Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]Cl.CCOC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:15][CH:14]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C([O-])Cc1ccccc1Br
Agent: Cl[Cu]
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Yield: 69.7 %

Procedure:
2-(2-Bromophenyl)acetate (10 g, 43.7 mmol) and 4-chlorophenol (5.61 g, 43.7 mmol) were dissolved in dioxane (150 mL) whiling warming to 50. To the resulting solution were added, under stirring in an inert nitrogen atmosphere, cesium carbonate (28.35 g, 87.4 mmol) and copper (I) chloride (1.73 g, 17.48 mmol). Finally N,N-dimethylglycine (0.9 g, 8.74 mmol) was added to the green suspension. The mixture was heated at 110 for 2 days while stirring. The mixture was filtrated over dicalite, which was washed with dioxane (20 mL). The dioxane was removed in vacuum to leave brownish oil. EtOAc was added to the oil and the pH of the resulting mixture was adjusted to 1 by addition of 1 M HCl. The organic phase was washed with saturated brine, dried over Na2SO4 and concentrated under vacuum to yield the crude product, which was purified by column chromatography to give 2-(2-(4-chlorophenoxy)phenyl)acetic acid (8 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][C:64]([F:67])([F:66])[F:65])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][C:64]([F:67])([F:66])[F:65])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.1 %

Procedure:
To a solution of 50 mg (0.26 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 82 mg of TBTU (0.26 mmol) in 4 ml DMF, were added 0.22 ml (1.28 mmol) of N,N-diisopropyl-ethyl amine. After stirring for 5 min at rt, 101 mg (0.33 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-amine were added. After stirring for 4 h at rt, the reaction mixture was diluted with 40 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:4) to give 106 mg light brown foam (43%). MS (ISP) 529.4 (M+H)+.
Reaction SMILES: CC1(O)C(=[N:8][CH:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)CC2CC1C2(C)C.Cl.NO.C([O-])([O-])=O.[K+].[K+]>C(O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C@H:9]([NH2:8])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:19]=1
Reactant: CC1(O)C(=NC(CCC2CCOCC2)c2cccnc2)CC2CC1C2(C)C
Agent: Cl
Agent: NO
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N[C@H](CCC1CCOCC1)c1cccnc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 2,6,6-trimethyl-3-(1-(3-pyridyl)-3-(4-oxanyl)propylimino]bicyclo[3.1.1]heptan-2-ol (1.85 g, 5.0 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (2.00 g, 28.8 mmol) and K2CO3 (3.98 g, 28.8 mmol) and the mixture was heated to reflux for 16 h. The reaction was then cooled to room temperature, filtered through Celite, washed with ethanol, concentrated by rotary evaporation and purified by column chromatography, using a gradient of chloroform:methanol:ammonium hydroxide (90:9:1 to 80:19:1) eluent, to yield 0.88 g of a light yellow oil (80% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:27][CH3:28])=[C:23]([Cl:26])[CH:24]=4)[N:19]=[C:18]([CH3:29])[C:17]=3[CH3:30])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[C:31]([Cu])#[N:32]>CN(C=O)C>[Cl:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:27][CH3:28])[N:19]=[C:18]([CH3:29])[C:17]([CH3:30])=[C:16]2[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([C:31]#[N:32])[CH:7]=2)[C:10]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: COc1cc2nc(C)c(C)c(N3CC4(CCOCC4)c4ccc(Br)cc43)c2cc1Cl
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1cc2nc(C)c(C)c(N3CC4(CCOCC4)c4ccc(C#N)cc43)c2cc1Cl
Temperature: 150 °C
Reaction time: 48 h

