Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:47]([N:42]1[CH2:43][CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41]1)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCN(C(=O)c2ccccc2)C1
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 36% yield. LCMS for C31H30ClN6O2 (M+H)+: m/z=553.2.
Reaction SMILES: [C:1](O)(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:17]([O:24][C:25](=[O:37])[NH:26][C:27]([C:33](=[NH:36])[NH:34][OH:35])([CH3:32])[CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:24][C:25](=[O:37])[NH:26][C:27]([CH3:32])([C:33]1[N:36]=[C:1]([CH3:2])[O:35][N:34]=1)[CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(CC1CC1)(NC(=O)OCc1ccccc1)C(=N)NO
Reactant: CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(CC2CC2)NC(=O)OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
To a solution of acetic acid (139 mg, 132 μl, 2.31 mmol) in dry DMF (8 ml) under an argon atmosphere was added carbonyldiimidazole (374 mg, 2.31 mmol) and the reaction mixture was stirred at room temperature for 45 minutes. Addition of a solution of [2-Cyclopropyl-1-(N-hydroxycarbamimidoyl)-1-methyl-ethyl]-carbamic acid benzyl ester (Example 66c, 0.64 g, 2.2 mmol) in dry DMF (4 ml) and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction was then stirred at 130° C. under microwave radiation for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (542 mg, 78%) as a yellow oil. MS (ESI, m/z): 316.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.[NH2:35][NH2:36]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:35][NH2:36])=[O:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)Cl)c12
Reactant: NN
Solvent: CC#N
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)NN)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbonyl chloride (240 mg, 0.491 mmol) was taken up in acetonitrile (4 ml). TEA (0.205 ml, 1.474 mmol) was added followed by the dropwise addition of hydrazine (0.046 ml, 1.474 mmol). The reaction was allowed to stir at rt overnight. The reaction mixture was concentrated in vacuo. The mixture was then resuspended in EtOAc and saturated NH4Cl was added. The products were extracted into EtOAc (3×) and the combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo to give 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbohydrazide. The products were carried forward without further purification. MS: [M+H]+ m/z 484.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[C:22]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Reactant: O=C(O)c1ccncc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)c2ccncc2)CC1

Procedure:
Intermediate 42 (152 mg, 0.5 mmol) was reacted with isonicotinic acid by Method E. Flash chromatography eluted with 9:1 DCM:MeOH afforded compound 47 (204 mg, 100%) as a white solid: Mp 210-212° C. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=6 Hz, 2H), 8.59 (s, 1H), 7.47 (d, J=9 Hz, 2H), 7.38 (d, J=6 Hz, 2H), 7.22 (d, J=9 Hz, 2H), 6.25 (d, J=8 Hz, 1H), 4.30 (d, J=12 Hz, 1H), 3.76 (s, 1H), 3.41 (d, J=12 Hz, 1H), 3.16 (t, J=12 Hz, 1H), 3.05 (t, J=12 Hz, 1H), 1.97-1.88 (m, 1H), 1.84-1.75 (m, 1H), 1.47-1.29 (m, 2H). Purity 92%. HRMS calculated for C19H19F3N4O3−H+ 407.1331. found (ESI(−), [M−H]) 407.1316.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][C:12]([CH3:15])=[N:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([CH3:15])[NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1
Reactant: CC1=Nc2c(c(-c3ccccn3)nn2C)C(c2ccc(Cl)cc2C)SC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1C1SCC(C)Nc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A mixture of 4-(4-chloro-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6-dihydropyrazolo[3,4-e][1,4]thiazepine (0.120 g, 0.31 mmol), acetic acid (0.054 mL, 0.94 mmol) and sodium triacetoxyborohydride (0.080 g, 0.38 mmol) in DCE (10 mL) was stirred at rt for about 16 h. Then more acetic acid (0.054 mL, 0.94 mmol) and sodium triacetoxyborohydride (0.080 g, 0.38 mmol) were added and stirring was continued for another 24 h. The resulting mixture was concentrated in vacuo and partitioned between 5% aqueous sodium bicarbonate (40 