Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=2)/[CH:9]=[CH:10]/[C:11](OCC)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].P(Br)(Br)[Br:26]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8](/[CH:9]=[CH:10]/[CH2:11][Br:26])[CH:16]=[CH:17][CH:18]=2)=[CH:2]1
Reactant: BrP(Br)Br
Reactant: CCOC(=O)/C=C/c1cccc(-c2ccsc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: BrC/C=C/c1cccc(-c2ccsc2)c1

Procedure:
1.0 g of the resulting ester compound was reduced in a customary manner with lithium aluminum hydride, and then brominated by phosphorus tribromide. 0.7 g of (E)-3-[3-(3-thienyl)phenyl]-2-propenyl bromide obtained thus was dissolved in 10 ml of dimethylformamide, and 0.6 g of potassium phthalimide was added. The mixture was stirred overnight at room temperature, and the solution was worked up in a customary manner to give (E)-N-[3-[3-(3-thienyl)phenyl]-2-propenyl] phthalimide. 0.7 g of the resulting phthalimide compound was dissolved in a mixture (3 ml) of tetrahydrofuran and ethanol (1:1), and 0.5 ml of hydrazine hydrate was added. The mixture was stirred at room temperature for 1 hour, and then worked up in a customary manner to give 0.42 g of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([F:30])[CH:29]=1)[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([F:30])[CH:29]=1)[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: NCCOc1cc(F)cc(F)c1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cc(F)cc(F)c3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 10.9 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(3,5-difluorophenoxy)ethylamine hydrochloride (767 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(3,5-difluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (56 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OB(O)c1ccccc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccccc4)cc32)N=C1N
Temperature: 120 °C
Yield: 7.8 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and phenylboronic acid (16 mg, 0.1 mmol). The mixture was heated under microwave at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 2′-amino-1′-methyl-2,6-diphenylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one (1.55 mg, 5%). 1H-NMR (MeOD): 2.42 (m, 1H), 2.61 (m, 1H), 3.27 (s, 3H), 5.83 (d, 1H), 7.10 (d, 1H), 7.29 (m, 1H), 7.40 (m, 5H), 7.59 (m, 5H).
Reaction SMILES: C1N(CCO)CCN(CC[S:12]([OH:15])(=[O:14])=[O:13])C1.[Na+:16].[Cl-].[Mg+2].[Cl-].[Cl-].C(S)[C@@H](O)[C@H](O)CS.C[C@H]1[C:35](=[O:36])[C:34](OC)=[C:33](OC)[C@H:32](O)[C@@H:31]1[CH2:42]/[CH:43]=[C:44](/[CH2:46][CH2:47]/[CH:48]=[C:49](/CCC=C(C)C)\C)\C>>[CH3:49][CH2:48][CH2:47][CH2:46][CH2:44][CH2:43][CH2:42][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][S:12]([O-:15])(=[O:13])=[O:14].[Na+:16]
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: COC1=C(OC)[C@H](O)[C@H](C/C=C(\C)CC/C=C(\C)CCC=C(C)C)[C@@H](C)C1=O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [Cl-]
Agent: [Mg+2]
Product: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reaction time: 3 h

