Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2Cl)CC1
Reaction time: 48 h
Yield: 61.2 %

Procedure:
A solution of 2-chloro-5-nitroaniline (1 g, 5.79 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.309 g, 11.59 mmol) in dichloroethane (15 mL) and acetic acid (0.995 mL, 17.38 mmol) was stirred at room temperature for 30 minutes. At this time, the reaction was treated with sodium triacetoxyborohydride (3.07 g, 14.49 mmol), and the resulting mixture was stirred over the weekend. Additional tert-butyl 4-oxopiperidine-1-carboxylate (2.309 g, 11.59 mmol), sodium triacetoxyborohydride (3.07 g, 14.49 mmol), and dichloroethane (15 mL) were added. Stirring was continued for 2 days. The mixture was then diluted with water and 1N sodium hydroxide (basified to pH 10) and then extracted with dichloromethane (3×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:19 ethyl acetate:hexanes, giving a yellow/orange foam (1.26 g, 61.1%). 1H NMR (DMSO-d6) δ 7.54 (d, J=8.7 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.39 (dd, J=8.7, 2.4 Hz, 1H), 5.76-5.63 (m, 1H), 3.99-3.90 (m, 2H), 3.74-3.62 (m, 1H), 3.05-2.80 (m, 2H), 1.89-1.80 (m, 2H), 1.49-1.32 (m, 11H); ESI-MS (m/z, %): 378 (M+Na, 100), 356 (MH+, 40), 300 (62).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[I-:11].[Na+].[C:13](Cl)(=[O:15])[CH3:14].OS([O-])=O.[Na+]>C(#N)C>[I:11][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:13](=[O:15])[CH3:14])[N:9]=[CH:10][C:3]=12
Reactant: [I-]
Reactant: Clc1ccnc2[nH]ncc12
Reactant: CC(=O)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)n1ncc2c(I)ccnc21
Yield: 42 %

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-b]pyridine (820 mg, 5.30 mmol), sodium iodide (2.4 mg, 16.0 mmol), and acetyl chloride (0.8 ml) in acetonitrile (6 ml) was refluxed 8 h. The mixture was then treated with a 10% aqueous solution of NaCO3 (10 ml), and a 10% aqueous solution of NaHSO3 (10 ml), and held 10 min. The mixture was extracted with ethyl acetate (50 ml), and the organics were washed with brine (10 ml), dried over MgSO4, and evaporated under reduced pressure. Purification by silica gel chromatography gave 1-(4-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone as a brown solid (650 mg, 42%). 1H NMR (300 MHz, CDCl3) δ 8.39 (d, 1H, J=5.0 Hz), 8.04 (s, 1H), 7.76 (d, 1H, J=5.0 Hz), 2.88 (s, 3H).
Reaction SMILES: [Li][C:2]#[N:3].C1(C)C=CC(S(O[CH2:14][C@H:15]([OH:26])[CH2:16][C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)(=O)=O)=CC=1.[C-]#N.[Na+]>CN(C=O)C>[OH:26][C@H:15]([CH2:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C:2]#[N:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)Cc2cc3ccccc3[nH]2)cc1
Reactant: [Li]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC[C@H](O)Cc1cc2ccccc2[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 0.5 M LiCN in DMF (30 mL) was added (R)-3-indol-2-yl-2-hydroxypropanyl p-toluenesulfonate (R)-2 (5.6 g, 16.2 mmol) and sodium cyanide (1.5 g, 30.6 mmol). The reaction mixture was stirred for 1 hour at 100° C., cooled to room temperature, poured into 80 mL ice-water, and extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with saturated sodium bicarbonate (2×50 mL), brine (2×30 mL), dried over anhydrous sodium sulfate, and evaporated to yield a deep red oil. The oil was purified by flash chromatography (hexane:ethyl acetate 2:3) to give 2.4 g (74%) of the title compound as a light yellow solid.
Reaction SMILES: [Na].[CH:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2O)[CH:7]=1.CS([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[C:27]([CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])[CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=O)=O.Cl>O.CO>[C:37]([NH:36][CH2:35][CH2:34][C:11]1[CH:10]=[CH:9][CH:8]=[C:6]2[C:5]=1[CH:4]=[C:3]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]3[C:31]([CH:30]=[CH:29][CH:28]=[C:27]3[CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:33]=1)[CH:2]=[CH:7]2)(=[O:39])[CH3:38]
Reactant: Oc1cccc2ccccc12
Reactant: CC(=O)NCCc1cccc2ccc(OCCCCCOS(C)(=O)=O)cc12
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(=O)NCCc1cccc2ccc(OCCCCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc12

