Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])C.C(=O)(O)O.[NH2:20][C:21]([NH2:23])=[NH:22]>C(O)C>[NH2:22][C:21]1[NH:23][C:4](=[O:3])[CH:5]=[C:6]([CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[N:20]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Agent: O=C(O)O
Solvent: CCO
Product: CCOC(OCC)c1cc(=O)[nH]c(N)n1

Procedure:
A solution of 4,4-diethoxy-3-oxo-butyric acid ethyl ester [Johnson, T. B. and Mikeska, L. A. J. Am. Chem. Soc. 41, 810 (1919)] (18.0 g, 82.5 mol) in ethanol (300 mL) was treated with guanidine carbonate (14.8 g, 82.5 mol) and this was stirred under reflux until no solid remained (˜4 hours). The mixture was concentrated, diluted with water and the solid was collected by filtration to give D1.1 (13.1 g, 74%) as a beige solid. 1H-NMR (DMSO-d6) δ: 10.78 (1H, br s), 6.61 (2H, br s), 5.63 (1H, s), 4.90 (1H, s), 3.51 (4H, m), 1.13 (6H, t, J=7.1 Hz). LC/MSc: ret. time: 0.757 min. (M+H)+: 214. M.p.: 198.0–202.7° C.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:9][N:8](C(=O)C(F)(F)F)[CH2:7][CH2:6][N:5]1[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O>[O:3]=[C:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a stirring solution of sodium hydroxide (1.38 g, 34.5 mmol), and H2O (5.0 mL), at 0° C., was added 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (5.0 g, 11.5 mmol) portionwise over 10 minutes. The mixture was stirred at ambient temperature for 30 minutes. The solution was cooled to 0° C. followed by the addition of 1.0 N HCl aqueous solution (34.5 mL, 34.5 mmol). The light yellow solution was azeotroped with MeOH (4×100 mL) at <30° C. The obtained solid was suspended in 50% MeOH in CH2Cl2 (200 mL) and stirred for 5 minutes. The mixture was filtered and the filtrate was evaporated to give the desired amine as light yellow solid (2.5 g, 7.4 mmol, 64% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=339.3; tR=0.51 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[C:13]([CH3:15])[C:12](I)=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:32]=[O:33].[ClH:35]>C1(C)C=CC=CC=1>[ClH:35].[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[C:10]([CH3:17])=[CH:11][C:12]([CH:32]=[O:33])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1I
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C=O
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a 1-liter 3-necked round-bottomed flask equipped with an overhead stirrer, temperature control and an addition funnel was added dibenzyl-(4-iodo-2,5-dimethylphenyl)amine (15 g, 35 mmol). Toluene (300 mL) was added and the resulting mixture was stirred for about 15 minutes. The reaction flask was purged with dry nitrogen and cooled to about −20° C. and 1.6 M n-butyllithium in hexanes (33 mL, 53 mmol) was added dropwise via the addition funnel. During the addition, the internal temperature of the reaction mixture was maintained below −10° C. When the addition was complete, the resulting mixture was stirred at about −15° C. for 15 minutes. N,N-Dimethylformamide (10 mL, 129 mmol) was then added dropwise while maintaining the internal reaction temperature below 0° C. The resulting mixture was then stirred at −20° C. to 0° C. for about 1 hour. Aqueous 1 M hydrochloric acid (200 mL) was then added over a 5 minute period and the resulting mixture was stirred for 15 minutes. The layers were then separated and the organic layer was washed with dilute brine (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide 4-dibenzylamino-2,5-dimethylbenzaldehyde hydrochloride (11.5 g, 90% yield, 95% purity) as thick oil that solidified upon standing. The product contained about 3 to 5% of the des-iodo by-product. 1H NMR (300 MHz, CDCl3) δ 2.42 (s, 3H), 2.50 (s, 3H), 4.25 (s, 4H), 6.82 (s, 1H), 7.10-7.30 (m, 10H), 7.62 (s, 1H), 10.15 (s, 1H); MS [M+H+] found 330.3.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[CH:9][CH:10]=1)[CH3:3].CC(C)([O-])C.[K+].Cl.Cl[CH2:23][CH2:24][NH2:25]>CN(C)C=O>[NH2:25][CH2:24][CH2:23][O:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)Cc1cccc(CCCO)c1
Reactant: NCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc(CCCOCCN)c1
Reaction time: 24 h
Yield: 6.1 %

