Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15](Cl)[CH:16]=[CH:17][CH2:18][CH2:19][CH3:20].[Cl-].[Na+]>CN(C)C=O>[CH2:7]([NH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH3:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: CCCC=CCCl
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC=CCNCc1ccccc1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
13 g of potassium carbonate and 20 g of benzylamine were added to 25 ml of N,N-dimethylformamide and, further, 20 g of 2-hexenyl chloride was added and stirred at 100°-120° C. for one hour. After the reaction, 100 ml of an aqueous solution of sodium chloride was added, extracted with ethyl acetate and dried with anhydrous sodium sulfate. After concentration in an evaporator, it was subjected to silica gel column chromatography (hexane/ethyl acetate=1/1, v/v) to obtain 18 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH:21]2[CH2:23][CH2:22]2)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16](C)C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.[NH2:24]N>CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH:21]2[CH2:23][CH2:22]2)=[C:6]([C:7]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][NH:16][N:24]=2)[CH:19]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1OC1CC1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]nc1-c1cc(Cl)ccc1OC1CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Ethyl 2-(5-chloro-2-cyclopropoxybenzoyl)-3-(dimethyl-amino)acrylate (24 g, 71 mmol) was dissolved in 150 mL of HOAc. The reaction mixture was cooled to 0° C. then 85% hydrazine in water (25 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 6 hours, then concentrated in vacuo. The residue was purified by EtOAc/Hexanes=1:2 to afford 24 g of the title compound as a syrup. 1H NMR (DMSO-d6, 400 MHz) δ: 13.41 (s, 1H), 8.26 (s, 0.5H), 7.88 (s, 0.5H), 7.49-7.24 (m, 3H), 4.07-3.99 (m, 2H), 3.82-3.74 (m, 1H), 1.17-1.10 (m, 3H), 0.73-0.46 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br)([O-:15])=[O:14].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 172.4 %

Procedure:
A mixture of 4-fluoroanisole-2-boronic acid (3.3 g, 19.4 mmol), 2-nitrobromobenzene (3.56 g, 17.6 mmol), triphenylphosphine (367 mg, 1.4 mmol), triethylamine (4.6 g, 45.8 mmol), and 40 mL of dimethylformamide was sparged with nitrogen for 5 minutes before adding palladium acetate (160 mg, 0.7 mmol) and heating the mixture to 100° C. for 5 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was shaken with 0.1N sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 2% ethyl acetate/hexanes followed-by 4% ethyl acetate/hexanes to give 7.5 g of the title compound. Yield: 86%. EA. MS(FD).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:9])=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].C(OCC)(=O)C>CS(C)=O>[N:21]([C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:9])=[CH:4][CH:3]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCc2ccc(Cl)cc2Cl)cn1
Temperature: 100 °C

Procedure:
6-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]pyridine-3-carboxamide (1 equivalent) and sodium azide (2.6 equivalents) were suspended in anhydrous DMSO (0.6 M) under nitrogen. The mixture was heated at 100° C. for four days. Ethyl acetate was added and the organic phase washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and the resultant residue dissolved in a 1:1 ethyl acetate/DCM mixture. This solution was purified by flash chromatography over silica (1:1 ethyl acetate/DCM). The fractions coeluting with the major band (Rf 0.53, eluent: 1:1 ethyl acetate/DCM) were combined and evaporated to dryness. The residue was recrystallized from acetonitrile to give 6-azido-N-[2-(2,4-dichlorophenyl)ethyl]-pyridine-3-carboxamide as pale yellow needles. LCMS (MH+) 336.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[N:15][C:14]([C:20](Cl)=[O:21])=[CH:13]2>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[N:15][C:14]([C:20]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:21])=[CH:13]2
Reactant: CCN(CC)CCO
Reactant: O=C(Cl)c1cc2cc(Br)ccc2nn1
Solvent: C1CCOC1
Product: CCN(CC)CCOC(=O)c1cc2cc(Br)ccc2nn1