Procedure:
In a 100 ml round-bottomed flask containing 30 ml of methanol, add sodium (0.07 g 0.0030 at. g.) in small portions. When the sodium has been completely used up, add naphthol (0.82 g, 3.6 mmol). Stir using a magnetic stirrer for 20 minutes. Remove the methanol by evaporation under reduced pressure. Take up the resulting residue in 15 ml of dimethylformamide. Add the compound obtained in Step C (1.2 g, 3 mmol) and heat at reflux for 12 hours. Allow the reaction mixture to cool and pour it into a mixture of 100 ml of water and 10 ml of 3M hydrochloric acid. Extract the aqueous phase twice with ethyl acetate. Wash the organic phase with an aqueous 10% sodium hydroxide solution and then with water. Dry over magnesium sulphate and remove the ethyl acetate by evaporation under reduced pressure. Recrystallise the resulting solid residue from acetonitrile.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([NH:18][NH2:19])(=[O:17])[C:13]([NH:15][NH2:16])=[O:14].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26].[OH2:27]>C1(C)C=CC=CC=1>[C:22]1(=[O:26])[N:16]([NH:15][C:13]([C:12]([NH:18][N:19]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:5])=[O:17])=[O:14])[C:9](=[O:27])[C:10]2=[CH:2][CH:1]=[CH:25][CH:24]=[C:23]12.[CH3:20][N:21]1[CH2:9][CH2:10][CH2:2][C:1]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O
Reactant: NNC(=O)C(=O)NN
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C(NN1C(=O)c2ccccc2C1=O)C(=O)NN1C(=O)c2ccccc2C1=O

Procedure:
Two moles of phthalic anhydride (296 g.) and one mole of oxalic dihydrazide (118 g.) in 500 ml. N-methyl-2-pyrrolidone and 500 ml. toluene were heated at reflux until two moles of water were removed (about two hours). The mixture was diluted with benzene and filtered. After washing with benzene, the white product was dried to constant weight at 50° C. giving an essentially quantitative yield of N,N'-bis(phthalimido)oxamide-N-methyl-2-pyrrolidone 1:2 complex.
Reaction SMILES: [C:1](=O)([O:17]N1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH2:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH:36][C:1]([O:2][CH2:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:17])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(OCc1cccc2c1Cc1ccccc1-2)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=O)OCc1cccc2c1Cc1ccccc1-2