Procedure:
A suspension of 3-[(N,N-dimethylamino)methyl] benzene propanol (2.5 g), potassium tertiary butoxide (0.56 g), 2-chloroethylamine hydrochloride (0.59 g) in dimethylformamide (10 ml) was stirred at 0°-5° under a nitrogen atmosphere for 24 h. The mixture was poured onto water (1 1) and extracted with ethyl acetate. The organic extract was evaporated to leave a yellow oil which was purified by column chromatography using methanol followed by methanol: 0.880 ammonia; (20:1) to give the title compound as a brown oil (73 mg). T.l.c. system B Rf 0.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][OH:11].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14]>C1COCC1>[C:13](=[O:14])([O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)[O:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cc2ccccc2o1
Solvent: C1CCOC1
Product: O=C(OCc1cc2ccccc2o1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of benzofuran-2-ylmethanol 59 (300 mg, 2.03 mmol) in THF (5 mL) was cooled to 0° C. TEA (280 μL, 2.03 mmol) was added dropwise followed by the portionwise addition of p-nitrophenyl chloroformate (282 mg, 3.05 mmol). The resulting solution was stirred at room temperature for 2 h. Solvent was evaporated off in vacuo and the crude residue was purified by flash chromatography, eluting with hexane:EtOAc (3:1) to give 60 (350 mg, 54%) as a white solid. H1 NMR (500 MHz, CDCl3): δ=8.31 (2H, m, ArH), 7.62 (1H, d, J=7.70 Hz, ArH), 7.54 (1H, d, J=7.70 Hz, ArH), 7.43-7.27 (3H, m, ArH), 7.29 (1H, t, J=7.72 Hz, ArH), 6.93 (1H, s, ArH), 5.43 (2H, s, CH2). 13C NMR CDEPT 135, (500 MHz, CDCl3): δ=125.47, 125.37, 123.23, 121.80, 121.66, 111.60, 108.53, 62.95.
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([OH:12])=[O:11].[CH3:19]O>>[CH3:19][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:7]([F:6])[CH:8]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 18 h

Procedure:
A 1 L round bottom flask equipped with a stir bar and reflux condenser was charged H2SO4 (4 mL), methanol (400 mL) and 3-fluoro-4-nitrobenzoic acid (10 g). The reaction mixture was heated at reflux temperatures with vigorous stirring for 18 h. The methanol was removed and the crude residue was triturated with hexane and concentrated to give a colorless solid (9.79 g) that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(O)cccc1OCCCCl
Temperature: 70 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
To a solution of 2′,6′-dihydroxy-acetophenone (500 mg, 3.28 mmol) in dimethylformamide (20 ml) were added potassium carbonate (680 mg, 4.93 mmol) and 1-bromo-3-chloropropane (0.34 ml, 3.45 mmol) and the mixture was stirred at 70° C. for 4 h. Water was added and the organics were extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-15%) to yield 6′-(3-chloropropoxy)-2′-hydroxy-acetophenone (348 mg, 46%) as a pale yellow solid. To a solution of 6′-(3-chloropropoxy)-2′-hydroxy-acetophenone (345 mg, 1.50 mmol) in acetonitrile (15 ml) was added potassium carbonate (416 mg, 3.0 mmol) and morpholine (0.396 ml, 4.52 mmol). The mixture was stirred for 18 hours at room temperature then 60° C. for 3 days. Water was added and the organics were extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography over silica gel (gradient ethyl acetate/methanol: 0-10%) to yield 2′-hydroxy-6′-(3-morpholino-4-yl-propoxy)-acetophenone (171 mg, 40%) as an orange oil that solidified.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[N+:14]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2)([O-:16])=[O:15]>>[CH2:1]([C:3]1([C:22]2[C:21]3[C:25](=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=[CH:19][CH:20]=3)[NH:24][CH:23]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Reactant: CCC1(O)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3c([N+](=O)[O-])cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-nitroindole, the title compound is prepared as in example 1. 0.37 g (42%). NMR (400 MHz, CDCl3): δ 0.85 (t, 3H), 2.18 (m, 2H), 2.35 (m, 1H), 2.53 (m, 1H), 3.00 (m, 2H), 6.83 (t, 1H), 6.92 (t, 1H), 7.01 (m, 2H), 7.08 (s, 1H), 7.44 (d, 1H), 8.09 (d, 1H), 9.76 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.FC(F)(F)S([O:43][S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])(=O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:43][S:44]([C:47]([F:48])([F:49])[F:50])(=[O:45])=[O:46])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(OS(=O)(=O)c4ccc(C)cc4)c(F)cc3c1=O)CCN2C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn2c3c(c(OS(=O)(=O)C(F)(F)F)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.8 g of the compound (169) obtained in Example 46 was added to 10 ml of pyridine, and while cooling on ice, 2.35 ml of trifluoromethanesulfonic anhydride was added to the solution through 20 minutes. The solution was stirred for 24 hours at room temperature. 200 ml of chloroform was added to the solution, and the solution was washed with aqueous 5% citric acid solution. The organic layer was separated and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and purified by column chromatography (silica gel, eluent solvent; chloroform: ethyl acetate=1:1). The solid matter was filtered off and washed with isopropyl ether to obtain 1.2 g of the subject compound (170).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[O:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])([CH3:4])([CH3:3])[CH3:2].[Cl-].C([NH+](CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+].Cl>O.CN1CCCC1=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:32][N:31]=[N:30][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(OCCCC#N)cc(C(C)(C)C)c1O
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)c1cc(OCCCc2nnn[nH]2)cc(C(C)(C)C)c1O
Temperature: 150 °C
Yield: 26.7 %

