Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].Br[C:12]1[C:16]([Br:17])=[CH:15][S:14][C:13]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=O>CN(C)C=O>[Br:17][C:16]1[C:12]([S:10][CH2:7][CH2:8][CH3:9])=[C:13]([CH2:18][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[S:14][CH:15]=1
Reactant: O=C(c1cccs1)c1scc(Br)c1Br
Reactant: CCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1c(Br)csc1Cc1cccs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cloudy solution of 80 mL of dimethylformamide containing 3.7 g of potassium-t-butoxide, under a nitrogen blanket and cooled to 0°,was added 3.0 mL of n-propanethiol. This mixture was stirred for 5 minutes and then 12 g of the product of Example 8 was added in one portion. After stirring for 3 hours at room temperature, the mixture was poured into 400 mL of ice-water and extracted with methylene chloride. The organic layer was washed with 1N NaOH (aq), water and dried (MgSO4). Filtration and concentration of the filtrate in vacuo afforded 7.5 g of the subject compound as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15]Br)[CH:5]=1.CC([O-])=[O:21].[K+].CO>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15][OH:21])[CH:5]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cccc(-c2nc(C)sc2CBr)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cccc(-c2nc(C)sc2CO)c1
Reaction time: 0.5 h

Procedure:
3-(5-bromomethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester was stirred in DMF (16 mL) together with KOAc (2.35 g) at 20° C. for 20 min. MeOH (32 mL) and naOMe (0.86 g) were added and stirring was continued at 50° C. for 30 min. The mixture was partitioned between AcOEt and brine and the organic layer was dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt/hexane (1:1) as eluent to give 3-(5-hydroxymethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester (2.93 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[S:8][CH:9]=1)=[O:4].O.O.[OH-].[Li+]>O1CCCC1>[C:14]([O:13][C:11]([NH:10][C:7]1[S:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
2-tert-Butoxycarbonylamino-thiazole-4-carboxylic acid methyl ester (15.5 g, 60.01 mmol) was dissolved in 4:1 tetrahydrofuran:water (300 mL) followed by the addition of lithium hydroxide monohydrate (5.29 g, 126.07 mmol). The solution was stirred overnight at room temperature. Tetrahydrofuran was removed under vacuum and the salt was neutralized with 2.0 N aqueous hydrochloric acid. The resulting precipitate was filtered and dried to give 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid (10.4 g, 71%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[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.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1ccc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
To a suspension of 4,5-diphenylimidazole (500 mg, 2.27 mmol) in 5 mL CH2Cl2 at rt were added TEA (348 μL, 2.50 mmol) and trityl chloride (664 mg, 2.38 mmol). The mixture was stirred at rt for 18 h, then was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 692 mg of Intermediate 19.1 as a pale green solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:37][C:38]([CH3:40])=[CH2:39]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([CH2:39][C:38]([CH3:40])=[CH2:37])[C:22]([O:24][CH3:25])=[O:23]
Reactant: C=C(C)CBr
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-(4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (60 mg, 0.179 mmol) in tetrahydrofuran (THF) (2 mL) was treated with LiHMDS (0.447 mL, 0.447 mmol, 1.0M in THF) and 3-bromo-2-methylpropene (0.271 mL, 2.68 mmol) at 0° C. The mixture was stirred at room temperature for 1 hour and then quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was used crude in the next step (65 mg, 94%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.43-8.56 (m, 1 H) 7.40-7.57 (m, 2 H) 7.09-7.20 (m, 1 H) 6.95-7.08 (m, 2 H) 6.78-6.86 (m, 1 H) 4.68-4.75 (m, 1 H) 4.44-4.54 (m, 1 H) 3.91-4.03 (m, 1 H) 3.68 (s, 3 H) 3.53 (s, 3 H) 2.40 (br. s., 3 H) 2.04 (s, 3 H) 1.59-1.68 (m, 2 H) 1.49 (br. s., 3 H). LC/MS (m/z) ES+=390 (M+1).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([OH:17])[CH3:16])[C:7]=1[C:8]([OH:10])=[O:9])([O-])=O.O.NN>>[NH2:3][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([OH:17])[CH3:16])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)c1cccc(N)c1C(=O)O
Yield: 97 %

