Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[C:6]([NH:9][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1)(=O)[CH3:7].Cl.[CH:19]([N:22]([CH:26]([CH3:28])[CH3:27])CCCl)([CH3:21])[CH3:20].[H-].[Na+]>C(O)C>[CH:19]([N:22]([CH:26]([CH3:28])[CH3:27])[CH2:7][CH2:6][NH:9][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1)([CH3:21])[CH3:20]
Reactant: CC(=O)Nc1nc(C)cc(C)n1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(NCCN(C(C)C)C(C)C)n1

Procedure:
To 600 ml of dry dimethylformamide is added 2-acetamido-4,6-dimethylpyrimidine (34.8 g., 0.21 mole) and 2-diisopropylaminoethyl chloride hydrochloride (48 g., 0.24 mole). The mixture is stirred under nitrogen and sodium hydride (50% in mineral oil) (24.7 g., 0.515 mole) is added in portions over one hour while the temperature is maintained below 45° C. The mixture is then heated at 75°-78° C. for 1/2 hour and then at 90°-95° C. for 31/2 hours. On cooling, ethanol, 25 ml, is added and the solvents removed under reduced pressure. The residue is suspended in 75 ml of 1-propanol and 400 ml of 5N sodium hydroxide and refluxed with stirring for 18 hours. On cooling the mixture is extracted with methylene chloride. The organic extracts are then extracted with dilute hydrochloric acid. The acid extracts are extracted with hexane and then made alkaline with a molar excess of sodium hydroxide. The crude product is extracted from the basic solution with diethyl ether. The ethereal extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under vacuum. The residue is distilled and the product diamine (37.2 g., 0.149 mole) collected at 130°-134° C./0.4 mm; melting point 79.5°-82° C.
Reaction SMILES: Cl.[OH:2][NH2:3].[Cl:4][C:5]1[N:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][CH:11]=[CH:10][CH:9]=2>N1C=CC=CC=1>[Cl:4][C:5]1[N:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[N:3][OH:2])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: NO
Reactant: O=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Reaction time: 2 h
Yield: 76.3 %

Procedure:
55.5 g Hydroxyamine hydrochloride is added to 53.6 g 3-chloro-1-phenyl-isoquinoline-4-aldehyde in 150 ml pyridine at 0° C. The resulting mixture is left to stand at room temperature for 2 hours. Then, successively, the solvent is removed in vacuo, the residue is partioned between water and toluene, the toluenic phase is dried and concentrated. 43.2 g 3-chloro-1-phenyl-isoquinoline-4-aldoxime having a melting point from 151° to 154° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:28][CH3:29].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:28][CH3:29])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (5.00 g, 14.95 mmol, Example E) in dry DMF (50 mL) was added dropwise to a suspension of sodium hydride 60% in mineral oil (0.7176 g, 17.94 mmol) in dry DMF (10 mL). The mixture was stirred at 0° C. for 1 hour and allowed to stir at room temperature for 2 hours. The mixture was then cooled to 0° C. and treated dropwise with iodoethane (1.315 mL, 16.45 mmol). The reaction mixture was stirred at 0° C. for 2 hours and allowed to warm to room temperature over 18 hours. Water (50 mL) was added, and the mixture was extracted into EtOAc (3×70 mL). The organic layers were combined, washed with water (3×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 20% EtOAc/hexane to provide (R)-benzyl 3-(tert-butoxycarbonyl(ethyl)amino)piperidine-1-carboxylate (5.01 g, 92% yield) as an oil. LCMS (APCI+) m/z 363 (M+H)+.
Reaction SMILES: N.[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([O:11]C(OC)=O)=[CH:6][C:4]=1[NH2:5]>C(O)C.O>[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[CH:6][C:4]=1[NH2:5]
Reactant: COC(=O)Oc1cc(N)c(F)cc1F
Agent: N
Solvent: CCO
Solvent: O
Product: Nc1cc(O)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Concentrated aqueous ammonia (20 ml) was added to a solution of 2,4-difluoro-5-methoxycarbonyloxyaniline (2.0 g, 9.85 mmol) in ethanol (100 ml) and the mixture stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and most of the organic volatiles were removed by evaporation. The aqueous residue was neutralised to pH7 and extracted with ethyl acetate. The extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation to give 2,4-difluoro-5-hydroxyaniline (1.2 g, 85%).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])[CH3:21])[CH:11]=2)[CH:2]=1.[NH3:32]>CO>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([NH2:32])=[O:17])=[C:12]([O:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:29])([F:30])[F:31])[CH3:21])[CH:11]=2)[CH:2]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OC(C)c1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3ccncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 92 mg of the above-synthesized methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 10 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture was allowed to come to room temperature, then another 10 ml of a saturated solution of ammonia in methanol were added and the procedure was repeated as described above. The solvent was removed under vacuum and the residue was purified by flash chromatography (n-hexane/ethyl acetate, elution gradient 10/0 to 3/7 (v/v)) to give the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([OH:24])=O)[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:28][CH:25]4[CH2:27][CH2:26]4)=[O:24])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C1CCCC1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1csc(C(=O)NC3CC3)c1)nn2C1CCCC1

