Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[N:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](O)=[O:25])=[CH:20][C:15]=2[O:14][CH2:13]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[OH-].[Li+].[OH-].[Na+]>CN(C)C=O.CO.O>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[N:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([NH:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=3[F:11])=[O:25])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Reactant: NCc1ccc(O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(O)cc1F)c1cccnc1Oc1ccc2c(c1)OCO2
Yield: 55.2 %

Procedure:
A solution of 4-aminomethyl-3-fluoro-phenol hydrochloride (4.75 g, 27 mmol) in N,N-dimethylformamide (20 ml) was added to a stirred solution of 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid (14 g, 54 mmol), 1-hydroxybenzotriazole hydrate (7.29 g, 54 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10.37 g, 54 mmol), and triethylamine (3.76 ml, 27 mmol) in N,N-dimethylformamide (130 ml) at room temperature and stirred over night. The reaction was quenched into dilute aqueous hydrochloric acid and extracted with diethyl ether, then ethyl acetate. The pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine. The solvents were stripped in vacuo to afford 12.2 g crude. The residue was dissolved in methanol (100 ml) and stirred with lithium hydroxide (10 ml, 1M) for 1 h to hydrolyze the ester of the bis-acylated product. Solvents were stripped in vacuo, the residue was diluted with water (200 ml) and saponified to pH 12 with sodium hydroxide. The precipitate was filtered off, and the filtrate was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (2×200 ml). The pooled organics were washed with 2N sodium carbonate, then brine and dried (MgSO4). The solvents were stripped in vacuo to afford pure product (5.7 g, 14.9 mmol) in 55% yield.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:39])[C@@H:15]([O:36][CH2:37][CH3:38])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[C:32]([F:35])([F:34])[F:33])[OH:17])C1C=CC=CC=1.[CH3:40][O-:41].[Na+]>CO>[CH3:40][O:41][C:14](=[O:39])[C@@H:15]([O:36][CH2:37][CH3:38])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][C:19]=1[C:32]([F:34])([F:35])[F:33])[OH:17]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described in example 1 b], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:7]=[C:6]([CH3:19])[C:5]=1[N:20]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21].FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[C:6]([CH3:19])[C:5]=1[N:20]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21]
Reactant: COC(=O)c1cc(C=CC(=O)OC(C)(C)C)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C=CC(=O)O)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 237.8 mg (0.5 mmol) of the product of Example 203 in 2 ml dichlocomethane, was added lml of trifluoroacetic acid and the reaction was stirre at room temperature for 2 h. The resulting mixture was concentrated in vacuo to provide 200 mg (95%) of the desired product as a white solid after trituration with hexane/ether (2:1). Electrospray Mass Spec 418(M-H).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4](=[S:21])[NH:3]1.[NH2:22][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[OH:33][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4](=[S:21])[NH:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCN(c2ccc(C=C3SC(=S)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-[4-(4-Oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Example 34) (0.16 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in 1,2-dichloroethane (10 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N sodium hydroxide (NaOH) and then poured into a saturated aqueous sodium bicarbonate (NaHCO3). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried and concentrated. The residue was purified by preparative thin layer chromatography (16% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp>220° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.50–1.70 (m, 2 H), 1.90–2.10 (m, 2 H), 2.60–3.40 (m, 7 H), 3.90–4.20 (m, 3 H), 6.70–7.15 (m, 6 H), 7.30 (d, J=8.8 Hz, 2 H); 7.38 (d, J=8.8 Hz, 2 H); MS (ES) m/z: 470.0 (MH+); HRMS Calcd. for C24H27N3O3S2(M+): 469.1494. Found: 469.1488.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20])=[C:13]([CH3:23])[CH:12]=1.[CH2:25]([O:29][C:30]1[CH:31]=[C:32]([C:40]2[NH:44][C:43](=[O:45])[C:42]3([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[N:41]=2)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:26][CH:27]=[CH2:28]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:19]([N:48]2[CH2:49][CH2:50][C:42]3([N:41]=[C:40]([C:32]4[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:30]([O:29][CH2:25][CH2:26][CH:27]=[CH2:28])[CH:31]=4)[NH:44][C:43]3=[O:45])[CH2:46][CH2:47]2)(=[O:21])=[O:20])=[C:13]([CH3:23])[CH:12]=1
Reactant: COC(=O)c1ccc(CCS(=O)(=O)Cl)c(C)c1
Reactant: C=CCCOc1cc(C2=NC3(CCNCC3)C(=O)N2)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)OC)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Triethylamine (1.27 ml, 9.11 mmol) and 4-(2-chlorosulfonyl-ethyl)-3-methyl-benzoic acid methyl ester (1.01 g, 3.65 mmol) were added to a solution of 2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (1.40 g, 3.83 mmol) in methylene chloride (35 ml) at 0° C. The mixture was stirred at room temperature for two hours, and then quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 4-{2-[2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid methyl ester (2.10 g). This compound was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][C:15]([NH:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CCOC(=O)CN=C=O
Reactant: Oc1c(Br)cc(Br)c2cccnc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CNC(=O)Oc1c(Br)cc(Br)c2cccnc12
Temperature: 25 °C