Procedure:
0.75 mol of aqueous sodium hydroxide solution (30%) are added to an aqueous solution of 0.5 mol of 2-nitro-6-(1-hydroxyethyl)-benzoic acid (sodium salt), and, at 90-95° C., 50 g of hydrazine hydrate (1.0 mol) are metered in over the course of 1 hour. Stirring is carried out at 90-95° C. for 4-6 hours until the nitro compound has been completely converted and, after isolation, 2-amino-6-(1-hydroxyethyl)-benzoic acid (sodium salt) is obtained in a yield of 97% of theory, based on 2-acetyl-6-nitrobenzoic acid (LC analysis).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([O:31][C:32]([NH:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.O1CCOCC1>[C:27]([O:31][C:32]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:39][NH:40][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:41][CH:42]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 89.3 %

Procedure:
Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.32 g, 0.76 mmol) with a solution of 4-(tert-butoxycarbonylamino)-benzylamine (0.338 g, 1.524 mmol) in anhydrous toluene/dioxane (4:1, 10 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:1 gradient over 30 min; 3:1 over 3 min; 3:1 to 1:1 gradient over 30 min and 1:1 over 3 min; 35 mL/min) to obtain the desired intermediate as a yellow oil (0.338 g, 89%). MS (ES+) m/z: 498.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][CH2:22][C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH2:24])[CH:9]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:43](Cl)([O:45]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]2[CH2:22][C@@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:24][C:43]2=[O:45])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC[C@H](N)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C[C@@H](c2ccccc2)NC1=O
Reaction time: 0.75 h

Procedure:
A solution of (1R)—N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine (96.0 mg, 0.22 mmol) in CH2Cl2 (15 mL) was cooled to 0° C. and DIPEA (230 μL, 1.32 mmol) was added followed by triphosgene (32.6 mg, 0.11 mmol). After 45 minutes, the reaction was poured into saturated NaHCO3 (25 mL). The mixture was extracted with EtOAc (75 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 10 to 60% EtOAc/hexanes afforded (4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl)}4-phenylimidazolidin-2-one. The minor enantiomer was removed by chiral HPLC using an AD chiral column and 15% IPA/heptanes to afford enantiomerically pure product. Rf=0.16 (40% EtOAc/hexanes). LCMS=469.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) (atropisomers present in 1:1 ratio, doubling of some peaks observed) δ 7.65 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.21-7.36 (m, 7H), 6.87-6.94 (m, 2H), 4.65-4.77 (m, 2H), 4.10-4.49 (m, 2H), 3.71 & 3.72 (2 singlets, 3H), 3.49-3.53 (m, 1H), 2.94-2.97 (m, 1H), 2.87 (m, 1H), 1.19-1.24 (m, 6H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][C@@H:4]2[CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:1][C@@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:9][C@@H:4]3[CH2:3]2)=[CH:21][CH:20]=1
Reactant: Oc1ccc(F)cc1
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(O[C@H]2C[C@H]3CN(Cc4ccccc4)CCN3C2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.3 %

Procedure:
A solution of 0.971 g (4.18 mmol) of (7R,8aS)-7-hydroxy-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Diafi, L. et al., J. Het. Chem., 1990, 27, 2181), 0.703 g (6.27 mmol) of 4-fluorophenol and 1.32 g (5.02 mmol) of triphenylphosphine in 20 mL of dry THF was treated with 0.79 mL (5.02 mmol) of diethyl azodicarboxylate and the solution stirred at room temperature for 21 hours. Excess HCl (g) in diethyl ether was added, the precipitate was collected on a Buchner funnel, washing with ethyl acetate. The gummy residue was dissolved in a mixture of ethyl acetate and aqueous ammonium hydroxide, the layers were separated, the aqueous phase was extracted with more ethyl acetate (2×), the combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by silica gel MPLC with 95:5 ethyl acetate:methanol gave 1.3 g (95%) of (7S,8aS)-7-(4-fluorophenoxy)-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[C:10]([N+:17]([O-])=O)=[C:11]([O:15][CH3:16])[CH:12]=[CH:13][CH:14]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O>[NH2:6][C:9]1[C:10]([NH2:17])=[C:11]([O:15][CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(N)c1N
Temperature: 25 °C
Yield: 71.1 %

