Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:26])=[C:12]([C:14]([NH:21][C:22](=[O:25])[CH2:23]Cl)([C:16]([F:20])([F:19])[CH2:17][OH:18])[CH3:15])[CH:13]=1>CC(O)(C)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:26])=[C:12]([C:14]2([CH3:15])[C:16]([F:20])([F:19])[CH2:17][O:18][CH2:23][C:22](=[O:25])[NH:21]2)[CH:13]=1
Reactant: CC(NC(=O)CCl)(c1cc(Br)ccc1F)C(F)(F)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(c2cc(Br)ccc2F)NC(=O)COCC1(F)F

Procedure:
To a solution of t-BuOK (0.36 g, 3.2 mmol) in t-BuOH (10 mL) was added N-(2-(5-bromo-2-fluorophenyl)-3,3-difluoro-4-hydroxybutan-2-yl)-2-chloroacetamide (1.0 g, 2.6 mmol) t-BuOH (10 mL) at rt and heated to reflux temperature for 1 h 30 min. Reaction mixture was monitored by TLC analysis. Reaction mixture was concentrated under reduced pressure and adjusted pH to ˜2 using 2 N HCl. Ethyl acetate was added to extract the product, organic layer was washed with water, brine solution followed by drying over anhy. Na2SO4 and concentrated under reduced pressure. The crude compound (0.9 g) was carried forward for the next step without purification. LCMS: RtH5=1.616 [M+H]+=337.8, 339.9 (56%); 1.482 [M+H]+=675.1, 676.8 (34%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[N:12][C:11]2[NH:10][CH:9]([CH2:14][OH:15])[CH2:8][O:7][C:6]=2[CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:13]=[N:12][C:11]2[NH:10][CH:9]([CH2:14][OH:15])[CH2:8][O:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)OCC(CO)N2
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)OCC(CO)N2
Reaction time: 8 h
Yield: 91.5 %

Procedure:
Into a 500 mL round bottom flask were combined (7-nitro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-yl)methanol (0.320 g, 0.00152 mol), 10%-palladium on carbon (0.06 g, 0.0005 mol) and methanol (50 mL). The apparatus was evacuated, then hydrogen was introduced and the mixture was allowed to stir overnight (at 1 atm presuure). The mixture was then filtered through celite and the filtrate was concentrated under vacuum to yield an oil (0.252 g, 89%) which was used directly in the next step without further purification. (0.252 g, 89%) LC-MS 0.29 min. M/Z=181.9 (M+1).
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17].[NH:31](C(OC(C)(C)C)=O)[C@H:32]([C:34](O)=[O:35])[CH3:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:31][C@H:32]([C:34]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17])=[O:35])[CH3:33]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CCCNC(=N)N[N+](=O)[O-])C(N)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)N)C(N)=O

