Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][CH2:29][CH2:30]Br>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:30][CH2:29][O:28][CH3:27])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-bromoethyl methyl ether, to give the product as a white solid (28%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5]2.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])(=O)C.[K+].BrC1C=CC2C(=CC=CC=2)N=1>C(O)C.O>[C:19]1([CH3:18])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5]2
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)C=Cc1cnc2ccc(Br)cc2c1
Agent: Brc1ccc2ccccc2n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(=O)C=Cc1cnc2ccc(-c3ccccc3C)cc2c1

Procedure:
5-Bromo-2-nitrobenzaldehyde 1 (6.03 g, 26.2 mmol) was dissolved in MeOH (200 mL) and treated with 5N HCl (10 mL). The mixture was heated to 70° C. and iron powder (7.32 g, 131 mmol) was added in five portions every 5 min. Upon completion (by TLC) the reaction was cooled and DCM (200 mL) was added before filtering through a pad of celite. The filtrate was concentrated under reduced pressure to 150 mL. To this material, a solution of 1,1,3,3-tetramethoxypropane (9.52 ml, 57.7 mmol) in 5N HCl (10 mL) pre-mixed for 45 min was added. The reaction mixture was stirred at 80° C. for 60 min. Toluene (100 mL) and acetic acid (40 mL) were added and the solution was heated to 110° C. for 3 h, then cooled and evaporated to dryness under reduced pressure. The crude material was purified using silica chromatography (20-60% ethyl acetate in hexane gradient) to give 6-bromoquinoline-3-carbaldehyde 2. Step 2 6-Bromoquinoline-3-carbaldehyde 2 (2.8 g, 12.0 mmol) and methyl(triphenylphosphoranylidene)acetate (4.0 g, 12.0 mmol) were dissolved in dry THF (50 mL) and heated to 50° C. After 40 min the solution was evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to 60% ethyl acetate in hexane gradient) gave methyl 3-(6-bromoquinolin-3-yl)acrylate 3 as a mixture of E and Z isomers. Step 3 Methyl 3-(6-bromoquinolin-3-yl)acrylate 3 (0.91 g, 3.1 mmol), 2-methylphenyl boronic acid (R1 substituted ring A in 4 above; 0.61 g), potassium acetate (1.0 g) and bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine)dichloropalladium (II) (0.19 g) were suspended in ethanol (70 mL) and water (5 mL) and heated to reflux for 90 min. LC/MS showed the bromoquinoline had been consumed the reaction was evaporated to dryness under reduced pressure. The crude was partitioned between ethyl acetate and water. The organic layer was separated and dried with magnesium sulfate, evaporated to dryness under reduced pressure and purified using silica chromatography (hexane to ethyl acetate gradient) to give methyl 3-(6-o-tolylquinolin-3-yl)acrylate 4 (representative compound 4 wherein ring A is ortho-toluene).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:13]1[C:14](=[O:28])[CH2:15][C:16]([CH3:27])([CH3:26])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]=1[OH:19])(=O)[CH2:9][CH2:10][CH3:11].Cl.[CH2:30]([O:33][NH2:34])[CH:31]=[CH2:32]>C(O)C>[CH2:30]([O:33][N:34]=[C:8]([C:13]1[C:14](=[O:28])[CH2:15][C:16]([CH3:27])([CH3:26])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]=1[OH:19])[CH2:9][CH2:10][CH3:11])[CH:31]=[CH2:32]
Reactant: C=CCON
Reactant: CCCC(=O)C1=C(O)C(c2ccccc2)C(C)(C)CC1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCON=C(CCC)C1=C(O)C(c2ccccc2)C(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Triethylamine (1.2 g) was added to a solution of 2-butyryl-5,5-dimethyl -3-hydroxy-4-phenyl cyclohex-2-ene-1-one (2.8 g) and O-allylhydroxylamine hydrochloride (1.2 g) in ethanol (50 ml). After stirring at ambient temperature overnight, the ethanol was evaporated in vacuo, water was added to the residue and the aqueous solution extracted with methylene chloride. After drying the organic extracts over anhydrous magnesium sulphate, the methylene chloride was evaporated in vacuo. The residue was chromatographed on a silica gel column using 5% (v/v) diethyl ether-methylene chloride as eluant to give the title compound (2.1 g) as a viscous, colourless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6].Cl.[OH:24][NH2:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:20][C:19](=[N:25][OH:24])[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([C:5](=[O:6])[CH2:4][CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[CH2:8][CH2:9]2)[CH:18]=1
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C#N)ccn2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Yield: 63.2 %