Procedure:
A solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (75.0 mg) obtained in Step A of Example 155, cyclopropylamine (0.023 mL), EDCI hydrochloride (62.8 mg) and HOBt (44.3 mg) in DMF (10 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (78.0 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][S:14]([CH3:17])(=[O:16])=[O:15].[CH3:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CC1CCc2ccccc2N1
Reactant: COC(=O)c1ccc(CBr)c(OS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2c3ccccc3CCC2C)c(OS(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 23 h
Yield: 73.5 %

Procedure:
A mixture of methyl 4-(bromomethyl)-3-[(methylsulfonyl)oxy]benzoate (0.70 g, 2.2 mmol), 2-methyl-1,2,3,4-tetrahydroquinoline (0.39 g, 2.6 mmol), potassium carbonate (0.60 g, 4.3 mmol) and N,N-dimethylformamide (14 mL) was stirred at 70° C. for 23 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (0.63 g, yield 75%) as a pale-yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18]1[NH:23][CH:22]([CH3:24])[CH2:21][NH:20][CH2:19]1>CS(C)=O.O>[CH3:24][CH:22]1[NH:23][CH:18]([CH3:17])[CH2:19][N:20]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:21]1
Reactant: CC1CNCC(C)N1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1CN(c2ccc([N+](=O)[O-])cc2)CC(C)N1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a suspension of 1-fluoro-4-nitrobenzene (2.12 mL, 20 mmol) and potassium carbonate (3.5 g, 25 mmol) in DMSO (10 mL) was added 3,5-dimethyl-piperazine (2.5 g, 22 mmol). The mixture was stirred at 100° C. for 2 hours. After cooing down, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford a yellow solid. Recrystallization from EtOAc/hexanes gave 3.9 g of 3,5-dimethyl-1-(4-nitro-phenyl)-piperazine, which was reduced via hydrogenation to give the title compound (purple solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.80 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 3.40 (br, 2H), 3.32 (d, J=9.5 Hz, 2H), 3.05 (m, 2H), 2.19 (t, J=10.5 Hz, 2H), 1.12 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH:28]([CH2:33][CH2:34][CH2:35][Cl:36])[C:29]([O:31][CH3:32])=[O:30].O>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:1])[CH:28]([CH2:33][CH2:34][CH2:35][Cl:36])[C:29]([O:31][CH3:32])=[O:30])(=[O:5])=[O:4])=[CH:7][CH:8]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Reactant: COC(=O)C(Br)CCCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCCl)C(=O)OC)cc1
Reaction time: 0.25 h

Procedure:
A solution of 7.17 g (30 mmol) N-methyl-[4-(2-butynyloxy)-phenyl]sulfonamide] in 25 ml of DMF was cooled to 0° C. and 30 ml of 1M sodium hexamethyldisilazide (30 mmol) was slowly added and this mixture was stirred for 15 min and then added to a solution of 6.89 g (30 mmol) of methyl 2-bromo-5-chloropentanoate in 25 ml of DMF and was stirred at room temperature for 18 hours. The mixture was combined with water and the precipitate was collected and purified by chromatography on silica gel using hexane-ethyl acetate, 4:1 to give methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-5-chloropentanoate Electrospray Mass Spec 410.2 (M+Na)+
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:18]1([S:24]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=3[Cl:11])[NH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Mix 3-amino-2-carbethoxy-4,6-dichloroindole (3.31 g, 12.1 mmol) and anhydrous pyridine (50 mL). Add, by dropwise addition, phenylsulfonyl chloride (2.35 g, 13.33 mmol). Stir for 48 hours at room temperature. Pourinto 1N hydrochloric acid (500 mL), extract with ethyl acetate and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give the title compound (3.15 g, 63%); mp 245°-7° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:11]([C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:48]3[CH:47]=[CH:46][C:45]([N:42]4[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:44][CH2:43]4)=[CH:50][CH:49]=3)[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]3[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH3:23])[CH2:17]3)[CH3:15])[C:5]=12)#[N:12]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C#N)c34)CC2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(C#N)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
Intermediate 5.64 (218 mg, 0.496 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (303 mg, 0.99 mmol), K3PO4 (420 mg, 2.0 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (18 mg, 0.025 mmol) were taken up in 1,4-dioxane (7 mL) and water (0.72 mL). The stirred reaction mixture was heated to 100° C. Once complete, the reaction mixture was partitioned between EtOAc, water, and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography to provide tert-butyl 4-(4-(3-cyano-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C37H44N7O5: 666.3; found: 666.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([B:19]([OH:24])[OH:20])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2cc(B(O)O)ccc2c1
Reaction time: 1.5 h