Procedure:
A solution of fluorenylmethyl succinimidyl carbonate (31.0 g, 0.092 mol) in acetonitrile (300.0 ml) was slowly added to mono tert-butyloxycarbonylethylenediamine (10.0 g, 0.063 mol) dissolved in 10% aq. Na2CO3 (250 ml). Acetonitrile was evaporated and the product was extracted with ethyl acetate, organic phase was dried over Na2CO3, concentrated and the product was allowed to crystallize by adding petroleum ether. The product was collected on filter, washed with petroleum ether. Yield 20.0 g (84%). TLC petroleum ether-diethylether 88:12 Rf 0.64. NMR (300 MHz, DMSO-d6, 25° C.) d: 1.37 (s, 9H, tBu), 2.99 (m, 4H, CH2CH2), 4.20-4.29 (m, 3H, Fmoc OCH2CH--), 6.76 (t, 1H, NH), 7.25 (t, 1H, NH), 7.33-7.89 (m, 8H, Fmoc). M.p. 146-148° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:21]([O:23]C)=O)[CH2:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:12]#[N:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Ni]>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C@H:11]1[CH2:12][NH:13][C:21](=[O:23])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1
Reactant: COC(=O)[C@H](CC(C#N)c1ccccc1F)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Ni]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CNC1=O
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-4-(2-fluorophenyl)-5-nitrilonorvalinate (3.88 g, 11.5 mmol) in ethanol (50 mL) was added Raney nickel (slurry in water, ca. 10 g). The mixture was placed under a balloon of hydrogen and the reaction was stirred at 23° C. for 4 h. The mixture was filtered and concentrated to afford a mixture of 4 diastereoisomers. A solution of this residue in ethanol (100 mL) was stirred in the presence of solid potassium carbonate (1.30 g, 9.44 mmol) at 60° C. for 2 h. The bulk of the ethanol was removed under reduced pressure and the remaining slurry was diluted with water to afford a white precipitate. The precipitate was filtered, washed with water and then dried under vacuum at 40° C. for 18 h. The enantiomers were separated using normal-phase HPLC using a ChiralPak® AD column, eluting with 40% hexane in ethanol (0.1% diethylamine used as a modifier) to afford the title compound as the second major enantiomer to elute. MS: m/z=331.1 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.CS([Cl:27])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:14][Cl:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: OCc1ccc(OCC(F)(F)F)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)COc1ccc(CCl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of the title compound from Step 2 (300 mg, 1.05 mmol) in DCM (10 mL) was cooled to 0° C. and treated with triethylamine (91 mg, 1.15 mmol) and methanesulfonyl chloride (142 mg, 1.25 mmol). The reaction mixture was warmed to room temperature and stirred overnight. It was then diluted with DCM (10 mL) and washed with 1 M hydrochloric acid (10 mL) and sat. NaHCO3 (10 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to afford the title compound (260 mg, 82%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, J=2.0 Hz, 1H), 7.32 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.53 (s, 2H), 4.42 (q, J=8.0 Hz, 2H)
Reaction SMILES: Br[CH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].ClC1C=C(C(F)(F)F)C=CC=1OC1C=CC([N+]([O-])=O)=C(O)C=1.ClC1C=C(C(F)(F)F)C=C(Cl)C=1OC1C=CC([N+]([O-])=O)=C(O)C=1.[Cl:59][C:60]1[CH:76]=[C:75]([C:77]([F:80])([F:79])[F:78])[CH:74]=[C:73]([F:81])[C:61]=1[O:62][C:63]1[CH:64]=[CH:65][C:66]([N+:70]([O-:72])=[O:71])=[C:67]([OH:69])[CH:68]=1.ClC1C=C(C(F)(F)F)C=CC=1OC1C=CC([N+]([O-])=O)=C(C=1)OC(C)(C(OCC)=O)C(OCC)=O>>[Cl:59][C:60]1[CH:76]=[C:75]([C:77]([F:80])([F:79])[F:78])[CH:74]=[C:73]([F:81])[C:61]=1[O:62][C:63]1[CH:64]=[CH:65][C:66]([N+:70]([O-:72])=[O:71])=[C:67]([CH:68]=1)[O:69][C:3]([CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CBr)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1O
Agent: CCOC(=O)C(C)(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC
Agent: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Agent: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1O
Product: CCOC(=O)C(C)(Oc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC

