Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K]>CC(C)=O>[C:1]([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:30]3[C:26](=[O:36])[C:27]4[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:29]3=[O:31])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CBr)cc2)c1
Agent: [K]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c1
Reaction time: 17.5 h

Procedure:
10 g (E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester (compound D2) is dissolved in acetone and 6.5 g potassium phthalimide is added and the mixture is stirred for 17.5 h. The suspension is filtered and the product is purified by crystallization.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](N2C(C)=NN=C2CO)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14](F)=[CH:13][CH:12]=[CH:11][C:10]=1F)=[O:8].P(Br)(Br)Br>>[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:6]1[CH:17]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: BrP(Br)Br
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 5, 5-chloro-2',6'-difluoro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with phosphorus tribromide to give 5-chloro-2',6'-difluoro-2-]3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[C:19]([OH:30])(=O)[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([NH:18][C:24](=[O:26])[C:23]4[CH:22]=[CH:21][C:20]([C:19]([NH:18][C:16]5[CH:15]=[CH:14][C:12]6[NH:13][C:9]([C:6]7[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=7)=[N:10][C:11]=6[CH:17]=5)=[O:30])=[CH:28][CH:27]=4)=[CH:17][C:11]=3[N:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(-c2nc3ccc(N)cc3[nH]2)cc1
Product: COc1ccc(-c2nc3cc(NC(=O)c4ccc(C(=O)Nc5ccc6[nH]c(-c7ccc(OC)cc7)nc6c5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 274 was prepared according to the procedure similar to that described in Scheme V from 2-(4-methoxyphenyl)-5-aminobenzimidazole and terephthalic acid. [M+H]+ calcd for C36H28N6O4: 609.22; found: 608.99.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[C:4]([F:11])[C:3]=1[I:12].[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[N:7][OH:8])[Cl:13])=[C:4]([F:11])[C:3]=1[I:12]
Reactant: ON=Cc1ccc(Cl)c(I)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1ccc(Cl)c(I)c1F
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chloro-2-fluoro-3-iodobenzaldehyde oxime (0.860 g, 2.87 mmol) in DMF (5 mL) at RT was added N-chlorosuccinimide (140 mg). The mixture was heated at 55° C. for 5 min. The mixture was allowed to cool below 50° C. and additional N-chlorosuccinimide (282 mg) was added, and heating continued at 55° C. for 20 min. The resulting reaction mixture was allowed to cool to RT and treated with water (20 mL), and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate layers were washed with brine, dried over magnesium sulfate and concentrated to afford 4-chloro-2-fluoro-3-iodobenzoyl chloride oxime as a light yellow amorphous solid. MS (ESI, pos.ion) m/z: 335 (M+1)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:19][C:20](=[O:33])[CH2:21][O:22][C:23]1[CH:31]=[CH:30][C:29]([SH:32])=[C:28]2[C:24]=1[CH2:25][CH2:26][CH2:27]2>>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:32][C:29]3[CH:30]=[CH:31][C:23]([O:22][CH2:21][C:20]([OH:33])=[O:19])=[C:24]4[C:28]=3[CH2:27][CH2:26][CH2:25]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(C(F)(F)F)cc3)on2)c2c1CCC2

