Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[CH:9]=2)C=NC=1.[Cl:23]C1N=C(N2CCOC[C@@H]2C)C=C(C2C=NC=C(F)C=2)N=1.FC1C=C(NC(NCCO)=O)C=CC=1B1OC(C)(C)C(C)(C)O1>>[Cl:23][C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[CH:9]=1
Reactant: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(Cl)n1
Reactant: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Agent: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Product: CSc1nc(Cl)cc(N2CCOC[C@@H]2C)n1
Yield: 25 %

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(5-fluoropyridin-3-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 7) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 13). Material was purified by prep HPLC (high pH) to afford a brown solid, (4 1 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[BH4-].[Na+].Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C(=O)N([Br:35])C(=O)C1>CO.C1(C)C=CC=CC=1.C1COCC1.[Cl-].[Na+].O.CCOC(C)=O.O>[Br:35][CH:5]1[CH2:4][C:3]2[C:7](=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[Cl:1])[CH:6]1[OH:12]
Reactant: O=C1CCc2c(Cl)ccc(F)c21
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: OC1c2c(F)ccc(Cl)c2CC1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chloro-7-fluoro-2,3-dihydro-1H-inden-1-one (CAS No. 1260018-63-0, 900 mg, 4.88 mmol) in MeOH (30 mL) was added sodium borohydride (221 mg, 5.85 mmol) at room temperature. The reaction mixture was stirred for 20 minutes at room temperature. To the reaction was added 2N HCl, AcOEt and water at 0° C. The layers were separated. The organic layer was washed with brine and dried over MgSO4, then the solvent was evaporated in vacuo. To a solution of the residue in toluene (50 ml) was added p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) and the reaction mixture was refluxed for 20 minutes. After cooling to room temperature, the reaction mixture was passed through NH silicagel and evaporated in vacuo. To a solution of the residue in THF (30 ml) and water (10 ml) was added NBS (842 mg, 4.73 mmol) and the reaction mixture was stirred for 20 hours at room temperature. AcOEt and brine were added to the mixture, and the layers were separated. The organic layer was successively washed with saturated aqueous Na2S2O3 and brine and then dried over MgSO4. The solvent was evaporated in vacuo. The residue was purified by silicagel flash column chromatography (Yamazen HI-FLASH™ column L size, 40 mL/min, gradient 0% to 40% AcOEt in n-heptane) to afford the title compound (675 mg, 2.54 mmol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH:30]([F:32])[F:31])[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.[I-].[Na+].Cl>O.C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH:30]([F:32])[F:31])[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18][N+:38]4[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: COc1ccncc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(F)F)c3csc(N)n3)[C@H]2SC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NOC(F)F)c4csc(N)n4)[C@H]3SC2)cc1
Yield: 13 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (3.0 g), 4-methoxypyridine (4.0 g), sodium iodide (8.0 g), acetonitrile (4.0 ml) and water (1.0 ml) was heated for 2.0 hours at 65° to 68° C., and then water (100 ml) was added thereto. The mixture was adjusted to pH 3.0 with 1N-hydrogen chloride and the resultant precipitates were filtered off. The aqueous layer was subjected to column chromatography on macroporus nonionic adsorption resin "Diaion HP-20" and the elution was carried out with 30% aqueous methanol. The fractions containing the object compound were collected, concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(4-methoxy-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.43 g).
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:15](=O)[NH:16]2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:25].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.C(OCC)(=O)C>[Br:25][C:15]1[C:14]([C:20]([F:23])([F:22])[F:21])=[N:13][C:12]2[C:17]([N:16]=1)=[CH:18][C:9]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])=[CH:10][CH:11]=2
Reactant: O=C(c1ccccc1)c1ccc2nc(C(F)(F)F)c(=O)[nH]c2c1
Reactant: BrP(Br)Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc2nc(C(F)(F)F)c(Br)nc2c1
Temperature: 0 °C
Yield: 53 %

