Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:14]S(C)(=O)=O)=[CH:8][C:7]=2[C:6]=1C(C1C=CC(OCCCN(CCCC)CCCC)=CC=1)=O.Cl>O>[NH2:14][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:6][C:7]=2[CH:8]=1
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Agent: Cl
Solvent: O
Product: CCCCc1cc2cc(N)ccc2o1

Procedure:
This method is very simple and economical as regards the number of the reaction steps. Its drawback is, however, that in the last step the hydrochloride salt of dronedarone is obtained in a rather contaminated form. This can be explained by the presence of the dibutylamino-propyl group in the Friedel-Crafts reaction. In the examples of WO02/48132 the yield is 90%, during the purification steps at first the raw dronedarone hydrochloride salt, then following treatment with hydrogen chloride solution in isopropanol, the purified dronedarone hydrochloride salt is obtained (90%). It means that the yield of the raw dronedarone hydrochloride is 90% and then the purification step has a yield of 90%. Another drawback of the method is that the reactants used in the Friedel-Crafts reaction and the obtained by-products are insoluble in water, thus they cannot be removed from the system by aqueous washing.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)([Cl:21])=O>>[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([Cl:21])=[O:18])=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3oc2c1
Product: O=C(Cl)c1ccc2c(=O)c3ccccc3oc2c1

Procedure:
9-oxo-9H-xanthene-3-carboxylic acid (9 g, 37.4 mmol) was added to thionyl chloride (28 mL, 334 mmol). The mixture was refluxed for 5 h. At that time, the thionyl chloride was removed under vacuum and the remaining residue was diluted with toluene and concentrated to dryness to give 9-oxo-9H-xanthene-3-carbonyl chloride. A portion of 9-oxo-9H-xanthene-3-carbonyl chloride (0.25 g, 0.96 mmol) was dissolved in acetonitrile (7 mL). Diisopropylethylamine (335 μL, 1.9 mmol) was then added to the mixture with the subsequent addition of pyrrolidine (113 μL, 1.3 mmol). After stirring 2 h, the solvent was concentrated and the residue was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10%- 90%) in water with trifluoroacetic acid (0.1%) to afford the 3-(pyrrolidine-1-carbonyl)-xanthen-9-one. MS m/z (MH+) 294.1.
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)=[CH:20][N:19]=2)=[CH:14][C:13]=1[CH3:41])[C:3]([O:5]C(C)(C)C)=[O:4]>FC(F)(F)C(O)=O.O>[CH3:1][C:2]([CH3:42])([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]([C:29]([F:32])([F:30])[F:31])=[CH:26][N:25]=3)=[CH:20][N:19]=2)=[CH:14][C:13]=1[CH3:41])[C:3]([OH:5])=[O:4]
Reactant: Cc1cc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)ccc1OCC(C)(C)C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)ccc1OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
In trifluoroacetic acid (5 mL) and water (0.5 mL) was dissolved tert-butyl 2,2-dimethyl-3-[2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]-2-pyridyl]phenoxy]propanoate (103 mg), and the mixture was stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in tetrahydrofuran, and 1N aqueous sodium hydroxide solution was added to the mixture to adjust a pH thereof to 7. To the mixture were added 0.1N phosphate buffer, ethyl acetate and water, and the liquids were separated. The organic layer was separated, dried over anhydrous sodium sulfate, and ether was added to the residue obtained by concentrating the solution under reduced pressure to pulverize the precipitates to obtain 2,2-dimethyl-3-[2-methyl-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoic acid (59.1 mg).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]1)=O)(C)(C)C.C(N(CC)CC)C>CO>[C:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCc1cn(C(=O)OC(C)(C)C)cn1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 4-(2-tert-Butoxycarbonylamino-ethyl)-imidazole-1-carboxylic acid tert-butyl ester, were added 100 mL of methanol and 800 mL (5.73 mol) of triethylamine The reaction mixture was allowed to stir at room temperature for four days and concentrated to oil. To the residue were added 40 mL of ether and 80 mL of hexane. This mixture was allowed to stand at room temperature resulting in precipitation of product, as a white solid, which were collected. The yield was 1.7 g (8.0 mmol, 40%) (LC/MS M+H 212.1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13]#[C:14][NH2:15].[Na]>>[CH2:1]([O:8][CH2:9][CH:10]1[O:11][C:14]([NH2:15])=[N:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: N#CN
Agent: [Na]
Product: NC1=NCC(COCc2ccccc2)O1

