Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[C:20]([CH3:22])[CH3:21]>CS(C)=O.O1CCCC1>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@@:13]12[CH2:21][C:20]1([CH3:4])[CH3:22]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)=C1C(=O)Nc2ccc(F)cc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(C)C[C@]12C(=O)Nc1ccc(F)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A solution of NaH (60%) (0.6 g, 15 mmol) and trimethylsulfoxonium iodide (3.3 g, 15 mmol) in dimethyl sulfoxide (30 mL) was stirred for 30 minutes at 25° C. Then a solution of 5-fluoro-3-isopropylidene-1,3-dihydro-indol-2-one (2.6 g, 13.6 mmol) in dry tetrahydrofuran (30 mL) was added dropwise over 20 minutes. After being stirred for 1 hour at 25° C. and 1 hour at 50° C., the reaction solution was poured into ice-cold water and extracted with ether (3×100 mL), washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ether to afford the title compound as white solid (2.39 g, 85%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:17])[NH:10][CH2:11][C@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([C:20]1[C:21]([F:32])=[CH:22][N:23]=[C:24]2[C:29]=1[N:28]=[C:27]([O:30][CH3:31])[CH:26]=[CH:25]2)=[CH2:19]>CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:17])[NH:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:19][CH2:18][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=4)[N:23]=[CH:22][C:21]=3[F:32])[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Reactant: O=C(NC[C@H]1CCNC1)OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2ncc(F)c(CCN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Reaction time: 24 h
Yield: 74.5 %

Procedure:
To a solution of phenylmethyl[(3S)-3-pyrrolidinylmethyl]carbamate (127 mg, 0.54 mmole) in DMF (1 mL) was added 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (0.10 g, 0.49 mmole). After 24 h at 100° C., the reaction contents were purified on silica gel (CHCl3/MeOH, 9:1, containing 5% NH4OH) to afford the title compound (0.16 g, 77%) as a light yellow oil: LC-MS (ES) m/e 439 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[O:8]1[C:9]2[C:4](=[CH:3][C:2]([N:1]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2c(c1)CCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: c1cc2c(cc1N1CCNCC1)CCCO2

Procedure:
A solution of 6-aminochroman from part 2 of this example (0.300 g, 2.013 mmol), bis-(2-choroethyl)amine hydrochloride (0.539 g, 3.020 mmol) and potassium carbonate (0.278 g, 2.013 mmol) in 10 mL chlorobenzene is heated at reflux for 24 h . The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic layer is separated, dried over Mg2SO4, filtered and concentrated. Purification by flash column chromatography (5% methanol-methylene chloride) affords 0.157 g (36%) of 1-(chroman-6-yl)piperazine as a white solid, TLC Rf 0.35 (elution with 10% hanol-methylene chloride).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[F:10][C:9]1[C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1cccnc1CCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2ncccc2F)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3-fluoropyridine hydrochloride (Weidmann, K. et al., J. Med. Chem. (1992), (35):438) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (25%) as a colorless solid: mp 247-249° C. (dichloromethane/ether); 1H NMR (300 MHz, CDCl3) δ 8.35 (td, J=4.6, 1.34 Hz, 1H), 7.43-7.33 (m, 1H), 7.27-7.11 (m, 3H), 7.02-6.95 (m, 1H), 6.80-6.75 (m, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 5.31 (dd, J=16.2, 1.5 Hz, 1H), 5.04 (dd, J=16.2, 1.4 Hz, 1H), 4.95 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 159.6, 156.2, 155.2, 145.4, 145.3, 144.5, 142.9, 142.8, 142.2, 138.3, 132.6, 128.6, 124.3, 123.8, 123.3, 123.1, 121.3, 112.2, 109.0, 99.2, 80.2, 64.5, 63.9, 58.1, 40.7; MS (ES+) m/z 404.7 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH3:21])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:22])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].O>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH3:21])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:22][CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:32])=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(N)nc3cc(OCC(=O)c4ccccc4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A warm solution of 4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (266 mg, 0.891 mmol) in DMF (20 mL) was cooled to approximately 0° C. Solid cesium carbonate (580 mg, 1.78 mmol) was added. After ten minutes, 2-bromoacetophenone (186 mg, 0.935 mmol) was added in one portion, and the reaction was allowed to warm to room temperature and was stirred overnight. An analysis by high-performance liquid chromatography (HPLC) indicated the presence of starting material. Additional 2-bromoacetophenone was added, and the reaction was stirred for six hours. The reaction was poured into deionized water (200-300 mL) and stirred for 15 hours. The resulting precipitate was isolated by filtration and purified by column chromatography on silica gel (eluting with chloroform:methanol ranging in ratios from 99.5:0.5 to 98:2). The product was then recrystallized from acetonitrile, isolated by filtration, and dried overnight under high vacuum to provide 222 mg of 2-(4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy)-1-phenylethanone as white crystals, mp 178.0-180.0° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:32])[C:29](O)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:32][C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:30]
Reactant: C1COCCN1
Reactant: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)O
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N1CCOCC1
Yield: 37 %

