Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCC(CC1)CC2[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)=[CH:12][CH:11]=1.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>CCOC(C)=O.CCO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[N:21]12[CH2:22][CH2:28][CH:27]([CH2:19][CH2:20]1)[CH:26]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][CH:20]=[CH:19]4)=[CH:14][CH:15]=1)[CH2:25]2
Reactant: c1cc2cc(-c3ccc(OC4CC5CCN4CC5)cc3)ccc2[nH]1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1cc2cc(-c3ccc(OC4CN5CCC4CC5)cc3)ccc2[nH]1

Procedure:
The product of Example 3A (80 mg, 0.25 mmol) was treated with fumaric acid (29 mg, 0.25 mmol) in EtOAc/EtOH (v. 1:1, 4 mL) at ambient temperature for 10 h. The title compound was obtained as solid (57 mg, yield, 52%). 1H NMR (300 MHz, CD3OD) δ 1.78-2.16 (m, 3H), 2.25-2.39 (m, 1H), 2.46-2.54 (m, 1H), 3.14-3.45 (m, 5H), 3.69-3.81 (m, 1H), 4.80-4.89 (m, 1H), 6.46 (dd, J=3.0, 1.0, 1H), 6.68 (s, 2H), 7.02 (dt, J=8.8, 2.5 Hz, 2H), 7.23 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.43 (dt, J=8.4, 0.8 Hz, 1H), 7.58 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 1.0 Hz, 1H) ppm. MS (DCI/NH3): m/z 319 (M+H)+. Anal. Calculated for C21H22N2O.C4H4O4: C, 69.11; H, 6.03; N, 6.45. Found: C, 69.23; H, 5.81; N, 6.59.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[N:7][CH:8]=1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:18][CH:17]([CH3:19])[CH2:16][CH:15]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:27])=[CH:23][CH:22]=1)[C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:13][C:12]=1[CH3:14]
Reactant: COc1cncc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)O)cc3)c(C)o2)c1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cncc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of 4-({1-[5-(5-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)benzoic acid (178 mg), ethyl 3-(methylamino)propanoate (71 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg), hydroxybenzotriazole monohydrate (83 mg) and triethylamine (75 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL), 1N lithium hydroxide (0.5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (119 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[H-].[Na+].[CH3:26]I.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:11]([CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH3:26])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CI
Reactant: CC(C)CC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@H]1CN(C)c1ccc2ncc(Br)n2n1
Reaction time: 0.25 h