Procedure:
In vitro prenylation reactions were performed in 20 μl reaction buffer (50 mM HEPES, pH 7.2, 50 mM NaCl, 5 mM MgCl2, 5 mM DTT, and 20 μM GDP) mixed with 3 μg FTase (Jena, Germany), 25 μM NBD-FPP, and 2 μg H-RasGST in the presence or absence of various concentrations of Antroquinonol. Reactions were incubated for 3 h at 37° C. and quenched by adding 20 μl 2×SDS-PAGE sample buffer and boiling at 95° C. for 3 min. Finally, the mixtures were resolved by 15% SDS-PAGE. The gel was scanned using a Typhoon 9400 scanner (GE Healthcare, UK) (excitation laser, 473 nm; emission cutoff filter, 510 nm) followed by staining with Coomassie blue. The fluorescent bands were quantified using Image-Pro Plus software (Media Cybernetics, Silver Spring, Md., USA).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:19][C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccncc1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: S=C(NN=Cc1ccncc1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.55 mmol) and 4-pyridine-carboxaldehyde (54 μL, 0.56 mmol) similar to Example 1 and isolated as a white solid (30 mg, 20%). 1H NMR (CDCl3): 10.74 (s, 1H), 8.66 (dd, J=1.5, 4.5 Hz, 2H), 7.93 (s, 1H), 7.51 (s, 1H), 7.48 (dd, J=1.5, 4.5 Hz, 2H), 6.24-6.13 (m, 2H), 4.29-4.24 (m, 1H), 3.05 (s, 1H), 2.97 (s, 1H), 1.94-1.87(m, 1H), 1.68 (d, J=9.0 Hz, 1H), 1.50(d, J=9.0 Hz, 1H), 1.45-1.39 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2([C:26]([F:29])([F:28])[F:27])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:32]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClCCCl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2([C:26]([F:27])([F:28])[F:29])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH:24]([Br:32])[CH3:25])=[CH:22][CH:23]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClCCCl
Product: CC(Br)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C

Procedure:
To a solution of 3.00 g of 5-[3,5-bis(trifluoromethyl)phenyl]-3-(4-ethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 15 mL of 1,2-dichloroethane, 1.29 g of N-bromosuccinimide and 0.10 g of α,α′-azobisisobutyronitrile were added and the resultant mixture was stirred at 75° C. for 3 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and then 10 mL of water was added to the reaction mixture. The resultant mixture was extracted with chloroform (20 mL×1). The organic phase was washed with water (10 mL×1) and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. To the resultant residue, hexane was added and a deposited crystal was filtered off to obtain 3.01 g of the objective substance as a white crystal.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:9]([O:28][CH3:29])[CH:8]=1)C.[OH-].[Li+:35]>O1CCOCC1.O>[CH2:31]([O:30][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:9]([O:28][CH3:29])[CH:8]=1)[C:4]([O-:33])=[O:3])[CH3:32].[Li+:35]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(OC)c1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.2 %

Procedure:
[rac]-2-Ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4yl)-ethoxy]-phenyl}-propionic acid ethyl ester (306 mg, 0.67 mmol) were dissolved in 3 ml dioxane and 2 ml water, 50 mg lithium hydroxide were added and the mixture stirred at r.t. during 24 hours. The reaction mixture was then chromatographed (MCI-gel; CH3CN/H2O) as lithium salt to yield 125 mg (43%) of the title compound as a white gum.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](S(C)=O)[N:22]=3)=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:8]1=[O:30])#[N:2].C(C1C=C(C=CC=1)CN1CC[C@H](NS(C2SC(C3C=CN=C(S(C)(=O)=O)N=3)=CC=2)(=O)=O)C1=O)#[N:35]>CCO>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:35])[N:22]=3)=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:8]1=[O:30])#[N:2]
Reactant: CS(=O)c1nccc(-c2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)s2)n1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)s2)n1
Solvent: CCO
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccnc(N)n4)s3)C2=O)c1
Temperature: 90 °C