Procedure:
The title compound was prepared in a manner analogous to Example 1F using 42C and 12C. MS m/z 464 (M+1).
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[NH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl[CH2:33][C@@H:34]1[CH2:38][O:37]C(C)(C)[O:35]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH2:33][C@@H:34]([OH:35])[CH2:38][OH:37])[CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(C[C@@H](O)CO)c1
Temperature: 100 °C
Yield: 26.9 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (0.15 g, 0.35 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.27 g, 1.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) was added N,N-dimethylformamide and the reaction mixture was heated to 100° C. overnight. The reaction was diluted with dichloromethane (20 mL) and washed with 1N hydrochloric acid (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL). The organics were dried over sodium sulfate and evaporated. The crude residue was purified by silica gel chromatography (eluting with 0-10% methanol in dichloromethane) to yield the product (47 mg, 27%). ESI-MS m/z calc. 499.16. found 500.2 (M+1)+. Retention time 1.53 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1.[CH2:29](O)[CH2:30][CH3:31]>>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH:30]([CH3:31])[CH3:29])[S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CN(C)CCCCOc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCCO
Product: CC(C)N(c1ccc(OCCCCN(C)C)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 14.1, reaction of N-[4-(4-Dimethylamino-butoxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide 69-2511 with 1-propanol yielded N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-isopropyl-4-trifluoromethyl-benzenesulfonamide, MS: 459 (MH+).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:25]([O:32][C:33]([CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:25]([O:32][C:33]([CH:35]1[CH2:39][CH2:38][N:37]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])=[N:15][CH:14]=2)[CH2:36]1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(OCc1ccccc1)C1CCNC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C(OCc1ccccc1)C1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)C1
Yield: 49.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg. 0.20 mmol), pyrrolidine-3-carboxylic acid benzyl ester hydrochloride (50 mg, 0.25 mmol) and sodium triacetoxyborohydride (55 mg, 0.26 mmol) to afford 52 mg (50%) of the desired product after purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]2[NH:7][C:8]([CH:10]3[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)=[N:9][C:5]=2[CH:4]=1.CO>O1CCOCC1>[NH:12]1[CH2:13][CH:10]([C:8]2[NH:7][C:6]3[CH:21]=[CH:22][C:3]([Cl:2])=[CH:4][C:5]=3[N:9]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Clc1ccc2[nH]c(C3CNC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
Hydrochloric acid, 4.0 m solution in 1,4-dioxane (16.25 mL, 65.0 mmol) was added to a solution of tert-butyl 3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate (2 g, 6.50 mmol) in dioxane (20 ml) under argon. MeOH (20 mL) was added to the resulting suspension to make a solution and the mixture was stirred for 2 h at RT, at which time it turned back to a suspension. The mixture was filtered and the collected solid was washed with dioxane and air dried to give product as a white solid (840 mg). The filtrate was then concentrated and then dissolved in a minimum of MeOH. Et2O was added slowly and the resulting suspension was filtered and dried to give an additional 560 mg product as a light grey solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][N:29]1[C:33]([NH2:34])=[CH:32][CH:31]=[N:30]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:34][C:33]3[N:29]([CH3:28])[N:30]=[CH:31][CH:32]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: Cn1nccc1N
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccnn3C)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 2-methyl-2H-pyrazol-3-ylamine according to procedure B followed by deprotection yielded the title compound as a pale brown waxy solid. MS (ESI): m/z=359.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14].FC1C(F)=CC=C([N+]([O-])=O)C=1C(C(OCC)=O)C(OCC)=O.Cl>>[F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1F
Agent: CCOC(=O)C(C(=O)OCC)c1c([N+](=O)[O-])ccc(F)c1F
Agent: Cl
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(F)c1F

Procedure:
The mixture of diethyl 2-(2,3-difluoro-4-nitrophenyl)malonate and diethyl 2-(2,3-difluoro-6-nitrophenyl)malonate from D15 (0.5 g) was heated with 11M hydrochloric acid (5 ml) at reflux overnight then evaporated to give 320 mg of the title compound (pale yellow solid) as a 1:1 mixture with 2,3-difluoro-6-nitrophenylacetic acid. M−−CO2H=172.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([NH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]1[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>ClCCl>[CH2:5]([NH:17][C:28](=[O:29])[CH2:27][CH2:26][CH:25]([OH:30])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCC1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)CCC(O)CCCCCCC
Reaction time: 4 h
Yield: 6.8 %

Procedure:
To a suspension of 19.0 g aluminum trichloride in 50 ml of dichloromethane, a solution of 46.5 g dodecylamine in 50 ml of dichloromethane was dropped in at 15-20° C. Then 19.3 g gamma-undecalactone were added quickly at room temperature and an additional 50 ml of dichloromethane was added. After 4 hours, the reaction mixture was quenched with water and filtered through celite. The filtrate was diluted with ether and washed with brine. The organic phase was dried, filtered and evaporated to dryness. The resulting brown solid was purified by recrystallisation to yield 2.65 g of colourless crystals.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([S:15](=[O:18])(=[O:17])N)=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[NH:10][CH:9]=[N:8][C:7]=2[CH:14]=1.[Cl:21]S(O)(=O)=O>O>[F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([S:15]([Cl:21])(=[O:18])=[O:17])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[NH:10][CH:9]=[N:8][C:7]=2[CH:14]=1
Reactant: O=S(=O)(O)Cl
Reactant: NS(=O)(=O)c1cc2c(cc1C(F)(F)F)N=CNS2(=O)=O
Solvent: O
Product: O=S(=O)(Cl)c1cc2c(cc1C(F)(F)F)N=CNS2(=O)=O

