Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[F:27][C:22]1[CH:21]=[C:20]([N:4]2[C:5]3[C:10](=[C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[CH:3]2)[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: Oc1ccc(Br)cc1F
Reactant: Cc1c[nH]c2cccc(OCc3ccccc3)c12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2ccc(O)c(F)c2)c2cccc(OCc3ccccc3)c12
Temperature: 190 °C

Procedure:
To a solution of 3-methyl-4-[(phenylmethyl)oxy]-1H-indole (R. A. Heacock et al. Canadian Journal of Chemistry, (1964), 42(3), 514) (617 mg, 2.60 mmol) in N-methyl-2-pyrrolidinone (10 mL) was added 4-bromo-2-fluorophenol (0.28 mL, 2.60 mmol), copper iodide (96 mg, 0.50 mmol) and potassium carbonate (867 mg, 6.28 mmol). The reaction mixture was heated in a Biotage Initiator™ Microwave Synthesizer at 190° C. for 3 hours. The mixture was filtered through a pad of Celite which was subsequently washed with ethyl acetate. The ethyl acetate solution was washed with water and then the aqueous layer re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and then concentrated in vacuo. The product was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexane to yield the title compound (D2) (147 mg).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:16][C@@H:15]2[N:17]([CH2:18][C:19]3[NH:24][C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[N:22][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[Cl:37])[C:20]=3[C:38]([O:40][CH3:41])=[O:39])[C@@H:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][C@@H:11]2[N:17]([CH2:18][C:19]3[NH:24][C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[N:22][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[Cl:37])[C:20]=3[C:38]([O:40][CH3:41])=[O:39])[C@@H:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1
Reactant: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(NC(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(N)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
To a solution of methyl (4R)-6-[[(1S,5R)-7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 60a (300 mg, 0.49 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at 25° C. for 5 h. The mixture was concentrated in vacuo to afford methyl (4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 60b (240 mg, 96%) which was used for next step without further purification. MS: calc'd (MH+) 506, measured (MH+) 506.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH3:22])[OH:19])[CH3:9].CN(C1C=CC=CN=1)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>ClCCl.C(OCC)(=O)C>[O:35]([C:33]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][S:21][CH3:22])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])=[O:34])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC1C(OC(=O)Oc2ccccc2)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Yield: 81 %

Procedure:
In dichloromethane (2 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (200 mg) and dimethylaminopyridine (115 mg). To the solution was added, under ice-cooling, phenyl chloroformate (95 μl ), and the mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (70 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane=1:4) to afford 4-O-phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (222mg: yield 81%) as a colorless oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:16])=[N:6][CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)cn1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a stirred solution of 5-bromo-2-methylpyridine (1.2 g, 4.78 mmole), in dry CCl4 (150 mL) at RT was added NBS (1.02 g, 5.73 mmole) and benzoylperoxide (0.12 g, 0.48 mmole). After 18 h at reflux, the reaction contents were cooled to RT and filtered through a scintered-glass funnel washing with CHCl3. Concentration under vacuum and purification on silica (EtOAc) afforded the title compound (1.12 g, 71%) as light yellow solid: (EtOAc): LC-MS (ES) m/e 330 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH:15](Cl)(Cl)Cl.CO>CO.OS(O)(=O)=O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc2cc(O)ccc2c1

Procedure:
