Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:15][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:13]2)=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:45][O:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:15][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:45][O:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][O:48]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)O)ccc4O3)C2)c2ccccc21
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)NOC5CCCCO5)ccc4O3)C2)c2ccccc21
Yield: 45.5 %

Procedure:
A suspension of (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (180 mg, 0.447 mmol) in DCM (5 ml) was treated with TEA (0.09 ml, 0.67 mmol) and then with EDC (128 mg, 0.67 mmol), HOBt (90 mg, 0.67 mmol) and NH2OTHP (67 mg, 0.57 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (102 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH:34]([NH2:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([NH:37][CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with isopropylamine, HATU and DIPEA in THF to give 339 as a colorless solid after reverse phase HPLC. MS: (ESI+) 526.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]2[O:15][C:16]([CH:18]=O)=[CH:17][C:7]1=2.C([O-])(=O)C.[Na+].[O-]S([O-])(=O)=O.[Mg+2].[CH3:35][NH:36][CH3:37].C([BH3-])#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]2[O:15][C:16]([CH2:18][N:36]([CH3:37])[CH3:35])=[CH:17][C:7]1=2
Reactant: COC(=O)c1cc2oc(C=O)cc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CNC
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2oc(CN(C)C)cc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 55 %

Procedure:
Methyl 4-(3,4-dichlorobenzyl)-2-formylfuro[3,2-b]pyrrole-5-carboxylate (0.25 g) was dissolved in methanol (5 mL) and THF (10 mL), and to this was added sodium acetate (116 mg) and a portion of MgSO4, followed by dimethylamine solution (2M in methanol, 0.53 mL). After 1 hour, a further 2.5 ml dimethylamine solution was added, followed after 30 min by sodium cyanoborohydride (0.45 g). The reaction was stirred for 18 hours and then quenched by addition of 1M potassium carbonate solution, and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography using ethyl acetate increasing to 10% methanol: ethyl acetate as eluent to give a yellow oil (0.15 g, 55%), NMR d(CDCl3) 2.3 (6H, s), 3.5 (2H, s), 3.8 (3H, s), 5.55 (2H, s), 6.15 (1H, s), 6.85 (1H, s), 6.95 (2H, dd), 7.2 (1H, d), 7.35 (1H, d). M/z (+) 383 (MH+), 381, 338, 336.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:12][CH:11]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:15]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Oc3c(C)cccc3C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C)c1Oc1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution (5.0 mL) of methyl 3-(4-((3-(2,6-dimethylphenoxy)benzyl)oxy)phenyl)propanoate (0.24 g, 0.62 mmol) in methanol was added 1N aqueous sodium hydroxide solution (1.2 mL), and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2-1/4) to give the title compound (0.15 g, yield 64%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C=C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:18][CH:13]=[CH2:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cccc(CCC(=O)O)c1
Solvent: C=CCO
Product: C=CCOC(=O)CCc1cccc(N)c1
Reaction time: 24 h

Procedure:
3-(3-Aminophenyl)propionic acid (1 g, 6.06 mM) was dissolved in allyl alcohol (25 ml), and toluene-4-sulfonic acid (1.21 g, 6.36 mM) added. The mixture was heated to reflux, the distillate being passed through 3 Å molecular sieves, for 24 hours. After neutralisation of the mixture with triethylamine, the solvent was removed, the residue dissolved in ethyl acetate, and washed with water, aqueous NaHCO3, brine, and dried (MgSO4), to give title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(C)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-methylphenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 11, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[N+:16]([O-])=O)[C:12](=[O:19])[N:11]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[CH2:10][CH2:9]2.C(OCC)(=O)C>C1COCC1.CCCCCC.[Fe]>[NH2:16][C:15]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:25]=3[C:26]([F:28])([F:29])[F:27])[C:12]2=[O:19])=[CH:7][C:6]=1[F:5]
Reactant: O=C1c2cc([N+](=O)[O-])c(F)cc2CCN1c1cnccc1C(F)(F)F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1cc2c(cc1F)CCN(c1cnccc1C(F)(F)F)C2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
Iron powder (431.4 mg, 7.72) and acetic acid (10 mL) were added to a stirred solution of 6-fluoro-7-nitro-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-79a: 550 mg, 1.54 mmol) in THF (5 mL). The resulting mixture was stirred for 4 hours at 70° C. The reaction was monitored by TLC (30% ethyl acetate in hexane). The catalyst was filtered through celite bed and the solvent concentrated under reduced pressure to afford 400 mg of the product (80% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8]CC)=[C:4](F)[C:3]=1F.[CH2:13]([Li])[CH2:14][CH2:15]C.CCCCCC>C1COCC1>[CH2:2]([CH:7]1[CH2:3][CH2:4][C:5](=[O:8])[CH2:6]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCOc1ccc(Br)c(F)c1F
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC1CCC(=O)C1
Reaction time: 1.5 h

