Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH3:2].[C:11](=[O:14])([O-])[O-:12].[K+].[K+].[OH-].[K+]>S([O-])([O-])(=O)=O.[Cu+2].CO>[CH2:11]1[O:14][C:6]2[CH:5]=[CH:10][C:1]([NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:2][C:7]=2[O:12]1
Reactant: CC(=O)Nc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(Nc2ccc3c(c2)OCO3)cc1
Yield: 167.1 %

Procedure:
A mixture of 90 g (0.448 mol) of 3,4-bromomethylenedioxybenzene, 50 g (0.37 mol) of acetanilide, 12 g (0.075 mol) of copper sulfate, and 80 g (0.579 mol) of potassium carbonate was reacted in the same manner as in Example 5 (2) to obtain a crude reaction product. A mixture of this crude product, 121.4 g (1.84 mol) of 85% KOH, and 200 ml of methanol was refluxed overnight and then concentrated. Water was added thereto. The resultant mixture was extracted with toluene twice. The toluene phase was washed with water three times, dried, and then concentrated. The residue was distilled under vacuum to obtain 65.91 g of N-3,4-methylenedioxyphenyl-N-phenylamine.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6]Cl)[CH3:2].[Si:8]([CH3:12])([CH3:11])(Cl)[Cl:9]>BrBr.CCOCC>[CH2:1]([S:3][CH2:4][CH2:5][CH2:6][Si:8]([Cl:9])([CH3:12])[CH3:11])[CH3:2]
Reactant: C[Si](C)(Cl)Cl
Reactant: CCSCCCCl
Agent: BrBr
Solvent: CCOCC
Product: CCSCCC[Si](C)(C)Cl

Procedure:
3-Ethylthiopropyl chloride (7.00 g, 50 mmol) was dropped slowly into Mg turnings (1.22 g, 50 mmol) activated with 2 drops of Br2 in Et2O (70 mL). After 12 h of reflux the Grignard reagent was added to Me2SiCl2 (25.8 g, 200 mmol) in diethyl ether (100 mL). After refluxing for 18 h under mechanical stirring the Mg salts were filtered off, washed with Et2O (2×25 mL), and the solvent was evaporated from the combined filtrates. The residue was fractionally distilled: 45° C./0.01 torr, 4.20 g, 42%.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][C:22]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:14][C:13]=1[O:42][CH3:43])(=[O:10])=[O:9])[CH2:5][CH2:6][CH3:7].O.C(O)(=O)C>O1CCCC1.CO.O>[CH2:4]([S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][C:22]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:14][C:13]=1[O:42][CH3:43])(=[O:9])=[O:10])[CH2:5][CH2:6][CH3:7]
Reactant: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)cc2OCc2ccc(F)cc2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)O)cc2OCc2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.9 %

Procedure:
0.4 g (1 mmol) of lithium hydroxide monohydrate is added to a solution of 0.3 g (0.5 mmol) of corresponding methyl 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-3-(4-fluorobenzyloxy)phenyl]propanoate in 10 ml of a tetrahydrofuran/methanol/water mixture (5/1/1). The reaction medium is stirred at room temperature for 15 hours, treated with water, acidified to pH 4 with acetic acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on a column of silica eluted with a 97/3 dichloromethane/methanol mixture. 0.24 g (85%) of 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-3-(4-fluorobenzyloxy)phenyl]propanoic acid is obtained in the form of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.C(OCC)(=O)C>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cn1
Temperature: 80 °C
Yield: 85.7 %