6-Hydroxy-2-naphthoic acid (5.0 g, 26.6 mmol) was dissolved in 125 mL of methanol and refluxed with 6 drops of conc. H2SO4 for 36 hours. TLC analysis (SiO2, 10:1 CHCl3 /MeOH) revealed only a trace of the acid left. The solution was cooled partially and concentrated to dryness on a rotary evaporator. The solid residue was dissolved in 200 mL of ether and washed successively with 100 mL of saturated aq. NaHCO3 and brine. Drying over MgSO4 and evaporating the solvent left 4.6 g of (85.5% ) slightly yellow solid which showed only one spot on TLC. The material is sufficiently pure for use in subsequent reactions but may be purified further by recrystallization from ether affording a white solid mp 169°-169.5° C.; 1H NMR delta 3.976 (s, 3H), 5.3 (br. s, 1H), 7.16-8.54 (m, 6H); IR (KBr) 3370, 1680, 1630, 1435, 1310, 1210 cm-1. ##STR25##
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>ClCCl.N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][C:6]=1[C:7]([Cl:25])=[O:8])(=[O:3])[CH3:2]
Reactant: CCCCCCCC(=O)c1ccc(OC(C)=O)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)c1ccc(OC(C)=O)c(C(=O)Cl)c1
Temperature: 35 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
5.5 g (18 mmol) of 2-acetyloxy-5-octanoylbenzoic acid are dissolved in 55 ml of dichloromethane with one drop of pyridine. 1.6 ml (21.5 mmol) of thionyl chloride are added dropwise and the mixture is stirred at 35° C. for 18 hours and then concentrated to dryness. 5.6 g of 2-acetoxy-5-octanoylbenzoyl chloride are obtained in the form of a red oil in a yield of 96%.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:7])[CH2:5][CH2:4][N:3]=[CH:2]1>ClCCl>[C:8]1([C:6]([N:1]2[CH2:5][CH2:4][N:3]=[CH:2]2)=[O:7])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC(c1ccccc1)N1C=NCC1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1C=NCC1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A suspension of 2-imidazolinyl-phenylmethanol (5.0 g.) in dichloromethane (250 ml.) was stirred at room temperature with deactivated precipitated manganese dioxide (50 g.) for 60 hrs. The product was isolated as in Example 1 and the residue crystallised from benzene/petroleum to yield the title compound as colourless prisms (3.15 g.), m.p. 141°-143°C. [Found C, 68.9; H, 5.8; N, 16.1%--C10H10N2O-- requires C, 68.9; H, 5,8; N, 16.05%].
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:42])[C:17]([O:20][C:21]1[CH:41]=[CH:40][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=3)[C:28]([CH3:38])=[C:27]2[CH3:39])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:24]2[CH:40]=[CH:41][C:21]([O:20][C:17]([CH3:19])([CH3:18])[C:16]([O:15][CH3:14])=[O:42])=[CH:22][CH:23]=2)[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)C(C)(C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)C(C)(C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Mg].BrCCBr.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[Cl-].[NH4+]>C(OCC)C>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][C:16]2([OH:15])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)=[CH:9][CH:8]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.4 %

Procedure:
To a suspension of magnesium (2.9 g) in diethyl ether (50 mL) was added dropwise 1,2-dibromoethane (0.90 mL) at room temperature, and the reaction mixture was vigorously stirred at room temperature for 20 min. To the reaction mixture was added dropwise a solution of 4-bromobenzyl bromide (25 g) in diethyl ether (150 mL) over 30 min or more at 0° C., and then added dropwise a solution of tert-butyl 4-oxopiperidine-1-carboxylate (16 g) in diethyl ether (200 mL) over 30 min or more 0° C. The reaction mixture was allowed to warm to room temperature, and stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution (200 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[O:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
A mixture of methyl(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)acetate (151) (1.00 g, 3.52 mmol) and AlCl3 (1.90 g, 14.07 mmol) were refluxed in benzene (40 mL) for 1 h and then cooled to 0° C. in an ice bath. Water (35 mL) was added slowly, and the mixture was extracted with ether (2×50 mL, each contained 15 mL of EtOAc). The combined ethereal extract washed with water, brine, and dried over Na2SO4. Concentration gave light brown oil, which was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc:hexanes to afford 0.86 g (90%) of compound 152 as colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 2H), 3.72 (s, 3H), 5.63 (br s, 1H), 6.89 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 8.24 (d, J=7.9 Hz, 1H). LCMS (ESI): m/z 271 (M+H)+, 269 (M−H)−.