Procedure:
THF (40 ml) was added to 1-bromo-4-ethoxy-2,3-difluorobenzene (3.56 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to −78° C. n-Butyllithium (1.65 M, in a hexane solution) (9.1 ml) was added dropwise at a temperature of −70° C. or lower. The stirring was continued at −78° C. for another 1.5 hour and 3-butyl-cyclopentanone (2.1 g) obtained in the first step, in a THF (20 ml) solution was added dropwise at a temperature of −70° C. or lower. After the mixture had been stirred at −78° C. for another 1 hour, it was warmed to room temperature, and a saturated aqueous solution of ammonium chloride (50 ml) was added. The mixture was separated, and the water layer was extracted with diethyl ether three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) to give 3-butyl-1-(4-ethoxy-2,3-difluorophenyl)cyclopentanol (2.8 g).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([NH:1][N:2]2[C:7](=[O:8])[C:6]3[S:9][CH:10]=[CH:11][C:5]=3[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3]2)=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.79 (s, 2H) 6.94-7.36 (m, 3H) 7.51-7.64 (m, 4H) 7.61-7.84 (m, 2H) 8.37 (d, J=5.19 Hz, 1H) 11.87 (s, 1H); MS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([NH2:17])=[C:12]([NH2:18])[CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[NH:18][C:12]3[CH:11]=[C:10]([Cl:9])[C:15]([Cl:16])=[CH:14][C:13]=3[N:17]=2)[S:5][CH:6]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=Cc1cc(Br)cs1
Product: Clc1cc2nc(-c3cc(Br)cs3)[nH]c2cc1Cl

Procedure:
2-(4-Bromothiophen-2-yl)-5,6-dichlorobenzimidazole was prepared from 4-bromo-2-thiophenecarboxaldehyde and 4,5-dichloro-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][CH2:2][CH2:3][CH:4]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: COC(=O)CCCCC(CCN)Cc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(CCNS(=O)(=O)c1ccc(Cl)cc1)Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 8-amino-6-(3-pyridylmethyl)-octanoate (0.5 g) is dissolved in 50 mL of methylene chloride and 3 mL of triethylamine is added. To this solution is added dropwise a solution of 0.5g of p-chlorobenzenesulfonyl chloride in 10 mL of methylene chloride. The reaction is stirred at room temperature for 1 hour, the solvent is evaporated and the residue thus obtained purified by chromatography over silica gel, using methylene chloride as eluent to obtain methyl 8-(p-chlorophenylsulfonamido)-6-(3-pyridylmethyl)-octanoate as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.[C:24](=O)(O)[O-].[Na+]>O1CCOCC1.O.CN(C)C=O>[CH3:24][C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1
Reactant: O=C([O-])O
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(Br)cc2C1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(C)cc2C1=O
Temperature: 150 °C