Procedure:
To a solution of (S)-1-(2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)pyrrolidin-1-yl)-3-methylbutan-1-one (380 mg, 1.0 mmol) in THF (10 mL) was added sodium hydride (120 mg, 3.0 mmol) at rt. After stirring for 15 min, methyl iodide was added dropwise. The reaction was stirred at it for overnight and worked up with ammonium chloride solution, extracted with ethyl acetate, concentrated and purified by ISCO column chromatography (10% MeOH/DCM) to give non-pure product. It was further purified by Prep HPLC (neutral) to give (S)-1-(2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)(methyl)amino)methyl)pyrrolidin-1-yl)-3-methylbutan-1-one as oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.65-7.75 (m, 1H), 7.44-7.52 (m, 1H), 7.04-7.22 (m, 1H), 4.45-4.61 (m, 1H), 3.45-3.92 (m, 4H), 3.19-3.23 (m, 3H), 1.90-2.32 (m, 7H), 0.78-0.92 (m, 6H); LRMS (ESI) m/e 394.1 [(M+H)+, calcd for C17H25BrN5O 395.3].
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])OCC[O:13]3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:13])[CH3:17])=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC1(c2ccc(-c3cnco3)cc2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(-c2cnco2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[4-(5-oxazolyl)phenyl]-2-methyl-1,3-dioxolane (711 mg, 3.08 mmol) in acetone (18 ml) and water (2.8 ml) was added pyridinium p-toluenesulfonate (116 mg, 0.46 mmol), and the mixture was heated at reflux temperature for 8 hours. The mixture was cooled down to room temperature, and concentrated in vacuo. The residue was dissolved in diethylether and washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The compound was used for next reaction without purification.
Reaction SMILES: [OH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]([CH3:14])[C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:22]I.[Cl-].[Na+]>O1CCCC1>[CH3:22][O:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]([CH3:14])[C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1c2c3c(cccc3n1C)C(O)CC2
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c3c(cccc3n1C)C(OC)CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
Ethyl 1,3,4,5-tetrahydro-5-hydroxy-1-methyl-benz[cd]indole-2-carboxylate (0.25 g, 0.96 mmol) was added to a suspension of 60% sodium hydride (0.039 g, 0.96 mmol) in tetrahydrofuran (10 ml), followed by stirring at room temperature for 20 minutes. After the reaction mixture was cooled to 0°-5° C., methyl iodide (0.27 g, 1.93 mmol) was added thereto and the resulting mixture was stirred at 0°-5° C. for 1 hour and then at room temperature for 2.5 hours. The reaction mixture was poured into a 5% aqueous sodium chloride solution, followed by extraction with ethyl acetate (twice). The extract solution was washed twice with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain ethyl 1,3,4,5-tetrahydro-5-methoxy-1-methyl-benz[cd]indole-2-carboxylate (0.16 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:20]([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1([CH3:31])[O:29][CH2:28][CH:27]([NH2:30])[CH2:26][O:25]1.FC1C=CC(N(CC2SC(C3C=CC(C=O)=CC=3)=CC=2)C(C)C)=CC=1.Cl.N(CC(O)=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:20]([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16][NH:30][CH:27]3[CH2:28][O:29][C:24]([CH3:31])([CH3:23])[O:25][CH2:26]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)N(CCCc1ccc(C=O)cc1)c1ccc(F)cc1
Reactant: CC1(C)OCC(N)CO1
Agent: CC(C)N(Cc1ccc(-c2ccc(C=O)cc2)s1)c1ccc(F)cc1
Agent: CNCC(=O)O
Agent: Cl
Product: CC(C)N(CCCc1ccc(CNC2COC(C)(C)OC2)cc1)c1ccc(F)cc1
Yield: 48 %

Procedure:
When the product of Step C and 2,2-dimethyl-1,3-dioxan-5-amine were substituted for 4-(5-(((4-fluorophenyl)(isopropyl)amino)methyl)-thiophen-2-yl)benzaldehyde and sarcosine hydrochloride in Example 22, Step C, the similar process afforded the title compound in 48% yield, as creamy paste. 1H-NMR (CDCl3) 7.24 (d, 2H, J=7.92 Hz), 7.11 (d, 2H, J=7.92 Hz), 6.87 (t, 2H, J=8.9 Hz), 6.69-6.62 (m, 2H), 3.95 (dd, 2H, J=11.7, 3.6 Hz), 3.83-3.69 (m, 4H), 3.06 (t, 2H, J=7.54 Hz), 2.66-2.58 (m, 3H), 1.83-1.76 (m, 3H), 1.41 (s, 3H), 1.4 (s, 3H), 1.08 (d, 2H, J=6.59 Hz).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](OC(=O)CC)(=O)[CH2:12][CH3:13]>>[CH2:12]([C:13]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1)[CH3:11]
Reactant: CCC(=O)OC(=O)CC
Reactant: Nc1ccccc1C(=O)O
Product: CCc1nc2ccccc2c(=O)o1
Temperature: 130 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
Anthranilic acid (10 g, 72.9 mmol) and propionic anhydride (20.9 g, 160 mmol) were mixed and stirred at 130° C. for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methylene chloride, the organic phase was washed with saturated sodium hydrogen carbonate aqueous solution and then distilled water and dried with anhydrous sodium sulfate. The target compound (12.5 g, 98%) was obtained as a colorless solid by filtering off the sodium sulfate and concentrating to dryness.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[NH:16][CH:15]=1)=[O:13].C(OCC)(=O)C.C(=O)(O)[O-]>O>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH3:23])[CH:21]=3)[NH:16][CH:15]=2)=[O:13])[C:4]([F:11])=[CH:5][CH:6]=1
Reactant: Cc1cnc2[nH]cc(C(=O)c3c(F)ccc([N+](=O)[O-])c3F)c2c1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To (2,6-difluoro-3-nitro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (16, 1.165 g, 3.672 mmol), 80 mL of ethyl acetate was added, followed by stannous chloride, dihydrate (2.86 g, 12.6 mmol). The suspension was stirred in an oil bath at 65° C. for 18 hours, then poured into a beaker with 200 mL each of water and saturated bicarbonate. The resulting milky suspension was treated with celite, then vacuum filtered through a thin pad of celite. The resulting clear layers of the filtrate were separated and the solvents were removed from the ethyl acetate layer. The resulting material was purified by silica gel column chromatography eluting with a gradient from 30 to 100% ethyl acetate in hexanes to give the desired compound with some impurities. This material was re-purified by silica gel column chromatography eluting with a gradient from 1 to 60% methanol in dichloromethante to give the desired compound (17, 760 mg). 1H NMR was consistent with the desired compound structure. MS (ESI) [M+H+]+=288.5.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1>>[F:37][C:34]([F:35])([F:36])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Yield: 88.5 %

