Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].O.Cl>CS(C)=O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])#[N:2]
Reactant: [C-]#N
Reactant: O=C(N(CCCCBr)c1ccc(O)cc1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCN(C(=O)C(F)(F)F)c1ccc(O)cc1
Temperature: 64 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
Sodium cyanide (17.2 g, 0.35 mol) was stirred mechanically in 325 mL DMSO under nitrogen and heated to 64° C. The 29.7 g of N-(4-bromobutyl)-N-(4-hydroxyphenyl)trifluoroacetamide in 125 mL of DMSO was dripped in over 13/4 hours. The reaction was stirred for two hours at 65°-72° C., cooled to -15° C., and poured into 3 L of ice and water. The cold mixture was immediately acidified with about 350 mL of 1N HCl and extracted three times with a total of 1.2 L of ethyl acetate. The ethyl acetate extracts were washed once with saturated sodium chloride solution and dried over magnesium sulfate. The solution was evaporated on a rotary evaporator to yield 11.5 g of N-(4-cyanobutyl)-N-(4-hydroxyphenyl)trifluoroacetamide.
Reaction SMILES: [Cl:1][C:2]([Cl:8])([Cl:7])[C:3](=[NH:6])OC.[N+:9]([C:12]1[CH:13]=[C:14](N)[C:15]([NH2:18])=[CH:16][CH:17]=1)([O-:11])=[O:10].O.C(OCC)(=O)C>C(O)(=O)C>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]2[N:18]=[C:3]([C:2]([Cl:8])([Cl:7])[Cl:1])[NH:6][C:14]=2[CH:13]=1)([O-:11])=[O:10]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2nc(C(Cl)(Cl)Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 6.3 g (35.9 mmol, 1.1 eq.) of methyl 2,2,2-trichloroethaneimidoate were added dropwise to a solution of 5.0 g (32.7 mmol) of 4-nitrobenzene-1,2-diamine in 150 ml of glacial acetic acid. The reaction mixture was stirred at RT for 3 h and then added to 400 ml of water, and 300 ml of ethyl acetate were added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed twice with in each case 130 ml of saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure and dried. The crude product was triturated with pentane and left to stand overnight. The solid was then filtered off, washed with pentane and dried under reduced pressure. Yield: 10.1 g (purity 77%, 85% of theory)
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[CH2:17]([OH:19])[CH3:18]>>[C:17]([NH:14][C:11]1[CH:12]=[CH:13][C:5]([Br:4])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:19])[CH3:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Reactant: CCO
Agent: Cl[Sn]Cl
Product: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
Tin(II) chloride (46.67 g, 206.84 mmol) was added portionwise to a solution of 2-bromo-5-nitro benzoic acid (12.71 g, 49.9 mmol) in dry ethanol (200 mL). The mixture was heated at 70° C. for 45 min, then ethanol was evaporated. The residue was cooled to 0° C., and acetic anhydride (43 mL) and pyridine (26 mL) were added. The solution was stirred at room temperature for 14 h and evaporated. The residue was partitioned between aq. 2M HCl and ethyl acetate (400 mL). The organic phase was washed with brine and dried over MgSO4. The residue from evaporation was crystallized from water to give 5-acetylamino-2-bromobenzoic acid (12.4 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][C:26]([OH:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH:10]([CH2:12][O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][C:26]([OH:35])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)[C:10](=[O:11])[CH2:12][O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=O)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 12 h
Yield: 75.1 %

Procedure:
Treat a solution of the alcohol from Step 1 (21.5 g, 39.8 mmol) in CH2Cl2 (600 mL) with PDC (22.5 g, 59.9 mmol). Stir the resulting black mixture for 12 h. Filter the reaction mixture through a plug of celite and wash plug with CH2Cl2 (200 mL) and EtOAc (200 mL). Concentrate the filtrate under reduced pressure to give the crude product as a black oil. Purify by silica gel chromatography (column: 10 cm ×24 cm; pack column in CH2Cl2 and elute using a gradient of 100% CH2 Cl2 to 5% CH3OH(NH3)/CH2Cl2) to obtain 16 g (29.9 mmol, 75%) of the title compound as a tan foam.
