Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:19][CH3:20])[C:11]=1[C:21]#[N:22]>C(O)(=O)C>[Br:1][C:15]1[CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[C:12]([NH:19][CH3:20])=[C:11]([C:21]#[N:22])[C:10]=1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3]
Reactant: CNc1c([N+](=O)[O-])ccc(-c2ccccc2Cl)c1C#N
Reactant: BrBr
Solvent: CC(=O)O
Product: CNc1c([N+](=O)[O-])cc(Br)c(-c2ccccc2Cl)c1C#N
Temperature: 86 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Bromine (0.54 mL, 10.43 mmol) was added slowly to a solution of Example 8A (2.0 g, 6.96 mmol) in acetic acid (20 mL) at r.t. The reaction was heated to 86° C. and stirred for 1 h. The cooled solution was quenched with sat. bisulfite solution and extracted with EtOAc. Organics were dried (MgSO4) and concentrated in vacuo to give 2.4 g (94%) of the title compound as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 8.50 (br s, 1H), 7.40-7.55 (m, 3H), 7.18-7.26 (m, 1H), 3.46 (d, 3H, J=4.8 Hz). MS (ES) [m+H] calc'd for C14H9N3O2BrCl, 366, 368, 370; found 366, 368, 370.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32]C)[CH:30]=3)[N:25]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:24]=2)[CH:3]=1.B(Br)(Br)Br.C(N(CC)CC)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[N:25]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:24]=2)[CH:3]=1
Reactant: COc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(O)cc34)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 213d (0.927 g, 1.514 mmol) in CH2Cl2 (50 mL) was added 1M BBr3 in CH2Cl2 (10.6 mL, 10.6 mmol) at −78° C. The reaction was slowly warmed to room temperature and stirred overnight. The solvent was evaporated. To a suspension of the residue in THF (60.0 mL) was added triethylamine (1.48 mL, 10.6 mmol) and Boc2O (0.380 g, 1.74 mmol). The reaction was stirred for 8 hours, diluted with 50% brine, and extracted with EtOAc. The organic layers was dried over MgSO4, filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]#[CH:16])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])[CH3:3].I[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1.C(NCC)C.C(OCC)(=O)C>C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]#[C:15][CH2:14][C@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:10]([O:12][CH3:13])=[O:11])=[CH:19][CH:20]=1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC#Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
A solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D64, 1.020 g, 4.49 mmol), prepared by an analogous procedure to the one described hereinabove, 4-Iodo-bromobenzene (1.524 g, 5.38 mmol), diethylamine (2.28 ml, 1.62 g, 22.12 mmol), CuI (84 mg, 0.441 mmol) and Pd(PPh3)2Cl2 (156 mg, 0.22 mmol) in diethyl ether (10 ml) was stirred at room temperature for 24 h. Ethyl acetate was added and the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4), filtered and evaporated under vacuum. The residue was purified via flash chromatography using a gradient of cyclohexanes and ethyl acetate (98:2 to 80:20) to afford the title compound (1.199 g, 69%). MS: (ES/+) m/z: 404, 406 [MH+], C17H20BrNO4 requires 404. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.56 (d, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 4.30 (m, 1H), 3.67 (s, 3H), 2.82 (m, 2H), 1.40 and 1.38 (2xs, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](F)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:29]#[N:30].CO>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:29]#[N:30])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3ccccc23)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C#N)c3ccccc23)CC1
Temperature: 100 °C

