Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([S:6][CH:7]1[N:10]([CH2:11][C:12]([O:14]C)=[O:13])[C:9](=[O:16])[CH2:8]1)[CH:4]=[CH2:5].Cl>C(O)C.O>[CH2:3]([S:6][CH:7]1[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9](=[O:16])[CH2:8]1)[CH:4]=[CH2:5]
Reactant: C=CCSC1CC(=O)N1CC(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCSC1CC(=O)N1CC(=O)O
Temperature: 25 °C

Procedure:
2.34 g of potassium hydroxide dissolved in a mixture of 285 ml of ethanol and 15 ml of water were added to 6.0 g of methyl 2-(4-allylthioazetidin-2-on-1-yl)acetate with stirring at room temperature. The solution was poured into 720 ml 1M hydrochloric acid, extracted into dichloromethane (2.650 ml), the organic layer extracted with saturated sodium bicarbonate solution and the aqueous phase acidified to pH1 with 5M hydrochloric acid. This solution was extracted into dichloromethane (5×650 ml), dried with MgSO4 and evaporated to leave a colorless oil.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH:5][CH3:6].C(N(C(C)C)CC)(C)C.Cl[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[F:2][CH2:3][CH2:4][N:5]([CH3:6])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CNCCF
Reactant: COC(=O)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(=O)N(C)CCF
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 2-fluoro-N-methylethanamine hydrochloride salt (1 g, 8.81 mmol) in CH2Cl2 (40.0 mL) was added drop-wise diisopropyl-ethylamine (5.59 mL, 32.0 mmol) followed by the drop-wise addition of methyl 2-chloro-2-oxoacetate (0.981 g, 8.01 mmol) and the resulting mixture stirred for 3 h under N2. The solution was concentrated and the residue was taken up in ethyl acetate (20 mL), washed with 1N HCl (2×15 mL) followed by saturated aqueous sodium bicarbonate (15 mL). The organic phase was dried (MgSO4), filtered, and concentrated to give the title compound as a clear oil (1.2 g, 92% yield). 1H NMR (500 MHz, CDCl3) δ: 4.46-4.73 (2 H, m) 3.82-3.93 (3 H, m) 3.60-3.77 (2 H, m) 3.01-3.20 (3 H, m). LCMS (M+H) calcd for C6H11FNO3: 164.07; found: 164.11.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[N:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH:15]=[N:14]2)=[CH:11][CH:12]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:27][C:23]1[CH:22]=[C:21]2[C:26]([C:18]([C:16]3[CH:15]=[N:14][N:13]([C:10]4[N:9]=[N:8][C:7]([NH2:6])=[CH:12][CH:11]=4)[CH:17]=3)=[CH:19][NH:20]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(CNc2ccc(-n3cc(-c4c[nH]c5cc(F)ccc45)cn3)nn2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-n2cc(-c3c[nH]c4cc(F)ccc34)cn2)nn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A mixture of N-(2,4-dimethoxybenzyl)-6-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)pyridazin-3-amine (80 mg; 0.18 mmol) and anisole (2.0 mL) in TFA (2.0 mL) was stirred at 120° C. for 2 hours in a microwave reactor. The reaction mixture was concentrated, and purified by a silica gel column chromatography (PE/EtOAc=4/1 to 2/1) to afford 30 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH2:19][CH2:20][CH3:21].C(O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCCC2=O)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCC1(c2cccc(OC)c2)CCCCC1=O
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 2-(3-methoxy-phenyl)-cyclohexanone (2.04 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) was added over 10 min to a mixture of sodium hydride (0.29 g, 12.0 mmol) in N,N-dimethylformamide (4 mL), the temperature being kept below 30° C. The reaction mixture was stirred at 20-25° C. for 2 h. A solution of 1-iodo-propane (1.17 mL, 12.0 mmol) in N,N-dimethylformamide (2 mL) was added over 10 min at 20-25° C. The mixture was stirred for 18 h, and then, ethanol (2 mL) was slowly added. The mixture was stirred for 0.5 h and then poured onto ice-water. The mixture was extracted with dichloromethane. The organic layer was separated, washed with water, and dried over sodium sulfate. Solvents were removed under reduced pressure and the remaining oil was purified by column chromatography on silica gel using heptane/diethyl ether (4:1, v/v) as eluent to give the title compound (0.74 g, ca. 30%) as pale-yellow oil. MS ISP (m/e): 247.3 [(M+H)+].