Procedure:
Similarly by using diethyl bromomethylmalonate in place of diethyl bromomalonate, and carrying out the reaction with 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenol, 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitrophenol or 5-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrophenol, diethyl 2-[5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenoxy]-2-methylmalonate (IV-2), diethyl 2-[5-(2,6-dichloro-4-trifluoromethylphenoxy)- 2-nitrophenxoy]-2-methylmalonate (IV-3) and diethyl 2-[5-(2-chloro-6-fluoro-4-trifluoro methylphenoxy)-2-nitrophenoxy]-2-methylmalonate (IV-4) were obtained. The physical properties of these compounds are shown in Table 2.
Reaction SMILES: [Li]CCCC.CCCCCC.C[Si](C)(C)CCOC[N:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:20]=[CH:19]1.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1.C1C[O:50]CC1>>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:21]2[N:20]=[C:19]([CH2:43][C:42]3([OH:50])[CH:45]=[CH:46][C:39]([F:38])=[CH:40][CH2:41]3)[NH:18][C:22]=2[C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: OC1(Cc2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)C=CC(F)=CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
1.6M n-BuLi in hexane (0.085 ml 0.13 mmol) is added at −40° C. to a solution of 1-(2-(trimethylsilyl)ethoxymethyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (Example 2; 50 mg 0.13 mmol) in THF (1.4 ml). After 15 min at −40° C. 4-fluorobenzaldehyde (0.018 ml 0.18 mmol) in THF (0.4 ml) is addded to the reaction mixture, which is warmed to r.t. and after 10 min. poured on water and extracted 3× with ethyl acetate. The combined organic phases are dried over Na2SO4, evaporated to dryness and render the desired is-protected title compound (64 mg). In order to remove the SEM protecting group, the latter material is dissolved in THF (2 ml), treated with Bu4NF (4.3 ml; 1M in THF) for 1 h at 60° C., poured on a saturated solution of NaHCO3 and extracted 3× with ethyl acetate. The combined organic phases are dried over Na2SO4, evaporated to dryness and chromatographed (SiO2 toluene/EtOH/NH3conc. 90/10/0.6) to yield the title compound as white crystals (32 mg 67% over 2 steps)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C.[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64][NH2:65]>CN(C=O)C>[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64][NH:65][C:49]([C:27]1[S:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)[C:34]=2[C:26]=1[CH3:25])=[O:50]
Reactant: CN(C)CCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCN(C)C)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
HATU (0.105 g, 0.28 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.097 g, 0.25 mmol) and Hünig's base (44 μL, 0.25 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. N,N-Dimethylethylenediamine (137 μL, 1.25 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the product purified by reverse phase preparative HPLC to yield off-white solid (0.026 g, 22%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6]1)[CH2:2][CH2:3][CH3:4].CI.N1C=C[C:21](=O)N=1.[C:25]1([N:31]2[C:35](=[O:36])[CH:34]=[C:33]([CH3:37])[NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+]>CN(C)C=O.O>[CH2:1]([N:5]([CH2:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[CH2:21][CH:34]1[C:33]([CH3:37])=[N:32][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:35]1=[O:36])=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1C=CN=N1
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CCCCN1Cc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCN(C)Cc1[nH]c2ccccc2c1CC1C(=O)N(c2ccccc2)N=C1C
Temperature: 25 °C

Procedure:
A solution of 2-n-Butyl-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 8.6 g., and methyl iodide, 2.6 ml. in dimethylformamide is stirred fifteen minutes, and then added all at once to a solution of the anion of the pyrazolone, prepared from 6.96 g. of 2-phenyl-5-methyl-3H-pyrazol-3-one and 2.0 g. fifty percent sodium hydride in dimethylformamide at 10°-20° C. The mixture is heated on a steam bath for one hour, then stirred at room temperature for sixteen hours. The reaction mixture is next poured into water, precipitating the product, 8.6 g., m.p. about 180°-200° with decomposition. Recrystallization from methanol gives 6.3 g., m.p. 195°-200° with decomposition.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:43])[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)[N:14]=[C:13]1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:39]=[CH:38][N:37]=[C:36]([NH2:40])[C:35]=2[CH:41]=[CH2:42])[CH2:30][CH2:29]1.CO>[Pd]>[CH3:8][N:9]([CH3:43])[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:25])[F:26])[CH:18]=2)[N:14]=[C:13]1[CH:28]1[CH2:29][CH2:30][N:31]([C:34]2[N:39]=[CH:38][N:37]=[C:36]([NH2:40])[C:35]=2[CH2:41][CH3:42])[CH2:32][CH2:33]1
Reactant: C=Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1
Temperature: 25 °C