Procedure:
5,7-Dibromo-8-hydroxyquinoline (19.7 g), ethyl isocyanatoacetate (13.0 g) and triethylamine (6.58 g) were mixed in 200 ml of toluene and heated at reflux temperature for about 47 hours. The solution was cooled to room temperature and the desired ethyl N-(((5,7-dibromo-8-quinolinyl)oxy)carbonyl)glycinate was obtained as a white, crystalline solid, m.p. 129.5° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:15]=1.C1(C(C2C=CC=CC=2)=[NH:38])C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(O[Pd]OC(=O)C)(=O)C.O1CCOCC1>[NH2:38][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:15]=1
Reactant: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccc(Br)cc34)ccc2F)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccc(N)cc34)ccc2F)CC1
Temperature: 95 °C
Yield: 13.9 %

Procedure:
6-bromo-4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)phthalazin-1 (2H)-one (98) (0.2 g, 0.42 mmol), diphenylmethanimine (0.076 g, 0.42 mmol) and cesium carbonate (0.275 g, 0.84 mmol) were added to dioxane (15 mL) and the system was degassed using nitrogen. To this was added diacetoxypalladium (0.019 g, 0.08 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.073 g, 0.13 mmol), the reaction was heated at 95° C. for 2 hours. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (3×50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. This was stirred with 2.0N HCl (5.0 mL) for 1 hour, the reaction mixture was quenched with 2M NaOH (10 mL), extracted with EtOAc (3×15 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford brown gum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (0.024 g, 13.87%); 1H NMR (500.133 MHz, DMSO) δ 1.47-1.38 (2H, m), 1.82-1.73 (2H, m), 2.89 (3H, s), 3.23-3.16 (2H, m), 3.27 (2H, s), 3.46-3.41 (1H, m), 4.13 (2H, s), 5.78 (2H, s), 6.87 (1H, d), 7.00 (1H, dd), 7.14 (1H, t), 7.22 (1H, dd), 7.38-7.34 (1H, m), 7.93 (1H, d), 11.60 (1H, s); m/z (LC-MS, ESI+), RT=1.56 (M+H 411).
Reaction SMILES: C(N)=[O:2].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[C:7]=1[CH2:8]NC=O>C(O)=O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[C:7]=1[CH:8]=[O:2]
Reactant: COc1cc(OC)c(CNC=O)c(OC)c1
Reactant: NC=O
Solvent: O=CO
Product: COc1cc(OC)c(C=O)c(OC)c1
Temperature: 200 °C
Reaction time: 0.05 h