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12](=[NH:14])[NH2:13])[CH:11]=1)=[O:6])[CH3:3].Cl[C:16]1[C:25](Cl)=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[NH:13][C:16]3=[N:17][C:18]4[C:23]([N:24]=[C:25]3[N:14]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:11]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnn(C(=N)N)c1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(-c2nc3nc4ccccc4nc3[nH]2)c1
Yield: 42.2 %

Procedure:
A solution of 1-carbamimidoyl-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (0.220 g, 1.00 mmol), 2,3-dichloro-quinoxaline (200 mg, 1.00 mmol), and Cs2CO3 (1.63 g, 5.00 mmol) in DMF (2 mL) was stirred for 4 h. H2O (3 mL) was added and the mixture was acidified to pH 2 with aqueous 1M HCl to form a white precipitate. The precipitate was filtered, triturated with anhydrous EtOH (2 mL), and filtered to yield the titled compound (0.130 g, 43%). MS (CI): mass calcd. for C15H12N6O2, 308.1; m/z found, 309.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.08 (s, 1H), 8.23 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.75 (t, J=7.1 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([O:9][C:8]([CH:5]1[CH2:6][CH2:7][CH:2]([N:1]([CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:4]1)=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1CCC(C(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
4-Amino-cyclohexanecarboxylic acid (16 g, 0.11 mol) was treated with K2CO3 (46.8 g) in MeCN (225 mL) at 80° C. under Ar. Benzyl bromide (46.6 mL) in MeCN (140 mL) was then added dropwise and stirred at 80° C. for approximately 20 hours and allowed to cool to RT, to yield 4-dibenzylamino-cyclohexanecarboxylic acid benzyl ester (55.04 g) after workup.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[C@H:14]([OH:26])[C@@H:13]1[OH:27])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].C(OC([NH:38][C@H:39]([C:55](O)=[O:56])[CH2:40][CH2:41][CH2:42][CH2:43][NH:44]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[ClH:1].[ClH:1].[NH2:38][C@H:39]([C:55]([NH:2][C@H:3]([C:8]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[C@H:14]([OH:26])[C@@H:13]1[OH:27])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5])=[O:56])[CH2:40][CH2:41][CH2:42][CH2:43][NH2:44]
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 Gram (2.42 mmol) of 5'-O-isoleucyl-5-fluorouridine hydrochloride was dissolved in dimethylformamide (20 ml), and 1.00 g (2.85 mmol) of Nα,Nε -di-benzyloxycarbonyllysine and 0.67 g (3.69 mmol) of diethylphosphoryl cyanide were then added. To this solution was added under ice-cooling 1.54 g (15.2 mmol) of triethylamine, and the mixture was stirred overnight at room temperature. After addition of ice water the reaction liquid was extracted with chloroform (200 ml). The organic layer was dried (over Na2SO4) and concentrated under reduced pressure, and the residue was subjected to separation/purification by way of silica gel column chromatography (first time: 2.5×11 cm, chloroform containing 4% methanol; second time: 5×14 cm, a linear gradient of ethyl acetate-n-hexane (1:1) containing 0→6% methanol) whereby 0.46 g (26%) of 5'-O-{N-(Nα,Nε -di-benzyloxycarbonyllysyl)isoleucyl}-5-fluorouridine was obtained as a colorless powdery solid.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=O)([O-])=O.C([O-])=O.[NH4+].[CH3:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][C:34]([CH:35]=O)=[C:29]3[N:28]=[C:27]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:23][CH:22]=1>CO.CCOCC.[Pd]>[CH3:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][C:34]([CH2:35][N:1]4[CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]4=[O:9])=[C:29]3[N:28]=[C:27]2[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(Cn2c(-c3ccccc3)nc3c(C=O)ccnc32)cc1
Reactant: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: CCCC1CC(=O)N(Cc2ccnc3c2nc(-c2ccccc2)n3Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of 3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde x225 (1 g, 1 eq, 2.9 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to yield 0.79 g of 1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x226.