Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([C:9]2[C:21]3[CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:18]=4)[C:13]=3[CH:12]=[C:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:10]=2)([CH3:8])[CH3:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.Cl[Si:36]([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[CH3:37][Si:36]([CH3:39])([CH3:38])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]([C:9]2[C:21]3[CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:18]=4)[C:13]=3[CH:12]=[C:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:10]=2)([CH3:8])[CH3:7])[CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(C)(C)C3C=CC=C3)c1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(C)(C)C3C=CC([Si](C)(C)C)=C3)c1C2
Yield: 84.3 %

Procedure:
In a 50 ml Schlenk flask purged with nitrogen, 1.44 g (3.74 mmol, 1 eq) of 2-(cyclopentadienyl)-2-(3,6-di-tert-butylfluorenyl)propane was placed at room temperature. Then, 20 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (light yellowish orange solution). To the solution, 2.5 ml (1.63 mmol, 1.09 eq) of n-BuLi (hexane solution) was dropwise added. The ice bath was removed, and the solution was stirred at room temperature for 19 hours (dark red solution). The solution was cooled with an ice bath, and to the solution, 2.7 ml (21.3 mmol, 5.70 eq) of chlorotrimethylsilane was dropwise added by a syringe. The ice bath was removed, and the solution was stirred at room temperature for 3 hours. The resulting yellow solution was poured into 80 ml of a diluted hydrochloric acid solution to perform quenching. After the soluble component was extracted with 100 ml of diethyl ether, the organic phase was washed with 50 ml of a saturated saline solution. The organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a light yellow solid. The solid was washed with 50 ml of methanol and vacuum dried to obtain 1.44 g a light creamy powder (yield: 84%)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:64](=[O:68])([O:66][CH3:67])[NH2:65]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].ClCCl>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([NH:65][C:64](=[O:68])[O:66][CH3:67])[CH:3]=[N:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:15]
Reactant: COC(N)=O
Reactant: CCc1ccc(-c2cncc(Br)c2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1ccc(-c2cncc(NC(=O)OC)c2)cc1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
Under argon and at RT, a solution of 16.8 g (64 mmol) of 3-bromo-5-(4-ethylphenyl)pyridine in 70 ml of dioxane was added to a suspension of 555 mg (0.96 mmol, 0.015 eq.) of Xantphos (4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene), 293 mg (0.32 mmol, 0.005 eq.) of tris(dibenzylideneacetone)dipalladium, 29.1 g (89 mmol, 1.4 eq.) of caesium carbonate and 5.8 g (77 mmol, 1.2 eq.) of methyl carbamate in 100 ml of dioxane. The reaction mixture was stirred at 90° C. for 20 h. Since the progress of the reaction was slow, a little at a time, three times in total, 555 mg (0.96 mmol, 0.015 eq.) of Xantphos and 293 mg (0.32 mmol, 0.005 eq.) of tris(dibenzylideneacetone)dipalladium were added to the reaction mixture, and in each case the mixture was stirred at 90° C. overnight. After addition of dichloromethane, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was stirred with acetonitrile and the residue that remained was repeatedly washed with cold acetonitrile and dried under reduced pressure. Yield: 15 g (90% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:24]([O:28][C:29](Cl)=[O:30])[CH2:25][CH2:26][CH3:27]>ClCCl>[CH2:24]([O:28][C:29]([N:13]1[CH2:14][CH2:15][CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])[CH2:12]1)=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: O=C(NC1CCNC1)OCc1ccccc1
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N1CCC(NC(=O)OCc2ccccc2)C1
Reaction time: 12 h

Procedure:
To a solution of 3.20 g pyrrolidin-3-yl-carbamic acid benzyl ester hydrotrifluoracetate in 50 ml dichloromethane were added dropwise 3.7 ml triethylamine and 1.3 ml butylchloro-formate at 0° C. After stirring for 12 h the reaction mixture was diluted with dichloromethane, washed with 0.1 M HCl, saturated NaHCO3 and brine. The crude product thus obtained was purified by flash chromatography on silica using ethyl acetate/heptane 1:2 as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:18]([O:20]CC)=O)=[C:4]([F:23])[CH:3]=1.[OH-].[Na+].[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH2:34])[CH2:29][O:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C.C(O)C>[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH:34][C:18]([C:10]2[S:11][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:17]3[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:23])=[O:20])[CH2:29][O:28]1
Reactant: CCOC(=O)c1sc2cnccc2c1Nc1ccc(Br)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CONC(=O)c2sc3cnccc3c2Nc2ccc(Br)cc2F)O1
Temperature: 65 °C
Reaction time: 66 h
Yield: 76.8 %