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[N:14][CH:13]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[Br:22][C:15]1[C:16]([C:18]([O:20][CH3:21])=[O:19])=[N:17][C:12]([NH:11][C@@H:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][C@@H:2]2[OH:1])=[CH:13][N:14]=1
Reactant: COC(=O)c1cncc(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of methyl 6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate (1.0 g, 3.5 mmol) in CH2Cl2 (35 mL) was added N-bromsuccinimide (0.69 g, 3.86 mmol). Stir at t for 2 hr. Wash the reaction with sat. aq. NaHCO3. The organic extract was dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 20% ethyl acetate/hexanes) to afford 380 mg (30%) of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate as a solid: 1H NMR (CDCl3) δ 3.01–3.06, 3.24–3.29, 4.00, 4.75–4.78, 5.45–5.46, 7.25–7.32, 7.94; MS (ESI+) for C15H14BrN3O3 m/z 386 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:35])[NH:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:35])[NH:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-({3-chloro-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.1015 g, 0.19 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature 2 h and evaporated. Isolate 0.127 g of crude product which was used without further purification.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:39](=[O:40])[NH:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is added to a solution of 72 mg (0.608 mmol) of phenyl isocyanate in 5 ml of toluene, and the reaction mixture is stirred at 100° for 2 hours. The white suspension is cooled and filtered. The title compound is obtained as white crystals of melting point 245° (decomposition). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.76, FD-MS: M+ =546.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.O[CH2:22][C:23]1[C:24](CO)=[C:25]([CH3:31])[C:26]([OH:30])=[CH:27][C:28]=1[CH3:29]>C1(C)C=CC=CC=1.C(O)(=O)C>[OH:2][C:1]1[CH:8]=[CH:7][C:6]([CH2:22][C:23]2[CH:24]=[C:25]([CH3:31])[C:26]([OH:30])=[CH:27][C:28]=2[CH3:29])=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1cc(O)c(C)c(CO)c1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(Cc2ccc(O)cc2O)c(C)cc1O
Temperature: 25 °C
Yield: 77.8 %

Procedure:
22.02 g of resorcinol, 1.90 g of p-toluene sulfonic acid, and 44.04 g of water are put in a 100 ml 4-necked flask, and 7.61 g of 4-hydroxymethyl(hydroxymethyl)-2,5-Xylenol is partly added thereto for one hour while maintaining at room temperature of 25° C. The mixture is reacted for 3 hours at the same temperature. Then, 50 g of acetic acid and 50 g of toluene are added to the reaction mass, separating a phase. The obtained organic layer is washed and concentrated. The obtained precipitate is filtered. The filtered product is rinsed with toluene, dried under reduced pressure for 24 hours, and treated through liquid chromatography, obtaining 7.94 g of 1,3-dihydroxy-4-(4-hydroxy-2,5-dimethyl benzyl)benzene having a purity of 99%.
Reaction SMILES: B(F)(F)F.CCOCC.[N:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]#[N:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.CO>C1COCC1>[N:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][NH2:23])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: N#CC1CCN(c2ccncc2)CC1
Agent: FB(F)F
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCC1CCN(c2ccncc2)CC1

Procedure:
At 0° C., BH3-DMS (1.089 ml, 11.336 mmol, 4 eq) and BF3-Et2O (355 4 2.83 mmol, 1 eq) were added to a solution of 1-(pyridin-4-yl)piperidine-4-carbonitrile (530 mg, 2.83 mmol, 1 eq) in THF (10 ml) and heated for 1 h at boiling temperature. The reaction mixture was hydrolyzed with MeOH (15 ml) and concentrated under reduced pressure. The white solid so obtained was used in the next stage without being purified further. Yield: quantitative
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].O[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([O:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:20][CH2:21]1
Reactant: OC(c1ccccc1)c1nc2ccccc2s1
Reactant: CN1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCC(OC(c2ccccc2)c2nc3ccccc3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of benzothiazol-2-ylphenylmethanol (0.36 g), 4-hydroxy-1-methylpiperidine (0.17 g) and para-toluenesulfonic acid (0.57 g) in toluene (22 mL) is heated overnight in a Dean-Stark apparatus. The mixture is cooled back to room temperature and poured into water, alcalinised with 1N sodium hydroxide and extracted twice with ethyl acetate. Pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 98/2 to 90/10) to give 2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole melting at 115° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(CO)ccc1Br
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(COc2ccccc2)ccc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
The product from Example 221a (0.5 g, 2.15 mmol) was combined with phenol (0.203 g, 2.15 mmol) and triphenylphosphine (0.735 g, 2.80 mmol) in anhydrous THF (7 mL) under nitrogen and the resulting solution cooled in an ice bath. To the cold solution was added dropwise diisopropylazodicarboxylate (0.467 mL, 2.37 mmol). Stirring at 0° C. was continued for 15 min then the cold bath was removed and the reaction mixture allowed to warm to room temperature and 90 min before quench and workup by pouring into dilute HCl and extraction with ether. The combined extracts were dried MgSO4, filtered and concentrated under vacuum giving the crude title compound that was purified by flash chromatography on silica gel eluting with EtOAc-hexanes to give the title compound (0.162 g, 25%).
