Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:33])[CH:8]([O:30][CH2:31][CH3:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C>O.O1CCCC1>[CH2:31]([O:30][CH:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)[C:7]([OH:33])=[O:6])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Lithium hydroxide hydrate (0.12 g; 2.82 mmole) dissolved in water (10 ml) was slowly added to a solution of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid ethyl ester (1.12 g; 2.56 mmole) in tetrahydrofuran (30 ml). After stirring at room temperature for 3 hours, water (50 ml) was added and tetrahydrofuran was removed by evaporation in vacuo. The water residue was acidified with hydrochloric acid (2 M) and extracted three times with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and the solvent was evaporated in vacuo to give 1 g (yield 96%) of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)-phenyl]propanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]([F:19])([F:18])[F:17].[CH:21](OC)(OC)OC.FC(F)(F)C(O)=O>CO>[F:18][C:16]([F:19])([F:17])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[C:7]2=[N:6][C:5]([OH:20])=[CH:4][CH:3]=[C:2]2[N:1]=[CH:21]1
Reactant: COC(OC)OC
Reactant: Nc1ccc(O)nc1Nc1ccccc1OC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Oc1ccc2ncn(-c3ccccc3OC(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
To a solution of 5-amino-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-ol (75.0 mg, 0.26 mmol) dissolved in MeOH was added trimethyl orthoformate (1.0 mL, 9.05 mmol) and catalytical amount of trifluoroacetic acid. The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (78 mg). LCMS m/z=296.0 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ ppm 6.63 (d, J=8.6 Hz, 1H), 7.66 (m, 3H), 7.81 (d, J=7.6 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 10.60-11.20 (broad s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH:29]1([CH2:35]Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH:29]1([CH2:35][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=2[O:28][CH2:15][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: BrCC1CCCCC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(OCC2CCCCC2)c(-c2cc(CCCC(=O)OC)ccc2OCC2CCCCC2)c1
Yield: 119.7 %

Procedure:
To 5 ml of a DMF solution containing 250 mg (0.6477 mmol) of 2,2'-dihydroxy-5,5'-bis(3-methoxycarbonylpropyl) biphenyl and 0.920 ml (6.477 mmol) of cyclohexylmethyl bromide, there was added 360 ml (2.5907 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at 100° C. The reaction mixture was filtered by suction through Celite to remove the solid matter, which was washed with ethyl acetate. After the solvent in the filtrate had been evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and saline solution in this sequence and was dried over anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 12 g of WAKO-gel C-200, eluent: hexane and hexane/ethyl acetate of 25/1) to obtain 224 mg (0.3877 mmol, 60%) of 2,2'-dicyclohexylmethoxy-5,5'-bis(3-methoxycarbonylpropyl) biphenyl as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][OH:6].[H-].[Na+].CS([C:17]1[N:22]=[C:21]([OH:23])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[N:18]=1)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][O:6][C:17]1[N:22]=[C:21]([OH:23])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[N:18]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CS(=O)(=O)c1nc(O)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a round bottom flask fitted with a magnetic stir bar and rubber septum was added 2 mL DMF, 3,4-difluorobenzyl alcohol (14 μl, 0.11 mmol) and sodium hydride (60% in oil, 4.5 mg, 0.12 mmol). The flask was flushed with nitrogen and 2-methylsulfonyl-4-hydroxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (from Step A) (43 mg, 0.1 mmol) in 500 μL DMF was added by syringe. After 1 h, the reaction was quenched with aqueous NH4Cl. A precipitate fell out of solution and it was filtered, washed with water and dried under reduced pressure. HPLC/MS: m/e=494 (M+); Rt=4.28 min; 1H-NMR 500 MHz (CDCl3): δ 5.39 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.15-7.22 (m, 4H), 7.22-7.28 (m, 1H), 7.41 (d, J=2 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.5 %

