Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.Cl.[NH2:41][O:42][CH:43]([CH3:45])[CH3:44].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:44][CH:43]([O:42][N:41]=[C:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:6][CH2:7]1)[CH3:45]
Reactant: CC(C)ON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=NOC(C)C)CC2)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), 2-(aminooxy)propane hydrochloride (0.43 g) and pyridine (10 mL) was stirred at 100° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 79%).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([N:25]1[CH2:28][C:27]3([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:26]1)[CH2:20][CH2:19]2.[CH:34]1([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][CH:38]=2)[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:34]1([C:37]2[CH:38]=[CH:39][C:40]([CH2:43][C:44]([N:31]3[CH2:30][CH2:29][C:27]4([CH2:26][N:25]([CH:21]5[C:22]6[C:18](=[CH:17][C:16]([C:11]7[N:12]=[CH:13][CH:14]=[CH:15][N:10]=7)=[CH:24][CH:23]=6)[CH2:19][CH2:20]5)[CH2:28]4)[CH2:33][CH2:32]3)=[O:45])=[CH:41][CH:42]=2)[CH2:36][CH2:35]1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Reactant: c1cnc(-c2ccc3c(c2)CCC3N2CC3(CCNCC3)C2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(C2CC2)cc1)N1CCC2(CC1)CN(C1CCc3cc(-c4ncccn4)ccc31)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.1 mL) was added to a solution of 2-(5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane dihydrochloride (5-1b, 80 mg, 0.2 mmol), 4-cyclopropylphenylacetic acid (SM-1ag, 31 mg, 0.2 mmol), and HATU (93 mg, 0.24 mmol) in dichloromethane (5 mL) in a vial. The reaction was stirred at room temperature overnight and was quenched with aqueous sodium bicarbonate. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) using a 12 g silica column with dichloromethane-methanol as eluant. The final product was obtained as off-white solid (89 mg, 92%). MS (APCI) 478.6 (M+H)+. 1H NMR (CDCl3) δ 0.65-0.69 (m, 3H), 0.92-0.97 (m, 2H), 1.67-1.71 (m, 2H), 1.83-1.90 (m, 2H), 2.19-2.22 (m, 1H), 2.89 (s, 1H), 3.18-3.26 (m, 5H), 3.31-3.35 (m, 2H), 3.51-3.55 (m, 2H), 3.66-3.70 (m, 3H), 4.01-4.06 (m, 1H), 7.00-7.04 (m, 2H), 7.10-7.13 (m, 2H), 7.17-7.21 (m, 1H), 7.41 (s, 1H), 8.31 (s, 2H), 8.79-8.82 (m, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([NH2:30])[C:23]2[C:24]([F:29])=[N:25][NH:26][C:27]=2[CH:28]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:29][C:24]1[C:23]2[C:22]([NH2:30])=[CH:21][C:20]([C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[CH:11]=[CH:12][NH:13]4)=[CH:28][C:27]=2[NH:26][N:25]=1
Reactant: Nc1cc(Br)cc2[nH]nc(F)c12
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]nc(F)c12
Temperature: 150 °C
Yield: 304.6 %

Procedure:
To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (24 mg) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (3 mg) at 20° C. in a microwave vial was added a solution of 6-bromo-3-fluoro-1H-indazol-4-amine (19 mg) in 1,4-dioxane (0.75 ml) followed by water (0.5 ml) and aqueous sodium carbonate (2M, 0.124 ml). The reaction vessel was sealed and heated under microwave irradiation at 150° C. for 15 min. After cooling, the black solution was loaded onto a 500 mg silica cartridge which was then eluted with methanol (4 column volumes). The eluant was blown to dryness, re-dissolved in methanol (3 ml), filtered and blown to dryness to give the title compound (67 mg) as a brown film.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:22])[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:23][CH:24]([CH3:30])[CH2:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:23][CH:24]([CH3:30])[CH2:25][CH2:26][C:27]([NH:1][CH2:2][C@H:3]([OH:22])[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:28]
Reactant: CC(C)CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCC(=O)NC[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To the resultant compound from Example 9 (94.6 mg, 0.299 mmol) in methylene chloride (5 mL) at 0° C. was added 4-methylpentanoyl chloride (52ul, 0.37 mmol) and triethylamine (71 μl, 0.51 mmol). The mixture was stirred at 0° C. for 90 min, diluted with ethyl acetate, washed sequentially with 0.5M H3PO4 solution, 2M NaOH solution and brine, and then dried over Na2SO4 and evaporated to afford 0.118 g (95%) of the desired compound, m.p. 179°-183° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[Cl:23])[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.[NH2:24][C:25]([NH2:27])=[NH:26]>>[CH:10]1([C:9]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][C:14]=3[Cl:23])[N:7]=[CH:6][C:5]=2[C:3]([NH:26][C:25]([NH2:27])=[NH:24])=[O:2])[CH2:11][CH2:12]1
Reactant: COC(=O)c1cnn(-c2ccc(S(C)(=O)=O)cc2Cl)c1C1CC1
Reactant: N=C(N)N
Product: CS(=O)(=O)c1ccc(-n2ncc(C(=O)NC(=N)N)c2C2CC2)c(Cl)c1