Procedure:
Added to a solution of 0.385 g of methyl 7-bromo-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate in 9.6 cm3 of dioxane, 2 cm3 of water and one drop of dimethylformamide, at a temperature close to 20° C., are 190 mg of sodium bicarbonate. The reaction medium is then degassed under an argon atmosphere, then 58 mg of methylboronic acid and 93 mg of tetrakis(triphenylphosphine)palladium are added. The mixture is heated at 150° C. in a microwave oven for 8 minutes, cooled to a temperature close to 20° C., filtered and concentrated to dryness under reduced pressure (5 kPa). The filtrate is taken up by 20 cm3 of dichloromethane and 10 cm3 of water. The organic phase is extracted, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa). The residual solution (around 4 cm3) is purified by flash chromatography over silica (column: 50 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 80% heptane/20% ethyl acetate then 60% heptane/40% ethyl acetate then 100% ethyl acetate). After concentrating the fractions under reduced pressure, 35 mg of methyl 7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are obtained in the form of a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24]#[N:25])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[C@@H:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1.C(OC(N1CCO[C@@H](C2C=CC(N)=C([Cl:47])C=2)C1)=O)(C)(C)C>>[ClH:2].[Cl:47][C:6]1[CH:7]=[C:8]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:3]=[CH:4][C:5]=1[NH:15][C:16](=[O:26])[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24]#[N:25])[CH:18]=1
Reactant: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)cc(C#N)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Agent: Cl
Product: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2Cl)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methyl-isonicotinic acid (described in example 112) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 29a) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[C:17]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][O:19][N:20]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClC(Cl)C.CN(C1C=CN=CC=1)C>[C:22]([NH:21][C:17]1[C:16]([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:2]=2[Cl:1])=[N:20][O:19][N:18]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1nonc1N
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1nonc1NC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
173 mg (0.5 mmol) of 2-chloro-4-(methylsulfonyl)benzoic acid and 191 mg (0.505 mmol) of N-(4-amino-1,2,5-oxadiazol-3-yl)acetamide are dissolved in 5 ml of dichloroethane at RT and treated with 0.071 ml (0.5 mmol) of triethylamine, 31 mg (0.25 mmol) of DMAP and 483 mg (0.76 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 24 h at RT and subsequently filtered through a glass frit. The residue is washed twice using in each case 1 ml of CH2Cl2. The filtrate is passed over a silica-gel-filled SPE cartridge and eluted twice using in each case 5 ml of a mixture of ethyl acetate/methyl tert-butyl ester (1:1). The organic phase is dried over Na2SO4 and evaporated. The residue is purified by preparative HPLC using acetonitrile/water. Yield 16 mg (9%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCCC1>[C].[Pd].C(O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.1 %

Procedure:
A mixture of ethyl (2E)-3-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]propenoate (0.78 g), 10% palladium carbon (containing 50% water, 0.15 g), tetrahydrofuran (10 mL) and ethanol (5 mL) was stirred under hydrogen atmosphere at room temperature for 2 days. The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.58 g, yield 79%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 543 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.COCC(O)C>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[N:17]([CH3:16])[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCC(C)O
Product: COc1cc2nccc(N(C)c3ccc([N+](=O)[O-])cc3)c2cc1OC
Temperature: 25 °C
Yield: 40 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (0.50 g, 2.24 mmol), N-methyl(4-nitrophenyl)amine; (0.564 g, 3.35 mmol) and p-toluenesulfonic acid (0.192 g, 1.12 mmol) in 1-methoxy-2-propanol (6.56 mL, 67.1 mmol) were heated to 120° C. for 8 h. The reaction was cooled to rt, triturated with ether and filtered to yield (6,7-dimethoxyquinolin-4-yl)methyl(4-nitrophenyl)amine (0.40 g, 40%). LCMS m/z=340 (M+1); 1H NMR (CDCl3) δ: 8.80 (d, 1H, J=4.8 Hz), 8.10 (d, 2H, J=9.4 Hz), 7.5 (brs, 1H), 7.16 (d, 1H, J=4.8), 6.84 (s, 1H), 6.64 (d, 2H, J=9.4 Hz), 4.05 (s, 3H), 3.81 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]1=[O:4].[CH2:15]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:1][CH:2]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]2=[O:4])=[O:28])=[CH:30][CH:31]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCCCC1CCC(OC(=O)c2ccc(OCc3ccccc3)cc2)C(=O)O1
Reaction time: 8 h
Yield: 58.5 %