Procedure:
A mixture of 7-benzoyl-3-trifluoromethylquinoxalin-2(1H)-one (3.0 g, 9.4 mmol) [J. Org. Chem. 57(21), 5630,1992] and 40 ml of phosphorous tribromide was refluxed for 5 hours. The mixture was cooled and poured into ice water and the precipitate was isolated. The crude solid was dissolved in a mixture of diethylether and ethyl acetate (1:1), followed by addition of Norite A and anhydrous magnesium sulfate. The mixture was filtered and the solvent evaporated under reduced pressure. The residue was triturated with hexane, filtered off and dried to yield 1.9 g (53%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)(=O)=O)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:32][CH:33]4[CH2:38][CH2:37][CH2:36][C@H:35]([OH:39])[CH2:34]4)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)(=O)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: NC1CCCC(O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCC[C@H](O)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 130 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-(methylsulfonyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (1.09 g, 2.34 mmol) and 3-aminocyclohexanol (0.32 g, 2.82 mmol) in THF was added DIEA (0.60 g, 4.69 mmol). The reaction mixture was heated at 130° C. in microwave for 10 min. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography to afford 550 mg of the desired product, 27a.
Reaction SMILES: [CH3:1][C@@H:2](CCCC1C=CC=CC=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:6][CH3:7])[O:8][CH3:9]
Reactant: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Reactant: BrCCCCc1ccccc1
Product: COP(=O)(CC(=O)[C@@H](C)CCCCc1ccccc1)OC

Procedure:
(S)-Dimethyl (3-methyl-2-oxo-7-phenylheptyl)phosphonate was prepared in the same manner as the second alternative preparation of (S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) using the same sequence of reactions except that (4-bromobutyl)benzene was used instead of (3-bromopropyl)benzene. The crude product was purified by silica gel chromatography. Elution with ethyl acetate-heptane (50:50 v/v) afforded the title compound (2.84 g) as a colorless oil; TLC Rf 0.54 (solvent system: 100 v ethyl acetate); MS (ESI+) m/z 313.1 (M+H)+; 1H-NMR (CDCl3) δ 7.22-7.17 (m, 2H), 7.12-7.07 (m, 3H), 3.82-3.68 (m, 6H), 3.07 (s, 1H), 3.01 (s, 1H), 2.71-2.62 (m, 1H), 2.53 (t, J=7.69 Hz, 2H), 1.66-1.47 (m, 4H), 1.28-1.22 (m, 2H), 1.02 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=0.052/(0.01998 g/1.5 mL)(0.5)=+7.81° (c=1.017, CHCl3).
Reaction SMILES: C([O:8][C:9]1[C:10]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)C1C=CC=CC=1.Br>C(O)(=O)C.ClCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]3[N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]4=[C:9]([OH:8])[C:10]=3[C:23]2=[O:24])=[CH:31][CH:30]=1
Reactant: COC(=O)c1cn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cn(Cc2ccc(F)cc2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O

Procedure:
A solution of methyl 10-(benzyloxy)-2-(4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylat (30 mg, 0.06 mmol) and hydrogen bromide in acetic acid (0.7 mL, 30% solution) in dichloromethane (10 mL) was stirred at room temperature for 6 hr. The reaction mixture was concentrated under vacuum, and the residue subjected to reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provided the title product.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[C:24]([Cl:25])[CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)c(Cl)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (77 mg, 81%), MS (ISP) m/z=379.6 [(M+H)+], mp 240° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:32]=[CH:33][CH:34]=1)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:15][N:14]=1)([O-])=O>C(O)C.[Zn]>[NH2:5][C:8]1[CH:9]=[C:10]([CH:32]=[CH:33][CH:34]=1)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3cccc([N+](=O)[O-])c3)nc2)CC1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3cccc(N)c3)nc2)CC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
A suspension of zinc powder (553 mg, 8.46 mmol) and calcium chloride (16 mg, 0.144 mmol) in ethanol (2.6 mL)-water (0.6 mL) was warmed to 90° C. followed by the addition of a solution of tert-butyl 4-[2-(3-nitrophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 30) (97 mg, 0.23 mmol) in ethanol (2 mL). The mixture was stirred at 90° C. for 1.5 hours, allowed to cool to room temperature and filtered through Celite pad. The filtrate was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1→100/2) to give the title compound (84 mg, yield 94%).
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[C:12]2S)[CH2:8][CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:21]([O-:24])([OH:23])=[O:22].[OH-].[Na+]>O>[N+:21]([O-:24])([OH:23])=[O:22].[CH:1]1([CH:7]([N:11]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[CH:12]2)[CH2:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCC(C1CCCCC1)n1c(C(=O)OC)cnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCCC(C1CCCCC1)n1cncc1C(=O)OC
Yield: 82.4 %