Procedure:
443 g of trifluoroacetate of H-Arg(NO2)Leu-NH2 are dissolved in 2 l of DMF. 200 g of Boc-Ala-OH, then 500 g of BOP are added. The pH is adjusted to 7 with pH paper (on small samples of the reaction medium) with the aid of NEM. The medium is stirred and the development of the reaction is followed by TLC. The reaction is terminated after 4 hrs. The medium is evaporated to dryness in vacuo at 25°. The residue is taken up in 2 l of water and 2 l of ethyl acetate. The organic phase is washed with a 5% aqueous solution of NaHCO3, with water, dried and evaporated. The tripeptide is recrystallized in ethyl-acetate/ether, and finally dried in vacuo. It is monitored by TLC and NMR.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[C:9]([N:14]=[N:15][C:16](Cl)([CH2:18][CH:19]([CH3:21])[CH3:20])[CH3:17])([CH2:12][CH3:13])([CH3:11])[CH3:10].[OH-].[Na+]>>[C:9]([N:14]=[N:15][C:16]([O:8][O:7][C:3]([CH3:6])([CH3:5])[CH3:4])([CH2:18][CH:19]([CH3:20])[CH3:21])[CH3:17])([CH2:12][CH3:13])([CH3:11])[CH3:10]
Reactant: CCC(C)(C)N=NC(C)(Cl)CC(C)C
Reactant: CC(C)(C)OO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)(C)N=NC(C)(CC(C)C)OOC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a cooled solution of 9.1 grams (.0407 moles) of 25% potassium hydroxide solution in a 100 ml. reaction flask equipped with a magnetic stirrer, thermometer and addition funnel was added 5.2 grams (.052 moles) of 90% t-butyl hydroperoxide. The reaction mixture was stirred for 30 minutes at 25° C and then cooled to 18° C. To the above solution was added 8.06 grams (0.037 moles) of 2-t-amylazo-2-chloro-4-methylpentane dropwise over 15 minutes holding the temperature at 18°-22° C with a cold water bath. After the addition was complete, the reaction was stirred for 10 minutes at 20° C, cooled to 5° C and stirred an additional 40 minutes. A small portion of 50% sodium hydroxide was then added to react with the excess t-butyl hydroperoxide and the reaction stirred for an additional 15 minutes, poured into 150 ml. of ice cold water and the product extracted with pentane. The pentane solution was washed with ice cold water, saturated NaHCO3 solution and water. The pentane solution was dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 8.3 grams (83% yield) of crude 2-t-amylazo-2-(t-butylperoxy)-4-methylpentane.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][O:26]C3CCCCO3)=[CH:19][C:18]=2[F:33])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]>CCO.Cl.O>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][OH:26])=[CH:19][C:18]=2[F:33])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
3,4-Difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}-N-(2-hydroxyethoxy)benzamide (115 mg, 0.25 mmol) was dissolved in EtOH (4 mL) to which was added 1 M HCl (5 drops). This reaction mixture was stirred overnight at RT, then the mixture was diluted with water (50 mL) and extracted with EtOAc (4×30 mL). The combined EtOAc fractions were washed with water (2×20 mL), brine (50 mL) and dried (Na2SO4) then the solvent removed under reduced pressure to afford a white solid which was purified by filtration through a plug of silica gel (EtOAc as eluant) to afford 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethoxy)benzamide as a cream solid (94 mg, 100%); m.p. (Et2O/hexane) 169-172° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.91 (br s, 1 H), 7.46-7.40 (m, 1 H), 7.29-7.19 (m, 2 H), 7.10 (dd, J=8.3, 1.6 Hz, 1 H), 6.78 (ddd, J=8.9, 8.9, 4.8 Hz, 1 H), 5.29 (t, J=5.9 Hz, 1 H), 4.76 (br s, 1 H), 4.27 (d, J=5.9 Hz, 2 H), 3.84 (t, J=4.8 Hz, 2 H), 3.56 (t, J=4.8 Hz, 2 H). Anal. calcd. for C18H15F3N2O4: C, 56.9; H, 4.0; N, 7.4. Found C, 56.8; H, 4.0; N, 7.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[S:18]1[CH2:22][CH2:21][NH:20][CH2:19]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:20]2[CH2:21][CH2:22][S:18][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1CSCN1
Reactant: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Solvent: C1COCCO1
Product: Clc1cc(N2CCSC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
There was dissolved, in 1,4-dioxane (2 mL), 5,7-dichloro-2-phenyl-pyrazolo-[1,5-a]pyrimidine (51.4 mg, 0.195 mM), then thiazolidine (30.7 μL, 0.390 mM) was added to the solution and then the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the resulting residue was diluted with water and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (48.5 mg, yield: 78%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.CCOCC>CO>[ClH:29].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(Cl)cc2Cl)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Clc1ccc(COc2ccc(OC[C@H]3CCCN3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 205.8 %

Procedure:
To a 25 mL vial which contained a solution of the product from step 2 (120 mg, 0.26 mmol) in MeOH (2 mL) was added HCl (2 N in ether, 4 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 24 h. The ether (10 mL) was added to the mixture and the solid which formed was filtered out to provide the crude which was further purified by recrystallization with MeOH-ether to yield the title product, (104 mg, 95%); LCMS; 100% APCI+, Calcd: 352.3; Found m/z 352.3 (M); 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.75 (m, 1H), 1.84-2.02 (m, 2H), 2.07-2.16 (m, 1H), 3.13-3.26 (m, 2H), 3.80-3.90 (m, 1H), 4.05-4.10 (m, 1H), 4.18 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 5.09 (s, 2H), 6.94-7.01 (m, 4H), 7.48 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.68 (d, 1H, J=2.0 Hz):
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS([C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[NH:19][CH:20]=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2[nH]ccc2[N+](=O)[O-])o1