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:35])=[C:20]([CH:34]=1)[C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[C:26]([Cl:33])[CH:25]=1)=[O:22].C(N(C(C)C)CC)(C)C>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:28]([C:27]3[CH:31]=[CH:32][C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:34]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=4[CH3:35])=[CH:25][C:26]=3[Cl:33])=[O:29])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.391 g of 4-[(5-fluoro-2-methylbenzoyl)amino]-2-chlorobenzoyl chloride and 0.158 g of diisopropylethylamine in 10 ml of dichloromethane is stirred at room temperature overnight. The mixture is washed with H2 O, 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is again passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and the solid crystallized from ethyl acetate to give crystals, m.p. 137°-140° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([OH:37])=[O:36])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO>[Pd].CN(C)C=O>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([OH:37])=[O:36])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The solution of 2.06 g. (3 mmoles) of Z-Tyr-D-Ala-Gly-Phe-Pro-OH (3rd step of Example 5) in a mixture of 40 ml. of methanol and 10 ml. of dimethyl formamide are hydrogenated in the presence of palladium as catalyst. At the end of the reaction the catalyst is filtered off, washed with a 1:1 mixture of methanol and dimethyl formamide, the combined solutions are evaporated, the residue is rubbed with ether, filtered, washed with ether, dried, redissolved in 4 ml. of ethanol and precipitated with ethyl acetate. The precipitate is filtered, washed with ethyl acetate and dried. Yield: 1.16 g. (70%) of the named pentapeptide; Rf4 0.3-0.4. Aminoacid analysis: Pro=1.02; Gly=1.0; Ala=0.98; Tyr=1.0; Phe=1 (reference basis).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][C:18]#[C:19][CH2:20][CH3:21])[CH:12]=O.C([CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32])=[O:27])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:16]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:25]/[C:26]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])=[CH:10][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[CH:21]
Reactant: CCC#COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 77.3 %

Procedure:
Piperidine (0.19 mL, 1.9 mmol) was added to a suspension of 3-methoxy-4-(but-1-ynyloxy)benzaldehyde (0.39 g, 1.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.39 g, 1.9 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-(but-3-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.48 g, 75%) as a yellow crystalline solid; mp 178-180° C.; δH (400 MHz, DMSO-d6) 2.61 (dt, J=6.8, 2.4 Hz, 2H, CH2CCH), 2.86 (t, J=2.4 Hz, 1H, CCH), 3.81 (s, 3H, OCH3), 4.06 (t, J=6.8 Hz, 2H, OCH2), 6.77 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.13 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.20 (d, J5,6′=8.0 Hz, 1H, H6′), 7.36 (s, 1H, H2′), 7.53 (d, J=15.6 Hz, 1H, CH═CHCO), 7.58 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.97 (d, J3,4=8.0 Hz, 1H, H3), 8.59 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 19.6, 56.4, 67.2, 73.2, 82.0, 111.5, 113.6, 117.3, 120.8, 121.0, 123.2, 123.3, 128.4, 131.8, 134.7, 141.7, 142.2, 149.8, 150.1, 164.8, 170.1; HRMS (ESI) calculated for C21H19NO5 [M+H]+ 366.1336. found 366.1337; vmax 755, 1263, 1512, 1603, 1689, 3257, 3401 cm−1.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[Br:22]Br.O>C(Cl)Cl>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([Br:22])[C:15](=[O:16])[CH3:17])[CH3:21]
Reactant: BrBr
Reactant: CCOC(=O)CC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(Br)C(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At −5° C. trimethylsilyl trifluoromethanesulfonate (36.9 mmol) is added dropwise to a solution of ethyl acetoacetate (30.7 mmol) and TEA (36.9 mmol) in DCM (50 mL). The solution is stirred for 90 min at 0° C. and treated over 30 min with a solution of bromine (30.7 mmol) in DCM (20 mL). After 60 min water (100 mL) is added, the layers are separated and the aq. layer is extracted three times with water (100 mL each). The organic layer is dried over MgSO4 and concentrated under reduced pressure to give the desired product which is used without further purification. 