Procedure:
A solution of 30 parts of methyl 1-(1-cyclohexylbutyl)-2-mercapto-1H-imidazole-5-carboxylate in 150 parts of concentrated nitric acid and 100 parts of water was stirred for 1 hour at room temperature (intense reaction). The whole was cooled in crushed ice and treated with a sodium hydroxide solution. The product was extracted with 1,1'-oxybisethane. The extract was washed twice with water, dried, filtered and evaporated. The residue was converted into the nitrate salt in 2,2'-oxybispropane. The salt was filtered off and dried, yielding 27 parts (82.4%) of methyl 1-(1-cyclohexylbutyl)-1H-imidazole-5-carboxylate mononitrate; mp. 128.9° C. (compound 26).
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:17])[CH3:16])=[N:13][CH:14]=1.O>C1COCC1>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:17])[CH3:16])=[N:13][CH:14]=1
Reactant: Brc1cccs1
Reactant: CN(C)c1ccc(Br)cn1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2cccs2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.5 %

Procedure:
To a suspension of magnesium (0.119 g, 4.97 mmol) in THF (3 mL) was added 2-bromothiophene (0.811 g, 4.97 mmol) and the reaction mixture was stirred for 3 h. Another equivalent of 2-bromothiophene (0.811 g, 4.97 mmol) was added and the reaction mixture was heated at the reflux temperature for 2 h, then allowed to cool to room temperature. The resulting mixture was added to a solution of 5-bromo-2-dimethylaminopyridine (1.0 g, 4.97 mmol) in THF (12 mL) and the reaction was heated at the reflux temperature for 11 h, then was allowed to cool to room temperature. The resulting mixture was treated with water (10 mL), extracted with EtOAc (3×30 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (10% EtOAc/hex) to give 5-(2-thienyl)-2-dimethylaminopyridine (0.3 g, 29%): TLC (10% EtOAc/hex) Rf 0.24; HPLC ES-MS m/z (relative abundance) 205 (MH+, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[OH:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[O:17][CH2:19][CH2:20][CH2:21][OH:22])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: Oc1cccc2nn(Cc3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCOc1cccc2nn(Cc3ccccc3)cc12

Procedure:
A mixture of 24 g. 2-benzyl-4-hydroxyindazole, 10.4 ml. 3-bromopropan-1-ol and 16 g. potassium carbonate in 100 ml. dimethylformamide is stirred for 30 hours at 70° C. After dilution with methylene chloride, the reaction mixture is filtered with suction, the filtrate is evaporated and the evaporation residue is purified chromatographically on silica gel (elution agent methylene chloride-ethyl acetate 9:1 v/v), 2-benzyl-4-(3-hydroxypropoxy)-indazole being obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH2:33][C@H:34]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:35][OH:36]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:33][C@@H:34]([CH2:35][OH:36])[CH2:37][CH:38]([CH3:40])[CH3:39])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CC(C)C[C@@H](N)CO
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Product: CC(C)C[C@H](CO)Nc1ccc(C(=O)c2sc(Nc3ccc(N4CCN(C)CC4)cc3)nc2N)cc1[N+](=O)[O-]