Procedure:
The mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (300 mg), 3-[(methyloxy)carbonyl]benzoic acid (180 mg), HBTU (417 mg) and DIPEA (690 μL) in dichloromethane (DCM, 25 mL) was stirred at room temperature overnight. It was concentrated. Separation via CombiFlash (MeOH, DCM) then afforded the desired product (670 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]([CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[CH:4][C:3]=1[C:30]1[N:34]([CH3:35])[N:33]=[CH:32][C:31]=1[Cl:36].NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:30]2[N:34]([CH3:35])[N:33]=[CH:32][C:31]=2[Cl:36])[CH:4]=1)=[O:8])[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)CC2CCCCC2)sc1Cl
Reaction time: 12 h
Yield: 70.7 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (303 mg, 0.55 mmol) in tetrahydrofuran (2.78 ml) and methanol (2.78 ml) at 25° C. was added hydrazine (0.17 ml, 5.55 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexyl methyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (190 mg, 0.389 mmol, 70.0% yield) as a yellow solid: LCMS (ES) m/z=415, 417 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (br. s., 1H) 8.06 (s, 4H) 7.74 (s, 1H) 4.25 (dd, J=8.84, 4.29 Hz, 1H) 3.77 (s, 3H) 2.87-2.93 (m, 2H) 1.71-1.79 (m, 1H) 1.64 (d, J=9.85 Hz, 3H) 1.54 (br. s., 1H) 1.48 (br. s., 1H) 1.37 (dd, J=13.26, 4.93 Hz, 1H) 1.14 (br. s., 1H) 1.17 (d, J=7.33 Hz, 2H) 0.93 (d, J=10.86 Hz, 1H) 0.82-0.89 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]P(=O)(OCC)OCC)[N:6]=1.[H-].[Na+].[CH3:18][O:19][CH2:20][O:21][C:22]1[C:26]([CH:27]=O)=[CH:25][N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]=1.O>O1CCCC1>[CH3:1][C:2]1[S:3][CH:4]=[C:5](/[CH:7]=[CH:27]/[C:26]2[C:22]([O:21][CH2:20][O:19][CH3:18])=[N:23][N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)[N:6]=1
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1csc(C)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C)n1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of diethyl [(2-methyl-1,3-thiazol-4-yl)methyl]phosphonate (2.32 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.32 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1, v/v) to give 2-methyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a pale-yellow oil (2.72 g, yield 83%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:15]>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[O:11][CH3:15])=[CH:4][CH:3]=1
Reactant: CI
Reactant: OC1CCc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCc2ccc(Br)cc21
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 6-bromoindanol (0.51 g, 2.4 mmol) in anhydrous tetrahydrofuran (10 mL), was added sodium hydride (0.097 g, 3.84 mmol) over a period of five minutes at room temperature. The reaction mixture was stirred at room temperature for fifteen minutes and iodomethane (0.22 mL, 3.6 mmol) was added. After thirty minutes at room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The ethyl acetate layer was washed with brine (20 mL), dried over sodium sulfate and concentrated to yield the title compound (0.485 g, 89%). 1H NMR (CDCl3) : □ 7.5 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H), 4.7 (m, 1H), 3.3 (s, 3H), 3.0 (m, 1H), 2.7 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([C:13]1[NH:14][C:15](=[O:18])[O:16][CH:17]=1)[CH3:12].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:11]([C:13]1[N:14]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:15](=[O:18])[O:16][CH:17]=1)[CH3:12]
Reactant: CCc1coc(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCc1coc(=O)n1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of o-chlorobenzoyl chloride (1.93 g.) and 4-ethyl-4-oxazolin-2-one (1.13 g.) in 30 ml. of benzene is cooled to 10° C. and reacted with 1.21 g. of triethylamine dissolved in 5 ml. of benzene. The reaction mixture is stirred at room temperature for 1 hour. The excess triethylamine and benzene is removed under reduced pressure to leave a light yellow oil (2.4 g.) which is triturated with ethanol whereupon a crystalline solid separates. The solid is removed and washed with a small amount of cold ethanol and dried. Yield 0.3 g.; m.p. 110°-112° C.
Reaction SMILES: [CH2:1]([O:5]C(=O)OCC(C)C)[CH:2](C)C.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:1](=[O:5])[CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CC(C)COC(=O)OCC(C)C
Product: CC(=O)NCc1ccccc1

Procedure:
After completion of the reaction, 1% hydrochloric acid (23 g) was dropwide added at 10° C. or lower and after stirred for 30 minutes, settled and separated. The obtained organic layer was washed with 9% salt water (7 g) at 5 to 10° C., settled and separated. The obtained organic layer was washed with an aqueous 5% sodium hydrogen carbonate solution (11.8 g) at 15 to 30° C., settled and separated After that, the organic layer was washed with ion-exchange water (6 g) at 25 to 35° C., settled and separated. The obtained organic layer was evaporated to obtain a solution (10.04 g) of a desired pale yellowish transparent solution or white solid. The content was found 86.5% by gas chromatography analysis. The pure product yield was 8.68 g (yield 87.8% based on acetic acid). The content of impurities are as follows; diisobutylcarbonate: 2.0%, and N-isobutyloxycarbonyl)-benzylamine: 2.5%.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]2[CH3:22])=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:14]=1>>[CH2:9]([O:8][P:1]([CH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]2[CH3:22])=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:14]=1)([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)cc(CBr)cc2n1C
Product: CCOC(=O)c1cc2c(C(F)(F)F)cc(CP(=O)(OCC)OCC)cc2n1C
Temperature: 140 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Under nitrogen, triethyl phosphite (589 μl, 3.43 mmol) was added to ethyl 6-(bromomethyl)-1-methyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (250 mg, 0.687 mmol), and the resulting mixture was stirred for 2 hours while being maintained at 140° C. The excess triethyl phosphite was distilled off as much as possible, and the resulting concentrated residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=15/1, 10/1, 3/1, 1/1, 1/4 and 0/10) to obtain 276 mg of ethyl 6-[(diethoxyphosphoryl)methyl]-1-methyl-4-(trifluoromethyl)-1H-indole-2-carboxylate as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[C:8]1(=[O:12])[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(c1)CCCC2=O
Reaction time: 18 h