Procedure:
coupling said 5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carboxylic acid methyl ester with guanidine to form N-{5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carbonyl}-guanidine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:28]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1>>[Cl:33][C:31]1[CH:30]=[C:29]([S:34]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)(=[O:35])=[O:36])[CH:28]=[C:27]([Cl:26])[CH:32]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cc(Cl)cc(Cl)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3,5-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]([NH2:26])=O)=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]#[N:26])=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 79 %

Procedure:
Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (1.00 g), trifluoromethanesulfonic anhydride (0.50 mL) as a dehydrating agent and trifluoroacetic acid (0.23 mL) as an acid, a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile was obtained (obtained amount: 754 mg, yield: 79%) by the same method of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[C:11]([F:16])[CH:10]=1.[OH-].[K+]>C1(C)C=CC=CC=1.O.[Br-].C[N+](C)(C)CCCCCCCCCCCCCCCC.[Cl-].[Na+].O>[F:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([F:16])[CH:10]=1)[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Fc1cc(F)cc(I)c1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cc(F)cc(Nc2ccccc2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
In a 5 mL microwave reaction vial was placed aniline (0.298 g. 3.20 mmol) and 1,3-difluoro-5-iodobenzene (0.768 g, 3.20 mmol) in toluene (3 mL). KOH (0.323 g, 5.76 mmol) in water (650 μL) and N,N,N-trimethylhexadecan-1-aminium bromide (6.30 mg, 0.017 mmol) were added to the vial with stirring. After the reaction was warmed to 90° C., bis[tri(t-butylphosphine]palladium[0] (0.016 g, 0.032 mmol) was added and the reaction was stirred at 150° C. for 4 h and then 160° C. for 2 h. The mixture was diluted with water and brine, and extracted with toluene. The toluene extract was subsequently washed with water, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography to provide the title compound as a brown oil (0.132 g). LCMS m/z=206.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.54 (tt, J=9.35, 2.27 Hz, 1H), 6.63 (dd, J=10.48, 2.15 Hz, 2H), 7.01 (dt, J=14.65, 1.14 Hz, 1H), 7.17 (dd, J=8.59, 1.01 Hz, 2H), 7.34 (t, J=7.83 Hz, 2H), 8.69 (s, 1H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][OH:15]>O1CCCC1>[CH3:18][O:17][C:13]([CH2:14][O:15][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1)=[O:16]
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
1.26 g of sodium hydride was added to a mixture of 5.0 g of 2-chloro-5-nitropyridine, 3.13 g of methyl glycolate and 50 ml of tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for 15 minutes, then at room temperature for 1 hour. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5.18 g of 2-(methoxycarbonyl)methoxy-5-nitropyridine.
Reaction SMILES: [N:1]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][C@H:2]1[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@@H:6]1[C:7]([O:9]CC1C=CC=CC=1)=[O:8])=[O:4]>[Pd].CO>[N:1]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][C@H:2]1[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@@H:6]1[C:7]([OH:9])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
2.05 g of Pd/C (ASCA-2, ca. Pd 5 wt %, 50% wet) was added to 41 ml of methanol solution of 4.10 g (10.2 mmol) of Boc-Pro-D-Pro-OBn obtained in Synthesis Example 1-1, followed by stirring for 20 hours at room temperature under a hydrogen atmosphere. After a reaction mixture was filtrated by celite, the filtrate was concentrated under reduced pressure, thereby obtaining the product with a yield of 100%.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:22]([C:31]([O:33]CCC#N)=[O:32])=[C:21]([CH3:38])[NH:20][C:19]=2[CH3:39])=[O:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>CO>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]([C:18]2[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:22]([C:31]([OH:33])=[O:32])=[C:21]([CH3:38])[NH:20][C:19]=2[CH3:39])=[O:17])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.30 ml (6.30 mmol) of 1 N aqueous sodium hydroxide solution was added to 1.67 g (3.15 mmol) of 4-[4-(3-chlorophenyl)-5-(2-cyanoethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl ester in 30 ml of methanol and stirred at room temperature for 2 hours. 6.30 ml (6.30 mmol) of 1 N hydrochloric acid was added and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained solid substance was filtered, washed with hexane/ethyl acetate (3/1) and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[O:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[C:1]([O:5][C:6](=[O:9])[CH2:7][CH:14]([CH:13]1[CH2:3][CH:1]2[CH2:4][CH:12]1[CH:11]=[CH:2]2)[OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)C1CC2C=CC1C2
Temperature: 70 °C