Procedure:
4-(4-Fluoro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester 28 (2.00 g, 4.9 mmol) was dissolved in DMF (20 mL). Sodiuim cyanide (1.2 g, 24.5 mmol) and tetra-n-butylammonium bromide (7.9 g, 24.5 mmol) were added and the reaction was heated to 100° C. overnight. The reaction was diluted with dichloromethane (100 mL) and charged to a separatory funnel. The organic layer was washed three times with water, brine and dried over MgSO4. Filtration and concentration in vacuo afforded a dark colored oil. Flash column chromatography (98:2 dichloromethane:methanol) afforded an oil that was rechromatographed (99:1 dichloromethane:methanol) to afford 29 as an orange solid. Wt.: 640 mg (31%). 1H NMR (300 MHz, CDCl3) δ 8.71 (m, 1H), 8.40 (m, 1H), 8.34 (d, 1H), 8.00 (d, 1H), 7.83 (m, 2H), 4.80 (d, 1H), 3.87 (m, 2H), 3.32 (m, 1H), 2.61 (m, 2H), 1.63 (m, 2H), 1.38 (s, 9H), 1.27 (m, 2H); LC/MS m/z 414 (M−H)−.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:5].C(N(CC)CC)C.[CH2:20]=[O:21].Cl>C(#N)C.C(OCC)C>[OH:12][C:7]1[C:6]([CH2:4][CH3:5])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:20]=[O:21]
Reactant: C=O
Reactant: CCc1ccccc1O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOCC
Product: CCc1cccc(C=O)c1O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Prepared according to Zaidlewicz, M.; et al; Tetrahedron:Asymmetry; 2003, 14, 1659-1664: Magnesium chloride (11.4 g, 120 mmol) was added at room temperature to a solution of 2-ethylphenol (9.77 g, 80 mmol) in acetonitrile (100 mL), followed by triethylamine (42 mL, 300 mmol). Paraformaldehyde (16.2 g, 540 mmol) was then added portionwise to the stirred suspension and the mixture was heated at reflux for 3 hours. The mixture was cooled to room temperature then poured into a vigorously stirred mixture of 250 mL of 5% HCl and 150 mL of diethyl ether. The organic phase was separated, and the aqueous layer re-extracted with 100 mL of ether. The combined organic extracts were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure to give 11.5 g of 9 as a yellow oil which was used without further purification:
Reaction SMILES: COC[O:4][C:5]1[CH:12]=[C:11]([O:13]COC)[CH:10]=[C:9]([CH2:17][O:18][CH3:19])[C:6]=1[CH:7]=[O:8].Cl>C1COCC1.CCOC(C)=O>[OH:4][C:5]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]([CH2:17][O:18][CH3:19])[C:6]=1[CH:7]=[O:8]
Reactant: COCOc1cc(COC)c(C=O)c(OCOC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cc(O)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
To a solution of 2,4-bis-methoxymethoxy-6-methoxymethyl-benzaldehyde (3.93 g, 14.45 mmol) in THF (30 mL) was added 6 N HCl (10 mL). The mixture was stirred at room temperature for 20 hours then diluted with EtOAc (200 mL). The mixture was washed with brine, dried and concentrated to give 2,4-dihydroxy-6-methoxymethyl-benzaldehyde (2.62 g, 100%). 1H NMR (400 MHz, CDCl3δ 12.40 (s, 1H), 10.10 (s, 1H), 6.41 (s, 1H), 6.30 (s, 1H), 5.60 (s, 1H), 4.61 (s, 2H), 3.40 (s, 3H).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][C:2]1=[O:13].[CH3:14][N:15]([CH3:18])[CH:16]=O>C(OCC)C>[CH3:14][N:15]([CH:18]=[C:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2](=[O:13])[CH2:3]1)[CH3:16]
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)c2ccccc2N1
Solvent: CCOCC
Product: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Temperature: 90 °C
Yield: 79 %

Procedure:
A mixture of 0.250 g (1.43 mmol) of 3,4-dihydro-1H-1-benzazepine-2,5-dione and 5.5 ml (4.93 g, 41.5 mmol) of N,N-dimethylformamide, dimethylacetal is heated at 90° C. for 1.5 hour. The mixture is cooled, diluted with diethylether and filtered. The solid is washed well with diethylether and dried to give 0.26 g of tan crystals, m.p. 203°-205° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>C(Cl)Cl>[CH2:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:2][OH:3])=[O:32])=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NO
Reactant: CCCCCCOc1ccc(CCCCCCCCC(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCOc1ccc(CCCCCCCCC(=O)NO)cc1
Yield: 10.8 %