Procedure:
5-Bromo-2-nitropyridine (5.6 g, 27.6 mmol), tetra-n-butyl ammonium iodide (0.510 g, 1.38 mmol), piperidine (2.58 g, 30.3 mmol) and potassium carbonate (3.85 g, 30.3 mmol) were mixed in DMSO (50 mL). The reaction mixture was warmed to 80° C. for 4 hours. The reaction mixture was diluted with ethyl acetate and filtered. The volume was reduced to remove ethyl acetate, the remaining solution was diluted with water (50 mL). A precipitate immediately formed and was collected by filtration and washed on the funnel with water to provide 6′-nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl as an orange-brown solid (4.90 g, 85.7%). 1H NMR δ (400 MHz, CDCl3) 7.76 (s, 1H), 7.15 (d, J=7.3 Hz, 1H), 6.49 (d, J=8.5 Hz, 1H), 3.84 (m, 5H), 3.00 (m, 4H), 2.60 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][CH3:18].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([N:17]([CH3:18])[CH3:16])=[O:15])[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-O-methyl-L-serine (2.00 g), 50% aqueous dimethylamine solution (0.987 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (2.36 g) in DMF (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.82 g) under ice-cooling. The reaction mixture was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (2.08 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][NH:15][C:16]([C:18]2[CH:19]=[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]3[C:26]=2[NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][NH:15][C:16]([C:18]2[CH:19]=[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]3[C:26]=2[NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[O:17])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(ONC(=O)c2cc3ccncn3c2Nc2ccc(I)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NOC1CCNCC1)c1cc2ccncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
4-{[7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carbonyl]-aminooxy}-piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.30 mmol) was dissolved in hydrochloric acid in dioxane (1 mL, 4M). The reaction was stirred at room temperature for 30 minutes then concentrated in vacuo. The resultant residue was subject to reverse phase HPLC (gradient 10-60% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The product was dissolved in ethyl acetate (5 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow solid (37 mg, 25%). 1H NMR (DMSO-d6): 8.73 (1H, s), 7.92 (1H, s), 7.49 (1H, dd, J=10.98, 1.92 Hz), 7.41-7.38 (2H, m), 7.16-7.13 (1H, m), 6.72 (1H, d, J=0.92 Hz), 5.93 (1H, t, J=8.84 Hz), 3.72-3.62 (1H, m), 2.87 (2H, dt, J=12.72, 4.49 Hz), 2.41-2.31 (2H, m), 1.67 (2H, dt, J=12.84, 4.01 Hz), 1.32-1.21 (2H, m). LCMS (Method A): RT=6.17 min, M+H+=496.
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.P(Cl)(Cl)([Cl:22])=O>C(#N)C.O1CCOCC1>[Cl:22][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: N#Cc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1

Procedure:
4-(4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile (2.36 g, 0.01 mol) are suspended in 40 ml acetonitril and 4.99 ml (0.02 mol) 4 N hydrochloric acid solution in dioxane. After addition of 3.66 ml (0.04 mol) phosphorus oxichloride the mixture is heated under reflux for 3 days. The solid is filtered off and the mother liquor evaporated. The residue and the solid are dissolved in 30 ml DMF at 60° C. and 25 ml of a conc. sodium bicarbonate solution and 25 ml water are added and the resulting suspension cooled, filtered and the solid washed with water. The title compound is dried at 100° C. for 6 h under reduced pressure; m.p. 296-297° C.; HPLC tR=11.59 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=3[CH:11]=2)=[O:8])=[CH:5][CH:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=3[CH:11]=2)=[O:8])=[CH:24][CH:25]=1)=[O:1]
Reactant: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccc(CO)cc3)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccc(C=O)cc3)ccc21
Yield: 95.8 %

Procedure:
A solution of the above alcohol (1.891 g, 5.61 mmol) in dichloromethane (35 ml) was added with manganese dioxide (3.905 g, 44.9 mmol), and the mixture was refluxed by heating for 2 hours with stirring. The reaction mixture was filtered through Cerite under reduced pressure, and Cerite was washed with chloroform. The solvent was evaporated, and then the residue was recrystallized to obtain the title compound (1.802 g, 96%) as colorless prisms.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:6]=1[O:27][CH3:28])C.CS(O[CH2:35][CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)(=O)=O>>[CH3:28][O:27][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:35][CH2:36][C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:5]=1[C:4]([OH:3])=[O:29]
Reactant: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC
Reactant: CS(=O)(=O)OCCc1cccs1
Product: COc1ccc(CN2CCC(c3cn(CCc4cccs4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.07 g (0.18 mmol) of 5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid ethyl ester and 0.05 g (0.25 mmol) of 2-thiophen-2-yl-ethyl methansulfonate. After the standard purification, 0.009 g (10% of yield) of the expected acid was obtained.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[CH2:21]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:33]2[CH2:34][CH2:35][N:30]([CH2:21][CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: C(=Cc1ccccc1)CN1CCNCC1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Product: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CC=Cc3ccccc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.81 g of cinnamylpiperazine (Example 27), yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[3-phenylprop-2-enyl]piperazine. The hydrochloride thereof melts at 188°-190°.
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]2[S:21][C:20]3[C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1.[F:35][C:36]1[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[C:38](I)[CH:37]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.C(O)(C)C>[F:1][C:2]1[C:3]([C:17]2[S:21][C:20]3[C:22]([C:38]4[C:39]([CH2:42][OH:43])=[CH:40][N:41]=[C:36]([F:35])[CH:37]=4)=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1
Reactant: OCc1cnc(F)cc1I
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCN5CCNC5=O)ncc4F)sc23)OC1(C)C
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C1NCCN1CCNc1ncc(F)c(-c2cc3cccc(-c4cc(F)ncc4CO)c3s2)n1
Temperature: 100 °C
Yield: 20.7 %

