Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[O:8])[O:4][N:3]=1.[CH2:9]([Mg]Br)[CH3:10]>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([OH:8])[CH2:9][CH3:10])[O:4][N:3]=1
Reactant: CC[Mg]Br
Reactant: Cc1cc(C=O)on1
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)no1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methylisoxazole-5-carbaldehyde (0.801 g, 7.21 mmol) in 10 mL of THF at −78° C. was added ethylmagnesium bromide (3.60 mL, 10.81 mmol) slowly. The reaction mixture was stirred at −78° C. for 2 h, then quenched with saturated aq. NH4Cl solution, and extracted with ether (3×80 mL). The combined organic layers were dried over Na2SO4 filtered and the filtrate was evaporated to provide the crude product. The crude product was purified by chromatography on silica gel, eluting with 10 to 60% EtOAc/hexane to provide the title compound. Mass Spectrum (ESI) m/z=142.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])[C:3]=1[C:20]([O:22]C)=O.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH2:31]>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:10])[C:3]=1[C:20](=[O:22])[NH:31][CH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1
Reactant: NCc1ccccn1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)NCc1ccccn1

Procedure:
Same procedure as described in preparation 133a was used from (S)-methyl 3-bromo-1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (374 mg, 0.96 mmols) and pyridine-2-ylmethanamine (0.30 ml, 2.87 mmols). After reverse phase chromatography the title compound was obtained (74 mg, 17%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]([CH:23]=[O:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:25](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:25])[CH:18]=[C:17]([CH:23]=[O:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1cc(C=O)cc(C=O)c1
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C=Cc1cc(C=O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A solution of 2.87 g of methyl (RS)-(4-cyano-phenylamino)-(3,5-diformyl-phenyl)-acetate in 20 ml of dioxan and 1.3 ml of DMF was treated with 3.18 g of methyltriphenylphosphonium bromid and 1.84 g of potassium carbonate. The suspension was heated for 3 days to 100° C. It was left to cool to room temperature, filtered and concentrated. The crude product was isolated by extraction isoliert and purified by chromatography on silica gel. There were obtained 1.31 g of methyl (RS)-(4-cyano-phenylamino)-(3-formyl-5-vinyl-phenyl)-acetate as a light yellow solid.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C)C=O>[NH2:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([C:5]([OH:4])=[O:15])=[C:7]([O:14][CH:16]=[CH:17][CH3:18])[CH:8]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC=COc1cc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (1.52 g, 0.038 mole) in anhydrous dimethylformamide (50 ml) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 0.030 mole), stirred at room temperature for 30 minutes, and treated with allyl bromide (4.60 g, 0.038 mole). The mixture was stirred at 95°±5° C. for one hour, cooled to room temperature, and added to water (250 ml). The solid was removed by filtration and saved, and the filtrate was extracted with ether (2×100 ml). The concentrated ethereal extracts were combined with the filtered solid, taken up in 20% aqueous ethanol (100 ml), treated with potassium hydroxide (10 g), and refluxed for 45 minutes. The ethanol was removed in vacuo and the aqueous solution was extracted with ether (50 ml) and petroleum ether (30°-60°, 50 ml), cooled (0° C.), and acidified to pH 4 with concentrated hydrochloric acid (17 ml). The suspension was filtered and solid was air dried, dissolved in methylene chloride (150 ml) containing a little methanol, dried (sodium sulfate), and concentrated in vacuo. Trituration from cold ether/petroleum ethers (30°-60°) and recrystallization from ethyl acetate/hexane (2 crops) afforded 4.25 g (62.2%) of the title compound as a pale tan solid; mp 136°-137° C.