Procedure:
To a cold, stirring suspension of 1.2 gms hydroxylamine hydrochloride and 1.7 gms sodium carbonate in 40 ml CH2Cl2 was added dropwise 4.2 gms 9(4-hexyloxyphenyl)nonanoyl chloride. The mixture was stirred for 1/2 hr in the cold, then 2 ml water was added, and the reaction was stirred at room temperature overnight. The suspension was then diluted with CH2Cl2, washed three times with water and once with NaCl solution, then dried over MgSO4. The drying agent was filtered off and the solvent was removed in vacuo to give a solid which was crystallized from CHCl3 :hexanes and then hexanes. Impurities were still present by thin layer chromatography, so the solid was dissolved in 3:1 benzene:hexanes, shaken with 150 gms silica gel, and the silica gel washed with ethyl acetate. The solid remaining on evaporation of the solvent was purified by column chromatography on silica gel with 30% ethyl acetate:CHCl3. The main fraction had Rf=0.4 by thin layer chromatography. The residue from the collected fractions was crystallized twice from CH2Cl2 to give 0.45 gms product of m.p. 94°-6°.
Reaction SMILES: C1CCCCCC1.N([O:10][C:11](C)(C)[CH3:12])=O.Cl[C:16]1[CH:17]=[C:18]2[C:23](=[O:24])N(O)C(=O)[C:19]2=[CH:26][CH:27]=1.C1(=NO)CCCCCC1.[N+](C1CCCCCC1)([O-])=O.C1(=O)CCCCCC1>C(O)(=O)C>[C:11]([O:24][CH:23]1[CH2:17][CH2:16][CH2:27][CH2:26][CH2:19][CH2:18]1)(=[O:10])[CH3:12]
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1O
Reactant: CC(C)(C)ON=O
Agent: C1CCCCCC1
Agent: O=C1CCCCCC1
Agent: O=[N+]([O-])C1CCCCCC1
Solvent: CC(=O)O
Product: CC(=O)OC1CCCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cycloheptane (1 ml), t-butyl nitrite (1 mmol), 4-chloro-N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cycloheptanone oxime, nitrocycloheptane, cycloheptanone, and cycloheptyl acetate were formed in yields of 16%, 4%, 6%, and less than 1%, respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:44][O:45][C:46](=[O:51])[CH2:47][C:48](Cl)=[O:49]>ClCCl>[CH3:44][O:45][C:46](=[O:51])[CH2:47][C:48]([NH:33][S:30]([C:28]1[CH:27]=[CH:26][C:18]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)=[N:16][C:17]=2[CH:29]=1)(=[O:32])=[O:31])=[O:49]
Reactant: COC(=O)CC(=O)Cl
Reactant: NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Product: COC(=O)CC(=O)NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reaction time: 1 h
Yield: 7 %

Procedure:
A solution of intermediate 69 (0.046 g, 0.1 mmol) in dichloromethane (0.700 mL) was cooled to 0° C. Lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran) (0.10 ml, 0.10 mmol) was added and the mixture was stirred for 1 hr. Methyl-3-chloro-3-oxo-propionate (0.011 ml, 0.10 mmol was added. The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and the residue purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product (0.005 g, 7%). 1H NMR (CDCl3) δ 8.60 (s, 1H), 8.16 (d, 1H, J=8.8 Hz), 7.85 (d, 1H, J=8.8 Hz), 7.64 (d, 2H, J=8.8 Hz), 7.50-7.38 (m, 5H), 7.21 (d, 2H, J=8.8 Hz), 5.18 (s, 2H), 4.49 (m, 1H), 3.70 (s, 3H), 3.35 (s, 2H), 2.30 (br m, 2H), 2.02 (br m, 4H), 1.82 (br m, 1H), 1.35 (br m, 3H); ESI-MS m/e 562.18(M+1); HPLC purity (UV) 99%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1cccc(O)c1
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)c1
Yield: 75.7 %

Procedure:
A solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.80 g, 5.07 mmol), 1-bromoundecane (1.58 ml, 7.60 mmol) and potassium carbonate (1.05 g, 7.06 mmol) in DMF (15 ml) was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.90 g (yield: 75.7%)
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=[C:12]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])(O)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]([N:5]2[CH2:4][C:1](=[O:2])[O:8][C:7](=[O:9])[CH2:6]2)[CH:11]=[C:12]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:13]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N2CC(=O)OC(=O)C2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.1 %