Procedure:
Using the same procedure as in Example 44, (2S)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (380 mg, 0.84 mmol) was reacted with morpholine to give the title compound as a white solid (158 mg, 37%); NMR Spectrum 1.58 (d, 3H), 3.40-3.75 (m, 8H), 5.88 (q, 1H), 6.04 (s, 2H), 7.29 (d, 1H), 7.36 (d, 1H), 7.66 (s, 1H), 7.73-7.78 (m, 3H), 7.88-7.90 (m, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.55 (s, 1H), 11.15 (br s, 1H); Mass spectrum MH+ 516.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[S:6][C:7]3[CH2:20][CH2:19][C:11]4[N:12]=[C:13]([NH:15]C(=O)C)[S:14][C:10]=4[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.Cl>CCO>[CH:1]1([CH2:4][C:5]2[S:6][C:7]3[CH2:20][CH2:19][C:11]4[N:12]=[C:13]([NH2:15])[S:14][C:10]=4[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(CC3CC3)sc1CC2
Agent: Cl
Solvent: CCO
Product: Nc1nc2c(s1)-c1nc(CC3CC3)sc1CC2
Temperature: 90 °C

Procedure:
N-(7-Cyclopropylmethyl-4,5-dihydro-benzo[1,2-d;3,4-d′]bisthiazol-2-yl)-acetamide (Stage V.2, 180 mg, 0.589 mmol) was dissolved in EtOH (10 mL) and 36% HCl (1.193 g, 11.79 mmol) added. The RM was heated to 90° C. for 16 h then cooled and extracted with EtOAc/H2O. The organic layer was dried over Na2SO4 and evaporated. The crude material was chromatographed with MPLC C18 H2O 0.1% TFA/CH3CN 0.1% TFA, gradient 0-50%. Product containing fractions were neutralized with NaHCO3, extracted with EtOAc and lyophilized from dioxane to give the title compound (M+H=264.2; M−H=262.1; tR 4.183 min (Method F)).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:39])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=3)[CH2:28][C:27](=[O:39])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1cc2c(cc1Cl)NC(=O)CC(c1ccnc(C#N)c1)=N2)C1CC1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(cyclopropyl-methyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example J11) (150 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (150 mg, 0.61 mmol) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (69 mg).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:23][C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]([CH2:23][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]3[CH:14]=[CH:15][C:16]([O:20][CH3:21])=[C:17]([O:18][CH3:19])[C:5]=3[O:4][CH3:3])[CH2:9][CH2:10]2)=[O:25])=[CH:28][CH:29]=1
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Reactant: COc1ccc(OC(=O)CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)CN2CCN(Cc3ccc(OC)c(OC)c3OC)CC2)cc1