Procedure:
1.96 g (10 mmol) of XII, 20 ml of formamide, and 2 ml of formic acid were placed in the GreenChem reaction vessel. The GreenChem reaction vessel was placed into the MARS-5 reaction system and the reaction mixture was quickly heated to 200° C. The reaction mixture was kept at 200° C. for 3 minutes and then cooled to 100° C. The GreenChem reaction vessel was removed from the MARS 5 system, the residual pressure was released, and the reaction vessel was opened. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature; the precipitated crystals were separated by filtration, rinsed with water and dried with vacuum. The filtrate was used as solvent in the next reaction. The reaction was repeated 10 times. The total of 9.6492 g of formic acid, and 34.5680 g of formamide were added to the reaction mixture over the ten cycles to compensate the losses. The total yield of 2,4,6-trimethoxybenzylformamide (XIII) is quantitative.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:26][CH3:27])=[N:13][C:12]=1[CH3:28])C>C1COCC1>[CH2:24]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:26][CH3:27])[C:18]=1[C:14]1[N:13]=[C:12]([CH3:28])[C:11]([CH2:10][OH:9])=[C:16]([CH3:17])[CH:15]=1)[CH3:25]
Reactant: CCOC(=O)c1c(C)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1cc(C)c(CO)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiAlH4 (2.4 mL of 1M solution in THF, 2.44 mmol) is added to a solution of 6-(2,6-diethyl-phenyl)-2,4-dimethyl-nicotinic acid ethyl ester (380 mg, 1.22 mmol) in THF (10 mL) at 0° C. The mixture is stirred for 1 hour at ambient temperature. After quenching with water, the mixture is extracted with EtOAc. The combined extracts are washed with saturated brine, dried (NaaSO4), and concentrated to give the crude alcohol as a colorless oil which is used in the next step without further purification. NMR (CDCl3) 7.26 (t, 1H), 7.13 (d, 2H), 6.93 (s, 1H), 4.82 (s, 2H), 2.68 (s, 3H), 2.46 (s, 3H), 2.37-2.28 (m, 4H), 1.05 (t, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[CH:4]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].O>CN(C=O)C>[Br:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(CBr)c1)OCC
Temperature: 150 °C
Yield: 72.3 %

Procedure:
To a solution of α,α′-Bisbromo-m-xylene (10.02 g, 37.95 mmol) in DMF (20 mL) was added triethyl phosphite (3.15 g, 3.3 mL, 19.98 mmol) via syringe. The mixture was heated to 150° C. for 2 minutes in a microwave. The reaction mixture was poured into water and product extracted with diethyl ether (3×25 mL). The combined organics were washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. Reduced volume in vacuo and purified product by flash column eluting 30-100% ethyl acetate in hexanes to give 4.64 g (76%) 60 as a colorless oil. LCMS: m/z for C12H18BrO3P++H observed 321.0 and 323.0 at 2.29 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: C[C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>C(Cl)(Cl)Cl>[CH2:28]([NH:32][C:12]([C:9]1[C:8](=[O:15])[N:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)c1cnc2ccccn2c1=O
Reaction time: 0.08 h
Yield: 75.9 %

Procedure:
A mixture containing i6.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -15° C. during 15 minutes. After stirring for 5 minutes, 6.43 g (0.088 mol) of butylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -10° C. and -15° C. during 50 minutes. The reaction mixture is stirred for 1 hour at the same temperature and then let to stand under cooling by ice. For working up, the mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate and evaporated to give 14.9 g (71.8%) of the named product as yellow crystals, m.p.: 127°-130° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[C:11]([C:14]1[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][S:17][CH:18]=1)([OH:13])=[O:12]>CN(C=O)C.O>[CH2:8]([O:13][C:11]([C:14]1[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][S:17][CH:18]=1)=[O:12])[CH2:9][CH3:10]
Reactant: CCCI
Reactant: COC(=O)Cc1cscc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cscc1CC(=O)OC
Reaction time: 3 h