Procedure:
1-(4,4-Dimethylpentanoyl)-4-(4-cyanopyridin-2-yl)piperazine (2.91 g) obtained in Example 53 was dissolved in ethanol (20 mL), and hydroxyamine hydrochloride (2.16 g) and potassium carbonate (5.38 g) were added thereto and heated under reflux for 2 hours. Then, the solvent was evaporated away, and the resulting residue was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away to obtain 2.04 g of the entitled compound.
Reaction SMILES: I[CH:2]([CH3:8])[CH2:3][C:4]([F:7])([F:6])[F:5].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[F:5][C:4]([F:7])([F:6])[CH2:3][CH:2]([S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: Sc1ccccc1
Reactant: CC(I)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(CC(F)(F)F)Sc1ccccc1
Yield: 79 %

Procedure:
To a solution of 54.9 mmol 3-iodo-1,1,1-trifluorobutane in 50 ml N,N-dimethylformamide were added 49.9 mmol thiophenol and 74.9 mmol potassium carbonate. The mixture was ultrasonicated at room temperature for 90 min. The reaction mixture was then diluted with ether and was washed three times with water. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil (yield 79%). MS (m/e): 221.3 (M+, 15%).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:14])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[OH:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1>>[CH3:14][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:3][CH2:2][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1
Reactant: CC(=CCBr)CCC=C(C)CC(C)C
Reactant: Oc1ccc2c(c1)OCCC2
Product: CC(=CCOc1ccc2c(c1)OCCC2)CCC=C(C)CC(C)C

Procedure:
Following the procedure of Example 1, 1-bromo-3,7,9-trimethyl-2,6-decadiene and 7-hydroxy-chromane are reacted to form 7-(3,7,9-trimethyl-2,6-decadienyloxy)-chromane, nD20 = 1.5920.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1.[NH2:21][OH:22].Cl.C([O-])(=O)C.[Na+]>C(O)C.O>[OH:22][N:21]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2cc(C(=O)N3CCC(=NO)CC3)ccc2N1

Procedure:
37 Grams of 6-(4-oxo-1-piperidylcarbonyl)-3,4- -dihydrocarbostyril, 30.3 g of hydroxylamine·hydrochloride and 83.5 g of sodium acetate were dissolved in 600 ml of ethanol and 300 ml of water, the mixture wa stirred overnight at room temperature. The crystals precipitated were collected by filtration, and recrystallized from ethanol to yield 16 g of 6-(4-hydroxylimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10](SC)[C:11]3[C:12](=[CH:14][S:15][CH:16]=3)[NH:13][C:7]=2[CH:6]=1)(=[O:4])=[O:3].O.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:11]3[C:12](=[CH:14][S:15][CH:16]=3)[NH:13][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: C1CNCCN1
Reactant: CSC1=Nc2ccc(S(C)(=O)=O)cc2Nc2cscc21
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc2c(c1)Nc1cscc1C(N1CCNCC1)=N2

Procedure:
A solution of 6-methylsulfonyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess piperazine and glacial acetic acid is heated in a bomb at 150° C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc3ccccc23)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc3ccccc23)cc1N