Procedure:
A mixture of 1-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (prepared by the method disclosed in Japanese Patent First Publication (Kokai) No. 32889/1973) (17.0 g), 4-methoxyphenyl chloroacetate (prepared by the method disclosed in U.S. Pat. No. 3,657,318) (10 g), potassium carbonate (27.6 g) and N,N-dimethylformamide (200 ml) is stirred at 50° C. for 4 hours. To the reaction mixture is added water (400 ml), and the mixture is extracted with chloroform (400 ml). The organic layer is washed with water twice and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to give crude 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(2,3,4-trimethoxybenzyl)piperazine (free base) (20 g) as an oily substance. This crude free base (20 g) is dissolved in ethanol (100 ml) and thereto is added a solution of hydrochloric acid in ethanol (10% w/w) (50 ml) and the precipitated crystals are separated by filtration. The crystals are recrystallized from methanol to give 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (11.5 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=S)[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1.O.[NH2:25][NH2:26]>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[N:25][NH2:26])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=NN
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-thioxopiperidin-3-yl]carbamate (100 mg, 0.29 mmol) in methanol (2.9 mL) was added hydrazine hydrate (55%, 780 μL, 8.76 mmol). The mixture was stirred 40 min, and then concentrated. Water was added, and the mixture was extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound. MS 341.2 (M+1).
Reaction SMILES: C1(C[O:5][C:6](=[O:33])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:24]=[CH:25][C:26]4[C:27]([CH:31]=3)=[N:28][S:29][N:30]=4)=[C:14]([Cl:32])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[N:30]1[S:29][N:28]=[C:27]2[CH:31]=[C:23]([C:15]3[C:16]([O:18][CH2:19][CH:20]4[CH2:22][CH2:21]4)=[CH:17][C:12]([CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:33])=[O:5])=[CH:13][C:14]=3[Cl:32])[CH:24]=[CH:25][C:26]=12
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc3nsnc3c2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc3nsnc3c2)c(OCC2CC2)c1
Yield: 46.4 %

Procedure:
2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.08 g, 0.19 mmol) was dissolved in a mixture of EtOH and H2O (9 mL /1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid as a yellow oil (0.038 g, 55%). 1H NMR (300 MHz, CDCl3/TMS): δ 8.02 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.68 (t, J=7.6 Hz, 1H), 2.04-1.96 (m, 1H), 1.78-1.69 (m, 1H), 1.63-1.55 (m, 1H), 1.10-1.00 (m, 1H), 0.97 (d, J=6.4 Hz, 6H), 0.50-0.39 (m, 2H), 0.22-0.12 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 157.2, 154.6, 154.0, 140.5, 136.7, 134.0, 132.9, 127.8, 122.9, 121.6, 120.1, 111.0, 73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C(Cl)Cl>CO>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[C:7]1[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Reactant: COc1ccccc1C=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1C=C1c2ccccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 72 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitrofluorene (1.05 g, 5 mmol) and 2-methoxybenzaldehyde (0.816 g, 6 mmol) in 20 mL of methanol was added KF—Al2O3 (0.75 g, 4.5 mmol). The resulting mixture was stirred at 72° C. After 6 hrs, TLC indicated that the starting material was gone. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was recrystallized from alcohol and CH2Cl2 to give 1.2 g of CYD-1-70 as a yellow solid. 1H-NMR (600 MHz, CDCl3) δ 8.84 (s, 0.36H), 8.26 (m, 1.65H), 8.10 (m, 3.05H), 8.02 (s, 0.57H), 7.55 (m, 4H), 7.24 (m, 1.24H), 7.10 (m, 0.91H), 3.84 (s, 3H)
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[F:9][C:10]([F:18])([F:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12]>ClCCl>[C:4]([O:3][C:1]([NH:2][C:11]([OH:12])([C:13]([F:16])([F:15])[F:14])[C:10]([F:18])([F:17])[F:9])=[O:8])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(N)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(O)(C(F)(F)F)C(F)(F)F