Procedure:
A mixture of [5-(2-methylsulfinyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin3-(S)-yl]-amide and [5-(2-methylsulfonyl-pyrimidin-4-yl)-thiophene-2sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide (0.20 g, 0.39 mmol) is dissolved in 10 mL of EtOH and NH3 gas is bubbled through the solution for 5 min. The resulting mixture is heated at 90° C. for 3 h in a stainless steel Parr high pressure reaction vessel. After this time, the solution is allowed to cool to room temperature and is concentrated in vacuo to give [5-(2-amino-pyrimidin-4-yl)-thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide (0.20 g) as a crude product. FAB MS, [M+H]+ =455. The crude [5-(2-amino-pyrimidin-4-yl)-thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide is converted to the title compound as described in EXAMPLE 1, Part F. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=O)=[CH:4][CH:3]=1.[CH3:29][C:30]([S@@:33]([NH2:35])=[O:34])([CH3:32])[CH3:31]>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:30]([S@@:33](/[N:35]=[C:6](/[C:5]1[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=1)\[C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:34])([CH3:32])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccc(F)cc3)cn2)CC1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(/C(=N\[S@@](=O)C(C)(C)C)c3ccc(F)cc3)cn2)CC1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a solution of tert-butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (4.0 g, 10.4 mmol), (S)-2-methylpropane-2-sulfinamide (2.5 g, 20.7 mmol) in THF (60 mL) was added titanium ethoxide (20 mL) at room temperature. The resultant solution was heated at 70° C. overnight. After that, the reaction was cooled to room temperature, diluted with ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (500 mL). The mixture was filtered through Celite. The filtrate was separated. Aqueous layer was extracted with ethyl acetate (200 mL×3). Then organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:ethyl acetate 2:1) to afford the title compound (3.3 g, yield 66%) as a yellow solid. MS (ES+) requires: 489, found 490 [M+H]+; purity: 95% (UV at 254 nm).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1)[CH3:5])C.Cl.[NH:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[NH2:21].C(N(CC)CC)C.O>ClCCl.CO>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C:7]2[N:20]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[N:21]=[C:4]([CH3:5])[N:6]=2)[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=1
Reactant: CCOC(C)=NC(=O)c1cc(OC)cc(OC)c1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(OC)cc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cc2)c1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
N-(1-ethoxy-ethylidene)-3,5-dimethoxy-benzamide 536 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3,5-dimethoxy-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (551 mg, yield: 69%) was obtained as a solid phase.
Reaction SMILES: N([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][O:16][CH2:17][CH2:18][OH:19])=[C:8](N)[N:7]=1>C(O)(=O)C>[Cl:5][C:6]1[NH:7][C:8](=[O:2])[C:9]2[N:10]=[CH:11][N:12]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]=2[N:14]=1
Reactant: O=N[O-]
Reactant: Nc1nc(Cl)nc2c1ncn2COCCO
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(Cl)nc2c1ncn2COCCO
Reaction time: 2 h
Yield: 49.8 %

Procedure:
Solid sodium nitrite (0.97g) was added at room temperature with stirring over a period of one hour to a solution of 2-chloro-9-(2-hydroxyethoxymethyl)adenine (0.5g) in glacial acetic acid (10ml). The reaction mixture was stirred for an additional 41/2 hours. The white solid was removed by filtration, washed with cold acetic acid and then well triturated with cold water to remove the sodium acetate present. The solid product was retained. The combined acetic acid filtrate and wash was evaporated at reduced pressure and 40° C. bath temperature and the residual oil triturated with cold water. The resulting solid material was combined with the previously isolated solid and the combined solids dried and recrystallized from ethanol to give 2-chloro-9-(2-hydroxyethoxymethyl) hypoxanthine (0.25g), m.p. >310° C. Elemental analysis and NMR spectrum were consistent with this structure.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=2)=[O:8])=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[CH:50]=[CH2:51]>CCOC(C)=O.O>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:10]=[C:11](/[CH:51]=[CH:50]/[C:49]([O:53][CH2:54][CH3:55])=[O:52])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1ccc(C(=O)c2cccc(Br)n2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)/C=C/c1cccc(C(=O)c2ccc(C)cc2)n1
Temperature: 130 °C