Procedure:
A solution of 2-diethylaminoethanol (1.4 g.) in dry tetrahydrofuran (15 ml.) was added to a solution of 6-bromocinnolin-3-yl carbonyl chloride (1.07 g.) in dry tetrahydrofuran (15 ml.). The resulting solution was heated under reflux for 2 hours, and the solvent was then evaporated in vacuo. The solid residue was dissolved in water (50 ml.), the solution extracted with ethyl acetate (3× 100 ml.), and the combined extracts dried (MgSO4). The solution was evaporated to a small volume, petroleum ether (b.p. 60°-80° C.; 50 ml.) was added, the resulting mixture was filtered to give, as the solid residue, 2-diethylaminoethyl 6-bromocinnolin-3-yl carboxylate, m.p. 90°-93° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:26]=[CH:25][C:15]([CH2:16][N:17]4[CH2:20][CH:19]([C:21]([O:23]C)=[O:22])[CH2:18]4)=[CH:14][CH:13]=3)[CH:10]=2)[O:5][C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:3]1.COC(C1CN(CC2C=CC(OCC3C4C=C(Cl)C=CC=4OC=3)=CC=2)C1)=O>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:26]=[CH:25][C:15]([CH2:16][N:17]4[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]4)=[CH:14][CH:13]=3)[CH:10]=2)[O:5][C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:3]1
Reactant: COC(=O)C1CN(Cc2ccc(-c3ccc4oc(-c5ccccc5)cc(=O)c4c3)cc2)C1
Agent: COC(=O)C1CN(Cc2ccc(OCc3coc4ccc(Cl)cc34)cc2)C1
Product: O=C(O)C1CN(Cc2ccc(-c3ccc4oc(-c5ccccc5)cc(=O)c4c3)cc2)C1
Yield: 36 %

Procedure:
When the product of Step D was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 36% yield, as creamy solid. 1H-NMR (CDCl3+CD3OD) 8.31 (broad s, 1H); 7.86 (broad s, 3H); 7.77-7.52 (m, 7H); 6.69 (s, 1H); 4.21 (broad s, 2H); 4.18-4.02 (m, 4H); 3.3 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5]1([P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)(=O)C>[C:18]1([P:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:2][C:3]#[N:4])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 125.7 %