Reaction SMILES: COC1C=CC(C2C[CH2:27][C:26]3C(=CC=[C:24]([O:29]C)[CH:25]=3)C2)=C(NCCC2C=CC(O)=CC=2)C=1.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH:47][C:48]2[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=2[CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)CC)C.C1(C(Cl)=O)CC1>O1CCCC1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][N:47]([C:48]2[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=2[CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)[C:24]([CH:25]2[CH2:26][CH2:27]2)=[O:29])=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C2
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(O)cc1)C2
Agent: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)C1CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesized from 4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamino]ethyl}phenol according to an analogous synthetic method to Example 201, to a solution of the resulting {2-[4-(tert-butyldimethylsilyloxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (2.3 g) in tetrahydrofuran (50 ml) was added triethylamine (895 mg), cyclopropanecarbonyl chloride (693 mg) was added dropwise thereto on an ice bath followed by stirring for 30 minutes at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.3 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.Cl.[NH2:53][CH2:54][C:55]1[N:56]=[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]2[CH:63]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:53][CH2:54][C:55]4[N:56]=[C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][N:58]5[CH:63]=4)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: NCc1cn2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn2ccccc2n1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.8 %

Procedure:
To a stirred solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (70 mg, 0.13 mmol) in CH2Cl2 (1 mL) were added N,N-diisopropylethylamine (85 μL, 0.49 mmol), 2-aminomethylimidazo[1,2-a]pyridine dihydrochloride (36 mg, 0.16 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34 mg, 0. 18 mmol), and 1-hydroxybenzotriazole (24 mg, 0.18 mmol). The suspension was allowed to stir at r.t. for 17 hr, and the solvent was removed under reduced pressure. The resulting solid was suspended in DMF (1 mL) and stirred for an additional 4 hr before being concentrated under reduced pressure, dissolved in CH2Cl2, filtered through Celite, and chromatographed on silica gel (gradient elution: 0%→20% MeOH in CH2Cl2) to afford the title compound as a yellow solid (22 mg, 35% yield). LC/MS (ESI) retention time: 1.53 min, m/z 683 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.13-1.21 (m, 1 H) 1.29-1.45 (m, 4 H) 1.57-1.67 (m, 1 H) 1.69-1.79 (m,2 H) 1.84-1.95 (m, 1 H) 1.96-2.12 (m, 3 H) 2.30-2.31 (m, 4 H) 2.57-2.75 (m, 2 H) 2.80-2.81 (m, 1 H) 3.60 (s, 4 H) 4.36 (s, 1 H) 4.80 (s, 2 H) 5.06 (s, 1 H) 6.74 (t, J=6.42 Hz, 1 H) 6.79 (s, 1 H) 7.07-7.18 (m, 1 H) 7.32-7.37 (m, 2 H) 7.39-7.46 (m, 2 H) 7.47-7.56 (m, 3 H) 7.60 (s, 1 H) 7.84 (d, J=8.56 Hz, 1 H) 7.99-8.10 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([I:12])[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:13]>CC(O)C.O>[Br:1][C:2]1[N:3]=[C:4]([I:12])[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:13])[C:6]=12
Reactant: N
Reactant: Clc1nccn2c(I)nc(Br)c12
Solvent: CC(C)O
Solvent: O
Product: Nc1nccn2c(I)nc(Br)c12
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-bromo-8-chloro-3-iodo-imidazo[1,5-a]pyrazine (250.00 mg, 0.696 mmol) in i-PrOH (8 mL) in a Parr bomb was added 7 mL ammonia in water (35%). The resulting solution was stirred at 95° C. overnight. The solvent was removed under reduced pressure and the crude material was passed through a short silica gel column (5% MeOH in DCM as eluent). The fractions were collected and combined, solvent was removed under reduced pressure to give a residue which was used in next step without further purification. MS (ES+): m/z: 338.80, 340.81 [MH+]. HPLC: tR=1.64 min (OpenLynx: polar—5 min).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.I[CH:13]([CH3:15])[CH3:14]>CCOC(C)=O.[Ag-]=O>[CH:13]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)([CH3:15])[CH3:14]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CC(C)I
Agent: O=[Ag-]
Solvent: CCOC(C)=O
Product: CC(C)OC1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-ol (0.5 g, 3.16 mmol) in 2-iodopropane (5.37 g, 31.6 mmol), silver (I) oxide (1.392 g, 6.01 mmol) was added and the reaction mixture was stirred at room temperature. Upon completion the resulting suspension was diluted with EtOAc and the suspension filtered under reduced pressure. The filtrate was concentrated under reduced pressure to give a pale yellow oil. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-30% EtOAc in iso-hexane to afforded the title compound;
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[C:8]([NH2:27])=[N:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:15](=[O:26])[O:16][C:17]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=2[C:19]=1[CH3:20].Br[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:20][C:19]1[C:18]2[CH:21]=[CH:22][C:23]([O:25][C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:24][C:17]=2[O:16][C:15](=[O:26])[C:14]=1[CH2:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:27])[C:7]=1[F:6]
Reactant: Brc1ncccn1
Reactant: Cc1c(Cc2ccnc(N)c2F)c(=O)oc2cc(O)ccc12
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cc2ccnc(N)c2F)c(=O)oc2cc(Oc3ncccn3)ccc12
Temperature: 115 °C
Reaction time: 3.5 h
Yield: 89.5 %

Procedure:
Under a nitrogen atmosphere, 3-(3-fluoro-2-aminopyridin-4-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran methanesulfonate (7.6 g, 19.2 mmol) and 2-bromopyrimidine (4.0 g, 24.9 mmol) were dissolved in DMF (122 mL), potassium carbonate (5.8 g, 42.2 mmol) was added, and the mixture was stirred at 115° C. for 3.5 hours. The reaction mixture was cooled to 28° C., water (122 mL) was added dropwise over a period of 0.5 hours at that temperature, and the mixture was stirred for 2 minutes. The mixture was further cooled to 0° C. and stirred for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water (61 mL) and acetonitrile (61 mL) in that order, and dried under reduced pressure to obtain the title compound as crystals (6.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[N+](C1C=CC([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35])=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
After dissolving 6-methoxy-4-(4-nitrophenoxy)quinolin-7-ol (1.0 g) in dimethylformamide (10 ml), there were added trifluoromethanesulfonic acid 4-nitrophenyl ester (640 mg) and potassium carbonate (1.3 g), and the mixture was stirred at room temperature for 5 hours. Water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was used for recrystallization to obtain the title compound (1.0 g).