Procedure:
Using 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (152 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole (212 mg), the same reaction as Example 2 was carried out to yield the titled compound (290 mg).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Cc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 25 °C
Yield: 107.4 %

Procedure:
In a 1-liter stainless steel autoclave equipped with stirrer were placed 71 g (0.217 mole) of 1,2-diphenyl-4-p-tolylbutane-1,4-dione, 100 ml of xylene, and 45 g (0.101 mole) of phosphorus pentasulfide. The autoclave was sealed, chilled in a Dry Ice-acetone bath, and charged with 120 g (3.52 moles) of hydrogen sulfide. The autoclave was then heated at 160°-190° C. (920-1130 psig) for 225 minutes. The autoclave was cooled to room temperature and the hydrogen sulfide vented into an aqueous sodium hydroxide solution. The residue in the autoclave was stirred with 150 ml of absolute ethanol. The slurry thus formed was filtered. The residue was dried to give 35.4 g (50.0%) of crude 2,3-diphenyl-5-p-tolylthiophene, m.p. 110°-112° C. Recrystallization from 190 ml. of toluene and 625 ml. of ethanol gave 30.1 g (42.5%) of pure 2,3-diphenyl-5-p-tolylthiophene, m.p. 114°-116° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].CC1C(C2SC(C(N3CCC[C@@H](NC(=O)C)C3)=O)=CC=2)=NOC=1C(F)(F)F.[CH3:46][N:47]([CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][NH:58][CH2:57]1)C(=O)OC(C)(C)C.[ClH:62]>O1CCOCC1.C(N(CC)CC)C.C1COCC1>[ClH:62].[CH3:46][NH:47][CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][N:58]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:57]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CN(C[C@@H]1CCCNC1)C(=O)OC(C)(C)C
Agent: CC(=O)N[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNC[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Reaction time: 4 h
Yield: 88 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and tert-butyl methyl[(3R)-piperidin-3-ylmethyl]carbamate (Preparative Example 33, 298 mg, 1.30 mmol) by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride (0.90 eq) was added to a THF solution of triethylamine and tert-butyl methyl[(3R)-piperidin-3-ylmethyl]carbamate. The reaction was allowed to stir 4 hr then partitioned between EtOAc (10 mL) and a 1 N aqueous HCl solution (10 mL). The organic portion was washed with a further portion of 1N HCl solution (10 mL) followed by a saturated aqueous NaHCO3 solution (10 mL) and brine (10 mL). The organic layer was then dried over MgSO4, filtered, and evaporated to a residue that was chromatographed on silica gel with EtOAc/hexane (40% then 60%) as eluant to afford Boc-protected intermediate as a yellow-tinted oil (423 mg, 67%). LC/MS 7.44 min, [M+1]+ 487. The intermediate was then treated with a 4 N solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred for 24 hr, after which time the reaction mixture was evaporated in vacuo to afford a free-flowing colorless powder (320 mg, 88%). LC/MS 4.91 min, [M+1]+ 388.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:9]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C(O)C>[CH3:1][S:2][CH:3]([C:9]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(SC)c1cc(C=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=O)cc1C(SC)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
Ethyl 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetate (4.80 g, 17.9 mmol), ethanol (30 mL) and 10% aqueous solution of sodium hydroxide (20 mL) were mixed and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured in ice water and made acidic with concentrated hydrochloric acid, which was then extracted with ethyl acetate. The extracte was washed with water, dried over anhydrous sodium sulfate, and then concentrated to afford 4.00 g of crude 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetic acid as yellow crystals (this compound was used for next reaction without further purification). Next, 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetic acid (4.00 g, 16.4 mmol) and N,N-dimethylformamide (50 mL) were mixed and, after anhydrous potassium carbonate (3.71 g, 26.8 mmol) and benzyl bromide (3.06 g, 17.9 mmol) were added at room temperature under stirring, the mixture was stirred for 5 hours. The reaction mixture was poured in ice water and extracted with ether. The extracted solution was washed with water and brine, and then dried over anhydrous sodium sulfate. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate n-hexane:ethyl acetate=6:1 v/v) to afford 4.50 g (76%) of the title compound as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:37](O)[CH2:38][OH:39]>CCOCC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH:12]2[O:39][CH2:38][CH2:37][O:24][CH:11]12
Reactant: CCCCCC(=O)C=C[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCC(O)C=C[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OC
Reaction time: 0.5 h