Procedure:
To a solution of 6-hydroxy-1-tetralone (2.62 g) in acetone (50 ml) was added anhydrous potassium carbonate (2.23 g) followed by methyl bromoacetate (1.52 ml) and the resulting mixture was stirred for 18 hours. The mixture was filtered and the solvent was evaporated to give a yellow solid. Recrystallisation from ethyl acetate gave methyl tetralone-6-oxyacetate (2.28 g): NMR (d6DMSO) δ 1.95-2.05(m,2H), 2.45-2.55(m,2H), 2.9(t,2H), 3.7(s,3H), 4.9(s,2H), 6.85-6.9(m,2H), 7.8(d,1H); m/e 235(M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@@H:15]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)[C@H:16](O)[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@@H:15]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:28][CH:27]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(O)cc2)cc1
Agent: CC[SiH](CC)CC
Product: CC(C)(C)c1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1

Procedure:
The target compound (18.2 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(d) using (S)-4-benzyl-3-[(2S,3R)-2-(4-t-butylphenoxy)-3-hydroxy-3-(4-hydroxyphenyl)propionyl]oxazolidin-2-one (25.3 g) obtained from Reference example 21(c) and triethylsilane (66 ml).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH2:66])[CH:61]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH:66][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:61]=1
Reactant: COc1ccc(OC)c(-c2cccc(N)c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC)c(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,5′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 83% yield: LCMS (ESI) m/z 432 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.S(Cl)(Cl)=O.C(OC([N:25]1[CH2:29][CH2:28][CH:27]([NH:30][CH2:31][C:32]([CH3:42])=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])[CH2:26]1)=O)(C)(C)C>C(N(CC)CC)C>[F:41][C:35]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=1[CH:33]=[C:32]([CH3:42])[CH2:31][N:30]([CH:27]1[CH2:28][CH2:29][NH:25][CH2:26]1)[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CC(=Cc1ccc(F)cc1F)CNC1CCN(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(C(=O)O)cc1OC
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(CC(C)=Cc2ccc(F)cc2F)C2CCNC2)cc1OC
Yield: 35 %

Procedure:
Experimental condition analogous to Example 18 were used with 3,4-dimethoxybenzoic acid 0.12 g (0.68 mmol), thionyl chloride 2 ml (1.68 mmol). The obtained acyl chloride was reacted with 3-[3-(2,4-difluoro-phenyl)-2-methyl-allylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester 0.2 g (0.56 mmol), triethylamine 0.2 ml. The reaction yielded the free amine, which was converted to the HCl salt 90 mg as an off-white solid: Yield: 35%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[O:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[O:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1

Procedure:
48.6 G. of 4-[2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester are dissolved in 750 ml. of glacial acetic acid. 18.9 G. of sodium borohydride are added in small portions within 20 minutes with stirring and cooling in such a manner that the temperature does not exceed 25° C. The mixture is stirred for an additional 30 minutes at 25° C. and then the glacial acetic acid is removed by distillation in vacuo. The residue is partitioned between chloroform and aqueous sodium hydroxide solution. The organic phase is separated and washed with water. The aqueous phases are extracted two additional times with chloroform. The combined chloroform extracts are dried over sodium sulfate, evaporated in vacuo, and there is obtained crude 4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:57][S:54]([CH:51]5[CH2:53][CH2:52]5)(=[O:56])=[O:55])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42), (80 mg, 0.147 mmol) and carbonyldiimidazol (48 mg, 0.295 mmol) in dry THF (25 mL) was stirred at reflux under nitrogen for 3 h. Then, the reaction mixture was cooled down to room temperature and cyclopropylsulfonamide (54 mg, 0.442 mmol) and DBU (52 mg, 0.34 mmol) were added. The resulting solution was stirred at 50° C. for 48 h. Then, the reaction mixture was partitioned between AcOEt ethyl acetate and water. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2/EtOAc, 95:05) to give the title product contaminated with cyclopropylsulfonamide. This solid was triturated 10 min in water and filtered, washed with water, dried under high vacuum, triturated again in diethylether and filtered to give 37 mg (39%) of the title product 43 as a white powder: m/z=647 (M+H)+; 1H-NMR (CDCl3): 10.40 (br s, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.55 (s, 1H), 7.15 (s, 1H), 7.10 (dd, J=9.12 Hz, 2.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 5.85 (br s, 1H), 5.65 (dd, J=18.2 Hz, 8.0 Hz, 1H), 5.15 (t, J=10.0 Hz, 1H), 4.8 (t, J=7.2 Hz, 1H), 4.10 (dd, J=11.3 Hz, 3.8 Hz, 1H), 3.9 (s, 3H), 3.60-3.70 (m, 1H), 3.6 (d, J=11.3 Hz, 1H), 3.10-3.20 (m, 1H), 2.90-3.00 (m, 1H), 2.85 (s, 3H), 2.4-2.6 (m, 3H), 1.90-2.20 (m, 3H), 1.25-1.60 (m, 7H), 0.90-1.10 (m, 2H).