Procedure:
Prepared from (4-naphthalen-1-yl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B7) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white solid (226 mg).
Reaction SMILES: I[Si](C)(C)C.C(OC([NH:16][C:17]1([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([S:36]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[C:44]([Cl:49])[CH:45]=4)[CH:40]=3)(=[O:38])=[O:37])[CH2:32][C:31]2=[O:50])[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=O)C1C=CC=CC=1.CO.[ClH:53]>ClCCl.C(OCC)(=O)C>[ClH:49].[ClH:53].[NH2:16][C:17]1([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([S:36]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[C:44]([Cl:49])[CH:45]=4)[CH:40]=3)(=[O:37])=[O:38])[CH2:32][C:31]2=[O:50])[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1
Reactant: O=C(NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1)OCc1ccccc1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Iodotrimethylsilane (2.51 ml) was added to a solution of 1-[4-benzyloxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (4.58 g) in dichloromethane (50 ml), and the mixture was stirred at room temperature for 4 hours. Methanol (10 ml) and 4N hydrochloric acid solution in ethyl acetate (8 ml) were added thereto. Methanol was added to obtain a solution, followed by concentration under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was washed with ether. The aqueous layer was made basic with 6N sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was washed successively with an aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried, and concentrated. Dilute hydrochloric solution was added to the residue, which was purified by CHP20 column chromatography (water:acetonitrile:1N hydrochloric acid=100:0:1→80:20:1) to obtain the colorless amorphous title compound (3.66 g).
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7][NH:6]1>C(O)C>[ClH:1].[OH:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7][NH:6]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(CCO)NCC2
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)C(CCO)NCC2
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.18 g, 8.43 mmol) in ethanol (100 ml) was added 10% Pd--C (0.4 g) and the solution hydrogenated on the Parr Hydrogenator for 2 h. The reaction mixture was filtered to remove the catalyst and the filtrate reduced to about 1/3 of the volume. The solution was warmed and ether (150 ml) was added. The precipitate was collected to give the title compound as a yellow solid (1.81 g, 94%), m.p. 199.5-200.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][C:13]2=[O:20])([O-:9])=[O:8].[CH2:21]([O:23][C:24](=[O:27])[CH2:25]Br)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:27])[CH2:25][N:14]1[C:13](=[O:20])[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=2)[C:15]1=[O:19])[CH3:22]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 611.2 %

Procedure:
Potassium carbonate (57.8 g) was added to a solution mixture of 5-nitro-isoindole-1,3-dione (26.2 g) and bromo-acetic acid ethyl ester (25.1 g) in actone (500 ml). The resulting mixture was refluxed overnight (18 h). After cooling, reaction mixture was filtered and rinsed with ethyl acetate. Filtrate was concentrated and the residue was triturated with ether (200 ml). Solid was collected and rinsed with ether. Dried in vacuo to give the title compound 231.9 g. 1H NMR (200 MHz, CDCl3) δ 8.69 (m, 2H), 8.07 (d, J=8.2 Hz, 1H), 4.48 (s, 2H), 4.24 (q, J=7.0 Hz, 2H), 1.30 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([N:3](CC)CC)C.[C:8](Cl)(=[O:18])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11](Cl)=[O:12]>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[C:8]1(=[O:18])[NH:3][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of MCH17-1 (520 mg), triethyl amine (0.82 mL) and DMAP (24 mg) in 10 mL dichloromethane at 0° C. was added phthaloyl chloride (0.36 mL). The mixture was stirred overnight at rt, diluted with ethyl acetate and washed with 1N HCl, aq. NaHCO3 and brine. It was dried over anhydrous MgSO4, filtered, concentrated and purified by chromatography eluting with 0% to 50% ethyl acetate in hexane to provide 338 mg of phthalimide protected intermediate which was stirred with 5 mL of trifluoroacetic acid at rt for 40 min. The reaction mixture was evaporated to dryness, the residue was suspended in aq. NaHCO3 and extracted 3× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness to obtain 220 mg MCH 17-2.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.N([O-])=O.[K+].[OH-].[Na+].[ClH:21]>O>[Cl:21][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(N)n1
Reactant: Cl
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)Nc1cccc(Cl)n1