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:30]([O:34][C:35](=[O:39])CCC)[C@@H:31]1[O:33]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN1CCCN(C)C1=O>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:30]([CH2:31][OH:33])[O:34][C:35]2=[O:39])[CH:13]=[CH:14][C:15]=1[N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH3:24]
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: Cc1nccn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Cc1nccn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
5-Benzyloxycarbonylamino-2-(2-methylimidazol-1-yl)fluorobenzene (54 g, 0.166 M) was dissolved in a mixture of dry tetrahydrofuran (600 ml) and 1,3-dimethyl-2,4,5,6-tetrahydro-2(1H)-pyrimidinone (100 ml) under nitrogen, cooled to −70°, and treated with a solution of n-butyllithium (1.6 M in isohexane, 114 ml), over 30 minutes. After stirring for 30 minutes at −70°, a solution of (R)-glycidylbutyrate (26.35 g, 0.183 M) in dry tetrahydrofuran (50 ml) was added over 15 minutes. Stirring was continued for 16 hours allowing the temperature to rise to ambient. The mixture was treated with aqueous sodium bicarbonate.(5%, 500 ml) and ethyl acetate (800 ml), the organic layer separated, and the aqueous extracted with further ethyl acetate (3×750 ml). The combined extracts were dried (magnesium sulfate) and evaporated, and the resulting oil triturated with diethyl ether. The resulting solid was recrystallised from isopropanol to give the title compound (21.5 g). NMR (DMSO-d6) δ: 2.16 (s, 3H); 3.56 (dt, 1H); 3.69 (dt, 1H); 3.88 (dd, 1H); 4.15 (t, 1H); 4.74 (m, 1H); 5.24 (t, 1H); 6.92 (s, 1H); 7.20 (s, 1H); 7.48 (dd, 1H); 7.53 (t, 1H); 7.74 (dd, 1H). MS (ESP): 292 (MH+) for C14H14FN3O3
Reaction SMILES: [C:1]([C:5]1([C:13]2[S:14][C:15]([S:18][CH2:19]C(O)=O)=[CH:16][CH:17]=2)[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[N+:23]([O-])([O:25]CC(C)C)=[O:24]>>[C:1]([C:5]1([C:13]2[S:14][C:15]([S:18][CH2:19][N+:23]([O-:25])=[O:24])=[CH:16][CH:17]=2)[O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CO[N+](=O)[O-]
Reactant: CC1(C)COC(c2ccc(SCC(=O)O)s2)(C(C)(C)C)OC1
Product: CC1(C)COC(c2ccc(SC[N+](=O)[O-])s2)(C(C)(C)C)OC1
Yield: 47 %

Procedure:
Using a similar nitration procedure to that described in Example 9, but starring from acid (C) and using isobutyl nitrate in place of isoamyl nitrate, there was obtained 2-t-butyl-5,5-dimethyl- 2-[2-(nitromethylthio)thien-5-yl]-1,3-dioxane (D) as an oil, in 47% yield; NMR: 0.6(s, 3H), 0.96(s, 9H), 1.2(s, 3H), 3.36(dd, 2H), 3.55(d, 2H), 5.32(s, 2H), 6.82(d, 1H), 7.22(d, 1H); m/e (chemical ionisation) 346 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11]Cl)[S:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][NH:21][CH3:22].C(Cl)Cl>CN(C=O)C>[CH3:20][N:21]([CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1)[CH3:22]
Reactant: CCOC(=O)c1csc(CCl)n1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(CN(C)C)n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
2-Chloromethyl-thiazole-4-carboxylic acid ethyl ester (500 mg, 2.431 mmol) and potassium carbonate (504 mg, 3.65 mmol) were dissolved in dry DMF. Dimethylamine hydrochloride (218 mg, 2.67 mmol) in dry DMF was added slowly to the reaction mixture and stirred at RT over three nights. DCM was added and the mixture was washed with concentrated NaHCO3 and water. Organic phase was evaporated to dryness and the product was purified by Flash-chromatography. Yield 34.2%. 1H-NMR (400 MHz; CDCl3): δ 1.41 (t, 3H), 2.49 (s, 6H), 3.99 (s, 2H) 4.43 (q, 2H), 8.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:33])[F:34])=[CH:27][N:26]=1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnc(Oc2c(Cl)cc(OCc3ccccc3)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Then, 0.85 g of 2,6-dichloro-4-benzyloxyphenol, 0.48 g of potassium carbonate, 0.75 g of 2,3-dichloro-5-trifluoromethylpyridine and 10 ml of N,N-dimethylformamide were charged into a reaction vessel, and stirred at 85° to 90° C. for 3 hours. Then, the reaction solution was cooled to room temperature, poured into water and extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 1.39 g of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-benzyloxybenzene, (yield, 98%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[C:17](=[N:19]/[N:20]=[C:21]([NH2:23])[NH2:22])/[CH3:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.CCO.[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1.Cl>O>[ClH:29].[ClH:1].[NH2:22][C:21](=[N:20]/[N:19]=[C:17](/[C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([NH:3][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=1)\[CH3:18])[NH2:23]