Procedure:
A solution of bromoacetonitrile (26.2 g, 218 mmol) and triphenylphosphine (52.0 g, 198 mmol) in ethyl acetate (240 mL) was stirred at 85° C. overnight, filtered and washed with petroleum ether. The filtrated cake was dried in air to give the title compound as a white solid (75 g), which was used without further purification. LCMS: rt=0.95 min, [M+H+]=302
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([N:18]([CH3:45])[C:19]3[CH:20]=[C:21]4[C:42](=[CH:43][CH:44]=3)[CH2:41][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[N:25](COCC[Si](C)(C)C)[C:24]3=[O:40])[CH2:22]4)=[O:17])[C:13](=[O:46])[C:12]([CH3:48])([CH3:47])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].C(N)CN>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([N:18]([CH3:45])[C:19]3[CH:20]=[C:21]4[C:42](=[CH:43][CH:44]=3)[CH2:41][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]3=[O:40])[CH2:22]4)=[O:17])[C:13](=[O:46])[C:12]([CH3:48])([CH3:47])[CH2:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN(C(=O)CN1C(=O)C(C)(C)CC[C@H]1c1cc(F)cc(F)c1)c1ccc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CN1C(=O)C(C)(C)CC[C@H]1c1cc(F)cc(F)c1)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-methyl-N-((2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide from Step B (38 mg, 0.057 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL) and the resulting mixture was stirred at ambient temperature for 1 h then concentrated to dryness in vacuo. The residue was dissolved in MeOH (1 mL) and the solution was adjusted to pH 10 by addition of 1 N aqueous NaOH and ethylenediamine (5.7 mg, 0.095 mmol). After 30 min, the mixture was partitioned between H2O (30 mL) and EtOAc (40 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 95:5, to give the title compound. MS: m/z=545 (M+1). HRMS: m/z=545.2388; calculated m/z=545.2359 for C31H31F2N4O3.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13]/[C:12]/2=[N:25]\[C:26]#[N:27]>CO>[NH2:27][C:26]1[N:3]([CH3:2])[O:4][C:12]2([C:11]3[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=3)[O:15][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)[N:25]=1
Reactant: N#C/N=C1\CC(c2ccccc2)Oc2ccc(O)cc21
Reactant: CNO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(O)cc32)N=C1N
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
To a solution of methylhydroxylamine HCl salt (28 mg, 0.326 mmol) in anhydrous MeOH (8 mL) was added NaOMe (25 wt. % in MeOH, 15.83 mg, 0.294 mmol), followed by (E)-N-(6-hydroxy-2-phenylchroman-4-ylidene)cyanamide (86 mg, 0.326 mmol). After stirred 10 minutes, the solvent was removed in vacuum. The residue was dissolved in DCM (15 mL) and filtered, and the solvent was removed in vacuum to give the crude product, which was purified by preparative TLC to give 3′-amino-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-6-ol (20 mg, 20%). 1HNMR(CDCl3): 7.30-7.51 (m, 5H), 6.95 (s, 1H), 6.69 (m, 2H), 5.15 (t, 3H), 2.98 (s, 3H), 2.28 (d, 2H), 1.17 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].CC(=O)CC(=O)C.[Cl:23][C:24]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:25]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:26][C:25]2[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:24]=2[Cl:23])[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)=O
Solvent: CC#N
Product: Cc1nn(Cc2ccc([N+](=O)[O-])cc2Cl)c(C)c1CC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester (2.6 g, 12.4 mmol, preparation according to WO2007/141267 by using 2,4-pentanedione instead of 3,5-heptanedione) and 2-chloro-4-nitrobenzyl bromide (3.11 g, 12.4 mmol) in acetonitrile (30 mL) is added K2CO3 (2.575 g, 18.6 mmol) and the mixture is stirred for 48 hours at room temperature and after that 2 hours at 60° C. The solid is filtered off and the solvent is removed by evaporation. The residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over MgSO4 and evaporated under reduced pressure to yield 4.4 g of [3,5-dimethyl-1-(2-chloro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=380). b) To a solution of [3,5-dimethyl-1-(2-chloro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid tert-butyl ester (4.40 g, 11.6 mmol) in methanol (80 mL) is added Raney nickel (440 mg) and the mixture is hydrogenated at 50 psi and room temperature for 12 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 2.4 g of the title compound (ESI mass spectrum: [M+H]+=350; Retention time HPLC: 0.76 min (method D)).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH2:22][CH2:23][CH2:24][CH:25]=[O:26])=[CH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1
Reactant: OCCCCc1ccnc2cc(Cl)ccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCCCc1ccnc2cc(Cl)ccc12
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
Oxalyl chloride (0.42 mL of a 2M solution in dry methylene chloride) was placed in an oven-dried flask, cooled to -78° C. and a solution of 99 mg methylsulfoxide in dry methylene chloride (2 mL) added drop by drop to the oxalyl chloride over 3 minutes and stirred for a further 3 minutes. A solution of 4-(7-chloroquinolin-4-yl)butan-1-ol (100 mg) in dry methylene chloride (1 mL) was added to the reaction flask over approx. 3 minutes followed by anhydrous triethylamine (0.42 mL) and the reaction mixture stirred for another 2.5 hours during which time it was allowed warmed up to room temperature. The reaction was quenched by the addition of saturated brine and then partitioned with methylene chloride. The aqueous layer was discarded and the methylene chloride extract dried over anhydrous sodium sulfate powder, filtered and concentrated in vacuo. The title compound was isolated by flash chromatography on silica gel (ethyl acetate:hexane, 2:1; then ethyl acetate), 57 mg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)(=[O:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22](Br)[CH:23]=[CH2:24].[CH2:26]1[CH2:30]OC[CH2:27]1>>[CH2:22]([CH:1]([S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)(=[O:4])=[O:3])[CH2:30][CH:26]=[CH2:27])[CH:23]=[CH2:24]
Reactant: C1CCOC1
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: C=CCC(CC=C)S(=O)(=O)c1cccc(Br)c1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-bromophenyl methyl sulfone (Tet. Left. 1994, 35, 9063; 4.74 g) in THF (200 ml) at −78° under nitrogen was added a solution of lithium bis(trimethylsilyl)amide (19 ml, 1.06M in THF) dropwise. The mixture was stirred for 25 min before a solution of allyl bromide (2.44 g) in THF (10 ml) was added. The mixture was allowed to stir at −78° for 1.5 h then quenched with an aqueous solution of ammonium chloride. The product was extracted with EtOAc, and the organic phase washed with brine, dried (MgSO4) and evaporated to dryness. The residual oil was purified on a silica SPE bond elut cartridge (100 g) using a gradient of 5%-40% diethyl ether in cyclohexane (Gradmaster™). The appropriate fractions were evaporated to give the title compound (1.66 g) LCMS RT=3.40 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Br)[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([O:15][CH2:20][CH3:21])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCBr
Reactant: COC(=O)c1nc(O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccccc2)c(C(=O)OC)n1

Procedure:
5.0 g (19 mmol) of methyl 3-benzyloxy-6-hydroxypicolinate, 2.1 g (19 mmol) of ethyl bromide and 2.9 g (21 mmol) of potassium carbonate were added to 100 ml of DMF, and the resultant mixture was reacted at 80° C. for 5 hours. After the reaction, the reaction content was poured into water, and was extracted with ethyl acetate, washed with water, dried and concentrated. The residue thus obtained was purified by column chromatography to obtain an aimed compound.
Reaction SMILES: C(OC(=O)C(OCC)CC1C=CC(O)=C(F)C=1)C.[C:19]1([C:25]2[S:26][CH:27]=[C:28]([CH2:30]CO)[N:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N)(=S)C1C=CC=CC=1.[Cl:42]CC(CCl)=O>>[Cl:42][CH2:30][C:28]1[N:29]=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:26][CH:27]=1
Reactant: OCCc1csc(-c2ccccc2)n1
Reactant: O=C(CCl)CCl
Agent: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: NC(=S)c1ccccc1
Product: ClCc1csc(-c2ccccc2)n1