Procedure:
This compound was prepared from the compound of Example 15 and (R)-2-amino-4-methyl-1-pentanol (Aldrich) by the procedure used in Example 57. Mass spectrum (ES) MH+=554.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[NH:33]N>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1cc(F)ccc1F
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1cc(F)ccc1F
Yield: 32 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 2,5-difluorophenylhydrazine according to the method described for Example 1 in 32% yield. MS: M=419.1 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[OH:20])[N:10]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[OH:28])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][OH:43].[I-].[K+]>C(O)COCCO.COC>[C:1]1([C:7]2[N:8]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][C:22]=3[OH:28])[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][OH:43])=[CH:15][C:14]=3[OH:20])[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Reactant: OCCCCCCCCCCCBr
Agent: COC
Agent: [I-]
Agent: [K+]
Solvent: OCCOCCO
Product: CCCCCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(OCCCCCCCCCCCO)cc3O)n2)c(O)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A mixture of 37.3 g of 2-phenyl-4,6-bis-(2,4-dihydroxy-phenyl)-1,3,5-triazine (0.100 moles ), 6.6 g of powdered KOH (Fluka, >85%, 0.100 moles), 25.9 g of 11-bromo-1-undecanol(Fluka, 97%, 0.103 moles), and 0.6 g (3.6 mmoles) of Potassium iodide (Merck, 99.5% ) in 160 mL of diethyleneglycol-dimethyl ether (Diglyme, Fluka, 99% ) is heated under stirring at 110° C. for 4 hours 30 min. After cooling to 50° C., there are added 6.6 g (0.100 moles) of powdered KOH (Fluka, >85% ) and 17.0 g (0.103 moles) of n-bromohexane (Fluka, 98%). The mixture is heated at 105° C. under stirring for 14 hours. The mixture is filtered hot and the filtrate evaporated (rotovapor). The product is submitted to a column chromatography [Kieselgel 60, 230-400 mesh; 10 cm diameter; h=30 cm; eluant: CH2Cl2 ]. The first eluted product is the di-hexyl-derivative, the second eluted product eluted is the desired title product and the third product is the product dialkylated by two groups 11-hydroxyundecyl. After drying at 60° C./60 mmHg for 24 hours, there are obtained 22.5 g (35.8% yield) of 2-phenyl-4-(2-hydroxy-4-n-hexyloxy-phenyl)-6-[2-hydroxy-4-(11-hydroxy-undecyloxy)-phenyl]-1,3,5-triazine, as a pale yellow solid, F. 96°-99° C.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[O:19]([C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24])[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:19]([C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)=[O:24])[CH3:20]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 2,6-dimethoxylbenzoyl chloride (20 mg, 0.0997 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: ICCI.[Sm].C(=O)=O.CC(C)=O.[CH2:13]([CH:15]1[CH:41]=[C:40]([CH3:42])[CH2:39][CH:38]([CH3:43])[CH2:37][CH:36]([O:44][CH3:45])[CH:35]2[O:46][C:31]([OH:50])([CH:32]([CH3:49])[CH2:33][CH:34]2[O:47][CH3:48])[C:30](=[O:51])[C:29](=[O:52])[N:28]2[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[C:22](=[O:53])[O:21][CH:20]([C:54]([CH3:74])=[CH:55][CH:56]2[CH2:61][CH2:60][CH:59]([C:62]3[CH:71]=[CH:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH:63]=3)[CH:58]([O:72][CH3:73])[CH2:57]2)[CH:19]([CH3:75])[CH:18]([OH:76])[CH2:17][C:16]1=[O:77])[CH3:14]>C1COCC1.C1COCC1.CO>[CH2:13]([CH:15]1[CH:41]=[C:40]([CH3:42])[CH2:39][CH:38]([CH3:43])[CH2:37][CH:36]([O:44][CH3:45])[CH:35]2[O:46][C:31]([OH:50])([CH:32]([CH3:49])[CH2:33][CH:34]2[O:47][CH3:48])[CH:30]([OH:51])[C:29](=[O:52])[N:28]2[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[C:22](=[O:53])[O:21][CH:20]([C:54]([CH3:74])=[CH:55][CH:56]2[CH2:61][CH2:60][CH:59]([C:62]3[CH:71]=[CH:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH:63]=3)[CH:58]([O:72][CH3:73])[CH2:57]2)[CH:19]([CH3:75])[CH:18]([OH:76])[CH2:17][C:16]1=[O:77])[CH3:14]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(c4ccc5ccccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: ICCI
Agent: O=C=O
Agent: [Sm]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(c3ccc4ccccc4c3)C(OC)C2)C(C)C(O)CC1=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 22.3 %

Procedure:
A solution of 1,2-diiodoethane (42 mg, 0.15 mmol) in dry THF (1 mL) was added dropwise to a stirred mixture of samarium metal (46.5 mg, 0.31 mmol) in dry THF (1 mL) and stirred for 1.5 hours. The reaction mixture was then cooled to -78° C. (dry ice/acetone) and treated with a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.109 mmol) in 1:1 THF/CH3OH. The mixture was maintained at -78° C. for 15 minutes then allowed to warm to room temperature. The reaction was quenched with cold saturated aqueous K2CO3 and quickly extracted with CH2Cl2. The extracts were combined, dried with Na2SO4, filtered and concentrated in vacuo. Purified by preparative TLC on silica gel (eluted with 7% CH3OH in CH2 Cl2) to give 22 mg of 17-ethyl-1,2,14-trihydroxy-12-[2'-(4"-(naphth-2-yl)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-3,10,16-trione (1H NMR and mass spectral analysis are consistent with the desired structure).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:29])[F:30])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of 4-Trifluoromethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.31 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.54-7.59 (m, 2H), 7.73 (d, 1H, J=8.0 Hz), 7.77 (d, 1H, J=9.2 Hz), 7.97 (d, 1H, J=8.0 Hz), 8.00 (s, 1H), 8.82 (dd, 2H, J=6.0 Hz, 1.2 Hz), 10.16 (s, 1H). MS: m/z 441.8 (M++1).