. for 2 hours, then further stirred at 60° C. for 2 hours. The reaction mixture was poured in a cold aqueous solution of sodium hydroxide, then extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation, and the thus obtained residue was recrystallized from ethyl acetate-ethanol-n-hexane to yield 5.3 g of 3-methyl-4-nitro-5,6,7,8-tetrahydroquinoline-N-oxide.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2ccc(F)cc2)c(-c2ccccc2)n1
Yield: 46.5 %

Procedure:
6-(4-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (99 mg, 46%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 4-fluorophenylboronic acid (0.112 g, 0.80 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([C:11](N)=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.[OH-:15].[K+].Cl>CCO.O>[CH3:1][C:2]1[C:7]2[C:8]([C:11]([OH:15])=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(C)c2c(C(N)=O)nsc2c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(C(=O)O)nsc2c1
Temperature: 85 °C
Yield: 74.6 %

Procedure:
To a solution of 4,6-dimethyl-1,2-benzisothiazole-3-carboxylic acid amide (20 mg, 0.097 mmol) in EtOH (10 mL) and H2O (2 mL) is added KOH (11′mg, 0.19 mmol). The solution is heated to 85° C. for 48 hours. The solution is cooled down and is placed in an ice bath. Conc. HCl is added to adjust the pH of the solution to 2. The precipitated solid is collected by means of filtration to afford 4,6-Dimethyl-1,2-benzisothiazole-3-carboxylic acid (15 mg, 75%).