Procedure:
To a precooled (−10° C.) suspension of 6-amino-2-(pivaloylamino)pyridine (28.00 g, 0.145 mol) in conc. aqueous HCl (150 mL) was added potassium nitrite (14.81 g, 0.174 mol) dissolved in water (8 mL) over a 1.5 h period. The resulting reaction mixture was stirred for 5 h at −10° C. under nirogen, before ajustment of the pH to 9 by addition of conc. aqueous NaOH. The aqueous solution was extracted with ethyl acetate (3×100 mL) and the organic fractions washed with 2M NaOH (3×40 mL). The organic phase was dried (MgSO4), evaporated in vacuo and recrystallised from n-hexane/ethyl acetae to give the desired product (17,70 g (58%) as a white powder (m.p. 86-87° C.). 1H NMR (DMSO-d6): δ 10.08 (s br, 1H), 8.04 (d, 8.1 Hz, 1H), 7.81 (t, 8.1 Hz, 1H), 7.17 (d, 8.1 Hz, 1H), 1.22 (s, 9H). 13C NMR (DMSO-d6): δ 177.4, 152.5, 147.8, 141.4, 119.0, 112.8, 39.4, 26.8. FAB+ MS (m/z): 213.06 M+H+, calc. for C10H13ClN2O+H+ 213.0795.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br-:7].C[C:9]1[S:13][CH:12]=[CH:11][S+:10]=1>C(O)C>[Br-:7].[S:10]1[CH:11]=[CH:12][S:13][C:9]1=[N+:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: Cc1scc[s+]1
Agent: [Br-]
Solvent: CCO
Product: c1csc(=[N+]2CCOCC2)s1
Yield: 71.5 %

Procedure:
1.0 g of morpholine and 2.3 g of 2-methyl-1,3-dithiolium bromide were treated in the same manner as in Example 26, and the product was recrystallized from ethanol, whereby 2.2 g (yield: 86.6%) of 4-(1,3-dithiol-2-ylidene)morpholinium bromide (Compound No. 28) was obtained as crystals having a melting point of 274° to 276° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([OH:22])[CH:14]=1.[K+].[Br-]>>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:23]=[CH:24][C:25]([NH2:26])=[C:2]([OH:1])[CH:3]=2)=[CH:14][C:15]=1[OH:22]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2Oc2ccc([N+](=O)[O-])c(O)c2)cc1O
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(Oc2ccccc2Oc2ccc(N)c(O)c2)cc1O
Yield: 75.1 %

Procedure:
1,2-Bis(4-amino-3-hydroxyphenoxy)benzene was synthesized in a manner analogous to Example 2 from 1,2-bis(3-hydroxy-4-nitrophenoxy)benzene. Yield: 75.1%; mp>180° C. (decompose); IR (KBr): 3362, 3295, 3035, 1601 cm−1; MS (EI) m/z 324 (M+, 100); Elemental Anal. Calcd. for C18H16N2O4: C, 66.67; H, 4.94; N, 8.64. Found: C, 66.28; H, 5.04; N, 8.52.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8](S(C)(=O)=O)[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([I:17])=[CH:4][N:3]=1.C1COCC1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([I:17])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)N(c1cc(Br)ncc1I)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(Br)ncc1I
Yield: 84.4 %

Procedure:
N-(2-Bromo-5-iodopyridin-4-yl)-N-(methylsulfonyl)methanesulfonamide (7) (228 mg, 0.50 mmol) was stirred with THF (1.3 ml) and 10% sodium hydroxide in water (1.3 mL) at r.t. for 3 hours. The THF was evaporated and the aqueous was neutralised using 10% citric acid solution. The deposited white solid was filtered off and washed with water, then dried in a vacuum desiccator over sodium hydroxide to give the title compound (159 mg 84%). 1H-NMR (d6-DMSO, 500 MHz): δ 3.29 (s, 3H), 7.54 (s, 1H), 8.64 (s, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:22][C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33]C(OC(C)(C)C)=O)=[CH:29][CH:28]=2)=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23](=[O:24])[NH:22][CH:16]([CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)NCc1ccc(N)cc1
Reaction time: 1 h
Yield: 91.3 %