Procedure:
A solution of 2-(5-dimethylaminomethyl-2-furyl-methylthio)ethylamine (3 g, 0.014 mol) and 2-methylsulphinyl-3-nitropyrrole (2 g, 0.011 mol) in ethanol (50 ml) was refluxed for 7 days, and it was then evaporated to dryness. The residue was purified by elution from a column of silica gel with ethyl acetate-petroleum ether (b.p. 60-80°)(4:1) to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)-ethylamino]-3-nitropyrrole, m.p. 67--67°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[CH:12]=[C:13]([C:16]4[C:17]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)=[N:18][N:19]([C:21]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:20]=4)[CH:14]=[CH:15][C:10]3=[N:9][CH:8]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1)CCC>>[F:46][C:43]1[CH:44]=[CH:45][C:40]([C:17]2[C:16]([C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C:5]5[S:6][C:2]([C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=6)=[CH:3][CH:4]=5)=[CH:8][N:9]=4)[CH:12]=3)=[CH:20][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]=2)=[CH:41][CH:42]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(Br)s4)n3c2)cc1
Product: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(-c5ccccn5)s4)n3c2)cc1

Procedure:
150 mg of 3-(5-bromo-2-thienyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridine obtained in Example 4 and 0.13 mL of 2-(tri-n-butylstannyl)pyridine were reacted in the same manner as in Example 21, to give 137 mg of the title compound as a yellow amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:15][C:4]1[CH:5]=[CH:6][C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)=[N:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(N2CC[C@H](O)C2)n1
Solvent: ClC(Cl)Cl
Product: COc1nc(N2CC[C@H](O)C2)ccc1Br
Temperature: 8 °C
Reaction time: 5 h
Yield: 8.3 %

Procedure:
To a solution of (3S)-1-(6-methoxypyridin-2-yl)pyrrolidin-3-ol (1.6 g, 8.24 mmol) in chloroform (90 mL), was added N-bromosuccinimide (1.47 g, 8.24 mmol) at 0° C. with an ice bath. The reaction was allowed to stir at room temperature (8° C.) for 5 hour. TLC (petroleum ether/ethyl acetate) showed that the reaction was complete. The reaction mixture was evaporated to remove chloroform, dissolved in DCM (20 mL) and diluted with water (15 mL). The resulting mixture was separated and the aqueous phase was extracted with dichloromethane (25 mL*3). The combined organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether, 0-25% to give the title compound (187 mg, 8.5%) as a yellow gum. 1H NMR (400 MHz, CDCl3) ppm 7.46 (d, 1H) 5.77 (d, 1H) 4.44-4.59 (m, 1H) 3.92 (s, 3H) 3.37-3.61 (m, 4H) 1.96-2.24 (m, 3H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH3:9][Si](Cl)(C)C>CO.C(Cl)Cl>[CH3:9][O:7][C:1](=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: C/C=C/C=C/C(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC=CC=CC(=O)OC
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of sorbic acid (1.12 g, 10 mmol) in dry methanol (50 mL) was added dropwise a solution of trimethylsilyl chloride (2M, 12 mL) in CH2Cl2. After stirring for 16 hours, the mixture was concentrated under reduced pressure to give a pale yellow oil that was purified by flash chromatography (9:1 60-80° C. petroleum ether:diethyl ether) to give the title compound (1.23 g, 99%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.OS(O)(=O)=O.O.[C:23]([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:23])=[O:15])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(OC)c(C(F)(F)F)cc1N

Procedure:
3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Int. B) 5.5 g, 23.29 mmol) was dissolved in MeOH (90 ml). H2SO4 (6.21 ml, 116 mmol) was added dropwise and the solution was heated to reflux for 4 hours. The reaction mixture was reduced in vacuo to approx. 15 ml and water (15 ml) was added. The pH was adjusted to pH 9 by careful addition of solid NaHCO3. Water (100 ml) was added and the mixture was extracted with DCM. The combined organic extracts were concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[C:17]([CH2:20][OH:21])[S:18][CH:19]=1>>[OH:21][CH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][S:13][CH2:12][CH2:11][NH:10][C:3]([NH:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])[N:16]=1
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1csc(CO)n1
Product: CNC(=C[N+](=O)[O-])NCCSCc1csc(CO)n1