1H-NMR (CDCl3): δ=1.34 (t, J=7.16 Hz, 3H); 2.46 (s, 3H); 4.31 (q, J=7.20 Hz, 2H); 4.77 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:27]([O:34]CC3C=CC=CC=3)=[CH:26][C:25]=2[O:42]CC2C=CC=CC=2)[O:8][N:7]=1)=[O:5])[CH3:2].C(Cl)Cl.B(Cl)(Cl)Cl>CO>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:27]([OH:34])=[CH:26][C:25]=2[OH:42])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(CC(C)C)c(O)cc2O)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in an. DCM and under a nitrogen atmosphere, was cooled to 0° C. 1M BCl3 in DCM (9 eq) was added dropwise and the solution was stirred for 30 minutes. Methanol (2 ml) was added and the reaction mixture was concentrated in vacuo. Purification of the sample by preparative LC/MS gave 5-(2,4-dihydroxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a white solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:37]3[CH:42]=[CH:41][C:40](F)=[C:39](F)[CH:38]=3)[CH:29]=[C:30]([C:32](=[O:36])[N:33](C)[CH3:34])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C3C=CC=CC=3)C=C(C(=O)NC[C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])C=2)C=1CCC(=O)NOCC)C.[OH-].[Na+]>C1COCC1.CCO>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:29]=[C:30]([C:32](=[O:36])[NH:33][CH2:34][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Reactant: CCONC(=O)CCc1c(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3)c2)cccc1OCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3)c2)c1CCC(=O)O
Yield: 80 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-bi phenyl-3-yloxy]-hexyl}-2-(2-ethoxycarbamoyl-ethyl)-phenoxy]-butyric acid ethyl ester (176 mg, 0.23 mmol) and 1.0 N aqueous NaOH (5 mL) in THF (5 mL) and EtOH (5 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-biphenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid (129 mg, 80%) as a white amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9])([O-])=O.O.[H][H]>[Pt].C(O)(C)C>[NH2:1][C:4]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Agent: [Pt]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(OCCO)c(N)c1
Temperature: 20 °C
Yield: 127.9 %

Procedure:
A 1 l autoclave reactor was filled with 120 g of 2-(2′,4′-dinitrophenoxy)ethanol, 3 g of a 1% platinum/carbon catalyst which included 50% water, and 400 ml of isopropanol. At a hydrogen pressure of 1 MPa and a temperature of 100° C., hydrogenation was carried out for 10 h. The system was then cooled to 20° C., and the reaction mixture was added dropwise under a nitrogen atmosphere through a filter into an initial charge of 240 g of 37% strength hydrochloric acid which had been previously flushed repeatedly with nitrogen. The resulting suspension was heated at reflux temperature for about 30 min and then cooled to 10° C. The product obtained after filtration was washed once with isopropanol to give 113.1 g of 2-(2′,4′-diamino-phenoxy)ethanol (89.1% yield) in 98% purity. Measuring the degrees of transmission of a 0.1% strength solution of the product in water in accordance with DIN 55945 gave, as results, Tx=99.4, Ty=98.9 and Tz=98.2.
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH2:7])=[O:6])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:19]([O:21][C:22]([CH3:24])=[CH2:23])=[O:20]>C1COCC1>[CH3:1][C:2]1([C:5]([NH:7][C:19](=[O:20])[O:21][C:22]([CH3:24])=[CH2:23])=[O:6])[CH2:4][CH2:3]1
Reactant: C=C(C)OC(=O)Cl
Reactant: CC1(C(N)=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.2 %

Procedure:
A −78° C. solution of 1-methylcyclopropanecarboxamide (1.35 g, 13.62 mmol) in THF (30 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1 M THF, 17.7 mL, 17.7 mmol), stirred for 0.5 h, treated drop-wise with a solution of isopropenyl chloroformate (1.94 mL, 17.7 mmol) in THF (5 mL), stirred at −78° C. for 1 h, then allowed to warm to RT and stirred for 1 h. The mixture was quenched with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford crude prop-1-en-2-yl (1-methylcyclopropanecarbonyl)carbamate (2.9 g, 116%) which was used without further purification.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=O.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([CH2:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: FC1(F)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3,3-difluoropyrrolidine hydrochloride (965 mg, 6.722 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (1.720 g, 8.066 mmol), DIPEA (955.6 mg, 1.288 mL, 7.394 mmol) and crushed 4A MS (965 mg) in DCE (30 mL) were stirred at ambient temperature for 3 hours. NaBH(OAc)3 (2.848 g, 13.44 mmol) was added and the reaction stirred at ambient temperature for a further 16 hours. The mixture was filter through Celite (washing with DCM) and the filtrate concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give the sub-title product as a colourless oil that was used directly into next step without further purification. LC-MS ES+: 305.1.