Procedure:
A mixture of 6-bromo-1-(6-chloro-7-methoxy-2,3-dimethylquinolin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.1 g, 0.205 mmol) and CuCN (0.0367 g, 0.41 mmol) in DMF (1 mL) was stirred at 150° C. After 48 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 100% gradient of EtOAc in hexane as eluent to give 1-(6-chloro-7-methoxy-2,3-dimethyl-4-quinolinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]-6-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.67 (1H, s), 7.59 (1H, s), 7.47 (1H, d, J=7.4 Hz), 7.12 (1H, dd, J=7.6, 1.4 Hz), 6.16 (1H, d, J=1.6 Hz), 4.10 (1H, d, J=9.8 Hz), 4.00 (3H, s), 3.82-3.94 (3H, m), 3.42-3.56 (2H, m), 2.66 (3H, s), 2.15 (3H, s), 1.98-2.11 (2H, m), 1.89 (1H, dd, J=13.7, 1.6 Hz), 1.74 (1H, dd, J=13.5, 1.0 Hz); Mass Spectrum (ESI) m/e=434.2 (M+1).
Reaction SMILES: [Cl:1][CH:2]([Cl:12])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)=[O:4].[CH2:13](O)[CH2:14][CH2:15][OH:16].C[Si](C)(C)Cl>>[CH2:15]1[O:16][C:8]2([CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH:2]([Cl:1])[Cl:12])[CH2:10][CH2:9]2)[O:11][CH:14]1[CH3:13]
Reactant: O=C1CCN(C(=O)C(Cl)Cl)CC1
Reactant: OCCCO
Agent: C[Si](C)(C)Cl
Product: CC1COC2(CCN(C(=O)C(Cl)Cl)CC2)O1
Yield: 66.3 %

Procedure:
A mixture of 19 g (0.09 mol) of N-dichloroacetyl-piperid-4-one, 7.5 g (0.099 mol) of propane-1,3-diol and 22.4 g (0.21 mol) of trimethylchlorosilane was boiled under reflux for 12 hours, while stirring. Thereafter, the reaction mixture was concentrated under reduced pressure and the residue was then subjected to brief incipient distillation under gravity reduced pressure. The resulting brown oil, which slowly crystallized completely, was recrystallized from 200 ml of toluene. 16 g (66.6% of theory) of N-dichloroacetyl-piperid-4-one propylene ketal of melting point 115° C. were obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].[Cl:29][C:30]([Cl:34])([Cl:33])[CH2:31]O.N1C=CC=CC=1>ClCCl>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:31][C:30]([Cl:34])([Cl:33])[Cl:29])=[O:27]
Reactant: O=C(O)CCCCCCCCCO
Reactant: OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCCCCCO)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution of N,N′-dicyclohexylcarbodiimide (DCC, 2.41 g; 14.1 mmol) in dry dichloromethane (15 mL) was added drop-wise to a stirred solution of 10-hydroxydecanoic acid (1.88 g; 10.0 mmol), 2,2,2-trichloroethanol (6.13 g; 41.0 mmol), and pyridine (4.1 mL) in dry dichloromethane (35 mL) cooled to 0° C. (bath temperature) under argon. After stirring one hour at 0° C., the mixture was stirred at ambient temperature overnight. The reaction mixture was vacuum filtered and acetic acid (3 mL) was added to the filtrate. After standing 30 min, the mixture was refiltered and the filtrate was diluted with diethyl ether (150 mL). The solution was washed with 1 M HCl (3×25 mL), water (3×25 mL), saturated NaHCO3 solution (2×25 mL), and saturated NaCl solution (1×25 mL). After drying (MgSO4), filtration, and evaporation, the residue was purified by flash chromatography on a 170×25 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1), collecting 12×25 mL fractions. Fractions 3-5 were evaporated and the residue was vacuum dried at 50° C. and 0.05 mm Hg on a Kugelrohr apparatus to remove excess 2,2,2-trichloroethanol. 2.1 g (66%) product was obtained (colorless oil).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([O:18][C:19]4[N:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[C:10]([CH3:25])=[N:9]2)=CC=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[CH3:25][C:10]1[NH:9][N:8]=[CH:12][C:11]=1[C:13]1[N:14]=[C:15]([O:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[S:16][CH:17]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Oc4ncccn4)n3)c(C)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]ncc1-c1csc(Oc2ncccn2)n1
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 6.7 %