mL) and ethyl acetate (40 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with water (15 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:1) to give 4-(4-chloro-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.100 g, 0.26 mmol, 84%) as a pale yellow solid as a mixture of two diasereomers (ratio 61:39): LC-MS (Table 1, Method e) Rt=8.51 min and 8.76 min, m/z 385 (M+H)+; Major isomer 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.33 (3H, d, J=6.4 Hz) 2.58 (3H, s) 2.62-2.72 (2H, m) 3.43-3.53 (1H, m) 3.84 (3H, s) 4.06 (1H, br s) 6.59 (1H, s) 6.99 (1H, dd, J=8.3, 2.1 Hz) 7.01-7.09 (1H, m) 7.11 (1H, d, J=8.3 Hz) 7.14 (1H, d, J=2.1 Hz) 7.58 (1H, td, J=7.9, 1.9 Hz) 7.77 (1H, d, J=8.0 Hz) 8.44 (1H, d, J=4.6 Hz); Minor diastereomer: 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.21 (3H, d, J=6.6 Hz) 2.55 (1H, dd, J=15.0, 8.0 Hz) 2.61 (3H, s) 2.95 (1H, dd, J=15.0, 4.3 Hz) 3.36-3.43 (1H, m) 3.86 (3H, s) 4.06 (1H, br s) 6.44 (1H, s) 6.96 (1H, dd, J=8.3, 2.1 Hz) 7.01-7.09 (1H, m) 7.06 (1H, d, J=8.0 Hz) 7.12 (1H, d, J=2.1 Hz) 7.56 (1H, td, J=7.9, 1.9 Hz) 7.76 (1H, d, J=8.0 Hz) 8.40 (1H, d, J=4.6 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[C:9]([F:10])=[CH:8][C:6](N)=[C:5]([O:11][CH3:12])[CH:4]=1.[BH4-].[Na+]>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([O:11][CH3:12])[CH:6]=[CH:8][C:9]=1[F:10]
Reactant: COc1cc(N(C)C)c(F)cc1N
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(F)c(N(C)C)c1

Procedure:
Using general method D, the product from Example 20 is diazotized and reduced with sodium borohydride to give Compound 21.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[CH2:30][N:29]([C:32]1[S:33][C:34]([CH2:42][CH2:43][CH2:44]I)=[C:35]([C:37]([O:39]CC)=[O:38])[N:36]=1)[CH2:28][CH2:27]2)=[O:21].Cl.[OH-].[Na+]>CN(C=O)C>[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[CH2:30][N:29]([C:32]1[S:33][C:34]([CH2:42][CH2:43][CH2:44][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:35]([C:37]([OH:39])=[O:38])[N:36]=1)[CH2:28][CH2:27]2)=[O:21]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccccc3)s1)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The title compound 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylic acid (2) was prepared by the following procedure: To phenol (22.6 mg, 0.24 mmol) in DMF (2 mL) was added NaH (60% oil dispersion) (24 mg, 0.6 mmol). After stirring at rt for 5 minutes, ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-iodopropyl)thiazole-4-carboxylate (2C) (127 mg, 0.2 mmol) was added and stirring was continued for 1 hour. The reaction mixture was acidified with 1N HCl and the precipitate was filtered and washed with water. The precipitate was slurried in Et2O, filtered and washed with additional Et2O. The resulting solid was purified by column chromatography on silica gel eluting with a gradient of 0 to 2% MeOH in DCM. To the purified material in DMF (1 mL) was added NaOH (4N aq) (0.5 mL, 2 mmol), heated at 50° C. for 5 hours, cooled to rt, and acidified with 1N HCl. The precipitate was filtered, washed with water, slurried in Et2O, filtered, washed with Et2O and dried in a vacuum oven to provide the desired product 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylic acid (2) in 37% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.89 (s, 1H), 12.49 (1H, s), 8.04 (1H, d), 7.79 (1H, d), 7.67 (1H, d), 7.44 (4H, m), 7.25 (2H, m), 6.88 (3H, m), 4.82 (2H, s), 3.96 (2H, t), 3.72 (2H, t), 3.17 (2H, m), 3.03 (2H, t), 2.00 (2H, m). MS (ESI(+)): m/z 571 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[CH:37](F)OC1C=CC(S(Cl)(=O)=O)=CC=1>>[CH3:37][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)F)cc1)CC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)F)cc2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(4-difluoromethoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 523.23 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 4-difluoromethoxy-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(4-difluoromethoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:19])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O-:23])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:2]3[C:7]([CH:20]=[O:23])=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:7]=[CH:6][CH:5]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(Nc2cccc(Br)c2)c2ccccc2n1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(Nc2cccc(-c3ccccc3C=O)c2)c2ccccc2n1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