Procedure:
Tin(II)chloride dihydrate (11.9 g, 52.6 mmol) was added to a solution of the above dinitroanisole (2.21 g, 8.76 mmol) in EtOAc (30 mL). The mixture was heated to reflux for 0.25 h upon which the solution became red in color. The solution was cooled to room temperature and poured onto aqueous 2.0 M NaOH. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with saturated aqueous NaHCO3. The organic layers were dried over sodium sulfate, eluted through a plug of silica gel (1% ammonium hydroxide in methylene chloride), and the filtrate was concentrated. The residue was dissolved in diethyl ether and extracted (3×) with 1.0 M HCl. The pH of the combined aqueous layers was adjusted to pH=12 with 2.0M NaOH and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated to provide diaminoanisole (860 mg, 52%) as a red oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]#[N:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:27][OH:28]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]([NH2:18])=[N:27][OH:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1

Procedure:
Benzyl-(2S,4S)-2-cyano-4-fluoropyrrolidine-1-carboxylate dissolved in absolute ethanol was treated with triethyl amine (1.5 eq.) and hydroxylamine hydrochloride (1.3 eq.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:15]([F:16])=[CH:14][C:10]([C:11]([O-:13])=O)=[C:9]([O:17][CH2:18][O:19][CH3:20])[CH:8]=1.[Li+].[NH2:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([NH2:30])=[O:29]>N1C=CC=CC=1>[Cl:6][C:7]1[C:15]([F:16])=[CH:14][C:10]([C:11]([NH:22][C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28]([NH2:30])=[O:29])=[O:13])=[C:9]([O:17][CH2:18][O:19][CH3:20])[CH:8]=1
Reactant: NC(=O)c1sccc1N
Reactant: COCOc1cc(Cl)c(F)cc1C(=O)[O-]
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COCOc1cc(Cl)c(F)cc1C(=O)Nc1ccsc1C(N)=O
Reaction time: 1 h

Procedure:
n-butyllithium was added to a diethyl ether solution of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene in a dry ice-acetone bath and stirred for one hour. The reaction solution was added to a mixture of dry ice and diethyl ether and stirred for two hours to give lithium 4-chloro-5-fluoro-2-(methoxymethoxy)benzoate. Phosphorus oxychloride was added to a mixture of the obtained lithium 4-chloro-5-fluoro-2-(methoxymethoxy)benzoate, 3-aminothiophene-2-carboxamide and pyridine in a MeOH ice bath and stirred for one hour to give 3-{[4-chloro-5-fluoro-2-(methoxymethoxy)benzoyl]amino}thiophene-2-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.[CH3:17][O:18][C:19]([C:21]1(OC)[CH2:25][CH2:24][CH:23](OC)O1)=[O:20].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:17][O:18][C:19]([C:21]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]3)[CH:23]=[CH:24][CH:25]=1)=[O:20]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]

Procedure:
7 g (27.1 mmol) of 6-amino-7-nitro-2,3(1H,4H)-quinoxalinedione, 5.1 g (27.1 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran and 4.5 g (54.2 mmol) of sodium acetate in 500 ml of glacial acetic acid were refluxed for one hour. The reaction mixture was concentrated and then the crude product was purified by column chromatography on silica gel (mobile phase: toluene/acetone/glacial acetic acid=10/10/1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](F)[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+].S(=O)(=O)(O)[O-].[K+]>CS(C)=O>[CH2:17]([O:24][C:25]1[N:26]=[C:27]([O:16][C@H:10]2[CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11]2)[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Reactant: Fc1cccc(OCc2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(OCc3ccccc3)n2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A 500 mL 3-neck round bottom flask under nitrogen was charged with Boc-L-4-hydroxyproline (Chem Impex) (2.00 g, 8.65 mmol) and DMSO (80 ml). Attached an addition funnel containing a solution of the product of Step 1 (1.758 g, 8.65 mmol) in DMSO (10 ml). Cooled reaction in an ice bath to +18° C. Added potassium-t-butoxide (2.91 g, 25.9 mmol) slowly keeping the internal temperature<20° C. Stirred 45 minutes at room temperature. Cooled to 15° C. Added contents of addition funnel dropwise. Warmed to room temperature. Stirred 1.5 hours. Poured into 2.5% potassium bisulfate. Extracted three times with ethyl acetate, washed combined organic portions with water then brine, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate to give the title compound as a white foam. (3.58 g, 8.65 mmol, 100% yield). LCMS (ES+) m/z 415.3 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]([CH3:24])([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH3:9])(=O)=O.[CH3:25][N:26](C=O)C.[C-]#N.[Na+]>O>[CH3:9][C:8]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)([CH3:24])[CH2:7][CH2:6][C:25]#[N:26]
Reactant: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ncnc3[nH]ccc23)cn1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CC(C)(CCC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 125 °C
Yield: 59 %