Procedure:
To 2.0 g (3.83 mmol) of N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine in 100 ml of methylene chloride stirred at room temperature was added 0.9 g (4.37 mmol)of dicyclohexylcarbodiimide The reaction mixture was stirred at room temperature for 17 hours. After cooling in an ice bath, the precipitate was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from hexane to give 1.7 g (88% yield, mp 62°-62°) of 4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([C@@H:14]2[CH2:18][N:17]([CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=3[F:35])[C@H:16]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:25][CH2:26]3)=[O:20])[CH2:15]2)[N:13]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Reactant: O=Cc1ccccc1F
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccccc2F)CC1
Yield: 8.2 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 2-fluoro-benzaldehyde (17 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (6.1 mg, 8.2%) as light yellow oil. MS m/e=573.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[N:29]([CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[C:30]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:30]([NH:29][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: S=C=NCCN1CCOCC1
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCN3CCOCC3)n(CC3CCOCC3)c12
Yield: 60 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and 4-(2-isothiocyanatoethyl)morpholine (50 mg) to give the title compound as beige solid (57 mg, 60%). LCMS (formate) Rt 0.51 min, MH+ 521
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:20][CH2:21][CH2:22]C#N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH:44]([OH:46])=[O:45]>>[CH2:1]([O:17][CH2:18][CH:19]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:20][CH2:21][CH2:22][C:44]([OH:46])=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCC#N
Reactant: O=CO
Agent: Cl
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCC(=O)O
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 1,3-di-O-(n-hexadecyl)-2-O-(2-cyanoethyl)-glycerol (4.8 g., 8.1 mmoles), concentrated hydrochloric acid (50 ml.) and formic acid (50 ml.) was stirred for 16 hours at reflux, then cooled and extracted with ether (3×100 ml.). The combined ether extract was washed with water (200 ml.), dried (MgSO4), filtered and evaporated in vacuo to yield 1,3-di-O-(n-hexadecyl)-2-O-(2-carboxyethyl)-glycerol solids (4.5 g.), which were purified by silica gel chromatography (elution with toluene:ethanol) [3.5 g., 71% yield, m.p. 43°-45° C., ir (CHCl3) 1740 cm-1, n.m.r. (CDCl3) δ 3.93 (t, J=6 Hz, 2, --OCH2CH2COOH) and 2.65 (t, J=6 Hz, 2, --OCH2CH2COOH)].
Reaction SMILES: N1C=CC(C2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)=CC=1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=1)[C:20](Cl)=O>>[F:16][C:17]1[CH:18]=[C:19]([C:20]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: Fc1cc(F)cc(-c2nnc3n2CCCN3)c1

Procedure:
The title compound is prepared according to the procedure for 3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (example 17a) from 3,5-difluoro-benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([OH:16])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N+:7]([O-:25])=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([OH:16])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccccc1Oc1nnc(Cl)cc1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1Oc1n[n+]([O-])c(Cl)cc1O
Reaction time: 48 h
Yield: 22.6 %

Procedure:
135 mg (0.572 mmol) of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 128) obtained in Example 1 and methylene chloride (6 mL) were mixed, 247 mg (purity 80%, 1.14 mmol) of m-chloroperbenzoic acid was added to the mixture and the resulting mixture was refluxed for 16 hours with stirring. The mixture was allowed to stand at room temperature for 2 days, the reaction mixture was poured in a saturated aqueous sodium sulfite solution, and washed with methylene chloride. The aqueous layer was made acidic with hydrochloric acid, extracted with methylene chloride, then washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (YMC GEL, SIL60, 350/250 mesh, eluted with ethyl acetate) to obtain 32.6 mg (0.129 mmol, Yield: 22.6%) of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol 1-oxide (Compound No. 129).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[S:28]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=S)c2ccccc12
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (1.8 g.) and phosphorus pentasulphide (2.5 g.) in xylene (100 ml.) was stirred and heated under reflux for 1 hour. The reaction solution was then cooled to room temperature, ethyl acetate (25 ml.) was added and the mixture was filtered through chromatographic silica (20 g.), the subsequent filtrate was evaporated and the residual solid obtained was recrystallised from ethanol to give ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-thioxophthalazin-4-ylacetate (1.1 g.), m.p. 124°-126° C.