Procedure:
A mixture of ethyl 3-(4-bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylate (63 mg, 0.16 mmol), 1N aqueous NaOH solution (0.17 ml, 0.17 mmol) and ethanol (2 ml) was heated at 65° C. for 45 minutes. The resultant reaction mixture was concentrated in vacuo then the residue was azeotroped with toluene (2×2 ml) to give a solid residue. The resultant solid residue was suspended in anhydrous THF (2 ml) before O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (38 mg, 0.32 mmol), EDCI (38 mg, 0.20 mmol), HOBt (30 mg, 0.22 mmol) and DIPEA (83 μl. 0.48 mmol) were added. After stirring for 66 hours at ambient temperature, the reaction mixture was concentrated in vacuo to afford a yellow residue. The resultant residue was dissolved in ethyl acetate (50 ml) and washed with water (20 ml), before the organic layer was isolated, dried over sodium sulfate, then concentrated in vacuo to afford a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 60:40 to 0:100) to afford the title compound as a yellow foam (61 mg, 77%). LCMS (method B): RT=3.02 min, M+H+=496/498.
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[C:9]([O:13][C:14]([C@@:16]12[CH2:32][O:31][CH:30]=[C:17]1[C:18](=[O:29])[N:19]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:20]2)=[O:15])([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([O:13][C:14]([C:16]12[CH2:32][O:31][C@H:30]3[CH2:1][C:17]13[C:18](=[O:29])[N:19]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:20]2)=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC[Zn]CC
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)COC=C2C1=O
Solvent: ICI
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CC2(C(=O)OC(C)(C)C)CO[C@H]3CC32C1=O
Reaction time: 0.25 h

Procedure:
To a solution of diethyl zinc (1M hexane solution, 22.3 ml) in dichloromethane (75 mL) was added dropwise diiodomethane (1.79 mL, 22.3 mmol) at −10° C., and the mixture was stirred for 15 min at the same temperature. A solution of (S)-6-oxo-5-[(R)-1-phenylethyl]-5,6-dihydro-4H-furo[3,4-c]pyrrole-3a-carboxylic acid tert-butyl ester in dichloromethane was added at −10° C., and the resulting mixture was stirred for 8 h at room temperature. The reaction mixture was quenched with 10% aq. citric acid. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% AcOEt in hexane to afford the title compound (1.96 g) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH:8]=[C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]#[N:11])[CH:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][O:24][CH:23]1[C:28]1[CH:29]=[C:30]([SH:34])[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[O:22]1[CH2:27][CH2:26][CH2:25][O:24][CH:23]1[C:28]1[CH:29]=[C:30]([S:34][C:2]2[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH:8]=[C:9]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:10]#[N:11])[CH:7]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])CC1CCOCC1
Reactant: Sc1cccc(C2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC(=Cc1cc(Sc2cccc(C3OCCCO3)c2)ccc1[N+](=O)[O-])CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(5-Fluoro-2-nitro-phenyl)-2-(tetrahydro-pyran-4-ylmethyl)-acrylonitrile (1.2 g, 4.07 mmol) and 3-[1,3]dioxan-2-yl-benzenethiol (0.8 g, 4.07 mmol) were added to a mixture of Cs2CO3 (2.78 g, 8.56 mmol) in DMF (100 mL). The resulting mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with H2O. The organic phase was separated, dried with MgSO4, and filtered. The solvent was removed to yield an oil, which was purified by silica column chromatography (40% EtOAc/heptane) to yield an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][OH:14]>C1C=CC=CC=1>[OH:14][N:13]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(=O)c1cccc(O)c1
Reactant: NO
Solvent: c1ccccc1
Product: O=C(O)C(=NO)c1cccc(O)c1
Reaction time: 0.42 h

Procedure:
A mixture of 3-hydroxyphenylglyoxylic acid (3.32 g.) and 1 N-methanol solution of hydroxylamine (45 ml.) was refluxed with stirring, for 25 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in 1 N-sodium hydroxide aqueous solution (50 ml.) and the solution was washed with ether, acidified with hydrochloric acid under cooling and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, dried and concentrated to give yellow oil. To the oil was added benzene and benzene was distilled off. The residue was crystallized with petroleum ether and the crystals were collected by filtration, washed with petroleum ether and dried to give 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture of syn and anti isomer) (2.9 g.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[N:18]O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B>>[NH2:18][CH:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C(CCc1ccccc1)CCc1ccccc1
Agent: B
Product: NC(CCc1ccccc1)CCc1ccccc1

Procedure:
According to the procedure of Feuer and Braunstein (J. Org. Chem. 1969, 34, 1817), the resultant compound of Example 31 was treated with borane to give the desired compound.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:15])[CH:5]([CH2:6][C:7](Cl)([Cl:9])[Cl:8])[CH:4]1[C:11]([O:13][CH3:14])=[O:12]>CO>[CH3:2][C:3]1([CH3:15])[CH:5]([CH:6]=[C:7]([Cl:8])[Cl:9])[CH:4]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Agent: [Na]
Solvent: CO
Product: COC(=O)C1C(C=C(Cl)Cl)C1(C)C
Yield: 80.5 %