Procedure:
By customary procedures, 3-chloro-4-hydroxybenzoic acid was reacted with dodecylbromide in a mixed solution of ethanol and water containing sodium hydroxide to produce 3-chloro-4-dodecyloxybenzoic acid, and this acid was reacted with thionyl chloride to obtain 3-chloro-4-dodecyloxybenzoic acid chloride. Separately, 100 mg of (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone and 200 mg of 4-benzyloxybenzoic acid were dissolved in 200 ml of benzene, 190 mg of diethyl azodicarboxylate and 250 mg of triphenylphosphine were added to the solution, and a reaction was carried out at room temperature with stirring overnight. The reaction mixture was concentrated under a reduced pressure, and the concentrate was separated and purified by the silica gel column chromatography to obtain 120 mg of 2-(4'-benzyloxybenzoyloxy)-5-hexyl-δ-valerolactone. This compound was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to obtain 2-(4'-hydroxy-benzoyloxy)-5-hexyl-δ-valerolactone. The obtained compound was dissolved in 20 ml of benzene, and 200 mg of 3-chloro-4-dodecyloxybenzoic acid chloride described above, 200 mg of triethylamine and 20 mg of N,N-dimethylaminopyridine were added to the solution, and a reaction was carried out with stirring overnight. The reaction liquid was treated by customary procedures and the intended product was separated and purified by the silica gel column chromatography. Recrystallization from ethanol gave 80 mg of (2R,5S)-2-[4-(3'-chloro-4'-dodecyloxybenzoyloxy)-benzoyloxy]-5-hexyl-δ-valeerolactone ##STR127##
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[C:20]([CH3:32])([CH3:31])[O:21][C:22](=[C:26]([C:29]#[N:30])[C:27]#[N:28])[C:23]=2[C:24]#[N:25])=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N:33]([O-])=O.[Na+].[F:37][B-:38]([F:41])([F:40])[F:39].[H+]>O>[F:37][B-:38]([F:41])([F:40])[F:39].[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]2[C:20]([CH3:32])([CH3:31])[O:21][C:22](=[C:26]([C:29]#[N:30])[C:27]#[N:28])[C:23]=2[C:24]#[N:25])[CH:15]=[CH:16][C:2]=1[N+:1]#[N:33])([OH:12])=[O:11]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1ccc(N)c(OCCCCCC(=O)O)c1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1ccc([N+]#N)c(OCCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-{2-amino-5-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-phenoxy}-hexanoic acid (0.30 g, 0.69 mmol) at 5° C. in 3.2 mls of fluoroboric acid (60%) was added a solution of sodium nitrite (0.29 g, 4.27 mmol) in 2 mls of water. The cooling bath was removed and the mixture was allowed to stir at room temperature for 2 hours. The resulting yellow solid, 2-(5-carboxy-pentyl oxy)-4-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-benzenediazonium tetrafluoroborate, was removed by vacuum filtration and air dried (0.35 g, 97%). 1H NMR (400 MHz, DMSO) δ: 8.66 (d, 1H, J=8.4 Hz), 8.07 (s, 1H), 7.97 (d, 1H, J=9.2 Hz), 7.86 (d, 1H, J=16.4 Hz), 7.55 (d, 1H, J=16.4 Hz), 4.52 (t, 2H, J=6.4 Hz), 2.27 (t, 2H, J=7.2 Hz), 1.86 (m, 2H), 1.83 (s, 6H), 1.61 (m, 2H), 1.53 (m, 2H). IR (neat): 2360, 2341, 2264, 2230, 1730, 1586, 1481, 1307, 1106.