Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[NH:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[NH:4].C(OC(=O)C)(=O)C.[H][H]>C(O)(=O)C.[Pd]>[C:11]([OH:13])(=[O:12])[CH3:10].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:23])[CH3:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:28][CH:29]=1)(=[NH:2])[NH2:4]
Reactant: CCOc1cc(C(Oc2ccc(C(=N)NO)cc2)C(=O)OC)ccc1OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc(C(Oc2ccc(C(=N)N)cc2)C(=O)OC)ccc1OC(C)C
Yield: 181.7 %

Procedure:
To 9B (575 mg, 1.43 mmol) in acetic acid (14 mL) was added acetic anhydride (0.155 mL, 1.64 mmol) and 10% Pd/C (90 mg). The mixture was hydrogenated with a hydrogen balloon at rt for 3.0 h. After removal of solvent, 9C (580 mg, 100% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (d, J=6.16 Hz, 6H) 1.30 (t, J=7.03 Hz, 3H) 1.69 (s, 3H) 3.66 (s, 3H) 4.00 (q, J=7.03 Hz, 2H) 4.46-4.50 (m, 1H) 6.09 (s, 1H) 6.90 (d, J=8.35 Hz, 1H) 6.97-7.14 (m, 4H) 7.72 (d, J=9.23 Hz, 2H). LC-MS 387 (M+H)+.
Reaction SMILES: [C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[CH:24](O)=[O:25]>>[C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([O:23][CH:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: O=CO
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(C)=O
Product: CCCCCC(CCCC(CCCCCCC(=O)O)C(C)=O)OC=O

Procedure:
A mixture of 8-acetyl-12-hydroxyheptadecanoic acid (8.2 g., 0.025 mole) and 97% formic acid (10 ml.) is heated at 60° for 24 hours. The mixture is cooled, dissolved in 100 ml. ether, washed with 3 portions of water and dried over sodium sulfate. Evaporation of the ether leaves the product 8-acetyl-12-formyloxyheptadecanoic acid as slightly yellowish viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([CH:16]=[C:17](O)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9].[N:25]([CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)=[N+:26]=[N-:27].C(=O)([O-])[O-].[K+].[K+].O>C(O)(C)C>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:42])([F:40])[F:41])[CH:32]=1)[CH2:28][N:25]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:16]([C:11]2[C:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:27]=[N:26]1
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(c1ccccc1Cl)c1cccnc1C=C(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The reaction can also be carried out using (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone (30.0 g; 72.3 mmol; 1.0 equiv) in isopropanol (225 mL). 1-azidomethyl-3,5-bistrifluoromethylbenzene (20.43 g; 76 mmol; 1.05 equiv) and potassium carbonate (5.0 g; 36.2 mmol; 0.5 equiv) are added, and the reaction mixture is heated to reflux for 21-24 hours. Cool the reaction mixture to 20° C., add water (120 mL), and stir for approximately 16 hours. Filter, wash with 120 mL isopropanol/water (1:1 v/v), and dry under reduced pressure at 50° C. to yield the title compound, which may be recrystallized as described above.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]3[CH2:23][CH2:24][C@@H:18]3[CH2:17][O:16][C:15]=2[C:14]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:11])=[O:10].[CH2:32]([N:34]([CH2:51][CH3:52])[CH2:35]/[CH:36]=[CH:37]\[Sn](CCCC)(CCCC)CCCC)[CH3:33]>O1CCOCC1.CS(C)=O>[CH2:32]([N:34]([CH2:51][CH3:52])[CH2:35]/[CH:36]=[CH:37]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]3[CH2:23][CH2:24][C@@H:18]3[CH2:17][O:16][C:15]=2[C:14]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:11])=[O:10])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@H]1CCN21
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC(C)(C)C)OC[C@H]1CCN21
Temperature: 95 °C
Reaction time: 17 h
Yield: 26.2 %