Procedure:
Potassium carbonate (670 mg) and, after 15 minutes, 1-iodopropane (0.26 ml) were added successively to a stirred solution of methyl (4-carboxy-3-thienyl)acetate (490 mg) in DMF (10 ml). After 3 h, the resulting mixture was diluted with water and extracted with ether. The extracts were washed with water, dried, and concentrated to give methyl [4-(prop-1-yloxycarbonyl)-3-thienyl]acetate (600 mg, quantitative yield) as a yellow liquid, pure by GC, IR (film): 1735, 1710 cm-1, 1H nmr: delta 1.00 (3H, t), 1.75 (2H, q), 3.69 (3H, s), 3.92 (2H, s), 4.20 (2H, t), 7.13 (1H, d J 3.5 Hz), 8.12 (1H, d J 3.5 Hz) ppm.
Reaction SMILES: CON(C)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:4]([C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1cccc(C)c1
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of N-methoxy-N,3-dimethylbenzamide (2.86 g, 16 mmol) in THF (50 mL) was added cyclopropylmagnesium bromide (2 N in THF, 40 mmol, 20 mL) dropwise at 0° C. After addition, the reaction mixture was stirred for 4 hours at room temperature and quenched with 30 mL of aqueous NH4Cl. The aqueous phase was separated and extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated to give crude product as a yellow oil (2.56 g, 100%). LC-MS (M+H): m/z 161. 1H NMR (400 MHz, CDCl3): δ ppm 7.817 (s, 2H), 7.367-7.332 (m, 2H), 2.697-2.635 (m, 1H), 2.417 (s, 3H), 1.247-1.209 (m, 2H), 1.046-1.000 (m, 2H).
Reaction SMILES: FC1C=C(CCC(O)=O)C=C[C:7]=1[O:8]C.Br[C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]3[CH:26]=[C:27]([CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])[CH:28]=[CH:29][C:30]=3[O:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36]C[CH2:34]3)[CH:22]=[CH:21][C:19]=2[N:20]=1>[OH-].[Na+]>[CH:33]1([CH2:32][O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:26][C:25]=2[C:23]2[CH:22]=[CH:21][C:19]3[N:20]=[C:16]([O:8][CH3:7])[S:17][C:18]=3[CH:24]=2)[CH2:34][CH2:36][CH2:37][CH2:38]1
Reactant: CCOC(=O)CCc1ccc(OCC2CCCCC2)c(-c2ccc3nc(Br)sc3c2)c1
Reactant: COc1ccc(CCC(=O)O)cc1F
Agent: [Na+]
Agent: [OH-]
Product: COc1nc2ccc(-c3cc(CCC(=O)O)ccc3OCC3CCCC3)cc2s1
Reaction time: 18 h

Procedure:
According to the procedure described in the synthesis method of Intermediate 9 provided that the reaction was carried out for 18 hours, Intermediate 76 (169 mg) and 2 N aqueous sodium hydroxide (500 μl) were reacted and treated to obtain the title compound (Compound No. V-88, 114 mg).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14].C(Br)C=C.[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:13]([O:15][C:16]([C:18]1([CH2:3][CH:2]=[CH2:1])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (15% solution in n-hexane; 24.5 mL, 0.057 mol) is added to a stirred solution of diisopropyl amine (8.38 mL, 0.059 mol) in tetrahydrofuran (140 mL) at −70° C. under an atmosphere of nitrogen and stirred for 30 minutes. A solution of piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (8.0 g, 0.0311 mol) in tetrahydrofuran (20 mL) is introduced at −70° C. Hexamethyl phosphoramide (15 mL) is added and reaction mixture is allowed to stir till the temperature reaches at −45° C. Reaction mixture again cooled to −70° C., allyl bromide (13.5 mL, 0.155 mol) is added and stirred for 1 hour. Saturated aqueous solution of ammonium chloride (100 mL) is added slowly into the reaction mixture at −30° C. and stirred for 10 minutes. It is extracted with ethyl acetate (3×60 mL). Combined organic layer is washed with brine solution (1×30 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gives a viscous liquid which is purified by column chromatography (silica gel 230-400, n-hexane:ethyl acetate, 9:1) to furnish 4-allyl piperidine-1,4-dicarboxylic acid-1-tert-butylester-4-ethyl ester.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[C:29]([CH3:41])=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[C:29]([CH3:41])=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: Cc1ncc(CN2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)n1Cc1ccc(C#N)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ncc(CN2CCN(c3cccc4ccc(O)cc34)C(=O)C2)n1Cc1ccc(C#N)c(F)c1
Reaction time: 4 h

Procedure:
To a solution of the benzyl ether from Step B (419 mg, 0.75 mmol) in 6 mL of 1:1 MeOH/EtOAc was added 10% palladium on carbon (250 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 4 hours, another portion of Pd/C was added (250 mg). After 16 hours, the solution was filtered through celite. Concentration in vacuo provided the titled product which was used in the next reaction without further purification.