Procedure:
A couple of Zn—Cu (50 g) and tetrahydrofuran (90 ml) were placed in a four-necked round flask equipped with a stirrer and reflux condenser and then, a mixing solution of t-butylbromoacetate (53 ml) and 5-norbornene-2-carboxaadehyde (36 ml) dissolved in tetrahydrofuran 180 ml was slowly added to the flask. The resulting solution was refluxed at 70° C. for 2 hours and cooled into room temperature. After separating a couple of Zn—Cu from the solution, the remaining solution was extracted, washed with a solvent and distilled under reduced pressure to obtain 3-bicyclo[2,2,1]hept-5-ene-2-yl-3-hydroxyl-propionic acid t-butyl ester (hereinafter referred to as “BHP”, M-I) as a monomer (39 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].[C:20](OCC)(=O)[C:21]([O:23]CC)=[O:22].C[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:2]2[O:1][C:20]([C:21]([OH:23])=[O:22])=[CH:18][C:17](=[O:19])[C:3]=2[CH:4]=[CH:5][C:6]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1O
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(OCc2ccccc2)ccc2c(=O)cc(C(=O)O)oc12
Yield: 95.4 %

Procedure:
A mixture of 1-[2-hydroxy-3-methyl-4-(phenylmethoxy)phenyl]-ethanone (0.098 mol) and ethanedioic acid, diethyl ester (0.11 mol) in toluene (100 ml) was added dropwise to a mixture of sodium methoxide (0.22 mol) in toluene (150 ml). The reaction mixture was stirred and refluxed for 2 hours. The solvent was evaporated. The residue was added to a mixture of acetic acid (150 ml) and hydrochloric acid (50 ml). The reaction mixture was stirred and refluxed for 1 hour. The mixture was poured out onto ice. The resulting precipitate was filtered off and dried (vacuum; 70° C.), yielding 29 g (95.4%) of 8-methyl-4-oxo-7-(phenylmethoxy)-4H-1-benzopyran-2-carboxylic acid (interm. 9).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH2:7][C@@H:8]([OH:28])/[CH:9]=[CH:10]/[CH:11]=[CH:12]\[CH:13]=[CH:14]\[CH:15]=[CH:16]\[C@@H:17]([OH:27])[C@@H:18]([OH:26])[CH2:19][O:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:4][CH:3]=1.[OH-].[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@H:8]([OH:28])/[CH:9]=[CH:10]/[CH:11]=[CH:12]\[CH:13]=[CH:14]\[CH:15]=[CH:16]\[C@@H:17]([OH:27])[C@@H:18]([OH:26])[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:29][CH:30]=1
Reactant: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C=C\C=C\[C@H](O)COc1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C(O)COC[C@H](O)[C@H](O)/C=C/C=C/C=C\C=C\[C@H](O)COc1ccc(F)cc1
Yield: 41499.6 %