Procedure:
According to Scheme 2, Step 6: To a solution of 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole (0.18 mmol, 67 mg) in TFA (1.8 mL) was added trifluoromethanesulfonic acid (1.77 mmol, 156 μl). The reaction mixture was stirred for 8 minutes at 80° C. under microwave conditions. The crude mixture was quenched with water and the aqueous phase was extracted with DCM. The organic layer was dried over MgSO4, was filtered and was evaporated to dryness. The crude residue was purified by preparative TLC using DCM/EtOH/NH3 (100:0:0 to 93:6.7:0.3) as eluent to yield 4-(5-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole (12 μmol, 3.2 mg, 7%) as a beige solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[OH-].[Ca+2:7].[OH-].[O-2].[Ca+2]>>[C:1]([O-:5])(=[O:4])[CH2:2][CH3:3].[Ca+2:7].[C:1]([O-:5])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)O
Agent: [Ca+2]
Agent: [O-2]
Agent: [OH-]
Product: CCC(=O)[O-]

Procedure:
The experiment was repeated using 30 g of 80% propionic acid, 10.81 g of calcium hydroxide and 0.91 g or calcium oxide. A non-dusty product without lumps was formed.
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:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1>C(O)C.CCCCCC>[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:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3cccc(OC)c3)oc2C)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1cccc(-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: 45.7 %

Procedure:
Ethyl 3-[{[4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1200 mg) which is a synthetic intermediate in Example 151 was dissolved in ethanol-hexane (6:4, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (6:4, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 11.1 min were collected, and concentrated. The obtained amorphous compound (598 mg) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), lithium hydroxide (2.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 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 (518 mg, 92%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(CC)CC)C.Cl[C:66]([O:68][CH2:69][CH3:70])=[O:67]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:66]([O:68][CH2:69][CH3:70])=[O:67])[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (40 mg) in methylene chloride (2 ml) is added triethylamine (10 μl), followed by ethyl chloroformate (15 μl) at 0° C. with stirring. The reaction mixture is warmed to room temperature and the reaction progress is followed by tlc analysis. The solution is quenched with a drop of methanol and purified by preparative tlc on silica to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:35]1(=[O:41])[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:39]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]4=[O:40])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CCl)cc2)c1
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CN3C(=O)CCC3=O)cc2)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of [5-({[1-(4-Chloromethyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (67 mg, 0.1 mmol), succinimide (12 mg, 0.1 mmol) and potassium carbonate (84 mg, 0.6 mmol) in 50 mL acetone was stirred at 80° C. for 24 h. The mixture was filtrated and concentrated in vacuo. The crude was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min) to yield the title compound. LCMS (method A) RtA=1.339 min; [M+H]+=547.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:16][C:17](=[O:18])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Product: CC(C)(C)OC(=O)NCCC(=O)OCC(=O)c1cccnc1

Procedure:
The product was obtained starting from 3-(tert-butoxycarbonylamino)propanoic acid (1 g, 5.29 mmol) and 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (1.48 g, 5.29 mmol) according to the method described in example 7, step 1 after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white solid (1.255 g, 4.07 mmol, 77.0%). MS: M=309.2 (M+H)+
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.Cl.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (587 mg, 2.5 mmol) in dichloromethane (4 ml) and pyridine (4 ml) was treated with a suspension of 6-chloro-3-pyridinesulfonyl chloride hydrochloride (D32) (700 mg, 3 mmol) in dichloromethane (4 ml). After stirring at room temperature for 15 minutes the mixture was evaporated and the residue co-evaporated with toluene (×2). The residue was then partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed in water, brine, dried and evaporated. The residue was triturated with ether/and dried to give the title product. MS (ES+) 411/413 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(CCF)CC2)CC1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (15.7 g, 78.7 mmol) and 1-(2-fluoroethyl)piperazine (5.2 g, 39 mmol) were dissolved in 150 mL 1,2-DCE. HOAc (3.4 mL, 59 mmol) and TEA (5.5 mL, 39 mmol) were added followed by sodium triacetoxyborohydride (12.5 g, 59.0 mmol). The reaction was stirred for 3 h. TLC revealed the presence of starting material and so an additional 1.5 eq (12.5 g, 59.0 mmol) of sodium triacetoxyborohydride were added. Reaction was allowed to stir overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was adsorbed onto silica gel and purified by flash chromatography to give title compound of step C (10.2 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39-4.57 (m, 2H), 3.90 (d, J=12.46 Hz, 2H), 2.61-2.73 (m, 2H), 2.47-2.61 (m, 2H), 2.36-2.47 (m, 8H), 2.24-2.35 (m, 1H), 1.69 (d, J=12.46 Hz, 2H), 1.37 (s, 9H), 1.14-1.26 (m, 2H).
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:98])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[C:70]([C:72]3[CH:76]=[CH:75][S:74][CH:73]=3)[CH:69]=[C:68]([C:77](=[O:90])[NH:78][CH2:79][C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=3[O:86][CH:87]([F:89])[F:88])[CH:67]=2)[C:54]=1[CH2:91][CH2:92][C:93]([O:95]CC)=[O:94])C.[OH-].[Na+]>C1COCC1.CCO>[C:93]([CH2:92][CH2:91][C:54]1[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[C:70]([C:72]3[CH:76]=[CH:75][S:74][CH:73]=3)[CH:69]=[C:68]([C:77](=[O:90])[NH:78][CH2:79][C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=3[O:86][CH:87]([F:88])[F:89])[CH:67]=2)=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:98])=[O:47])([OH:95])=[O:94]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccsc3)c2)c1CCC(=O)O
Yield: 96.8 %

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-[3-(2-difluoromethoxy-benzylcarbamoyl)-5-thiophen-3-yl-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (177 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-[3-(2-difluoromethoxy-benzylcarbamoyl)-5-thiophen-3-yl-phenoxy]-hexyl}-phenoxy)-butyric acid (158 mg, 97%) as a dark brown solid.
Reaction SMILES: [C:1](ON1C(=O)CCC1=O)(=[O:3])[CH3:2].[NH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[N:29]=[N:30][C:31]([N:34]([CH3:45])[CH:35]4[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]4)=[CH:32][CH:33]=3)[C:23]([OH:27])=[CH:24]2)=[CH:19][CH:18]=1.CCOCC>CS(C)=O>[OH:27][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][NH:12][C:1](=[O:3])[CH3:2])=[CH:26]2)=[CH:21][C:22]=1[C:28]1[N:29]=[N:30][C:31]([N:34]([CH3:45])[CH:35]2[CH2:40][C:39]([CH3:41])([CH3:42])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]2)=[CH:32][CH:33]=1
Reactant: CN(c1ccc(-c2cc3ccc(OCCCN)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC(=O)ON1C(=O)CCC1=O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)NCCCOc1ccc2cc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
N-Acetoxysuccinimide (98 mg, 0.624 mmol) was added to a solution of Example 20-5 (50 mg, 0.108 mmol) and TEA (0.747 ml, 5.39 mmol) in DMSO (2 ml) at RT. The reaction mixture was stirred at RT for 30 min then concentrated in vacuo to remove excess Et3N. The resulting residue was purified by preparative HPLC (eluting with 5-80% MeCN/H2O with 0.1% TFA modifier). The appropriate fractions containing product were combined then adsorbed onto a MeOH conditioned SCX column (5 g, BSA Varian brand). The column was washed several times with MeOH then eluted with 3 N NH3 in MeOH. Evaporation of the solvent afforded a yellow oil. Et2O was added to the oil then concentrated to dryness affording the title compound as a yellowish orange solid (30 mg, 55% yield). LCMS Rt=0.52 min (LCMS method Q); MS (M+1)=506.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.27 (br. s, 1H), 8.35 (s, 1H), 8.28 (d, J=10.10 Hz, 1H), 7.77 (d, J=9.09 Hz, 2H), 7.35 (d, J=9.60 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J=2.02 Hz, 1H), 6.95 (dd, J=9.09, 2.53 Hz, 1H), 4.92-5.04 (m, 1H), 4.11 (t, J=6.32 Hz, 2H), 3.20-3.28 (m, 2H), 2.98 (s, 3H), 1.87-1.96 (m, 2H), 1.82 (s, 3H), 1.55-1.63 (m, 2H), 1.44-1.55 (m, 2H), 1.30 (s, 6H), 1.14 (s, 6H).