Procedure:
The 2-tert-butoxy-4,4-bis(trifluoromethyl)-1,3-oxazabuta-1 ,3-diene of formula II can be obtained by the method described by Steglich et al., Chemische Berichte 107:1488 (1974). The starting materials are tert-butyl carbamate ((CH3)3C—O—CO—NH2) and anhydrous hexafluoroacetone, which are initially reacted, for example, in a solvent such as dichloromethane at room temperature, to give 2-tert-butoxycarbonylamino-2-hydroxy-1,1,1,3,3,3-hexafluoropropane. This intermediate is then converted, for example, in a solvent such as diethyl ether at temperatures from about 0° C. to about 10° C., by treatment with trifluoroacetic anhydride in the presence of a base (e.g., quinoline), into the compound of formula II, which can be purified by distillation. Details of the preparation are described below.
Reaction SMILES: [CH2:1]([N:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:20]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([N:3]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:20])=[CH:9][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCN(CCOc1ccc(O)cc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCN(CCOc1ccc(OC)cc1)c1ccccc1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a mixture of 3 (78 mg, 0.3 mmol), K2CO3 (95 mg, 0.69 mmol), in acetone (50 mL), 1 mL (16 mmol) of MeI was added. The reaction mixture was heated to reflux for 48 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 50 mL water. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/CH2Cl2 (2/1) to provide compound 24 (49 mg, 0.18 mmol, 60% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.23 (m, 2H), 6.83 (m, 4H), 6.73 (d, J=8.4 Hz, 2H), 6.68 (t, J=7 Hz, 1H), 4.07 (t, J=6.4 Hz, 2H), 3.77 (s, 3H), 3.70 (t, J=6.4 Hz, 2H), 3.47 (q, J=7 Hz, 2H), 1.20 (t, J=7 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 153.93, 152.91, 147.62, 129.38, 115.95, 115.40, 114.67, 111.80, 66.01, 55.74, 49.76, 45.59, 12.30; HRMS (ESI, positive) m/z calcd. For C17H22NO2 [M+H]+: 272.1645, found: 272.1646.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:24])=[O:23].O[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32]>CN(C)C=O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([O:24][N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32])=[O:23]
Reactant: O=C(O)c1ccccn1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccccn1
Reaction time: 8 h

Procedure:
The N-picolinoyloxysuccinimide is prepared by adding 8.4 g of N,N'-dicyclohexylcarbodiimide to a solution of 5.0 g of picolinic acid and 4.7 g of N-hydroxysuccinimide in 50 ml of dimethylformamide. The mixture is stirred overnight, triturated with ether and recrystallized from ethyl acetate, methylene chloride (1:1). The solid is collected and dried; mp. 174°-175°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C(O)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: NC(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCc1cc(Nc2ccc(CC(N)=O)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 108 °C
Yield: 62.4 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g, 0.59 mmol) and 2-(4-aminophenyl)acetamide (0.107 g, 0.71 mmol) and 4M HCl in dioxane (2 drops) in acetic acid (3 mL) was heated for 2 h at 108° C. After this time, the mixture was cooled to rt, neutralized with saturated NaHCO3, extracted with EtOAc, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with methylene chloride and methanol to afford the title compound (0.135 g, 62%) as a white solid. MW=366.84. 1H NMR (DMSO-d6, 500 MHz) δ 9.57 (s, 1H), 8.33-8.29 (m, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.58-7.54 (m, 2H), 7.43 (br s, 1H), 7.27 (d, J=8.5 Hz, 2H), 6.86 (br s, 1H), 6.59 (s, 1H), 3.35 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H); ESI MS m/z 367 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])[CH3:3].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21].[OH-].[NH4+]>O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])[CH3:1]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1sccc1N=NN(C)C
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1sc([N+](=O)[O-])cc1N=NN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.6 %

Procedure:
Methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (2 g, 9.38 mmol) was added slowly for 15 min at 0 to −5° C. to concentrated sulfuric acid (20 mL). Then concentrated nitric acid (0.54 mL, 70%, 10.7 mmol) was added to the above reaction mixture for 10 min and stirred at the same temperature for 1 h and rt for 16 h. The mixture was poured into ice cooled water and basified with ammonium hydroxide. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (80:20) as eluents to give the product as a yellow color solid (450 mg, 26%), mp 128-130° C.