Procedure:
161 (469 mg) was dissolved in 4 ml of DCM and 4 ml of TEA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 162 as a white solid (350 mg, 91%). 1H NMR (DMSO): δ 1.28 (t, 3H, J=6.5 Hz), 3.04 (m, 2H), 4.13 (d, 2H, J=4.1 Hz), 4.19 (q, 2H, J=6.5 Hz), 4.56 (m, 1H), 5.02 (s, 2H), 5.21 (s, 2H), 6.29 (d, 1H, J=8.3 Hz), 6.45 (m, 1H), 6.62 (d, 2H, J=7.3 Hz), 6.89 (d, 1H, J=7.3 Hz), 7.00 (m, 3H), 7.33 (t, 1H, J=7.3 Hz), 7.53 (t, 1H, J=7.3 Hz), 7.57 (d, 1H, J=6.7 Hz). HPLC method B tr=21.65 mn (97.4%). ESI-MS m/z: 448.3 [M+H]+.
Reaction SMILES: [NH:1]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:2]([C:8]([NH:10][C@@H:11]([C:24]([NH:26][C@H:27]([C:35]([O:37]CC1C=CC=CC=1)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15](C=O)[CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[OH-].[Na+].CO.O>C1COCC1>[NH:1]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:2]([C:8]([NH:10][C@@H:11]([C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
A mixture of Boc-Gln-D-Trp(CHO)-Phe-OBzl (1.2 g) and 1N sodium hydroxide (3.6 ml) in a mixture of THF (30 ml), methanol (10 ml) and water (5 ml) was stirred for 1.5 hours. After adding water (10 ml), the organic solvent was evaporated. The resulting aqueous solution was washed with diethyl ether, acidified with 10% citric acid solution and allowed to stand in a refrigerator overnight. The precipitates were filtered, washed with water and recrystallized with a mixture of ethanol and water to give Boc-Gln-D-Trp-Phe-OH (0.80 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C1COCC1.O>[F:19][C:2]([F:1])([F:20])[C:3]1[C:4]([N:9]2[CH2:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1=CCN(c2ncccc2C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1=CCN(c2ncccc2C(F)(F)F)CC1
Reaction time: 2 h

Procedure:
Methyl 3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylate (15 mL) in THF (30 mL) was treated with 1N NaOH (27 mL) and stirred for 2 hours. The mixture was treated with additional 1N NaOH (16 mL), stirred for 1 hour, treated with 1N NaOH (14.5 mL), and stirred for 1 hour. The mixture was diluted with water and extracted with CH2Cl2. The aqueous layer was then acidified with concentrated HCl and extracted with CHCl3. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH2:1]([NH:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:20](OCC)=[O:21]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[CH2:1]([N:9]([CH:10]1[CH2:11][C:12]([CH3:18])([CH3:19])[NH:13][C:14]([CH3:17])([CH3:16])[CH2:15]1)[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: CCOC=O
Agent: [Ti]
Solvent: CCCCO
Product: CCCCCCCCN(C=O)C1CC(C)(C)NC(C)(C)C1

Procedure:
93 g of 4-(N-octylamino)-2,2,6,6-tetramethylpiperidine and 33 g of tetrabutyl orthotitanate in 175 ml of ethyl formate were refluxed for 10.5 hours. Working up as in Example 2 gave 4-(N-octyl-N-formylamino)-2,2,6,6-tetramethylpiperidine as a colorless oil of boiling point 145°-147° C./0.5 mmHg