Reaction SMILES: C=O.Cl.CON=C[C@H:8]([F:33])[C@H:9]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C@@H:10]([Br:22])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[C:34](=O)([O-])[OH:35].[Na+]>CC(C)=O.C(OCC)(=O)C>[Br:22][C@@H:10]([CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C@@H:9]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C@H:8]([F:33])[CH:34]=[O:35]
Reactant: CON=C[C@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](Br)COCc1ccc(OC)cc1
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(COC[C@H](Br)[C@@H](OCc2ccc(OC)cc2)[C@H](F)C=O)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
4.2 mL of a 35% formaldehyde solution and 4.2 mL of 2 mol/L hydrochloric acid were added to a solution of 857 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 17 mL of acetone at room temperature, and the obtained mixture was then stirred at room temperature for 1.75 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 598 mg of colorless oily (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal and a water adduct thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)C>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:22][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)N
Reactant: CN(C)C(=O)Nc1ccc(OCC2CO2)c(Cl)c1
Solvent: CCO
Product: CC(C)NCC(O)COc1ccc(NC(=O)N(C)C)cc1Cl
Reaction time: 4 h

Procedure:
A solution of 40 g of 1-[o-chloro-p-(N',N'-dimethyl-ureido)-phenoxy]-2,3-epoxy-propane and 40 g of isopropylamine in 40 ml of ethanol is heated to boiling for 4 hours. Thereafter the mixture is concentrated by evaporation in vacuo and the residue is dissolved in 2 N hydrochloric acid. After extraction with ether, the hydrochloric acid layer is separated off and rendered alkaline by adding concentrated sodium hydroxide solution. The base which has separated out is extracted by shaking with methylene chloride. After evaporation of the solvent and after recrystallisation of the residue from ethyl acetate, the 1-[o-chloro-p-(N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of formula ##STR18## is obtained in crystals of melting point 130° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[N:10]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2>C1(C)C=CC=CC=1.CO>[Br:8][C:9]1[N:10]([CH2:28][CH2:29][C:30]([O:32][CH3:1])=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCC(=O)O)c2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
1.6 eq of (Trimethylsilyl)diazomethane (2 M solution in hexanes) was added dropwise to a solution of 3-[2-bromo-3-cyclohexyl-6-(methoxycarbonyl)-1H-indol-1-yl]propanoic acid in a mixture toluene:MeOH (7:3; 0.2 M) and the solution stirred at RT for 1 h. Excess trimethylsilyl diazomethane was quenched with acetic acid and then the solution was concentrated in vacuo. The crude was purified by flash chromatography (Biotage cartridge Si40S, 1:9 EtOAc/PE) to afford the title compound (63% over two steps); MS (ES+) m/z 422 (M+H)+, m/z 424 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([F:4])[F:3].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].N1C=CC=CC=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:2]([F:4])([F:3])[F:1])[CH3:20]
Reactant: CCOC(=O)CC#N
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C#N)=C(c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of trifluoromethylphenylketone [C.A.S. 434-45-7] (5 g, 28.71 mmol) and ethyl cyanoacetate [C.A.S. 105-56-6] (3.61 mL, 31.58 mmol) in DCM (100 mL) was flushed with nitrogen, then cooled to 0° C. and maintained under a nitrogen atmosphere. Neat titanium(IV) chloride (6.79 mL, 60.30 mmol) was added dropwise, the reaction mixture was stirred for 10 min at 0° C. and then pyridine (1.5 mL) was added dropwise. When the addition was complete, the ice bath was removed, the reaction reaction was stirred for 30 min at r.t., additional pyridine was added (5 mL) and the reaction mixture was stirred for a further 20 h at r.t. The mixture was then diluted in DCM (100 mL) and washed with HCl 2N (2×200 mL), water (300 mL) and brine (100 mL). The organic phase was evaporated to yield intermediate compound D42 (4.8 g, 61%) as a mixture of E/Z isomers, as a colourless oil which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]Cl)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21](=[O:34])[CH2:22][C@@H:23]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:24]#[C:25][CH3:26].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:19][O:20][C:21](=[O:34])[CH2:22][C@@H:23]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:12][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=3)[CH:16]=[CH:15][CH:14]=2)=[CH:31][CH:32]=1)[C:24]#[C:25][CH3:26]
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Benzyl chloride 2.3 (28.0 g, 103 mmol) and phenol 1 (21.5 g, 98 mmol) were dissolved in acetone (150 mL) and treated with Cs2CO3 (39.9 g, 122 mmol). The reaction was stirred at 50° C. for 16 h then filtered and concentrated to an pale yellow oil which was purified by column chromatography (silica gel, 33% to 66% dichloromethane in hexanes). Eluant containing compound 2.4 was concentrated to a colorless oil (40.0 g, 92%).