Procedure:
A mixture of tert-butyl (R)-6-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (Intermediate 43, 0.061 g) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.096 g) in dioxane (3 mL) and DMSO (0.3 mL) was purged with nitrogen and tris-(dibenzylideneacetone)dipalladium (0) (0.006 g) and tri-tert-butylphosphonium tetrafluoroborate (0.004 g) were added. The reaction mixture was heated at 95° C., under an atmosphere of nitrogen for 1.5 hours. Further N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.096 g), tris-(dibenzylidene-acetone)dipalladium (0) (0.006 g) and tri-tert-butylphosphonium tetrafluoroborate (0.004 g) were added and heating was continued for a further 17 hours. After cooling, the mixture was diluted with ethyl acetate and washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20% to give tert-butyl (R)-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (0.017 g) as a light brown foam.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][N:16]([CH:18](OC)OC)[CH3:17]>>[CH3:15][N:16]([CH:18]=[C:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Product: CN(C)C=C1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a stirred mixture of tert-butyl 3-oxopiperidine-1-carboxylate (1 g, 5 mmol) was added DMF-DMA (2 mL). The mixture was stirred at 100° C. for 2 hours. The mixture was concentrated by vacuum and the residue was directly for the next step (1.20 g, yield: 94%).
Reaction SMILES: C([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[CH:17][N:16](C)[N:15]=2)[CH:10]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)C1C=CC=CC=1.[CH3:27]O>[Pd]>[OH:8][CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH3:27])[CH:17]=[N:16][N:15]=2)[CH:10]1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1
Reactant: Cn1cnc(C2CCC(OCc3ccccc3)C2c2ccc(F)cc2)n1
Reactant: CO
Agent: [Pd]
Product: Cn1cnnc1C1CCC(O)C1c1ccc(F)cc1

Procedure:
A solution of 275 mg of product from Step C in 5 mL of methanol and 0.5 mL of TTA was stirred with 100 mg of 10% Pd/C under a hydrogen balloon for 60 h. The reaction was filtered and concentrated. The residue was purified by flash chromatography eluting with 5 to 10% methanol in methylene chloride to obtain 220 mg of title compound. T.l.c. (5% methanol in methylene chloride) Rf =0.25. Mass spec (NH3 /CI): 262 (M+1).
Reaction SMILES: Br[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[CH:8]=[O:9].C(=O)([O-])O.[Na+].[ClH:15]>>[Cl:15][C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[CH:8]=[O:9]
Reactant: Cc1nc(C=O)c(Br)[nH]1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(C=O)c(Cl)[nH]1

Procedure:
5-Bromo-2-methylimidazole-4-carbaldehyde (400 mg) was dissolved in conc. hydrochloric acid (6 ml), and the mixture was refluxed under heating for 24 hr. Saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling until the mixture assumed weak alkalinity and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. Hexane was added to the residue and the crystals were collected by filtration to give 5-chloro-2-methylimidazole-4-carbaldehyde (222 mg) as yellow crystals.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][OH:8].[C:9]1(=[O:19])[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.OS(O)(=O)=O>O>[CH:17]1[CH:18]=[C:10]([C:9]([OH:14])=[O:19])[C:11]([C:12]([O:7][OH:8])=[O:13])=[CH:15][CH:16]=1
Reactant: OO
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1C(=O)OO
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
Deionized water (125 ml), Na2CO3 (31.0 g, 0.25 mol) and 35% H2O2 (29.15 g, 0.3 mol) are successively charged in a 500 ml four-neck flask, and the mixture was stirred in a dry ice-methanol bath at −5° C.–0° C. Thereto was added phthalic anhydride (37.0 g, 0.25 mol) and the mixture was stirred for 30 min. The bath was removed, ethyl acetate (100 ml) was added to the mixture, and the reaction system was neutralized in a solution obtained by diluting 98% H2SO4 (15 ml) with deionized water (50 ml). After partitioning, the aqueous layer was extracted with ethyl acetate (60 ml). The obtained organic layer (0.64 g) was taken up and saturated NaI-IPA (isopropyl alcohol) solution (5 ml) and 10% acetic acid-IPA solution (20 ml) were added thereto. The mixture was boiled for 5 min. It was titrated with 0.1N aqueous sodium thiosulfate solution. As a result, mono-perphthalic acid was present in 33.5 g and the yield was 76.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18](Br)[CH3:19].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH2:18][CH3:19])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CS)cc1
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
4-chloro-4'-mercaptomethylbenzophenone (16.0 g), ethyl bromide (7.4 g) and potassium hydroxide (4.3 g) were added to methanol (250 ml), and the mixture was stirred for 30 minutes under reflux. The reaction mixture was cooled to room temperature and then concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain the desired product 14.0 g, melting point: 33° to 34° C., yield: 79%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[F:13][C:14]([F:21])([F:20])[C:15](B(O)O)=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:12][C:4]1[CH:3]=[C:2]([C:15]([C:14]([F:21])([F:20])[F:13])=[CH2:16])[CH:7]=[C:6]([CH3:8])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C=C(B(O)O)C(F)(F)F
Reactant: Cc1cc(Br)cc(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(C)c([N+](=O)[O-])c(C)c1)C(F)(F)F
Temperature: 25 °C
Yield: 105.1 %