To a stirred suspension of 71 (411 mg, 1.31 mmol) in toluene (12.8 mL) under N2 were sequentially added saturated NaHCO3 (aq. 0.5 mL), a solution of 99 (303 mg, 2.02 mmol) in EtOH (8.9 mL), and PdCl2(Ph3P)3 (52 mg, 0.07 mmol). The reaction was heated at 80° C. for 41 hours before it was allowed to cool to room temperature and extracted with ethyl acetate (50 mL). The ethyl acetate extracts were washed with water (30 mL), brine (30 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 100 as a yellow solid (166 mg, 37.4%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].CCOCC>C(OC(=O)C)(=O)C>[CH2:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Fuming nitric acid (0.8 ml) was added over 10 minutes to a stirred solution of 4'-isobutyl-2-biphenylsulphonyl chloride (3.09 g) in acetic anhydride (18 ml) at -20° C. The solution was kept at -20° C. for 1.5 hours and then allowed to warm to ambient temperature. The solution was stirred for 1.5 hours and then added to ice (300 g) with vigorous sextracted with ether 30 minutes and extracted with ether (3×100 ml) while still below 10° C. The ethereal solution was dried (MgSO4) and the solvent was removed by evaporation. The resulting oil was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v), to give 4'-isobutyl-3'-nitro-2-biphenylsulphonyl chloride (2.01 g); 1H NMR (CDCl3): 0.95 (d,6H), 1.9-2.05 (m,1H), 2.9 (d,2H), 7.35-7.5 (m,2H), 7.6 (d,1H), 7.7 (d,1H), 7.8 (t,1H), 8.0 (s,1H), 8.25 (d,1H); mass spectrum (EI): 353(M+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13]C=C)=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)[CH:7]=[CH:6]2.[CH2:24]([C:33]([CH2:44][CH2:45][CH2:46][C:47]([F:53])([F:52])[C:48]([F:51])([F:50])[F:49])([C:39]([O:41]CC)=[O:40])C(OCC)=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH:33]([CH2:44][CH2:45][CH2:46][C:47]([F:52])([F:53])[C:48]([F:49])([F:50])[F:51])[C:39]([OH:41])=[O:40])=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH:7]=[CH:6]2
Reactant: C=CCCCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Reactant: C=CCc1c(-c2ccc(OC)cc2)ccc2cc(OC)ccc12
Product: O=C(O)C(CCCCCCCCCCc1c(-c2ccc(O)cc2)ccc2cc(O)ccc12)CCCC(F)(F)C(F)(F)F

Procedure:
Starting with 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene and separately prepared diethyl 2-(8-nonenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate, the same procedures as shown in Examples 1, 2 and 3 were repeated to give 12-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=1.[F:31][C:32]1([F:47])[CH2:37][CH2:36][N:35]([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>C(Cl)Cl.CCN(CC)CC>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:41]2[CH2:40][CH2:39][C:38]([C:44]([NH2:46])=[O:45])([N:35]3[CH2:34][CH2:33][C:32]([F:31])([F:47])[CH2:37][CH2:36]3)[CH2:43][CH2:42]2)=[O:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:19][CH:18]=1
Reactant: NC(=O)C1(N2CCC(F)(F)CC2)CCNCC1
Reactant: CS(=O)(=O)CCCOc1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCCOc1ccc(-c2cc(C(=O)N3CCC(C(N)=O)(N4CCC(F)(F)CC4)CC3)sc2-c2ccc(F)cc2Cl)cc1
Reaction time: 3 h
Yield: 119.1 %

Procedure:
0.3 g of the compound obtained in stage 22A), 0.3 g of 4,4-difluoro-1,4′-bipiperidine-4′-carboxamide (described in Preparation 5, page 23, of Application WO 2008/068423), 0.45 ml of Et3N and 0.25 g of TBTU are added in order to 10 ml of CH2Cl2. After 3 hours at AT, the mixture is concentrated to dryness and the residue is taken up in AcOEt, washed with water, dried and concentrated to dryness. After purifying by chromatography on silica (elution gradient: CH2Cl2 up to CH2Cl2/MeOH 98/2), the compound obtained is dissolved in CH2Cl2, ethereal hydrochloric acid is added down to a pH of 1 and then the mixture is concentrated to dryness. 0.28 g of the expected compound is obtained.