Procedure:
Combine 1-(2-{5-fluoro-4-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-2-yl]-pyrimidin-2-ylamino}-ethyl)-imidazolidin-2-one (120 mg, 0.25 mmol), (6-fluoro-4-iodo-pyridin-3-yl)-methanol (100 mg; 0.32 mmol), (1,1′-bis(di-phenylphosphino)ferrocene)palladium(II) chloride (10.14 mg; 0.01 mmol), 2-(di-tert-butylphosphino)biphenyl (2 mg, 0.01 mmol) and sodium carbonate (2 M, 0.2 mL, 0.4 mmol) in 5 mL of dioxane in a pressure tube. Heat the mixture at 100° C. overnight in oil bath. Cool the mixture down to room temperature, dilute it with chloroform-isopropyl alcohol (3/1). Wash the organic phase with saturated aqueous sodium chloride, dry it over sodium sulfate and concentrate it to an oily residue. Purify the crude by flash column chromatography (10% methanol in dichloromethane) to afford the title compound (25 mg, 21%). MS (ES) m/z 483 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.B(F)(F)F.CCOCC.[CH2:27]([O:34][CH:35]1[CH2:41][CH2:40][CH:39]2[CH:37]([O:38]2)[CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>C1COCC1>[CH2:27]([O:34][CH:35]1[CH2:41][CH2:40][CH:39]([OH:38])[CH:37]([C:2]2[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: c1ccc(COC2CCC3OC3C2)cc1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1CCC(OCc2ccccc2)CC1c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A solution of 5-bromo-2-chloro-1-trifluoromethyl-benzene (1.09 mL, 7.34 mmol) in THF (20 mL) was stirred at −78° C. and treated with n-butyllithium (1.6 M in hexane, 4.59 mL, 7.34 mmol). The resulting solution was stirred at −78° C. for 30 min and then treated with boron trifluoride etherate (924 μL, 7.34 mmol). After stirring for an additional 10 min, a solution of (1RS,3RS,6SR)-3-(benzyloxy)-7-oxa-bicyclo[4.1.0]heptane (prepared according to the procedure of Chini et al., J. Org. Chem. 1990, 55, 4265; 1.00 g, 4.90 mmol) in THF (4.0 mL) was added over a 5 min period. Upon completion of addition, the mixture was stirred at −78° C. for 70 min and then poured into saturated aqueous ammonium chloride. This mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 20-60% ethyl acetate-hexanes, to provide (1SR,2RS,4RS)-4-(benzyloxy)-2-(4-chloro-3-(trifluoro-methyl)phenyl)cyclohexanol as a colorless gum (958 mg, 51%). 1H NMR (400 MHz, CDCl3) δ 1.40 (bd, J=3.6 Hz, 1 H) 1.50-1.64 (m, 2 H) 1.82-1.97 (m, 2 H) 2.05-2.12 (m, 1 H) 2.12-2.20 (m, 1 H) 2.95-3.05 (m, 1 H) 3.65-3.74 (m, 1 H) 3.74-3.80 (m, 1 H) 4.54 (ab, J=12.2 Hz, 2 H) 7.27-7.40 (m, 6 H) 7.45 (d, J=8.7 Hz, 1 H) 7.55 (d, J=2.0 Hz, 1 H).
Reaction SMILES: C(OC[C:10]1(C)[C:15]2([CH2:17][CH2:16]2)[S:14](=[O:19])(=[O:18])[N:13]=[C:12]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[O:11]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH:21]1([NH:20][C:12]2[O:11][CH:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3([CH2:17][CH2:16]3)[S:14](=[O:19])(=[O:18])[N:13]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(COCc2ccccc2)OC(NC2CCCCC2)=NS(=O)(=O)C12CC2
Agent: [Pd]
Solvent: CCO
Product: O=S1(=O)N=C(NC2CCCCC2)OC(c2ccccc2)C12CC2
Reaction time: 16 h
Yield: 93.9 %