Procedure:
The title compound was prepared from 2-benzyloxymethyl-oxirane and sodium hydrogen cyanamide according to the procedures employed for the preparation of the compound in Step 2 of Example 1.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:39][CH2:40][OH:41]>O1CCCC1>[OH:41][CH2:40][CH2:39][N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:22]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:23])[CH2:26][CH2:27]1
Reactant: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCNCC1
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(CCO)CC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea (0.05 g, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and 2-bromoethanol (0.019 mL, 0.15 mmol) were dissolved in tetrahydrofuran (3 mL) and stirred at 60° C. for 7 h. The reaction mixture was evaporated. The residue was subjected to column chromatography (basic silica gel, methylene chloride/methanol 19:1, 9:1) to yield the title compound (0.023 g, 41%) as a white solid; MS: m/e=446.8 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([NH2:5])[CH2:3][NH2:4].[C:7]1([CH2:13][C:14](Cl)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[CH3:1][C:2]([NH2:5])([CH3:6])[CH2:3][NH:4][C:14](=[O:15])[CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(N)CN
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(N)CNC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of 1,1-dimethylethylenediamine (8.8 g.) in ether (250 ml.) was added during 2 hours to a stirred solution of phenylacetyl chloride (15.4 g.) in ether (250 ml.). This mixture was further stirred for 2 hours. The solid was separated by filtration, and dissolved in warm water (150 ml.). The solution obtained was filtered. The filtrate was basified by addition of an excess of saturated aqueous sodium carbonate solution (50 ml.), and then extracted with chloroform (3×250 ml.). The extracts were dried (MgSO4) and evaporated to give an oil which crystallised on addition of a 1:1 v/v mixture of ether and petrol (60°-80°) to give 1,1-dimethyl-2-(2-phenylacetamido)ethylamine (13.1 g., 63%), m.p. 47°-48° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](O)(=[O:22])[C:19]([CH3:21])=[CH2:20]>>[C:18]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)CCCCCCOc1ccc(C(=O)O)cc1

Procedure:
A solution of 4-(6-hydroxyhexyloxy)benzoic acid (24.0 g, 0.10 mol, prepared as described in Example 3) was treated with methacrylic acid as described above to give 4-(6-methacryloylhexyloxy)benzoic acid after recrystallization from tetrahydrofuran-hexane (1:2) (19.9 g, 67%): mp 81°-94° C., nematic mesophase; NMR (CDCl3) 9.82(bs, 1H), 8.0(d, 2H), 6.87(d, 2H), 6.05(s, 1H), 4.15(t, 2H), 4.0(t, 2H), 1.9(s, 3H), 1.85(m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[N:21][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29](OCC)=[O:30])[CH:27]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.CO.[CH3:36][NH2:37]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[N:22]=[N:21][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]([NH:37][CH3:36])=[O:30])[CH:27]=4)=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Solvent: O
Solvent: CO
Product: CNC(=O)Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flask was placed ethyl 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)acetate (45 mg, 0.1 mmol) and MeOH (2 mL) was added. Then, 40 wt % CH3NH2(aq) (8 mL) was added. The resulting mixture was stirred at room temperature for 30 min and H2O (10 mL) was added. The solid was filtered and washed with H2O (5 mL×3), then dried to yield 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)-N-methylacetamide as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.CN(C=O)C.[H-].[Na+].I[CH2:14][CH2:15][CH2:16][C:17]#[CH:18]>O>[CH2:18]([N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH2:17][CH2:16][C:15]#[CH:14]
Reactant: c1c[nH]nn1
Reactant: C#CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCn1ccnn1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
To a 50 mL round-bottomed flask equipped with a magnetic stirbar was added 1-H-1, 2, 3-triazole (0.192 g, 2.78 mmol) and DMF (10 mL) and then cooled to 0° C. while stirring. Then, sodium hydride (60% dispersion in mineral oil) (0.133 g, 3.33 mmol) is added to the reaction mixture and was slowly allowed to warm to ambient temperature. Then, 1-iodo-4 pentyne (0.647 g, 3.33 mmol) was added dropwise. The reaction mixture was then heated to 80° C. and allowed to stir for 2.5 hours. Water (20 mL) was then added to the reaction mixture and then extracted with ethyl acetate (2×20 mL). The organic phase was dried with sodium sulfate and concentrated de vacuo followed by a purification by column chromatography (ethyl acetate/hexane) to produce 1-Pent-4-ynyl-1H-[1,2,3]triazole (0.349 g, 93%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), δ 7.59 (s, 1H), δ 4.53 (t, 2H), δ 2.20 (t, 2H), δ 2.17 (m, 2H), δ 2.04 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 133.9, 123.9, 82.2, 70.4, 48.7, 28.9. 15.7 ppm; HRMS (ESI) calcd for C7H10N3 (M+) 136.0869. Found 136.0866.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:37]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[C:31](=[O:38])[NH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)=[O:5]>[Pd].ClCCl.CO>[N:6]1([C:4]([C:3]2[CH:23]=[C:24]([CH:25]=[CH:26][C:2]=2[F:1])[CH2:27][C:28]2[C:37]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[C:31](=[O:38])[NH:30][N:29]=2)=[O:5])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c3CCCC4)ccc2F)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F)N1CCCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of EXAMPLE 544 (584 mg, 1.13 mmol) in 1:1 dichloromethane/methanol (20 mL) was added 10% Pd/C (150 mg) under nitrogen. The suspension was purged with hydrogen, and stirred under hydrogen at room temperature for 18 hours. Solid material was filtered off, and the filtrate was concentrated to provide the title compound. MS (DCI/NH3) m/z 385 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[N:31]=[CH:30]1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:35](=[O:36])[CH2:34][C:32]1[NH:31][CH:30]=[N:29][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OCC1CC1
Reactant: O=C(O)Cc1c[nH]cn1
Product: O=C(Cc1cnc[nH]1)N1CCN(c2ccc(OC(F)F)c(OCC3CC3)c2)C[C@@H]1Cc1ccccc1
Yield: 35 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-piperazine and (1H-imidazol-4-yl)-acetic acid to afford the title compound as colorless solid (62 mg, 35%). LC/MS (Method B) 2.80 min, [M+1]+ 497.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[CH:3]=1.[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[C:3]=1[F:18]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1c(Cl)cc(=O)n2c1CCCC2
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)c(F)c(=O)n2c1CCCC2
Yield: 45.3 %