Procedure:
A mixture of ketone 3 (16.90 g, 61.2 mmol), triphenylphosphine (1.64 g, 6.25 mmol), tributylamine (15 mL), and ethyl acrylate (16 mL) was stirred and heated (hot bath at 125-135° C.) for 7 h. Two additional aliquots of ethyl acrylate (7 mL each) were added at 4 h and 6 h. After the reaction was cooled to room temperature, the reaction mixture was poured over water (300 mL) and EtOAc (300 mL). The aqueous layer was extracted further with EtOAc. The combined organics were dried with Na2SO4, filtered, and evaporated to dryness. Chromatography over silica gel using heptane/EtOAc (starting at 8:1) gave 15.49 g of 5c as a yellow crystalline solid. The structure was confirmed by 1H NMR. (Keto-acrylates 5e and 5f were similarly prepared using isobutyl acrylate and cyclopentyl acrylate, respectively.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:17][CH:16]1[CH2:29][C:30]([O:32]C)=[O:31])=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[OH-].[Na+].[Cl:38]CCl.[ClH:41]>O.CCOCC.CC(C)=O.O1CCOCC1>[ClH:38].[ClH:41].[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:17][CH:16]1[CH2:29][C:30]([OH:32])=[O:31])=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2
Reactant: COC(=O)CC1CN(CCSc2cccs2)CCC1CCCc1c(F)cnc2ccc(OC)cc12
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2ncc(F)c(CCCC3CCN(CCSc4cccs4)CC3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 480 mg of methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-acetate, 5 cm3 of dioxane and 2.25 cm3 of a 1 N aqueous sodium hydroxide solution was heated, with stirring, at a temperature in the region of 60° C. for 1 hour 30 minutes. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature the region of 40° C., the residue obtained was taken up in 50 cm3 of water and 20 cm3 of ether. The aqueous phase was separated after settling out and then washed twice with 10 cm3 of ether, it was then acidified by pouring 2.25 cm3 of 1 N hydrochloric acid. The precipitate formed was dissolved by adding 75 cm3 of dichloromethane. The organic phase was separated after settling out, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The product obtained was then stirred in 30 cm3 of acetone. 4 cm3 of 4 N hydrochloric acid in dioxane were then poured over this solution. The reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then 15 cm3 of acetone were added. This operation was repeated 5 times until a yellow solid was obtained, which solid was drained and then dried in a desiccator under reduced pressure (10 Pa) at a temperature of about 45° C. 395 mg of (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-acetic acid dihydrochloride were obtained in the form of a solid, which was off-white in color.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:17])([F:16])[F:15])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:15])([F:16])[F:17])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OC(F)(F)F)c(C(=O)O)c1
Yield: 29 %

Procedure:
A mixture of 5-nitro-2-trifluoromethoxybenzoic acid (6.43 g, 25.6 mmol) and 128 mg of 10% Pd/C in 10 mL of absolute ethanol was stirred in a hydrogen atmosphere overnight at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was triturated with diethyl ether and the crystals were filtered off and dried to afford 1.644 g (29%) of 5-amino-2-trifluoromethoxybenzoic acid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[OH2:38]>C(#N)C.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:38])=[O:32])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1cccc(CCCCCCO)c1)(c1ccccc1)c1ccccc1
Reactant: O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](OCc1cccc(CCCCCC(=O)O)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 6-[3-(t-Butyldiphenylsilyloxymethyl)-phenyl]-hexanol (5.9 g, 13.2 mmol) in acetonitrile (28 mL) is added CCl4 (28 mL) and water (43 mL). To this mixture is added NaIO4 (11.7 g, 54 mmol) and RuCl3(H2O) (100 mg, 0.5 mmol). The resulting mixture is stirred for 2 h then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and activated charcoal, filtered through celite and concentrated. The residue is purified by flash chromatography (silica, 20% ethyl acetate/5% dichloromethane in hexanes) to give the title compound (3.46 g) as an oil. MS (ESI) 461 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([CH:13]1[NH:17][C:16](=[O:18])[C:15]([CH3:20])([CH3:19])[C:14]1=[O:21])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:4]1[CH:3]=[C:2]([N:17]2[CH:13]([CH2:11][CH3:12])[C:14](=[O:21])[C:15]([CH3:20])([CH3:19])[C:16]2=[O:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CCC1NC(=O)C(C)(C)C1=O
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 4-bromo-2-chlorobenzonitrile (219 mg), 5-ethyl-3,3-dimethylpyrrolidine-2,4-dione (120 mg), cesium carbonate (378 mg), tris(dibenzylideneacetone)dipalladium(0) (71 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (89 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 147 mg, 65%).