Procedure:
Under inert gas, 80 mg of (8-benzyloxymethyl-8-methyl-4,4-dioxo-7-oxa-4lambda6-thia-5-azaspiro[2.5]oct-5-en-6-yl)cyclohexylamine were initially charged in 6 ml of ethanol and, with addition of 5 mg of 5% Pd/C, stirred under a hydrogen atmosphere for 16 hours. The completeness of the conversion was checked by LCMS and the reaction was once again admixed with 5 mg of 5% Pd/C, and the mixture was stirred under a hydrogen atmosphere for a further 2 hours. After filtration to remove the solid residues, the filtrate was freed of the solvent under reduced pressure. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation, then taken up again in 10 ml of a mixture of acetonitrile and water (9:1) and lyophilized. This gave the product (32 mg) with a molecular weight of 302.4 g/mol (C13H22N2O4S); MS (ESI): m/e=303 (M+H+).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:29]=[CH:28][N:13]([C@@H:14]2[O:27][C@H:24]([CH2:25][OH:26])[C@@H:22]([OH:23])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12](=[O:30])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[C:34]([O:53][CH3:54])=[C:35]([CH:50]=[CH:51][CH:52]=1)[C:36](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([NH:9][C:10]1[CH:29]=[CH:28][N:13]([C@@H:14]2[O:27][C@H:24]([CH2:25][O:26][C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:35]3[CH:50]=[CH:51][CH:52]=[C:33]([O:32][CH3:31])[C:34]=3[O:53][CH3:54])[C@@H:22]([OH:23])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12](=[O:30])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 69.5 %

Procedure:
N4-Benzoyl-2'-O-pentylcytidine (3.0 g, 0.007 mol) was treated with dimethoxytrityl chloride (2.7 g, 1.1 eq) as per the procedure of Example 72 to give 3.5 g of pure product. Anal. Calcd. for C42H45N3O8.1/2H2O: C, 69.21; H, 6.36; N, 5.76. Found: C, 69.51; H, 6.30; N. 5.71.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)([OH:8])[CH2:5][O:6][CH3:7].C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)([OH:8])[CH2:5][O:6][CH3:7])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: COCC(O)(CCN)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(O)(CCNC(=O)CCl)c1ccc(Cl)c(Cl)c1
Reaction time: 0.33 h

Procedure:
To a solution of (2RS)-4-amino-2-(3,4-dichlorophenyl)-1-methoxybutan-2-ol (3.00 g) and triethylamine (1.60 mL) in THF (50 mL) was added dropwise chloroacetyl chloride (0.91 ml) under ice-cooling, and the mixture was stirred for 20 min. The reaction mixture was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-100%)) to give the title compound (2.13 g).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:32].[Cl:33]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([F:32])=[CH:4][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:26])([CH3:27])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:28])(=[O:29])[CH2:8]2)=[CH:30][C:31]=1[Cl:33]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc(N)c(F)c4)CS(=O)(=O)C[C@@H]32)c1
Solvent: CC#N
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(Cl)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
A solution of (3aR,7S,7aS)-7-(4-amino-3-fluoro-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (4.0 g, 8.69 mmol, example 81) and N-chlorosuccinimide (1.276 g, 9.55 mmol) in ACN (130 mL) was heated at reflux for 2 h. The reaction mixture was evaporated and the residue was purified by chromatography (Combi Flash, 120 g silicagel, hexane-EtOAc) to provide the title compound as a colorless solid: TLC (toluene-EtOAc 3:1) Rf=0.42; UPLC RtD=1.887 min; [M+NH4]+=512, 514; 1H NMR (600 MHz, DMSO-d6): δ 7.38 (s, 1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.13 (d, 1H), 6.93 (s, 1H), 6.89 (d, 1H), 5.28 (s, 2H), 4.42 (d, 1H), 4.21 (d, 1H), 4.11 (t, 1H), 3.68 (m, 2H), 3.46 (t, 1H), 3.05 (m, 2H), 2.78 (d, 1H), 2.50 (m, 2H), 1.26 (s, 9H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:4]2[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: Oc1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(F)cc2)cc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
The compound prepared in Example 34 (4.73 g) was dissolved in DMF (40 mL), added with 4-fluorophenol (2.34 g) and potassium phosphate (5.32 g) and stirred overnight at 80° C. The reaction solution was diluted with ethyl acetate, sequentially washed with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate before distillation of the solvent. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→1:1) to give the titled compound (4.81 g) having the following physical properties.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH3:20].ClCl>B(Br)(Br)Br>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH3:20]
Reactant: CCc1cc2c(OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Agent: ClCl
Product: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 69.3 %

Procedure:
By the method used in Example 1, Part D, 911 mg (2.6 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-4-methoxy-1H-indole was O-demethylated by treating it with 10 mL of 1M BBr3 /CH2 Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 590 mg (69% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-4-hydroxy-1H-indole as an oil.