Procedure:
Methyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylate (7b, 1.23 g, 5.1 mmol, 1 eq) was dissolved in DMF (10 ml) at 88° C. Selectfluor (3.61 g, 10.2 mmol, 2 eq) in DMF (10 ml) was added drop wise and the mixture heated for 2 hours. After concentration in vacuo the residue was purified by flash chromatography using 20-70% EtOAc/Hexane as eluent to give the title compound as an off-white solid (600 mg, 45%). [M+H] calc'd for C11H11ClFNO3, 260. found, 260
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.C(O)(=O)C.C(O)(=O)C.[CH3:25][N:26]([CH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1)[CH3:27]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([CH2:28][N:26]([CH3:27])[CH3:25])[CH2:30][CH2:31]1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Solvent: CC(=O)O
Product: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (150 mg, 0.54 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine diacetic acid salt (190 mg, 0.68 mmol) to afford the desired product (150 mg, 68%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.84 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.70-7.60 (m, 1H), 7.57 (d, J=8.8 Hz, 1H), 5.05-4.95 (m, 1H), 3.09 (s, 3H), 2.34-2.24 (m, 8H), 2.18 (d, J=7.0 Hz, 2H), 2.00-1.92 (m, 2H), 1.57-1.50 (m, 1H), 1.42-1.30 (m, 2H), 1.24-1.12 (m, 2H); ESI MS m/z 397 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]4[CH:37]=[C:36]([NH:38][C:39](=[O:48])[C:40]5[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=5)[CH:35]=[CH:34][C:33]=4[Cl:49])=[CH:26][N:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[Cl:49][C:33]1[CH:34]=[CH:35][C:36]([NH:38][C:39](=[O:48])[C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)=[CH:37][C:32]=1[C:31]([NH:30][C:27]1[CH:26]=[N:25][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[N:29][CH:28]=1)=[O:50].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc3)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)C5CCNCC5)cc4)nc3)c2)cc1
Reaction time: 18 h