Procedure:
5-bromo-1,3-dimethyl-2-nitrobenzene (10.0 g), [1-(trifluoromethyl)vinyl]boronic acid (purity: 60%, 13.4 g) and potassium carbonate (14.4 g) was dissolved in the mixed solvent of THF and water, which was then degassed three times. To the solution was added dichloro bis(triphenylphosphine) palladium (II) (1.5 g), and the mixture was heated to reflux for 3 hours under argon atmosphere. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 1,3-dimethyl-2-nitro-5-[1-(trifluoromethyl)vinyl]benzene (11.2 g). 1H-NMR (CDCl3) δ: 2.34 (6H, s), 5.78-5.80 (1H, m), 6.03-6.04 (1H, m), 7.20 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[CH:15]=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.C1C(=O)N([I:25])C(=O)C1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([I:25])=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ccc2n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(I)c2n1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridine (700 mg, 3.04 mmol) in THF (25 mL) was treated with n-iodosuccinimide (753 mg, 3.34 mmol, Alfa-Aesar). The reaction was stirred at 23° C. under N2. After 30 min, the solution was diluted with EtOAc (250 ml) and washed with brine (175 ml), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 15-40% EtOAc/hexane), affording 5-(2,6-difluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (255 mg, 78%). MS (ESI, pos. ion) m/z: 356.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([C:32]1[CH:48]=[CH:47][C:35]([C:36]([O:38][CH2:39][CH2:40][CH2:41][CH:42]2[O:46][CH2:45][CH2:44][O:43]2)=[O:37])=[CH:34][CH:33]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:30][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH2:40][CH2:41][CH:42]3[O:43][CH2:44][CH2:45][O:46]3)=[O:37])=[CH:47][CH:48]=2)[CH2:21][CH2:22]1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(C(=O)OCCCC2OCCO2)cc1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCN(Cc3ccc(C(=O)OCCCC4OCCO4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a stirred solution of tert-butyl(phenyl(3-(piperidin-4-ylmethoxy)phenyl)-methyl)carbamate (0.335 g, 0.84 mmol) and 3-(1,3-dioxolan-2-yl)propyl 4-formylbenzoate (0.706 g, 2.67 mmol) in DCM (5 mL), was added sodium triacetoxyborohydride (0.213 g, 1.01 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. The organic phase was dried with anhydrous magnesium sulfate, and the solvent evaporated at reduced pressure. The residue was triturated with iso-hexane/diethyl ether (3:1) to afford the title compound (0.286 g, 0.44 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].O>CN(C)C=O>[CH2:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 13 h
Yield: 65.5 %

Procedure:
In an argon atmosphere, 5-nitrosalicylaldehyde (334 mg, 2.00 mmol) was dissolved in dimethyformamide (5 mL), and the solution was mixed with benzyl bromide (0.238 mL, 2.00 mmol) and sodium hydride (88 mg, 2.4 mmol), followed by stirring at 70° C. for 13 hours. The reaction solution was cooled with ice, and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether to obtain 2-benzyloxy-5-nitrobenzaldehyde (337 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH:18]([O:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH2:34][O:35][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:15]=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[Na]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH:18]([O:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH2:34][OH:35])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:15]=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(OCCn2ccnc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Agent: [Na]
Solvent: CO
Product: O=C(O)c1ccc(C(OCCn2ccnc2CO)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Yield: 83 %