Procedure:
6-Trifluoromethyl-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide (0.2 mole) is added portionwise with stirring to chlorosulfonic acid (300 ml.) cooled in an ice-bath over 30 minutes. The mixture is then heated for 2 hours on the steam bath, cooled and poured onto a mixture of ice and water. The solid is collected on the filter, washed with cold water and air-dried at room temperature and recrystallized from acetone-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][OH:26])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[S:39](Cl)(Cl)=[O:40]>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[NH:27][S:39](=[O:40])[O:26][N:25]=3)=[CH:22][CH:23]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=N)NO)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C3=NOS(=O)N3)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 9.2 %

Procedure:
A solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-N-[4-(N-hydroxycarbamimidoyl)-phenyl]-benzamide (110 mg, 0.23 mmol) in tetrahydrofuran (7.0 ml) under argon was treated with pyridine (37 mg, 2 equiv.) and cooled to 0° C. A solution of thionyl chloride (28 mg, 1.01 equiv.) in dichloromethane (1.0 ml) was then added dropwise in 6 min. The mixture was stirred at 0° C. for 20 min and then at room temperature for 45 min. The solvent was evaporated and the residue diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Purification via preparative HPLC (Column: ZORBAX ECLIPSE XDB-C18, 21.2×50 mm, 5 um, PN 970050-902, SN USDN001082. Gradient: 0-1.2 min: 10% CH3 CN in (water+0.1% HCO2H), 1.2-4.7 min: increasing of CH3CN from 10% to 95%, 4.7-5.7 min: 95% of CH3CN, 5.7-59 min: decreasing of CH3CN from 95% to 10%. Program end at 6 min. Flow:30 ml/min) yielded the title compound as a light green solid (11 mg, 9%), MS (ISP): m/e=519.1 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:3](=[O:6])[CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.Br[C:28]1[CH:29]=[N:30][C:31]2[NH:40][C:39](=[O:41])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[CH2:33][C:32]=2[CH:42]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([CH2:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:3](=[O:6])/[CH:4]=[CH:5]/[C:28]1[CH:29]=[N:30][C:31]2[NH:40][C:39](=[O:41])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[CH2:33][C:32]=2[CH:42]=1
Reactant: O=C1Nc2ncc(Br)cc2CN2CCC[C@@H]12
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN2CCC[C@H]2C(=O)N3)oc2ccccc12
Yield: 82 %

Procedure:
A solution of N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.210 g, 0.920 mmol) in propionitrile (3 mL) and DMF (0.65 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.24 mL, 1.4 mmol) and (S)-6-bromo-1,2,3,4,9,10a-hexahydro-3a,8,9-triazabenzo[f]azulen-10-one (0.200 g, 0.708 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.015 g, 0.070 mmol) and P(o-tol)3 (0.067 g, 0.14 mmol) were then added and the solution was deoxygenated with Ar for 20 min. The solution was heated to reflux for 18 h, then allowed to cool. The solution was diluted with CH2Cl2 (50 mL) and was washed with H2O (3×100 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 98:2) gave the title compound (0.25 g, 77%) as a glassy yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.60-8.50 (m, 1H), 7.75-7.67 (m, 2H), 7.49-7.48 (m, 1H), 7.42-7.40 (m, 1H), 7.28-7.16 (m, 3H), 4.83-4.71 (m, 2H), 3.99-3.82 (m, 2H), 3.59-2.57 (m, 1H), 3.23-3.08 (m, 3H), 2.89-2.86 (m, 2H), 2.53-2.44 (m, 1H), 2.31-2.30 (m, 3H), 2.04-1.68 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:20]1[C:33]2[C:32](=[C:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[S:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:37]2[CH2:38][CH2:39][C:34](=[C:32]3[C:33]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[S:25][C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:35][CH2:36]2)=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Sc1ccccc1C2=C1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)N2CCC(=C3c4ccccc4Sc4ccccc43)CC2)cc1
Yield: 40.5 %