Procedure:
In a 10 mL round-bottom flask containing 6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-vinyl-pyrimidin-4-ylamine; compound with trifluoro-acetic acid (25.00 mg; 0.04 mmol; 1.00 eq.) in methanol (2.00 ml; 49.37 mmol; 1231.95 eq.) under argon was slowly poured 10% Pd/C (80.00 mg; 0.75 mmol; 18.76 eq.). The round-bottom flask was vacuumed and then filled with H2. The procedure was repeated for 4 more times before the mixture was stirred at rt for O/N under H2 (balloon). The obtained mixture was filtered and then purified with Waters pre-HPLC. LC-MS: (M+1=506, obsd.=506).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][CH3:13])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23]Br>CN(C=O)C>[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][O:5][C:4](=[O:6])[C:3]1[C:7]([NH:12][CH3:13])=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1]
Reactant: CNc1cc(F)cc(F)c1C(=O)O
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(F)cc(F)c1C(=O)OCC(OC)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of example 12a (3.83 g, 20.5 mmol) and potassium carbonate (2.0 g, 14.4 mmol) in DMF (20 mL) was heated at 90° C. After stirring for 1 h, the mixture was cooled to r.t. Bromoacetaldehyde dimethyl acetal (3.74 g, 21.52 mmol) was added dropwise. After addition, the reaction mixture was heated to 130° C. for 11 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether and passed through a silica plug, and concentrated under reduced pressure to yield 3.64 g (65%) of clean desired product as an orange oil. 1H NMR (400 MHz, DMSO-d6): δ 7.52 (bs, 1H), 6.31-6.46 (m, 2H), 4.66 (t, 1H, J=5.2 Hz), 4.23 (d, 2H, J=5.2 Hz), 3.34 (s, 6H), 2.81 (d, 3H, J=4.8 Hz). MS (ES) [m+H] calc'd for C12H15F2NO4, 276; found 276.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[OH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16][CH:15]=1>CS(C)=O.C(O)(=O)C.C(OCC)(=O)C>[OH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: O=Cc1ccc(O)c2ccccc12
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(NN=Cc1ccc(O)c2ccccc12)c1ccc(O)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 ml) was added 4-hydroxynaphthaldehyde and a catalytic amount of glacial acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO4. The organic volume was concentrated in vacuo to give the crude product. The product was purified by silica gel column chromatography using CH2Cl2/MeOH as the mobile phase.
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:21]12CC(C=C1)C=[CH:22]2.CCN(CC)CC>C1(C)C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:22]=[CH:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC(F)(F)F)cc1
Reactant: C1=CC2C=CC1C2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccn(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 70 °C
Yield: 78.5 %

Procedure:
A stirred mixture of hydrazonoyl chloride 65 (1.55 g, 4.99 mmol), bicyclo[2.2.1]hepta-2,5-diene (1.25 mL, 24.6 mmol) and Et3N (2.0 mL, 14.3 mmol) in toluene (10 mL) was heated to 70° C. for 1 h. The mixture was cooled and filtered, the filter cake was washed with toluene (10 mL) and the organic fractions were combined and evaporated. The residue was refluxed in xylenes (30 mL) for 2 h. Column chromatography on silica gel, eluting with hexanes, firstly gave xylenes, and then further elution with CH2Cl2 gave ethyl 1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-3-carboxylate (66) (1.176 g, 79%) as a white solid: mp 76-78° C.; 1H NMR (CDCl3) δ 7.91 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.9 Hz, 2H), 7.33 (d, J=8.9 Hz, 2H), 7.00 (d, J=2.5 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). APCI MS m/z 301 [M+H]+.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C1COC(=O)C1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a stirring solution of 1.6 g (16 mmol) of tetronic acid in 75 mL of methylene chloride is added 2.5 mL (17.86 mmol) of triethylamine and 640 mg of 4-dimethylaminopyridine at 0° C. Next, 5.0 g (17.6 mmol) of stearoyl chloride is added and the reaction is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted with two 100 mL portions of methylene chloride. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording crude compound. Pure material was obtained by trituration with ethyl acetate as affording 3.3 g (58%) of 4-hydroxy-3-(1-oxooctadecyl)-2(5H)-furanone.