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-(2-phenyl-thiazol-4-yl)-ethanol (prepared from thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a] to give 4-chloromethyl-2-phenyl-thiazole followed by side chain elongation in analogy to the sequence described in examples 13 a] to 13 d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]2-ethoxy-3-{3-fluoro-4-[2-(2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]2-ethoxy-3-{3-fluoro-4-[2-(2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid as a light yellow gum.
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[H-].[Na+].[CH2:33]([O:40][C:41]1[C:46]([C:47]2[CH:48]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[C:50]([O:55][CH3:56])=[C:51]([CH:54]=2)[CH:52]=O)=[CH:45][CH:44]=[C:43]([CH3:61])[N:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([O:40][C:41]1[C:46]([C:47]2[CH:54]=[C:51]([CH:52]=[CH:9][C:8]3[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:30][CH:29]=3)[C:50]([O:55][CH3:56])=[C:49]([C:57]([CH3:59])([CH3:58])[CH3:60])[CH:48]=2)=[CH:45][CH:44]=[C:43]([CH3:61])[N:42]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(C=O)cc(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C=Cc2ccc([N+](=O)[O-])cc2)cc(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
step 4—To a solution of 4-nitro-benzyltriphenylphosphonium bromide (829 mg, 1.734 mmol) in DMF (5 mL) at 0° C. was added NaH (60% in oil dispersion, 133 mg, 3.32 mmol). The reaction was stirred for 30 min at 0° C. and followed by addition of a solution of 66 (215 mg, 0.553 mmol) in DMF (5 mL). The resulting mixture was gradually warmed to RT and stirred overnight. The reaction was quenched with 1N aqueous HCl solution (6 mL) then diluted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 4% EtOAc) to afford 180 mg (64%) of 2-benzyloxy-3-{3-tert-butyl-4-methoxy-5-[2-(4-nitro-phenyl)-vinyl]-phenyl}-6-methyl-pyridine (68) as an orange oil.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(#N)C.[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:33])[CH:31]=[CH2:32].[CH2:34](OCC1OC1)[CH:35]1[O:37][CH2:36]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CC(N(C)C)=O>[OH:37][CH:35]([CH2:36][O:19][C:18](=[O:20])[CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]2[S:9][C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2](=[O:1])[C:15]=2[CH:14]=1)[CH2:34][O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:33])[CH:31]=[CH2:32]
Reactant: O=C(O)COc1ccc2sc3ccccc3c(=O)c2c1
Reactant: C(OCC1CO1)C1CO1
Reactant: C=CC(=O)OCCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Br-]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: C=CC(=O)OCCCCOCC(O)COC(=O)COc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 25 °C
Yield: 144.2 %

Procedure:
A reaction mixture containing (9-oxo-9H-thioxanthen-2-yloxy)acetic acid (4.0 g, 14 mmol), acetonitrile (55 ml), dimethylacetamide (10 mL), tetrabutylammonium bromide (0.5 g, 1.4 mmol) and 2,6-di-tert-butyl-4-methylphenol (0.03 g, 0.114 mmol) was heated to reflux. At this temperature 4-hydroxybutylacrylate glycidylether (2.3 g, 11.4 mmol) was added and the mixture was allowed to stir at reflux temperature for 16 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to provide 8.0 g of a yellow oil. The product was purified on a Prochrom LC80 Column using dichloromethane/ethyl acetate (60/40) as eluent on Kromasil Si60A 10 μm, to afford 1.8 g of a yellow oil.
Reaction SMILES: [OH:1][N:2]=[CH:3]/[C:4](/[CH3:18])=[CH:5]/[C@@H:6]1[C@@H:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:7]1([CH3:17])[CH3:16].I[CH2:20][CH2:21][CH3:22].[OH-].[Na+].Cl>CN(C)C=O>[CH3:16][C:7]1([CH3:17])[C@H:6](/[CH:5]=[C:4](\[CH3:18])/[CH:3]=[N:2][O:1][CH2:20][CH2:21][CH3:22])[C@H:8]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CCCI
Reactant: C/C(C=NO)=C\[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.58 g of t-butyl (1R)-trans-3-[(E)-3-hydroxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate, 2.0 g of 1-iodopropane and 10 ml of anhydrous dimethylformamide (hereinafter, abbreviated as DMF) was added 0.10 g of sodium hydroxide (60% dispersion in mineral oil) and the mixture was stirred at room temperature overnight. Thereafter, 1 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.56 g of t-butyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-propoxyimino-1-propenyl]cyclopropanecarboxylate: