Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=3)[NH:25][CH:24]=2)[C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1>CN(C)C=O>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]([CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=3)[N:25]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[CH:24]=2)[C:19]([OH:21])=[O:20])(=[O:15])=[O:16])=[CH:12][CH:13]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(C)cc23)C(=O)O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2cn(Cc3ccc(OC)cc3)c3ccc(C)cc23)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
In a 20 mL vial, NaH (60% in mineral oil) (0.033 g, 0.831 mmol) was added to a solution of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-(5-methyl-1H-indol-3-yl)-propionic acid (Example 1) (0.100 g, 0.234 mmol) in anhydrous N,N-dimethylformamide (2 mL) at 0° C. The reaction mixture was placed in a shaker for 20 min. at 0° C. 4-Methoxy-benzyl chloride (0.032 mL, 0.234 mmol) was added to the solution and allowed to react for 10 hours at 0° C. The reaction mixture was quenched with H2O and acidified with HCl. The solution was extracted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated. The residue was purified by RP-HPLC to give 0.086 g (67%) of the title compound as a pale yellow solid. 1H NMR (DMSO-d6): 400 MHz δ 12.58 (bs, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.53 (d, J=11.6 Hz, 2H), 7.20 (d, J=8.0 Hz, 1H), 7.09 (s, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.00 (s, 1H), 6.92-6.80 (m, 5H), 5.17 (s, 2H), 4.76 (q, J=2.4 Hz, 2H), 3.82 (q, J=8.0 Hz, 1H), 3.69 (s, 3H), 3.00 (dd J=14.4, 6.8 Hz, 1H), 2.79 (dd J=14.4, 7.6 Hz, 1H), 2.32 (s, 3H), 1.82 (t, J=2.4 Hz, 3H); HRMS: calcd for C30H31N2O6S (ESI+, [M+H]1+), 547.1897; found 547.1896; LCMS m/z (ESI) [M−H] 545, retention time=2.76 min.
Reaction SMILES: [Pt:1].[C:2]([O:19]C(=O)CCCCCCCCCCCCCCC)(=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(=O)(O)[O-].C([NH+](CC)CC)C.C(O)(C)C.O.[Pd]>[C:2]([Pt:1])(=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCC
Reactant: [Pt]
Agent: [Pd]
Agent: CC[NH+](CC)CC
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[Pt]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Preparation used the same procedure as the platinum cluster conjugate: an estimated 30 nmol of amino-derivatized 2-3 nm palladium cluster, dissolved in 0.6 M triethylammonium bicarbonate in 20% isopropanol/water, was evaporated to dryness five times from methanol, dissolved in 3 mL of dichloromethane, then treated with 200 nmol of palmitic anhydride. The mixture was stirred for one hour at room temperature, washed three times with 0.1 M sodium phosphate buffer at pH 6.5, evaporated to dryness, redissolved in 2:1 methanol/chloroform and separated by gel filtration (GH25, Amicon, eluted with 2:1 methanol:chloroform). After evaporation to dryness, lipid conjugation was demonstrated by extraction of the cluster label into the chloroform layer when the palmitoyl palladium cluster conjugate was shaken in a chloroform/water mixture with a small amount of methanol as a phase transfer agent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([C:23]5[C:31]6[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=6)[N:25]([CH3:33])[N:24]=5)[N:21]=4)[N:16](COCC[Si](C)(C)C)[CH:15]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CC(=O)OCC.C(=O)(O)[O-].[Na+]>C1COCC1.O.C(#N)C.CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([C:23]5[C:31]6[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=6)[N:25]([CH3:33])[N:24]=5)[N:21]=4)[NH:16][CH:15]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2(c4ccc(Br)cc4)CC2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(c5ccc(Br)cc5)CC4)c3n2)c2ccc(F)cc21
Temperature: 85 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(4-bromo-phenyl)-cyclopropyl]-amide (50 mg, 0.078 mmol) in THF (3 mL) was added a solution of TBAF (1.0 M in THF, 1.18 mL, 1.18 mmol) at room temperature. The resulting light brown solution was heated to 85° C. and stirred for 3 h at which time TLC analysis (EA, Rf=0.3) indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and 3 mL of acetone and 9 mL of saturated sodium bicarbonate solution were added and the resulting suspension was stirred for 1 h. The reaction suspension was diluted with water and the organic compound was extracted into EtOAc (3×25 mL) and the combined extracts were washed with brine solution and dried over MgSO4. Filtration of the drying agent and removal of the solvent under vacuum gave the crude solid which was dissolved in acetonitrile with heating. The resulting greenish solution was stored in the refrigerator for 15 h and the solids were collected by filtration and washed with acetonitrile. After drying in air, 25 mg (63%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(4-bromo-phenyl)-cyclopropyl]-amide was isolated as a off-white solid. LC-MS (M+H)+=507; 1H NMR (300 MHz, DMSO-d6) δ: 12.91 (s, 1H), 9.11 (s, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 8.39-8.51 (m, 1H), 7.68 (dd, J=9.7, 1.9 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 7.14 (td, J=9.0, 2.0 Hz, 1H), 4.14 (s, 3H), 1.44 (s, 4H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(O)cc12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(Oc3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
1-(1′-Acetyl-5-hydroxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (40 mg, 0.122 mmol) was dissolved in methylene chloride (1.5 mL). Thereafter, 4-fluorophenylboronic acid (34 mg, 0.244 mmol), copper(II) acetate (22 mg, 0.122 mmol), triethylamine (62 mg, 0.610 mmol), and molecular sieves 4A (40 mg) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 18 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate) to obtain 1-(1′-acetyl-5-(4-fluorophenoxy)spiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (30 mg, 56%) in the form of a light yellow solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C@H:9]1[C:18](=[O:19])[C:17]3[C:12]4=[C:13]([N:20](COCC[Si](C)(C)C)[N:21]=[C:11]4[CH2:10]1)[CH:14]=[N:15][CH:16]=3)[CH2:2]2.[ClH:30]>O1CCOCC1>[ClH:30].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C@H:9]1[C:18](=[O:19])[C:17]3[C:12]4=[C:13]([NH:20][N:21]=[C:11]4[CH2:10]1)[CH:14]=[N:15][CH:16]=3)[CH2:2]2
Reactant: C[Si](C)(C)CCOCn1nc2c3c(cncc31)C(=O)[C@H](C1CN3CCC1CC3)C2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2cncc3[nH]nc(c23)C[C@H]1C1CN2CCC1CC2
Temperature: 115 °C
Yield: 18 %

Procedure:
To a sealed tube containing a solution of (S)-7-(quinuclidin-3-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydropyrazolo[3,4,5-de]isoquinolin-6(2H)-one (0.71 g, 1.73 mmol) from Step D above in dioxane (10 mL) was added 6N HCl (20 mL). The reaction mixture was flushed with argon, sealed and heated to 115° C. for 30 min, cooled to ambient temperature and concentrated under reduced pressure. The residue was preabsorbed on silica gel and purified first by column chromatography (5 to 20% 6:3:1 dichloromethane/methanol/concentrated ammonium hydroxide in 9:1 dichloromethane/methanol) and subsequently by reverse phase semi-preparative HPLC (isocratic, 10% acetonitrile in water—both eluents contained 0.05% trifluoroacetic acid as modifier). The solvents were removed in vacuo and the desired product trifluoroacetate salt was dissolved in a solution 1.25 N HCl in methanol (4×5 mL) and the solvent removed (4×) to exchange the trifluoroacetate salt to the hydrochloride salt form. Recrystallization of the desired product hydrochloride salt from ethanol (10 mL), followed by lyophilization from acetonitrile/water (1:5, 6 mL) afforded (S)-7-(quinuclidin-3-yl)-7,8-dihydropyrazolo[3,4,5-de]isoquinolin-6(2H)-one, hydrochloride salt (85.9 mg, 18%) as an amorphous white solid: 1H NMR (500 MHz, d6-DMSO) δ 13.15 (s, 1H), 10.15 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.75 (dd, J=7.0, 7.0 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 5.32-5.14 (m, 2H), 4.79 (t, J=9.5 Hz, 1H), 3.78-3.47 (m, 4H), 3.32-3.16 (m, 3H), 2.26-2.18 (m, 1H), 2.03-1.80 (m, 3H), MS (ESI+) m/z 283 (M+H)+; HPLC 98.8% (AUC), tR7.29 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16].C([O-])([O-])=O.[K+].[K+].[CH2:23]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:24][CH2:25][CH3:26].CCOC(C)=O>CC#N.O>[CH2:23]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:16])[CH2:29][CH2:28]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCC1CCNCC1
Reactant: Cc1ccc2ccc(=O)n(CCCCl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCCC1CCN(CCCn2c(=O)ccc3ccc(C)cc32)CC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 8.9 %

Procedure:
A 4 mL vial was charged with 1-(3-chloro-propyl)-7-methyl-1H-quinolin-2-one 107LH40 (0.130 g, 0.56 mmol), KI (0.170 g, 1.0 mmol), K2CO3 (0.140 g, 1.0 mmol) and 4-butylpiperidine (100 μl, 0.60 mmol) in CH3CN (2 mL). The mixture was shaken at 50° C. for 72 h and then poured onto The compound EtOAc (25 mL) and water (15 mL). The water phase was extracted (2×25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 1:4) to give the title compound (0.017 g, 6%). 1H NMR (CD3OD) δ 7.84 (d, J=9.4 Hz), 7.56 (d, J=8.0 Hz, 1H), 7.43 (brs, 1H), 7.14 (brd, J=8 Hz, 1H), 6.58 (d, J=9.4 Hz), 4.36 (d, J=7.2 Hz, 2H), 3.02-2.95 (m, 2H), 2.57-2.48 (m, 2H), 2.51 (s, 3H), 2.09-1.91 (m, 4H), 1.75-1.65 (m, 2H9, 1.36-1.16 (m, 9H), 0.89 (t, J=6.8 Hz, 3H); 13C NMR (CD3OD) δ 163.3, 142.2, 140.3, 139.1, 129.1, 124.1, 119.3, 119.0, 114.7, 55.6, 53.8, 40.4, 36.1, 35.5, 31.8, 28.9, 24.6, 22.7, 21.1, 13.2; HPLC-MS (ammonium acetate) [M+H]+=341.3.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[CH:6]1([C@@H:9]2[C:16]3[CH:15]=[N:14][NH:13][C:12]=3[CH2:11][N:10]2[S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:8][CH2:7]1>CC#N.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[CH:6]1([C@@H:9]2[C:16]3[CH:15]=[N:14][NH:13][C:12]=3[C:11](=[O:2])[N:10]2[S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:7][CH2:8]1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1Cc2[nH]ncc2[C@H]1C1CC1
Agent: [Cr+3]
Agent: [O-2]
Solvent: CC#N
Product: O=C1c2[nH]ncc2[C@@H](C2CC2)N1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 28.9 %

Procedure:
To periodic acid (176 mg, 0.770 mmol) in CH3CN (2 mL) was added chromium(III) oxide (2.1 mg, 0.021 mmol). The reaction was stirred several minutes until it turned fluorescent orange and all solids were dissolved. The reaction was cooled to 0° C. and a solution of (R)-4-cyclopropyl-5-(4-(trifluoromethyl)phenylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (12) (50 mg, 0.14 mmol) in CH3CN (1 mL) was added. The reaction was stirred for 1 hr until TLC monitoring showed the disappearance of starting material. The reaction was filtered through a plug of Celite and concentrated in vacuo. The residue was taken up in EtOAc (2 mL) and washed with water (2 mL), 5% NaHSO3 (2 mL), brine (2 mL), dried over Na2SO4, and concentrated in vacuo. The resulting crude product was purified via column chromatography using EtOAc/hexane gradients to yield (R)-4-cyclopropyl-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (23) (15 mg, 28%) as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]3[C:18]4[C:23]([C:24]([C:31]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH:34]=[CH:33][CH:32]=5)=[C:25]5[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]5)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[CH:43]1[C:60]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]=2[CH:46]=[CH:45][C:44]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>ClC1C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CO.O.C(O)C>[C:31]1([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[CH:16][C:7]([C:44]5[CH:45]=[CH:46][C:47]6[C:48]7[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=7)[C:54]7[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=7)[C:60]=6[CH:43]=5)=[CH:8]4)=[CH:13][CH:12]=3)=[C:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc2c3ccccc3c3ccccc3c2c1
Reactant: O=S(=O)(Oc1ccc2ccc(-c3c4ccccc4c(-c4cccc5ccccc45)c4ccccc34)cc2c1)C(F)(F)F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: Clc1ccccc1
Solvent: O
Product: c1ccc2c(-c3c4ccccc4c(-c4ccc5ccc(-c6ccc7c8ccccc8c8ccccc8c7c6)cc5c4)c4ccccc34)cccc2c1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
Under the nitrogen atmosphere, 7-(10-(naphthalen-1-yl) anthracen-9-yl)naphthalen-2-yl trifluoromethane sulfonate (3.0 g) as the fifth intermediate compound, 2-triphenylene boronic acid (2.1 g), Pd(dba)2 (0.03 g), tricyclohexyl phosphine (0.03 g), potassium phosphate (2.2 g), and a mixture solvent (22 ml) of toluene, ethanol and water (toluene/ethanol/water=9/1/1 (volume ratio)) were added to a flask and refluxed for 2 hours. Once the heating is completed, the reaction solution was cooled to room temperature and added with methanol. The precipitates were collected by suction filtration. The obtained solid was washed with water followed by methanol, and washed further with ethyl acetate. The obtained crude product was dissolved in chlorobenzene, and colored components were removed by passing through a silica gel short column. After re-crystallization with chlorobenzene, 2-(7-(10-(naphthalen-1-yl)anthracen-9-yl)naphthalen-2-yl)triphenylene (1.9 g) was obtained as the target compound represented by Formula (1-38). The scheme is shown in the following “Reaction 10”.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=1>>[F:19][C:18]([F:21])([F:20])[C:14]1[N:13]=[C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: OCCc1ccc(O)cc1
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 4-(2-hydroxyethyl)phenol and 2-chloro-6-(trifluoromethyl)pyridine, LC-MS (ESI): m/z 284 [M+H]+; 3.00 min (ret time).
Reaction SMILES: FC1C(F)=CC(C2C=CN=CC=2N([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[C:40]([O:44][C:45](=[O:64])[NH:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][C:52]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[O:59][C:60]([F:63])([F:62])[F:61])([CH3:43])([CH3:42])[CH3:41].ClCCS(C)(=O)=O>CCCCCC.CCOC(C)=O>[C:40]([O:44][C:45](=[O:64])[N:46]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][C:52]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[O:59][C:60]([F:61])([F:62])[F:63])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1-c1ccccc1OC(F)(F)F
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Agent: CS(=O)(=O)CCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)c1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 298, intermediate b, from [4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester and 1-chloro-2-(methylsulfonyl)ethane and using a gradient of n-hexane:EtOAc (50:50 to 40:60) for the chromatographic purification. Colourless sticky solid (96%). MS (ESI): m/z=461.4 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([OH:31])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:30])[C@H:13]([CH:27]([CH3:29])[CH3:28])[NH:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(Cl)(=O)C(Cl)=O.CS(C)=O>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:30])[C@H:13]([CH:27]([CH3:29])[CH3:28])[NH:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[O:31]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(O)c1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)c1nccs1

Procedure:
38 (0.15 g, 0.33 mmol), oxalylchloride (0.05 ml, 0.59 mmol), DMSO (0.06 ml, 0.82 mmol), TEA (0.12 ml, 1.32 mmol)
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([OH:28])[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][C:23]=2[CH2:36][CH3:37])[C:12]=1[CH2:38][CH2:39][CH3:40].[Na]>>[CH2:38]([C:12]1[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([OH:28])[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][C:23]=2[CH2:36][CH3:37])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:41])=[O:2])[CH2:39][CH3:40]
Reactant: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: [Na]
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1Oc1ccccc1C(=O)O
Yield: 79.6 %

Procedure:
2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid methyl ester (21.5 g, 38.5 mmoles) was hydrolyzed as described above for the preparation of Example 7. The acid was converted to the sodium salt and purified as described in Example 7 to provide 16.7 g (77%) of the desired title product as a white amorphous solid: NMR (DMSO-d6) 10.50 (bs, 1H, --OH), 7.51 (m, 3H), 7.20 (t, J=7.4 Hz, 1H), 7.13 (m, 2H), 7.00 (m, 2H), 6.95 (s, 1H), 6.67 (dd, J=8.2, 3.3 Hz, 2H), 6.62 (s, 1H), 6.26 (d, J=8.2 Hz, 1H), 4.14 (t, J=5.8 Hz, 2H), 4.02 (t, J=5.7 Hz, 2H), 2.60 (t, J=6.8 Hz, 2H), 2.47 (q, J=7.3 Hz, 2H), 2.16 (t, J=5.9 Hz, 2H), 1.45 (hextet, J=7.5 Hz, 2H), 1.07 (t, J=7.5 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H); MS-FAB m/e 568 (38, p+1), 567 (100, p), 544 (86), 527 (77), 295 (65), 253 (45); IR (KBr, cm-1) 3407 (b), 2962, 1603, 1502, 1446, 1395, 1239, 1112. Analysis for C33H32O6FNa: Calc: C, 69.95; H, 5.69; F, 3.35; Found: C, 69.97; H, 5.99; F, 3.52.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=[O:30])[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[S:22][CH2:21]1)[C:14]([O:16]CC)=[O:15].C(O)(=O)C.O.CO>[OH-].[Na+]>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=[O:30])[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[S:22][CH2:21]1)[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)[C@H](CCCCCCCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: NCCCCCCCCC[C@H](N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Yield: 52.4 %

Procedure:
A solution of 3(R)-[10-amino-1(S)-ethoxycarboxyldecyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (0.28 g) obtained in Example 74 in 1N sodium hydroxide (7 ml) stands for 1 hour at room temperature. After addition of acetic acid (2 ml) and water (5 ml), the mixture is subjected to Amberlite XAD-2 column chromatography (methanol:water=1:1). The eluate is concentrated under reduced pressure. The deposited crystal is collected by filtration and dried to yield 3(R)-[10-amino-1(S)-carboxydecyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (0.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[CH:22]1[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23]1.[Li+].[OH-].CO>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:22]1[CH2:26][CH2:25][S:24](=[O:27])(=[O:28])[CH2:23]1
Reactant: COC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)cn(C(=O)OC(C)(C)C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 80 °C
Yield: 30.4 %

Procedure:
To a microwave vial was added 1-(1,1-dimethylethyl) 7-methyl 5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-1,7-dicarboxylate (432 mg, 0.91 mmol), LiOH (109 mg, 4.5 mmol), MeOH (6 mL) and H2O (3 mL). The mixture was heated to 80° C. for 30 min in the microwave. The reaction mixture was then purified via Gilson HPLC (TFA buffer) to give 99 mg of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:28]=[O:29])[CH2:2][CH2:3][CH3:4].O.P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.CCCCCC>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:11][CH:10]=[C:9]2[C:28]([OH:32])=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: O=P([O-])(O)O
Reactant: CCCCOc1cc2c(C=O)cnc(C(=O)c3cccc(OC)c3)c2cc1OC
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: CCCCCC
Solvent: O
Product: CCCCOc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OC)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.9 %

Procedure:
To a stirred solution of afforded 6-butoxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde (131 mg, 0.33 mmol) in t-butanol (2 mL) and water (2 mL) solution was added sodium dihydrogenphosphate monohydrate (184 mg, 1.33 mmol), 2-methyl-2-butene (0.226 mL, 2.00 mmol) and sodium chlorite (181 mg, 2.00 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichlormethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate and hexane to afford 6-butoxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (35 mg, 62% yield) as a light yellow solid. HR-MS m/e calcd for C26H21N1O6 (M−H+) 444.1442, found 444.1442; 1H NMR (300 MHz) compatible.