Procedure:
Methyl 2-(4-fluorophenyl)4-{1-(4-fluorophenyl)-2-[2-(tert-butyldiphenylsilyloxymethyl)imidazol-1-yl]ethoxymethyl}benzoate (4 g; 5.58 mmol) in methanol (50 ml) was treated with 2N aqueous sodium hydroxyde solution (5 ml; 11.1 mmol) at 80° C. for 7 hours. After evaporation of the methanol, the residue was taken up in water, the pH adjusted to with 6N HCl and extracted with dichloromethane/ethanol (95/5) to give 2-(4-fluorophenyl)-4-[1-(4-fluorophenyl)-2-(2-hydroxymethylimidazol-1-yl)ethoxymethyl]benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccn(-c5ccc(F)c(F)c5)n4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccn(-c2ccc(F)c(F)c2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 16 h
Yield: 61.3 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(1-(3,4-difluorophenyl)-1H-pyrazol-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.067 g, 0.121 mmol) in 3:1 THF/MeOH (1 ml) was added 1M sodium hydroxide (0.133 ml, 0.133 mmol), and the reaction was allowed to stir for 16 hours. The reaction was concentrated, acidified with dilute HCl, and extracted twice with EtOAc. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired product (0.039 g, 0.0742 mmol, 61.3% yield). MS (apci): m/z=526.1 (M+H).
Reaction SMILES: ClC(Cl)C.[Br:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N:13]([CH2:18][CH:19](OCC)OCC)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]=1[CH3:26].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:5][C:6]1[C:11]([CH3:12])=[C:10]2[C:9](=[CH:8][C:7]=1[CH3:26])[N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:18]=[CH:19]2
Reactant: CCOC(CN(c1cc(C)c(Br)c(C)c1)S(C)(=O)=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: Cc1cc2c(ccn2S(C)(=O)=O)c(C)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A 1 M solution of titanium(IV) chloride in dichloroethane (5.3 ml, 5.3 mmol) was added to a solution of N-(4-bromo-3,5-dimethyl-phenyl)-N-(2,2-diethoxy-ethyl)-methanesulfonamide (2.09 g, 5.3 mmol) in toluene (17 ml) at room temperature, and the mixture was heated with stirring at 100° C. for two hours. An aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5-bromo-4,6-dimethyl-1-methanesulfonyl-indole (1.28 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10](O)[C:9]2=[O:18])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1C(O)c2ccccc2N1Cc1ccc(Cl)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2ccccc2N1Cc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.8 %

Procedure:
To a solution of 345-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chloro-2-thienyl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (4.90 g, 10.3 mmol) in dichloromethane (100.0 mL) were added trifluoroacetic acid (12.9 g, 113.2 mmol) and triethylsilane (13.2 g, 113.2 mmol). The reaction mixture was stirred at ambient temperature for 4 h, then concentrated in vacuo to dryness. The gummy residue was diluted with ethyl acetate (100.0 mL), washed with water (3×100.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with diethyl ether, filtered and dried to afford 345-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one (2.90 g, 61%) as a colourless solid: mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ9.11 (s, 1H), 7.3-7.27 (m, 5H), 7.18 (dd, J=7.5, 7.5 Hz, 1H), 7.09 (d, J=3.8 Hz, 1H), 7.06 (dd, J=7.9 Hz, 1H), 6.97-6.86 (m, 3H), 6.79-6.68 (m, 3H), 5.04 (ABq, 2H), 4.91 (s, 2H), 4.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ175.9, 151.5, 149.7, 142.8, 138.8, 137.8, 130.2, 128.8, 128.2, 128.1, 128.1, 128.0, 127.4, 126.8, 125.2, 124.2, 122.7, 117.6, 117.6, 116.3, 114.9, 109.1, 70.2, 48.1, 38.6; MS (ES+) m/z 464.3 (M+1), 462.3 (M+1).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]=[CH:23]2>N1C=CC=CC=1>[CH2:30]([O:29][CH2:28][C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[C:18]([N:17]=[C:4]1[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]1)[CH:27]=[CH:26][CH:25]=2)[CH3:31]
Reactant: CCOCc1cc2c(N)cccc2cn1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: CCOCc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Temperature: 20 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (7.2 g) is added to a solution of 5-amino-3-ethoxymethylisoquinoline (4.1 g) in pyridine (150 cc). The suspension is stirred for 24 hours at a temperature of about 20° C. The insoluble material gradually dissolves. The solution is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C. The residue is dissolved in a mixture of methylene chloride (100 cc) and N sodium hydroxide solution (100 cc). The organic phase is decanted, washed with water (50 cc), dried over magnesium sulphate and filtered and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallised from isopropyl alcohol (80 cc). (S)-3-[(3-Ethoxymethylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (5.2 g) is thus obtained in the form of a pale yellow solid melting at 88° C.