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([O:10][C@@H:11]([C:17]1[C:26]([CH:27]=O)=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOC(C)=O>[C:6]([O:10][C@@H:11]([C:17]1[C:26]([CH:27]=[CH2:2])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:7])([CH3:8])[CH3:9]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C=O)cc2ccccc2c1-c1ccc(Cl)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (60 mg, 0.168 mmol) in THF (1 mL) at −78° C. was added dropwise n-BuLi (1.6 M in hexanes, 90 μL), followed after 30 min by a solution of (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate (12 mg, 0.028 mmol) in THF (1 mL). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. This mixture was added to another mixture, which was made by adding n-BuLi (1.6 M in hexanes, 300 μL) to a suspension of methyltriphenylphosphonium bromide (200 mg, 0.56 mmol) in THF (2 mL) and stirred at −78° C. for 15 min. Then the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with sat. NH4Cl, and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 7.4 mg of the desired product. 1H-MNR 400 MHz (CDCl3) δ: 7.95 (s, 1H), 7.78 (d, J=4.2 Hz, 1H), 7.57-7.50 (m, 1H), 7.43-7.17 (m, 6H), 5.62 (dd, J=8.1, 2 Hz, 1H), 5.25 (dd, J=5.3, 1.8 Hz, 1H), 5.07 (s, 1H), 4.06-4.02 (m, 2H), 1.10 (t, J=7 Hz, 3H), 0.93 (s, 9H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])[N:10]=2)[N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])[N:10]=2)[N:7]=1
Reactant: CN(C)CC(=O)Nc1cn2nc(I)ccc2n1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Yield: 83.8 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-N2,N2-dimethylglycinamide (517 mg, 1.5 mmol), 3-aminophenol (491 mg, 4.5 mmol), potassium carbonate (415 mg, 3.0 mmol) and N,N-dimethylformamide (3.0 mL) was stirred using a microwave synthesizer at 180° C. for 40 min. The reaction mixture was diluted with water, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (410 mg, 84%) as a brown powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH2:34]([C:36]1[S:40][C:39]([C:41](Cl)=O)=[CH:38][CH:37]=1)[CH3:35]>>[CH2:34]([C:36]1[S:40][C:39]([CH2:41][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:38][CH:37]=1)[CH3:35]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(C(=O)Cl)s1
Product: CCc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(F)c23)s1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 5-ethylthiophen-2-carbonyl chloride were treated in a manner similar to Example 2-(4), (5), (6) and (7) to give the titled compound as a colorless powder. APCI-Mass m/Z 439 (M+NH4). 1H-NMR (DMSO-d6) δ 1.17 (t, J=7.5 Hz, 3H), 2.69 (q, J=7.5 Hz, 2H), 3.20-3.48 (m, 4H), 3.67 (m, 2H), 4.20 (s, 2H), 4.53 (br, 1H), 5.08 (br, 1H), 5.20 (br, 2H), 5.38 (d, J=9.2 Hz, 1H), 6.60 (d, J=3.3 Hz, 1H), 6.65 (d, J=3.2 Hz, 1H), 6.77 (dd, J=11.1, 7.8 Hz, 1H), 7.09 (m, 1H), 7.31 (s, 1H), 7.39 (d, J=8.3 Hz, 1H).