Reaction SMILES: [CH3:1][C:2]([OH:5])([CH3:4])[CH3:3].[Li]CCCC.C(Cl)C=CC.[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[C:18]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:19])/[CH:17]=[CH:16]/[CH3:20]
Reactant: C1CCOC1
Reactant: CC(C)(C)O
Agent: CC=CCCl
Agent: [Li]CCCC
Product: C/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of t-BuOH (0.50 mol, 37.1 g, 47.8 mls) in THF (500 mls) is cooled to 5° C.; then over a 30 minute period n-BuLi (0.56 mol., 350 ml, 1.6 M) is added to the solution. The resulting mixture is stirred for 40 minutes at room temperature. Crotyl chloride (0.50 mol., 52.3 g, 47.9 mls) in THF (250 mls) is added to the reaction mixture at room temperature over a 15 minute period. The resulting mixture is heated under reflux for 50 minutes. The reaction mixture is cooled to 0° C. and ice-water (800 mls) is added. The layers are separated and the aqueous layer is extracted with Et2O (3×600 mls). The organic phases are combined, dried over Na2SO4, filtered and concentrated by rotary evaporation to give a red oil. Distillation (55° C., 22 mm) yields t-butyl crotonate: 1H NMR (300 MHz, CDCl3) δ1.46 (s, 9H), 1.83 (dd, J is 6.9, 1.7 Hz, 3H), 5.74 (dq, J is 15.5, 1.7 Hz, 1H), 6.85 (dq, J is 15.5, 6.9 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cccc2[N+](=O)[O-])CC1
Yield: 74.4 %

Procedure:
To a stirred solution of 1.01 g (5.0 mmol) of 1-chloro-2, 6-dinitrobenzene and 0.93 g (5.0 mmol) of 1-tert-butyloxycarbonylpiperazine in acetonitrile (5 mL) was added 1.38 g (10 mmol) of K2CO3. The mixture was heated to reflux for 48 h. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 mL) and 20 mL of H2O. The organic layer was washed with H2O (2×20 mL), dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% EtOAc/hexanes) provided 1.31 g (85%) of 4-(2,6-dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester TLC (silica, 20% EtOAc/hexanes): Rf=0.35. 1H NMR (400 MHz, CDCl3): 7.75 (d, J=8.2 Hz, 2H), 7.25 (t, J=8.2 Hz, 1H), 3.30 (m, 4H), 2.95 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:10]([OH:21])[CH:9]1[CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[CH:10]([O:21][S:45]([CH3:44])(=[O:47])=[O:46])[CH:9]1[CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C(O)C1CCNC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C(OS(C)(=O)=O)C1CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing crude 8 (500 mg, 1.01 mmol) in DCM (15 mL) was cooled to 0° C. DIPEA (261 mg, 2.02 mmol) was added followed by the addition of MsCl (117 mg, 1.02 mmol) and DMAP (13 mg, 0.1 mmol). After 2 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 578 mg (quant.) of crude 9 as a tan-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.35 (m, 5H), 5.90 (m, 1H), 5.10 (m, 2H), 4.67 (m, 1H), 4.40 (m, 1H), 4.11 (m, 2H), 3.94 (m, 0.5H), 3.80 (m, 0.5H), 3.74 (app dd, J=12.2, 5.0 Hz, 1H), 3.51 (m, 0.5H), 3.31 (m, 0.5H), 3.02 (s, 3H), 1.96 (m, 0.5H), 1.85 (m, 0.5H), 1.46 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H) ppm. Mass spectrum, m/z [595.2] (M+Na)+.