Procedure:
A solution of 6-methoxy-2-bromonaphthalene (25 g) in tetrahydrofuran (300 ml) was cooled at −78° C. under a nitrogen atmosphere. n-Butyllithium (2.66 M solution in hexane) (42 ml) was added dropwise thereto over 1.5 hours, and the solution was stirred for 30 minutes. Triisopropyl borate (26.5 ml) was added dropwise thereto for 30 minutes, then the solution was stirred for 40 minutes while warming from −78° C. to 0° C. 1N hydrochloric acid (200 ml) and ethyl acetate (200 ml) were sequentially added thereto, the solution was stirred, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo, the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (18 g).
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([CH2:40][CH3:41])([OH:39])[CH2:37][CH3:38])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[CH2:37]([C:36]([OH:39])([CH2:40][CH3:41])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:11]([OH:10])[CH:12]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:38]
Reactant: CCOCOc1cc(C=Cc2cccc(C=CCCCCC(O)(CC)CC)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(CC)CCCCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.3 ml of concentrated sulphuric acid in 7 ml of methanol with 700 mg (1.41 mmol) of 9-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-3-ethylnon-8-en-3-ol in 7 ml of methanol and 7 ml of THF, after purification on a silica column (ethyl acetate 40-heptane 60), beige crystals (m=477 mg; Y=77%) are obtained. m.p.=98-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:30])=[O:31])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(OCCN3CCCC3)cc12
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.359 g, 0.555 mmol) and pyrrolidine (1.0 mL, 12 mmol) in THF (8 mL) was stirred at 70° C. in a sealed tube for 2 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. It was then partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo at 80° C. for 20 minutes to give 1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-5-(2-pyrrolidin-1-yl-ethoxy)-1H-indazole as a yellow semi-solid (0.266 g, 87.8%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried at 82° C. in vacuo for 14 hours to yield the hydrochloride as a light orange foam (0.205 g); Mass Spectrum (+EI, [M+H]+) m/z 546. 1HNMR (500 MHz, DMSO-d6): δ10.18-10.19 (s, 1H), 8.73-8.75 (m, 1H), 8.55-8.57 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.57-7.64 (m, 2H), 7.15-7.29 (m, 5H), 7.04 (d, 1H, J=7.69 Hz), 5.73 (s, 2H), 4.33-4.35 (m, 2H), 3.55 (br, s, 4H), 3.07-3.15 (s, br, 2H), 1.81-2.02 ppm (br, m, 4H). Elemental Analysis for C30H28ClN3O3S.1.00 HCl.0.70 mole H2O: Calcd: C, 60.54; H, 5.15; N, 7.06; Found: C, 60.16; H, 5.11; N, 6.74.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)[CH3:2]>CO.CCOCC.[Pd]>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:12][CH:11]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)CCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
The compound 34-2 (64 mg) according to the same procedure as described in Step 1 was dissolved in methanol (10 ml) and to the solution was added a catalytic amount of 10% palladium/carbon, followed by stirring at room temperature under hydrogen gas atmosphere for 2 hours. The resulting mixture was diluted with ether, filtered through celite, and then concentrated under reduced pressure to yield the compound 34-3 (60 mg, 93%)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[Si](C)(C)[N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[C:57]([O:59][Si](C)(C)C)=[O:58]>C1COCC1.C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([N:52]3[CH2:56][CH2:55][CH2:54][C@H:53]3[C:57]([OH:59])=[O:58])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)OC(=O)[C@@H]1CCCN1[Si](C)(C)C
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)N3CCC[C@H]3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (15 mg, 0.044 mmol), TEA (0.019 mL, 0.133 mmol), and HATU (25.4 mg, 0.067 mmol) in THF (0.5 mL) and DCM (0.500 mL) was added (S)-trimethylsilyl 1-(trimethylsilyl)pyrrolidine-2-carboxylate (23.07 mg, 0.089 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue purified by HPLC to give the title compound. LCMS m/z=435.4 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:3]1[CH:4]=[C:5]([C:16]([O:18]CC)=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.[OH-].[Li+].OS(O)(=O)=O>O1CCOCC1.O>[OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:3]1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2ccccn2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3ccccn3)c2)cc1
Temperature: 25 °C

Procedure:
Ethyl 5-(hydroxy(pyridin-2-yl)methyl)-4′-methylbiphenyl-3-carboxylate (319 mg, 0.92 mmol) was dissolved in 1,4-dioxane (6 mL) and water (0.3 mL). To the stirred solution was added lithium hydroxide (120 mg, 5.0 mmol) and the reaction mixture was stirred at room temperature until the reaction was complete. The mixture was cooled and acidified with 2N aq. H2SO4 to pH 5-6 and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to yield a light yellow solid. 1H NMR (400 MHz, CD3OD): 8.47 (m, 1H), 8.13 (t, 1H, J=1.6 Hz), 8.02 (t, 1H, J=1.6 Hz), 7.91 (t, 1H, J=1.6 Hz), 7.87 (td, 1H, J=7.6, 1.6 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.51 (d, 2H, J=8.0 Hz), 7.31 (ddd, 1H, J=7.6, 5.2, 1.2 Hz), 7.27 (d, 2H, J=8.0 Hz), 5.93 (s, 1H), 2.37 (s, 3H).