Procedure:
A mixture if 9,15-dioxoprost-13-enoic acid methyl ester (2.0 g) benzene (50 ml), p-toluenesulfonic acid (37 mg) and ethylene glycol (372 mg) is refluxed for 2.5 hours, diluted with ether, washed neutral with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue containing 9-ethylenedioxy-15-oxoprost-13-enoic acid methyl ester is taken up in methanol (20 ml) and treated with sodium borohydride (300 mg) in small portions with stirring which is continued for 30 minutes. The solvent is evaporated under reduced pressure, the residue taken up in ether, washed to neutrality with water, dried over magnesium sulfate, and the solvent evaporated under reduced pressure. The residue is chromatographed on silica gel (140 g) and eluted with 40% ether in hexane to yield 9-ethylenedioxy-15-hydroxyprost-13-enoic acid methyl ester, γmaxFilm 3460, 1740, 1037, 975, 950 cm-1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](OC)=[O:20].CCOCC>O1CCCC1>[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](=[O:20])[CH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: Cc1cccnn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1cccnn1)c1ccc(F)cc1F
Yield: 29.1 %

Procedure:
Treatment of 3-methylpyridazine (4.70 g) with lithium diisopropylamide (0.05 mole) in dry tetrahydrofuran followed by methyl 2,4-difluorobenzoate (8.60 g) according to the method of Example 11(i) gave the title compound, (3.40 g), m.p. 115.5°-117.5° (from ether).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:25]O)=[C:5]([C:20]([O:22]CC)=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[CH2:25][O:22][C:20](=[O:21])[C:5]=2[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Yield: 61 %

Procedure:
A solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (592.5 mg) and p-toluenesulfonic acid (catalytic amount) in ethanol (6 ml) was refluxed for 4 hours. After the resultant solution was concentrated, diethyl ether was added to the residue. The precipitating crystals were collected by filtration to give ethyl 2-methyl-4-(2-chlorophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (317.5 mg). The crude product was recrystallized from ethyl acetate to give colorless granules (210.3 mg), m.p. 211° to 212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[C:47]3([CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:46](=[O:53])[NH:45][C:44]2=[O:54])=[CH:39][CH:38]=1.C(N(CC)C(C)C)(C)C.CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:50]3[CH2:49][CH2:48][C:47]4([N:43]([C:40]5[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=5)[C:44](=[O:54])[NH:45][C:46]4=[O:53])[CH2:52][CH2:51]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC(=O)C2(CCNCC2)N1c1ccc(F)cc1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)NC(=O)N4c3ccc(F)cc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 85 °C

Procedure:
Combine the 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5.0 mmol), 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride (7.5 mmol, 1.5 eq.), N,N-diisopropylethylamine (15 mmol), and DMF (8 mL). Heat the mixture at 85° C. for 48 h. Cool to ambient temperature and add ethyl acetate (100 mL). Extract with water (25 mL), 1N HCl (2×25 mL), saturated NaHCO3 (25 mL), and saturated NaCl (25 mL). Dry over MgSO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](O)[CH3:18]>[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])CCC=CCCCc1ccccc1
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
First, 831 mg of et - 8-phenyl-4-octenoate was dissolved in 17 ml of absolute ethanol, and after adding 83 mg of 5% palladium on carbon, the mixture was stirred under a hydrogen gas flow at a room temperature for 80 minutes. After filtering off the catalyst, the filtrate was evaporated to obtain 795 mg of ethyl 8-phenyloctanoate as a colorless liquid.