Procedure:
To a magnetically stirred, ice-cooled solution of p-dimethylaminobenzoyl chloride (0.02 mole) and triethylamine (20 ml) in methylene chloride (300 ml) under an argon atmosphere was added dropwise a solution of 4-(9-thioxanthylidene)-piperidine (0.0133 mole) in methylene chloride (100 ml) over a twenty minute period. After stirring for 48 hours at room temperature, water (250 ml) was added and the mixture stirred for an additional 30 minutes. The layers were separated and the organic layer was washed with water (100 ml), 5% sodium hydroxide (2×200 ml) and water (250 ml), and then dried over sodium sulfate, filtered and stripped under reduced pressure to a dark orange oil. The product was purified by low pressure column chromatography using a 25×1000 mm column packed with 250 g. of silica gel absorbent and eluted with ethyl acetate to yield 2.3 grams of the product. Recrystallization from toluene yielded 2.1 g. of product, m.p. 178°-186° C. (decomp.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][C:13]2[C:8](=[C:9]([O:19][CH3:20])[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15]([NH2:16])=[CH:14][C:13]2[C:8](=[C:9]([O:19][CH3:20])[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2c(OC)cccc2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c(OC)cccc2cc1N

Procedure:
Palladium-on-carbon (10%, 1.281 g, 1.204 mol, 0.1 equiv) was added under an atmosphere of argon to a solution of 8-methoxy-3-nitro-naphthalene-2-carboxylic acid ethyl ester (3.313 g, 12.04 mmol) in EtOH (50 ml). The atmosphere was replaced by hydrogen gas, and the mixture was stirred at room temperature for 3 hours (hydrogen balloon). The atmosphere was changed back to argon, the catalyst was filtered off and the filtrate was concentrated in vacuo to afford the title compound (2.820 g, 96%, inseparable 1:1.15 mixture of regioisomers A:B) of adequate purity for direct use in the next transformation. 1H NMR (400 MHz, CDCl3): δ=8.88 (s, 1H isomer B), 8.44 (s, 1H isomer A), 7.36 (s, 1H isomer A), 7.32-7.26 (m, 1H isomer A+1H isomer B), 6.91 (s, 1H isomer B), 6.73 (d, J=7.4 Hz, 1H isomer A), 6.50 (d, J=7.6 Hz, 1H isomer B), 4.41 (q, J=7.0 Hz, 2H isomer B), 4.40 (q, J=7.1 Hz, 2H isomer A), 3.97 (s, 3H isomer B), 3.96 (s, 3H isomer A), 1.44 (t, J=7.1 Hz, 3H isomer B), 1.44 (t, J=7.0 Hz, 3H isomer A). MS (ES+): 246 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:21][CH:22]1[C:23]([O:65]C(OCC)C)([CH3:64])[CH2:24][CH2:25][CH:26]([O:58]C(OCC)C)[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:57])=[CH:37]/[CH:38]=[CH:39]/[CH:40]([CH3:56])[CH2:41][CH:42]2[O:55][CH:43]2[CH:44]([CH3:54])[CH:45]([O:48]C(OCC)C)[CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]1)=[O:29])(=[O:20])[NH2:19]>CO>[C:18]([O:21][CH:22]1[C:23]([OH:65])([CH3:64])[CH2:24][CH2:25][CH:26]([OH:58])[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:57])=[CH:37]/[CH:38]=[CH:39]/[CH:40]([CH3:56])[CH2:41][CH:42]2[O:55][CH:43]2[CH:44]([CH3:54])[CH:45]([OH:48])[CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]1)=[O:29])(=[O:20])[NH2:19]
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(N)=O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(N)=O)/C=C/C1C
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(N)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(N)=O)C=CC1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridinium p-toluenesulfonate (1.2 mg, 4.8 μmol) was added to a solution of (8E,12E,14E)-7-carbamoyloxy-3,6,21-tri(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (3.6 mg, 4.77 μmol) in methanol (1 mL), followed by stirring at room temperature for 3 hours. The reaction mixture was evaporated, ethyl acetate, water and a saturated sodium bicarbonate aqueous solution were added to the resulting residue, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by thin layer chromatography (MERCK Silica gel 60 F254, 0.2 mm, developing solution; methanol-dichloromethane, 1:29) to give the title compound (1.9 mg, 74%) as a colorless oil.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([NH2:14])[CH2:12][NH2:13]>>[CH2:2]([C:1]1[NH:13][CH2:12][CH2:11][N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: NCCN
Product: CCCCCCCC1=NCCN1
Yield: 95 %

Procedure:
The procedure described in Example 5 is followed except that 288 parts of n-octanoic acid and 132 parts of ethylenediamine are employed. 319 parts of 2-n-heptylimidazoline (95% of theory, based on octanoic acid employed) of boiling point 133° C./5.32 mbar are obtained.