Procedure:
To 80 ml of methanol solution containing 0.92 g of metallic sodium were added 7.8 g of methyl 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropanecarboxylate (purity: 87.8%, cis/trans ratio: 88/12) to heat the resulting mixture for 35 hours under reflux. After distilling off the methanol, the mixture was diluted with water, acidified with diluted hydrochloric acid, subjected to extraction with ether. After washing the ether layer with sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, the ether was distilled off. Vacuum distillation was carried out to obtain 5.4 g of methyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylate, b.p. 64°-72° C./1.2 mmHg, cis/trans ratio 90.9/9.1, purity 87.8%, yield 79.8%. Further, the sodium bicarbonate aqueous wash solution was acidified to obtain 0.5 g of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:6]([C:13]([O:15]CC)=[O:14])=[C:7]([C:9]([OH:12])([CH3:11])[CH3:10])[N:8]=1)[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([S:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:6]([C:13]([OH:15])=[O:14])=[C:7]([C:9]([OH:12])([CH3:11])[CH3:10])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(SCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCSc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.3 %

Procedure:
1.00 g of ethyl 2-ethylthio-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 107(b)] and 256 mg of lithium hydroxide monohydrate were added to a mixture of 10 ml of water and 10 ml of dioxane. The mixture was then stirred at room temperature for 24 hours after which it was concentrated by evaporation under reduced pressure. The resulting residue was dissolved in water, and then 6.1 ml of 1N aqueous hydrochloric acid were added. The oily matter which appeared was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 955 mg of the title compound as an amorphous powder.
Reaction SMILES: O=[C:2]([CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:10]=1[N+:17]([O-])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CCO.C(O)(=O)C.[Fe]>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][C:12]=1[Cl:16])[NH:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8]2
Reactant: CCOC(=O)C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Cl)c(Cl)cc2[nH]1
Yield: 92 %

Procedure:
A mixture of ethyl α-oxo-3-(2-nitro-4,5-dichlorophenyl)propanoate (100 g, 327 mmol) and iron powder (160 g) in EtOH (625 ml) and acetic acid (625 ml) was refluxed for two hours. After cooling, the resulting mixture was evaporated under vacuum and the solid residue was dissolved in THF (1000 ml) and chromatographed on Florisil (500 g) eluting with THF (5000 ml). Evaporation of the collected fractions gave pure title compound (77.5 g, 301 mmol, yield 92.0%) as a light brown powder, m.p. 215°-218° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[BrH:10].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:10][CH:2]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])[OH:1]
Reactant: Br
Reactant: OCC(CO)(CO)CO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: OCC(CO)(CO)C(O)Br
Yield: 70 %

Procedure:
In a 2 liter, three-necked flask equipped with a reflux condenser and an addition funnel are placed 200 g pentaerythritol (1.47 mole) and 16 ml 48% hydrobromic acid in about 500 ml glacial acetic acid. The mixture is refluxed for about one-half hour until all pentaerythritol is dissolved. Then, 170 ml 48% hydrobromic acid are added, followed by 310 ml acetic anhydride and the mixture is refluxed for 3 hours. Then, 94 ml 48% hydrobromic acid followed by 150 ml acetic anhydride are added and the mixture is refluxed for an additional 3 hours. The acetic acid is then removed as completely as possible on a rotary evaporator. Ethanol (95%, 750 ml) and 17 ml 48% hydrobromic acid are then added to the residue. The flask is equipped with 1 m Vigreux column and the azeotrope ethyl acetate/ethanol is slowly distilled off. When 500 ml distillate has been collected, an additional 750 ml 95% ethanol is added and the distillation is continued until about 400 ml is left over. After cooling, the precipitated pentaerythritol is filtered off. The solvent is evaporated and the residue is dissolved in water. The aqueous phase is extracted twice with carbon tetrachloride and twice with ether. The water is evaporated on the rotary evaporator and the last traces of water are removed by azeotropic distillation with toluene using a Dean-Stark trap. The solid is recrystallized from chloroform containing 10% acetonitrile. The first crop yielded 190 g monobromopentaerythritol. The total yield is 70%.
Reaction SMILES: C(O[C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:24][NH2:25]>CCO>[CH3:6][CH:5]1[N:7]2[C:8]([CH2:9][O:10][C:11]3[C:12]2=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=3)=[N:25][NH:24][C:4]1=[O:22]
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(C)c([N+](=O)[O-])cc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1[N+](=O)[O-])N1C(=NNC(=O)C1C)CO2
Temperature: 120 °C
Yield: 76.9 %