Reaction SMILES: C([NH:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32](=[O:52])[C@H:33]([CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[NH:34][C:35]([O:37][CH3:38])=[O:36])[O:12][CH2:11]1)C1C=CC=CC=1.[H][H]>FC(F)(F)CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32](=[O:52])[C@H:33]([CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[NH:34][C:35]([O:37][CH3:38])=[O:36])[O:12][CH2:11]1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNCc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: OCC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of tert-butyl (2R,5R)-5-[(benzylamino)methyl]-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in 2,2,2-trifluoroethanol (0.17M) was added Pd(OH)2 (0.33 eq.). The reaction mixture was stirred for 16 hrs under one atmosphere of hydrogen. The reaction mixture was filtered on celite and the filtrate was concentrated under reduced pressure. The residue was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([O:12]CC)=O)[NH:4][N:3]=1.[OH-].[NH4+:16]>>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([NH2:16])=[O:12])[NH:4][N:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1[nH]nc(C)c1[N+](=O)[O-]
Agent: [OH-]
Product: Cc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Yield: 95.8 %

Procedure:
Ethyl 3-methyl-4-nitropyrazole-5-carboxylate (82.5 g, 0.41 mol) was heated at reflux in 600 ml of concentrated ammonium hydroxide for 2 hours. Concentrated ammonium hydroxide (100 ml) was added and the solution was heated at reflux for an additional three hours. The solution was concentrated in vacuo until the product began to crystallize. The crude material was recrystallized from 700 ml of water to give 47 g product, m.p. 218°-220° (decomp). From the mother liquor was recovered 25 g of 3-methyl-7-nitropyrazole-5-carboxylic acid. Based on the amount of nitro acid consumed, the yield was 95.8%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[O:15]CC1C=CC=CC=1)=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].C1COCC1.[Br-].[CH2:30]([Zn+])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH4+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1ncc2cc(Br)ccc2c1OCc1ccccc1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 16.2 %

Procedure:
To a mixture of 4-benzyloxy-7-bromo-isoquinoline-3-carboxylic acid methyl ester (150 mg, 0.40 mmol), Pd(PPh3)4 (47 mg, 0.040 mmol) and THF (4 mL) was added benzylzinc bromide (2 mL, 1.0 mmol, 0.5 M in THF), and the resulting mixture was refluxed for 16 h under nitrogen atmosphere. After cooling the mixture to r.t., saturated NH4Cl (50 mL) and CH2Cl2 (50 mL) were added. The aqueous layer was extracted with additional CH2Cl2, and the organic layers were combined and dried over MgSO4. After evaporating the solvent, the crude product was purified by column chromatography (0-35% EtOAc/hexanes) to give 19 mg of the title compound as a yellow solid. MS: (+) m/z 294.05 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.Cl.[N:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.O1CCOCC1>[N:20]([C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=3[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)=[CH:25][CH:24]=1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Reactant: CCOc1ccc(I)cc1-c1cc(Cl)nc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: CCOc1ccc(I)cc1-c1cc(Nc2ccc(N=[N+]=[N-])cc2)nc(N)n1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
To a mixture of 4-chloro-6-(5-iodo-2-ethoxy-phenyl)pyrimidin-2-ylamine (7.0 mg, 0.02 mmol) and 4-azidoaniline hydrochloride (5.0 mg, 0.03 mmol) in tert-butanol (1 ml) was added a 1 M hydrogen chloride in dioxane (0.2 ml). The mixture was heated at 90° C. for 2 hours. After cooling to room temperature, the mixture was treated with 1 M aqueous sodium bicarbonate solution (1 ml) and extracted with ethyl acetate (2×1 ml). The combined extracts were concentrated under reduced pressure and the residue was purified by preparative TLC eluting with 35% ethyl acetate-hexane to provide the title compound (6 mg, 68% yield) as a light brown solid. 1H NMR (CDCl3) δ 8.20 (d, J=2.3 Hz, 1H), 7.60 (dd, J=2.3, 8.70 Hz, 1H), 7.38 (d, J=8.70 Hz, 2H), 7.04 (d, J=8.70 Hz, 2H), 6.77 (s, 1H), 6.72 (d, J=5.0 Hz, 1H), 6.63 (br s, 1H), 4.91 (br s, 2H), 4.09 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).