Reaction SMILES: [Br-].C(CCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[Br-].[C:28]([CH2:31][CH:32]([CH3:56])[CH:33]([CH3:55])[CH2:34][CH2:35][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:30])=[O:29].[CH2:57]([O:59][C:60]1([CH2:68][CH2:69]CC=O)[CH:64]=[CH:63][CH:62]([O:65][CH2:66][CH3:67])[O:61]1)[CH3:58].C(OC1(CC=O)C=CC(OCC)O1)C>C(O)C>[CH2:57]([O:59][C:60]1(/[CH:68]=[CH:69]\[CH2:35][CH2:34][CH:33]([CH3:55])[CH:32]([CH3:56])[CH2:31][C:28]([OH:30])=[O:29])[CH:64]=[CH:63][CH:62]([O:65][CH2:66][CH3:67])[O:61]1)[CH3:58]
Reactant: CCOC1C=CC(CCCC=O)(OCC)O1
Reactant: CC(CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(C)CC(=O)O
Agent: CCOC1C=CC(CC=O)(OCC)O1
Agent: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCO
Product: CCOC1C=CC(/C=C\CCC(C)C(C)CC(=O)O)(OCC)O1

Procedure:
Adaptation of the above-described procedures to the preparation of the other compounds of this invention essentially involves the lengthening or shortening of, or the introduction of one or two lower alkyl groups into, the side-chains in furans (I) or (XVII) or in phosphonium derivative (III). These adaptations can be accomplished by procedures well-known to the art. For example, isopropyl γ-(2-furyl)-butyrate provides 2,5-dihydro-2,5-di-n-propoxy-2-(3'-carboisopropoxypropyl)furan in n-propanol whereas methyl δ-(2-furyl)valerate provides 2,5-dihydro-2,5-diethoxy-2-(4'-carbomethoxybutyl)furan in ethanol when treated in the manner described for the conversion of (I) to (II). Similarly, ω-(2-furyl)caproic acid and ω-(2-furyl)enanthic acid provide 2,5-dihydro-2,5-diethoxy-2-(5'-carboxyentyl)furan and 2,5-dihydro-2,5-diethoxy-2-(6'-carboxyhexyl)furan when treated in ethanol in the manner described for the conversion of (XVII) to (XVIII). Optionally, the furyl acids may be first esterified prior to oxidative alkoxylation, and all 2,5-dihydro-2,5-dialkoxy-2-(carboalkoxyalkyl)furans may be converted to the corresponding aldehydes in the manner described for the conversion of (II) to (IV). Also, the reaction of 3-carboxypropyltriphenylphosphonium bromide and 5-carboxy-3,4-dimethylamyltriphenylphosphonium bromide with 2,5-dihydro-2,5-diethoxy-2-(4'-oxobutyl)furan and 2,5-dihydro-2,5-diethoxy-2-(2'-oxoethyl)furan, respectively, provides the 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-4'-cis-heptenyl)furan and 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-5',6'-dimethyl-2-cis-heptenyl)furan.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1
Reactant: C1=COCCC1
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1ccc(OCCCCCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,4-Dihydro-2H-pyran (24.7 g) was added drop wise at room temperature to a solution of 4[(6-hydroxyhexyl)oxy]benzoic acid (35 g), toluene-4-sulfonic acid monohydrate (1.8) in diethylether (440 ml) and stirred at room temperature for 18 h. The resulting mixture was filtered over Hyflo Super Cel (FLUKA), organic solvents were removed in vacuum. The residue (60 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (1:1) as eluent, to give after crystallisation from ethyl acetate/hexane (5:40) 4{[6(tetrahydro-2H-pyran-2-yloxy)hexyl]oxy}benzoic acid.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].C(N(CC)C(C)C)(C)C>CCO>[OH:17][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC(O)c1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(NCC(O)c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A flask, containing 4-fluoro-3-nitrobenzoic acid (8.00 g, 43.2 mmol) and 2-amino-1-phenylethanol (8.89 g, 64.8 mmol) dissolved in EtOH (80 mL), was purged with N2. Anh. N,N-diisopropylethylamine (19 mL, 108 mmol) was added and the reaction mixture was heated at reflux for 24 h. Later the reaction was cooled to rt and concentrated under reduced pressure. The solid residue was dissolved in EtOAc, washed (1 M aq HCl (3×), H2O (2×), brine), dried (Na2SO4) and evaporated to dryness to afford the title compound as a bright yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.67 (t, J=5.2 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 7.92 (ddd, J=0.4 Hz, 2.0 Hz, 9.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (t, 7.2 Hz, 2H), 7.28 (tt, J=1.2 Hz, 6.8 Hz, 1H), 7.18 (d, J=9.2 Hz, 1H), 5.89 (d, J=4.4 Hz, 1H), 4.91 (q, J=3.6 Hz, 1H), 3.72-3.63 (m, 1H), 3.53-3.45 (m, 1H). MS (ES+): m/z 285.1 (100) [MH+−18]; HPLC: tR=2.80 min (OpenLynx, polar—5 min).