Procedure:
Under a nitrogen atmosphere a mixture of 8.66 g (0.030 mole) of 4-(3,5-di-t-butyl-4-hydroxyphenoxy)butyronitrile, 6.42 g (0.047 mole) of triethylammonium chloride, 5.79 g (0.089 mole) of sodium azide and 250 ml of 1-methylpyrrolidinone was heated about 150° C. for about 72 hours. The reaction mixture was poured into water. The pH was adjusted to pH 1 with 10% hydrochloric acid and then the mixture was extracted eight times With 100 ml portions of diethyl ether. The diethyl ether extracts were combined, washed with brine, dried over magnesium sulfate and then evaporated to provide a yellow orange oil. The oil was purified by silica gel chromatography eluting with 2:1 hexane:acetone containing 3 ml of acetic acid per 2000 ml of solvent, followed by recrystallization from a mixture of ethyl acetate and hexane to provide 2.66 g of 5-[3-(3,5-di-t-butyl-4-hydroxyphenoxy)propyl]tetrazole as a white solid, m.p. 179°-180° C. Analysis: Calculated for C18H28N4O2 : %C, 65.0; %H, 8.5; %N, 16.8; Found: %C, 65.3; %H, 8.5; %N, 16.8.
Reaction SMILES: [Br-].[Li+].BrCC=CCBr.[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10].C=CC=C.O=O.C(OC(C=C)C)(=O)C.[C:30]([O:33][CH2:34][CH:35](OC(=O)C)[CH:36]=[CH2:37])(=[O:32])[CH3:31].C(OCC=CCOC(=O)C)(=O)C>C(O)(=O)C>[C:9]([O:12][C:34]([O:33][C:30](=[O:32])[CH3:31])=[CH:35][CH2:36][CH3:37])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(COC(C)=O)OC(C)=O
Agent: BrCC=CCBr
Agent: C=CC(C)OC(C)=O
Agent: C=CC=C
Solvent: CC(=O)O
Product: CCC=C(OC(C)=O)OC(C)=O
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 22 %

Procedure:
Another run was conducted according to the process of this invention in the same apparatus employed in the previous runs. In this run, the reactor was charged with 5.0 grams of a finely ground tungstic oxide (WO3) on silica catalyst (8 percent by weight WO3, 1.7 mmol WO3), 6.5 grams (75 mmol) lithium bromide, 4.6 grams (22.5 mmol) 1,4-dibromo-2-butene, 50 ml acetic acid, 25 ml acetic anhydride and 12.5 grams (231.5 mmol) butadiene from the vapor phase. The reactor was pressured to 30 psig with oxygen, placein in an oil bath and heated to 140° C. After about 45 minutes required to reach the reaction temperature, the reaction was conducted for 5 hours. At the end of the reaction period, the reactor was opened and the unreacted butadiene distilled into a Dry Ice/acetone cold trap which recovered 1.3 grams butadiene. The reaction mixture was filtered and the filtrate distilled under reduced pressure. The middle fraction of the three taken was found to contain 26.8 mmol of 3-buten-2-yl acetate, 9.7 mmol 1,2 -diacetoxy-3-butene and 42.6 mmol 1,4-diacetoxy-2-butene for a diacetoxybutene yield of 22 percent based on the butadiene charged. Surprisingly, the yield of monoacetoxy butene was 27 percent based on the butadiene charged.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:22])[N:3]=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.[CH2:65]([NH:67][CH3:68])[CH3:66]>CC(=O)OCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:65]([N:67]([CH3:68])[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:22])[N:3]=1)[CH3:66]
Reactant: CCNC
Reactant: Cc1cc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Product: CCN(C)c1cc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)cc(C)n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (549 mg, 1.74 mmol) and Na tert.-butylate (346 mg, 3.60 mmol) in ethyl-methylamine (10 mL), Xantphos (106 mg, 0.18 mmol) and Pd(OAc)2 (47 mg, 0.21 mmol) is added. The mixture is stirred in an autoclave at 80° C. for 24 h. The dark mixture is cooled to rt, diluted with EA (200 mL), washed three times with sat. aq. NaHCO3-solution, dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with EA containing 20% of methanol to give 4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenol (119 mg) as a yellow solid; LC-MS: tR=0.83 min; [M+1]+=339.10; 1H NMR (D6-DMSO): δ 1.12 (m, 3H), 2.26 (s, 6H), 2.43 (s, 3H), 2.88-2.98 (m, 2H), 3.07 (s, 3H), 7.00 (s, 1H), 7.08 (s, 1H), 7.67 (s br, 1H), 7.68 (s, 1H), 8.94 (s br, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:15]1[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][N:16]=1.O>CS(C)=O>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:23])[CH3:24])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: CC(C)Oc1cc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 92.9 %