Procedure:
The process of claim 1 wherein the N-[2-[[[2-(hydroxymethyl)-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine is prepared by reaction of 2-methylamino-2-methylthio-1-nitroethylene with 4-[[(2-aminoethyl)thio]methyl]-2-hydroxymethyl thiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3,3-dimethylindan-1-one (LXIV) (16.3 g, 50.9 mmol) (Harms, W. M. and Eisenbraum, E. J. Org. Prep. Proc. Int. 1972, 4, 67-72) in 56 mL of sulfuric acid was slowly added 4.18 mL of 70% nitric acid in 20 mL of sulfuric acid at 0°-5° C. After being stirred for 1 hour, the reaction mixture was poured into 600 g of ice. The precipitates was filtered and washed with water. The solids collected were dissolved in 600 mL of ethyl acetate and washed with NaHCO3 (80 mL×2), dried over magnesium sulfate, and evaporated. The residue was triturated with methanol to give 22.2 g of the title compound as yellow solids; 1H-NMR (CDCl3) δ1.49 (s, 6H), 2.71 (s, 2H), 7.68 (d, J=8.4 Hz, 1H), 8.48 (dd, J=2.0, 8.4 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H); MS m/e 206 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([O:21]CC)=[O:20].[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1c1ccc(OC)c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2CCCC[C@H]2C(=O)O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
To a stirred solution of 1.22 g (3.8 mmol) of trans-ethyl 2-(2,3,4-trimethoxyphenyl)cyclohexane-1-carboxylate in 20 mL of THF and 10 mL of methanol was added 10 mL of 10% aqueous NaOH. The mixture was stirred at room temperature for 18 h and heated at reflux for 18 h. After cooling, the bulk of the organic solvents was removed in vacuo and the residue was diluted with 100 mL of 5% aqueous NaOH and washed with 100 mL of ether. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted with two 100 mL portions of ether. These ether extracts were combined, dried over MgSO4 and the solvent removed in vacuo to leave 0.88 g of trans-2-(2,3,4-trimethoxyphenyl)cyclohexane-1-carboxylic acid as an oil. 1H NMR (CDCl3) -- 1.3-2.2 (m, 8H), 2.65 (m, 1H), 3.1 (m, 1H), 3.8 (s, 9H), 6.6 (d, 1H), 6.8 (d, 1H).
Reaction SMILES: [CH2:1]1[CH2:16][O:15][C:3]2([CH2:12][CH2:11][CH2:10][C:9]3[C:4]2([CH3:14])[CH2:5][CH2:6][C:7](=[O:13])[CH:8]=3)[O:2]1.C[O-].[Na+].[CH:20](OC)=[O:21]>C1COCC1>[CH2:16]1[CH2:1][O:2][C:3]2([CH2:12][CH2:11][CH2:10][C:9]3[C:4]2([CH3:14])[CH2:5][C:6](=[CH:20][OH:21])[C:7](=[O:13])[CH:8]=3)[O:15]1
Reactant: COC=O
Reactant: CC12CCC(=O)C=C1CCCC21OCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC12CC(=CO)C(=O)C=C1CCCC21OCCO1
Reaction time: 0.5 h
Yield: 26103 %