Procedure:
3-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (2.97 g, 8.50 mmol), DMF (120 mL) and sodium cyanide (6.21 g, 0.127 mol) were distributed evenly into six 20 mL microwavable vessels, each of which was heated in the microwave reactor for 4000 seconds at 125° C. The contents of the vials were combined and were diluted with 400 mL water and extracted with five 150 mL portions of ethyl acetate. The combined extracts were dried over sodium sulfate, and the solvent was removed in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.40 g, 59%).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=O)=[CH:16][C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.Cl.[Cl:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH:41]=[C:40]([S:45]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46])[CH:39]=[CH:38]2>>[ClH:34].[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:51]3[CH2:50][CH2:49][N:48]([S:45]([C:40]4[CH:39]=[CH:38][C:37]5[C:42](=[CH:43][CH:44]=[C:35]([Cl:34])[CH:36]=5)[CH:41]=4)(=[O:47])=[O:46])[CH2:53][CH2:52]3)=[O:19])=[CH:16][C:11]=2[NH:10][CH:9]=1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: COC(=O)c1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=C(c1ccc2nc[nH]c2c1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 3, 4 or 10 except for the use of methyl N-triphenylmethyl-5-benzimidazolecarboxylate and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])=[N-].S(=O)(=O)(O)[OH:32]>O1CCOCC1.O>[C:4]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH2:3][OH:32]
Reactant: O=S(=O)(O)O
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)C=[N+]=[N-])OC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)CO)OC(C)=O
Yield: 96 %

Procedure:
A clear, yellow solution of ethyl 8-diazoacetyl-12-acetoxyheptadecanoate (8.4 g., 0.02 mole) in dioxane (50 ml.) is vigorously stirred at 20° and treated with 2N sulfuric acid (30 ml.) added dropwise over 5 minutes. The resulting turbid solution is warmed to and maintained at 65° for 30 minutes. The reaction solution is cooled to 20°, diluted with water to a total volume of one liter and extracted with ether (5 × 200 ml.). The organic extract is washed with water (2 × 200 ml.), 5% aqueous sodium bicarbonate (200 ml.), water (200 ml.), and saturated brine (2 × 200 ml.), dried over sodium sulfate and filtered. Evaporation (in vacuo at 40°-65°) of the filtrate gives the title compound as a deep yellow oil (7.9 g., 96%), pmr (CDCl3) δ 0.86 (3H,t), 1.28 (27H,e), 2.0 (3H,s), 2.25 (3H,t), 3.36 (H,b), 4.10 (2H,q), 4.21 (2H,s) and 4.84 (H,b).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]#N)[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C[OH:46]>ClCCl.O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[CH:32]=[O:46])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C=O)c1Cl)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-cyanopyrrole (2.44 g) in dichloromethane (25 ml) was added diisobutylaluminum hydride (1.5 M solution in toluene, 4.9 ml) under nitrogen atmosphere in water bath, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was cooled in ice water bath, and to the mixture were added dropwise methanol (1 ml) and water (1 ml). The mixture was stirred for 1 hour, quenched with 1N sodium hydroxide solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (20:1, V/V) to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-formylpyrrole (1.9 g) as an oil.