Procedure:
A solution of (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid, methyl ester, (25 mg, 59 nMol) in methanol (6 mL) was treated with 1 N NaOH (aq) (25 μL, 25 μmol) solution and shaken and allowed to stand. Upon completion, the reaction was treated with saturated potassium monophosphate. Purification by chromatography on an HP20 column eluted with an aqueous methanol gradient gave 10 mg of (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid; 1H NMR (CD3OD) δ3.6 (m, 3H), 3.88 (m, 4H), 4.18 (m, 1H), 4.52 (m, 1H), 5.84 (m, 2H), 6.03 (m, 2H), 6.34 (m, 2H), 6.74 (m, 1H), 6.95 (m, 5H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:25])[C@@H:13]2C(=O)[CH2:17][CH2:16][CH2:15][C@H:14]2[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CO[CH:28]([O:31][CH3:32])[O:29][CH3:30].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:25])[C@@H:13]2[C:28]([O:29][CH3:30])([O:31][CH3:32])[CH2:17][CH2:16][CH2:15][C@H:14]2[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(OC)OC
Reactant: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1C(=O)CCC[C@H]1N1CCCC1
Agent: Cl
Solvent: CO
Product: COC1(OC)CCC[C@@H](N2CCCC2)[C@@H]1N(C)C(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
To a solution of trans-(±)-3,4-dichloro-N-methyl-N-[6-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, prepared as described in Part B hereinabove, in 50 ml of dry methanol there is added 5 ml of trimethylorthoformate and 0.5 ml of 4M methanolic hydrogen chloride. The resulting mixture is refluxed for about 16 hours, cooled, and the solvent is removed in vacuo. The residual oil is crystallized from a hot methanol solution thereof, diluted with diethyl ether until the mixture becomes cloudy to obtain the titled trans-(±)-3,4-dichloro-N-methyl-N-[6,6-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, which is converted to a hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[CH:28]([CH3:32])[C:29](=[O:31])[CH3:30]>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:20][CH:28]([CH3:32])[C:29](=[O:31])[CH3:30])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: CC(=O)C(C)Cl
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC(C)C(C)=O)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of 2.76 g (0.01 mole) of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (D. E. Schwartz, W. Vetter, and G. Englert, Arzneim.-Forsch. (Drug Res.) 1970, 20, 1867; G. Rey-Bellet and R. Reiner, Helv. Chim. Acta 1970, 53, 945) in 40 mL of dry dimethyl sulfoxide was added 1.12 g (0.01 mole) of potassium t-butoxide. To the resulting suspension was added in one portion 1.16 g (0.0109 mole) of 3-chloro-2-butanone. The mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum and the residue was partitioned between 100 mL of methylene chloride and 100 mL of 0.1N sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with an additional 100 mL of methylene chloride. The organic layers were combined, washed with 100 mL of water, dried (MgSO4) and concentrated to give a quantitative yield (3.58 g) of the title compound. Recrystallization from 95% ethanol gave an analytical sample; mp 167.5°-168.5°. Anal. Calc'd for C17H22N4O4 : C, 58.95; H, 6.40; N, 16.17. Found: C, 58.77; H, 6.42; N, 16.13.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)C.C(=O)([O-])[O-].[Ca+2:20]>O>[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Ca+2:20].[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCC(=O)[O-]
Reaction time: 0.08 h

Procedure:
To a one-liter three-necked flask equipped with a thermometer, mechanical stirrer, and a reflux condenser, were added decanoic acid (20.0 g, 116 mmole) and absolute ethanol (0.19 L). The mixture was stirred vigorously for 5 minutes. The clear solution was then diluted with water (30 ml). Solid calcium carbonate (5.5 g, 55 mmole) was added in one portion and the resulting white suspension heated under reflux for 12 days. Water (10 ml) was added to the reaction each day except the last one. On the last day, excess water (100 ml) was added to complete the reaction. The mixture was cooled to 45° C. (water bath) and filtered through a coarse glass funnel. This gave a white solid which was washed with absolute ethanol (50 ml), tert-butyl methyl ether (2×50 ml) and air-dried for 2 hours. The solid was then dissolved in boiling methanol (1.3 L) and the cloudy solution filtered on a Celite pad. The clear filtrate was cooled and concentrated to 300 ml. The white precipitate was filtered under suction (water aspirator) using a coarse glass funnel (1 L) and air-dried for 3 hours. The resulting solid was kept under high vacuum at 20° C. for 18 hours. The pure acid calcium salt was isolated as a snow-white solid. Yield of product: 14.0 g (63%); mp=172-76° C., 1H NMR (CD3OD, 400 MHz) δ: 2.18 (t, J=7.63 Hz, 4H); 1.61 (m, 4H); 1.30 (m, 24H); 0.91 (t, J=7.04 Hz, 6H); 13C NMR (D2O, 400 MHz) δ: 183.0, 38.0, 32.4, 30.2, 30.1, 30.0, 29.8, 26.9, 23,1, 13.9.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([OH:25])=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH3:26][O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:25][C:20]2[C:19]([C:9]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]4[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=4[N:10]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:33][CH:32]=1
Reactant: Oc1ncccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1
Reactant: COC(=O)COc1ccc(CBr)cc1
Product: COC(=O)COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2ccccc2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 3-(1-benzyl-5,6-difluoro-1H-benzoimidazol-2-yl)-pyridin-2-ol and (4-bromomethyl-phenoxy)-acetic acid methyl ester (CAS Reg. No. 104508-23-8). Brown solid (65%). MS (Turbo Spray): m/z=516.3 (M+H).