Procedure:
To a solution of 2-(7-methyl-6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.130 g, 0.40 mmol) in EtOH (8 mL) was added hydrazine hydrate (98%, 1.4 mmol, 0.070 g) and the reaction mixture was heated at 120° C. for 4 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give 4,7-dimethyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.085 g, 75%) as yellow solid, which was used directly in the next step. TLC (eluting with 25% EtOAc in petroleum ether) Rf=0.4.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[O:16][CH2:15][CH2:14][C:13]3=[O:20])=[CH:6][CH:5]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O.N1CCCC1>C(O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[C:14]1[C:13](=[O:20])[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=3)[CH:11]=2)[O:16][CH2:15]1
Reactant: O=C1CCOc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Reactant: O=Cc1ccccn1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1C(=Cc2ccccn2)COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21

Procedure:
A solution of 400 mg 6-(4-(trifluoromethoxy)phenyl)chroman-4-one (1.3 mmol, 1.0 eq), 150 μL 2-pyridine carboxaldehyde (1.6 mmol, 1.2 eq) and 130 μL pyrrolidine (1.6 mmol, 1.2 eq) in 10 mL ethanol was refluxed 3 h. The reaction was concentrated and purified on silica gel column eluting with EA:Hex. 160 mg of a yellow solid was collected. m/z=398.0
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=2)[C:28](O)=[O:29])[CH:24]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=2)[C:28]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH2:13][C:14](=[O:18])[NH:15]4)=[CH:11][CH:10]=3)[CH:3]=2)=[O:29])[CH:24]=1
Reactant: Nc1cccc(Nc2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
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
Solvent: CCOC(C)=O
Product: Cc1cn(-c2cc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(3-Amino-phenylamino)-1,3-dihydro-indol-2-one (36 mg, 0.15 mmol) and 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoic acid (53 mg, 0.195 mmol) in DMF (1.5 mL) is added N,N-diisopropylethylamine (78 μL, 0.45 mmol) followed by addition of HATU (63 mg, 0.165 mmol). The mixture is stirred at ambient temperature overnight. The mixture is diluted with EtOAc and washed with 10% Na2S2O3 aqueous solution and brine. The organic layer is separated, dried over MgSO4, and concentrated. The crude product is used in the next step without further purification: LC-MS: 492.1 (MH+).
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O.[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18].FC(F)(F)C(O)=O.[OH-].[Na+]>C(O)C.O>[N:23]1([CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[CH:3]=[CH:4][C:5]2[CH2:13][C:12]3[C:7]([C:6]1=2)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: COC(CC1Cc2ccccc2C1=O)OC
Reactant: CC(=O)NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCn1ccc2c1-c1ccccc1C2
Yield: 21.6 %

Procedure:
A solution of 1.7 g of (RS)-2-(2,2-dimethoxyethyl)-1-indanone, 25 g of N-acetylethylenediamine and 30 ml of trifluoroacetic acid in 500 ml of ethanol was boiled under reflux for 96 hours. After cooling and adding 21.5 g of sodium hydroxide in 100 ml of water, the mixture was evaporated to about 100 ml. The mixture was treated with 200 ml of ethyl acetate and washed in succession with 100 ml of saturated sodium chloride solution, 1N hydrochloric acid (4×100 ml), 2N sodium hydroxide solution (4×100 ml) and 100 ml of water. The aqueous washings were extracted with 100 ml of ethyl acetate and the organic phases were combined, dried with magnesium sulfate and evaporated in a vacuum. The residue was purified on basic aluminum oxide (III, dichloromethane) and then on silica gel (ethyl acetate). 0.4 g (22%) of N-[2-(1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-ethyl]-acetamide was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH3:20][NH:21][O:22][CH3:23].C1C=CC2N(O)N=NC=2C=1.CNC(N=C=NCC)CCNC>C(Cl)Cl.CCOC(C)=O>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16](=[O:18])[N:21]([O:22][CH3:23])[CH3:20])([CH3:1])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Agent: CCN=C=NC(CCNC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of Boc-D-cyclohexylglycine (10 g, 39 mmol) in DCM (200 mL), N,O-dimethylhydroxyamine HCl salt (4.6 g, 46 mmol), HOBT (7 g, 51 mmol), and TEA (11 mL) were added followed by addition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 10 g, 51 mmol). The reaction mixture was allowed to warm to room temperature and then stirred overnight. EtOAc (300 mL) was added. The resulting solution washed with aqueous citric acid solution, aqueous NaHCO3 solution, and aqueous NaCl solution. The organic layer was separated, dried with MgSO4, and then evaporated to yield [cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester as a colorless oil, which was used in the next step without further purification.