Procedure:
A stirred suspension of intermediate 28 (Example 41) (0.075 g, 0.104 mmol) in DCM (8 mL) was treated with TFA (0.200 mL) and stirred for 18 h. Solvents were then removed yielding desired product as TFA salt (0.064 g, 99%). 1H NMR (DMSO-d6): δ 1.64-1.70 (m, 2H), 2.01-2.04 (m, 2H), 2.86-2.88 (m, 2H), 3.44-3.48 (m, 1H), 3.84 (s, 3H), 7.08 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.9 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.90 (dd, J=8.7 Hz, J=2.5 Hz, 1H), 7.98 (d, J=8.9 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 8.23 (d, J=2.5 Hz, 1H), 8.24 (br s, 1H), 8.68 (br s, 1H), 8.90 (s, 2H), 10.37 (s, 1H), 10.39 (s, 1H), 10.78 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[NH:16][C:17]([CH:19]1[C:24](=O)[C@@:23]2(C)[C:26]([CH3:28])([CH3:27])[C@@H:20]1[CH2:21][CH2:22]2)=O)=O)(C)(C)C>ClCCl>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:15]1[C:13](=[O:12])[C:19]2[C@@H:20]3[C:26]([CH3:28])([CH3:27])[C@@:23]([CH3:24])([CH2:22][CH2:21]3)[C:17]=2[NH:16]1
Reactant: CC(C)(C)OC(=O)N(NC(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
Trifluoroacetic acid (55 mL) was added slowly over 1-2 min to a solution of N-(2-chloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (23.4 g, 56 mmol) in dry dichloromethane (55 mL), and the resulting solution was stirred at room temperature for 3 h. The solvent was evaporated and dichloromethane (350 mL) was added. The solution was washed with water (3×150 mL) and brine (150 mL), dried (sodium sulfate), filtered, evaporated, and dried under high vacuum over the weekend to give (4S,7R)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (16.07 g, 95%) as a pale solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Cl-].[NH4+]>ClCCl>[Br:8][C:4]1[N:3]=[C:2]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Br)n2)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-dibromopyridine (34 g) in dichloromethane (740 ml) is added dropwise, at −78° C. under argon, n-butyllithium (1.6 M in tetrahydrofuran, 100 ml). The reaction mixture is stirred at −78° C. for 20 minutes and then tert-butyl 4-oxopiperidine-1-carboxylate is added. The mixture is stirred at room temperature for 20 minutes. The reaction mixture is subsequently admixed with saturated ammonium chloride solution at 30° C. and the aqueous phase is removed. After the aqueous phase has been extracted with dichloromethane, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (60 g).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[CH2:16](O)[CH3:17]>OS(O)(=O)=O>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([O:13][CH2:16][CH3:17])=[O:12])=[CH:6][CH:5]=1
Reactant: CCO
Reactant: CC(C)=Cc1ccc(C(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(C=C(C)C)cc1

Procedure:
A solution of 2-(4-dimethylvinylphenyl)propionic acid (11.5 g) in anhydrous ethanol (250 ml) and 2.5 ml of 98% H2SO4 was refluxed for 4 hours. After cooling the solvent was removed and the oily residue was treated with a saturated NaHCO3 solution, extracted with two 100 ml portions of ether and dried over Na2SO4. Evaporation of the solvent gave a white oil which was dried at 40° in a vacuum stove for 3 hours to yield the title ester (12.5 g) as an oily product. Found: C% 75.65 (Calc 75.44); H% 8.62 (8.42).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)#[CH:2].C(NC(C)C)(C)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][C:45](I)=[CH:44][CH:43]=2)=[CH:26]/[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:18][C:19]1[CH:20]=[CH:21][C:22](/[C:25](/[C:42]2[CH:43]=[CH:44][C:45]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=3)=[CH:46][CH:47]=2)=[CH:26]/[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2ccc(I)cc2)cc1C
Reactant: C#Cc1ccc(CO)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2ccc(C#Cc3ccc(CO)cc3)cc2)cc1C
Temperature: 25 °C

Procedure:
(4-Ethynylphenyl)methanol (200 mg, 1.51 mmol) and diisopropylamine (360 mg, 3.56 mmol) were added to a solution of methyl (Z)-[4-[3-(4-bromophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (445 mg, 0.75 mmol) in anhydrous tetrahydrofuran (15 mL). The solution was degassed and bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) and copper(I) iodide (15 mg, 0.078 mmol) were added. The reaction solution was degassed again and then stirred under inert atmosphere at ambient temperature over night. The reaction mixture was filtered through a paddle of silica gel; the paddle was thoroughly washed with ethyl acetate (4×20 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl (E)-[4-[3-(4-bromophenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.