Procedure:
A solution of 201 (20 g, 0.090 mmol) in THF (200 mL) was cooled to −5° C. in an ice/methanol bath. NaOMe (19.45 g, 0.360 mol) was added and the mixture stirred for 30 minutes. After slow addition of a cooled solution of methyl formate (55.5 mL, 0.900 mol) in 60 mL THF, the mixture was stirred at room temperature for 24 hours. The mixture was poured into ice-water-HCl (˜50 mL conc. HCl in 500 mL H2O), stirred for 5 minutes and then transferred to a separatory funnel. The aqueous layer was extracted with ether (3×100 mL) and the pooled organic extracts were washed with brine, dried (MgSO4), and concentrated. The yellow residue was flash chromatographed (0-50% EtOAc-hexanes) to yield 203 (5.88 g, 26%) as a yellow oil. 1H NMR (CDCl3) δ 1.22 (s, 3H), 1.6-1.9 (m, 4H), 2.02 (d, J=14 Hz, 1H), 2.2-2.5 (2H), 2.91 (d, J=14 Hz, 1H), 3.94.1 (m, 4H), 5.86 (d, J=2.0 Hz, 1H), 7.37 (s, 1H); 13C NMR (CDCl3) 188.72, 166.86, 165.35, 165.12, 124.59, 124.25, 111.92, 106.39, 65.33, 65.17, 65.04, 64.89, 46.00, 29.87, 21.33, 20.74, 20.59.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH2:7])([O-])=O>[Pd].C(OCC)(=O)C>[C:6]1([NH2:7])[CH:5]=[C:4]([NH2:1])[CH:10]=[C:9]([NH2:11])[CH:8]=1
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(N)cc(N)c1
Yield: 99.6 %

Procedure:
A mixture of 1.0 g of 3,5-dinitroaniline, 0.5 g of 10% palladium on carbon catalyst and 100 ml of ethyl acetate is hydrogenated in a Parr shaker, filtered and evaporated to give 670 mg of 1,3,5-benzenetriamine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].N1CCCCC1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=[C:29]4[NH:23][C:24](=[O:25])[NH:26][C:27]4=[O:28])=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)(C)c1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1cccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-tert-butylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (39 mg, 0.133 mmol) in EtOH was added hydantoin (28 mg, 0.280 mmol) and piperidine (13 μL, 0.133 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and air dried to yield 5-((5-(3-tert-butylphenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=377)
Reaction SMILES: [C:1]1([C:7]2[O:13][CH:12]3[CH:9]([C:10](=[O:41])[N:11]3[C@H:14]([C:31]([CH2:33][O:34]C(=O)C(F)(F)F)=[CH2:32])[C:15]([O:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C(Cl)Cl>[C:1]1([C:7]2[O:13][CH:12]3[CH:9]([C:10](=[O:41])[N:11]3[C@H:14]([C:31]([CH2:33][OH:34])=[CH2:32])[C:15]([O:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(COC(=O)C(F)(F)F)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(c3ccccc3)OC21
Solvent: CO
Solvent: ClCCl
Product: C=C(CO)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(c3ccccc3)OC21
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
To a solution of 240 mg of diphenylmethyl (2R)-2-(3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-3-trifluoroacetyloxymethyl-3-butenoate in 10 ml of a mixture (4:1) of methanol and methylene chloride is added 4.8 g of silica gel containing 10% water, and the mixture stirred for 30 minutes and filtered. The filter cake, silica gel, is washed several times with a mixture of methanol and methylene chloride. The combined filtrate and washings are evaporated under reduced pressure. The oily residue is chromatographed on 12 g of silica gel. Elution with a mixture (2:1) of benzene and ethyl acetate yields 106 mg of diphenylmethyl (2R)-2-(3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-3-hydroxymethyl-3-butenoate in 53% yield and 90 mg of the starting material in 35% recovery.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][N:22]2[C:26](=[O:27])[CH2:25][NH:24][C:23]2=[S:28])[N:17]=[CH:16]1.N1CCCCC1>ClCCl>[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][N:22]2[C:26](=[O:27])/[C:25](=[CH:13]/[C:11]3[O:12][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=4)=[CH:9][CH:10]=3)/[NH:24][C:23]2=[S:28])[N:17]=[CH:16]1
Reactant: O=C1CNC(=S)N1CCc1c[nH]cn1
Reactant: O=Cc1ccc(-c2cccc(I)c2)o1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1/C(=C/c2ccc(-c3cccc(I)c3)o2)NC(=S)N1CCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
5-(3-Iodophenyl)furan-2-carbaldehyde (30 mg, 0.1 mmol) synthesized by the same method as in Example 1 and 3-(2-(1H-imidazol-4-yl)ethyl)-2-thioxoimidazolidin-4-one (21 mg, 0.1 mmol) were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 3 hours. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform/methanol (9/1 (volume ratio)) as an eluent, to give compound 3 in a yield of 25 mg (yield 51.0%).