Reactant: Clc1ccnc2ccccc12
Reactant: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(N)cc2)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(Nc3ccnc4ccccc34)cc2)c1

Procedure:
To a solution of triamine F5 (0.35 g, 0.91 mmol) in 1:2 EtOH:H2O (30 mL) were sequentially added 4-chloroquinoline (0.64 g, 3.90 mmol) and c.HCl (0.25 mL, 8.24 mmol), and the resulting solution was refluxed for 20 h (reaction progress followed by TLC, eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:acetic acid; product Rf=0.51, yellow spot after staining with KMnO4). After this time, solvent was removed under reduced pressure, and the residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH:EtOAc to give Cpd. JJ2 (91 mg, 20%) as a pale yellow amorphous solid; mp 240-244° C. (powder-glue), 264-268° C. (glue-liquid); 1H NMR (400 MHz, DMSO): δ 14.67 (br s, 1H, quinolinyl-N+—H), 11.19 (s, 1H, hydrazonyl-N+—H), 11.07 (s, 1H, ArC(O)NHAr), 10.48 (s, 1H, ArNHAr), 8.72 (d, J=8.52 Hz, 1H, ArH), 8.61 (d, J=6.90 Hz, 1H, ArH), 8.24 (m, 3H, ArH), 8.08 (m, 2H, ArH), 7.95 (d, J=8.10 Hz, 1H, ArH), 7.82 (m, 6H, ArH & ═C(NH2)2), 7.68 (d, J=8.38 Hz, 2H, ArH), 7.43 (t, J=7.97 Hz, 1H, ArH), 7.01 (d, J=6.90 Hz, 1H, ArH), 2.37 (s, 3H, Ar(CH3)2═N—); LCMS (APCI+): 438 (100%); HPLC: 96.4%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:21])[C:13]4=[CH:12][C:11]=3[O:10][CH2:9][C:8]=2[CH:22]=1)(=[O:3])[CH3:2].C(Cl)Cl.CO.[Br-:28].[Br-:29].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CCOC(C)=O>[Br:28][CH:19]1[CH2:18][CH2:17][C:14]2=[CH:15][C:16]3[C:7]4[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH2:2][Br:29])=[CH:22][C:8]=4[CH2:9][O:10][C:11]=3[CH:12]=[C:13]2[C:20]1=[O:21]
Reactant: [Br-]
Reactant: CC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
A 20 mL vial with a stir bar was charged with 3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (100 mg, 0.366 mmol), 9:1 CH2Cl2/MeOH (3.4 mL) and pyridinium tribromide (246 mg, 0.769 mmol). The solution was heated to 35° C. After 30 minutes, the reaction was judged complete. The mixture was cooled to ambient temperature, diluted with EtOAc (50 mL) and sequentially washed with saturated aqueous Na2S2O3 (20 mL), 2% aqueous NaHCO3 (20 mL), water (20 mL), and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure resulting in 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (68 mg, 41%): 400 MHz 1H NMR (CDCl3) δ 8.03-8.01 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74 (dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m, 1H), 2.59-2.46 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[Na+].Br[CH2:13][CH2:14][O:15][CH3:16]>C(O)C.O>[CH3:16][O:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: OCc1cccc(O)c1
Reactant: COCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCOc1cccc(CO)c1
Temperature: 25 °C

Procedure:
To a solution of 3-hydroxybenzyl alcohol (27A) (12.41 g, 100 mmol) in ethanol (150 mL) was added aqueous NaOH (10 N, 10 mL), followed by 1-bromo-2-methoxyethane (27B) (13.9 g). The reaction mixture was heated to reflux overnight. Then the reaction mixture was allowed to cool to RT, and diluted with water. The mixture was subsequently extracted with CH2Cl2, and the combined organic phase was dried with anhydrous MgSO4 filtered, and concentrated in vacuum to give the product (27C) a yellow oil, which was used for the next reaction without further purification. 1H NMR (300 MHz, CDCl3): δ 1.82 (br, 1H), 3.44 (s, 3H), 3.74 (t, 2H, J=4.8 Hz), 4.12 (t, 2H, J=4.8 Hz), 4.65 (s, 2H), 6.84-6.95 (m, 3H), 7.22-7.26 (m, 1H). LCMS: purity >94%. ESI-MS: M/Z 183(M+H)+.