Procedure:
383 mg of potassium carbonate and 185 mg of 1-methylpiperazine are added to a solution of 400 mg of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridine in 3.7 ml of DMSO. The reaction medium is heated for 1 hour at 105° C. After cooling, the mixture is run into water, extracted with ethyl acetate, washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in diisopropyl ether, and the insoluble material is filtered off and dried under vacuum, so as to give 481 mg of 1-methyl-4-[5-nitro-4-(propan-2-yloxy)pyridin-2-yl]piperazine in the form of an orangey-coloured solid.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5](=[O:22])[C@@H:6]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][C:8](Cl)=[O:9]>CCOCC.C1COCC1.[Cu]I>[CH3:3][O:4][C:5](=[O:22])[C@@H:6]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][C:8](=[O:9])[CH3:1]
Reactant: [Li]C
Reactant: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)[C@H](CC(C)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
To a cooled to 0° C. suspension of copper (I) iodide in ether (20 mL) under N2 is slowly added methyl lithium (1.6 M solution in ether, 21.3 mmol, 13.3 mL). The mixture is stirred at 0° C. for 10 min then cooled to −78° C. A solution of 3.55 mmol of (S)-2-Benzyloxycarbonylamino-3-chlorocarbonyl-propionic acid methyl ester (Ref: Synth. Comm 1993, 23(18), 2511-2526) in 12 mL of dry THF is added drop wise. The mixture is stirred at −78° C. for 30 min then quenched by adding methanol (2 mL). The mixture is poured into saturated NH4Cl (80 mL) and extracted with ether (2×40 mL). The organic layers are dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 35 g silica gel, eluted with EtOAc:Heptane (1:1) to afford (S)-2-benzyloxycarbonylamino-4-oxo-pentanoic acid methyl ester (261 mg, 26%).
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][N:19]=4)=[O:17])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=4)=[O:17])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4(C)CCC3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCCc3cc(NC(=O)c4ccc(C(=O)O)cn4)cc(c31)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A suspension of methyl 6-[(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carbamoyl]nicotinate (0.176 g) in ethanol (10 ml) was added with 2 N aqueous sodium hydroxide (2 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.153 g, yield: 91%) as pale yellow needles (melting point: 212-213° C.).
Reaction SMILES: [I-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH2:7].[O:8]([CH2:16][CH2:17]Br)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(O)C>[O:8]([CH2:16][CH2:17][NH:7][CH2:6][CH2:5][O:4][CH3:3])[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COCCN
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: COCCNCCO[Si](C)(C)C(C)(C)C
Yield: 55 %

Procedure:
Sodium iodide (14.48 g) is added to a solution of 2-methoxyethylamine (14 ml) and 2-(t-butyldimethylsiloxy)ethyl bromide (7.00 g) in ethanol (65 ml), and the mixture is refluxed overnight with stirring. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the whole is extracted with chloroform. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 4.13 g (55%) of the titled compound (Reference compound No. 14-1).
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)([OH:3])=O.[C:14]([O:18][C:19](=[O:32])[NH:20][CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][C@H:23]1[NH2:31])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:14]([O:18][C:19](=[O:32])[NH:20][CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][C@H:23]1[NH:31][C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)=[O:3])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1c2ccccc2C[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.7 %

Procedure:
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 4, 472 mg, 2.0 mmol), tert-butyl[(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]methylcarbamate (Method 13; 524 mg, 2.0 mmol), DIPEA (348 μL, 2.0 mmol), HOBT (270 mg, 2.0 mmol) and EDCI (480 mg, 2.5 mmol) were dissolved in DCM (10 mL) and stirred at ambient temperature for 20 hours. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (50 mL), washed with water (3×25 mL), brine (25 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (900 mg, 93%) as a pale brown foam.