Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[O:4]C(C(OC)=O)C(OC)=O.Cl.[C:21]([NH2:24])(=[NH:23])[CH3:22]>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[O:4][N:23]1[C:3](=[O:4])[CH:14]=[C:15]([OH:18])[N:24]=[C:21]1[CH3:22]
Reactant: COC(=O)C(Oc1cc(OC)ccc1Cl)C(=O)OC
Reactant: CC(=N)N
Agent: Cl
Product: COc1ccc(Cl)c(On2c(C)nc(O)cc2=O)c1

Procedure:
In analogy to Example 1, paragraph d), dimethyl (2-chloro-5-methoxy-phenoxy)malonate was condensed with acetamidine hydrochloride to give (2-chloro-5-methoxy-phenoxy)-2-methyl-6-hydroxy-4(3H)-pyrimidinone. Therefrom in analogy to Example 1, paragraph e), there was obtained 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-2-methyl-pyrimidine, m.p. 125°-130° C., and therefrom in analogy to Example 1, paragraph f), there was obtained 4-tert-butyl-N-[6-chloro-5-(2-chloro-5-methoxyphenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulfonamide, m.p. 182° C. (from MeOH).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:8]=1
Reactant: C[O+](C)C
Reactant: COC(=O)c1ccccc1CCC1CCCCC(=O)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1CCC1CCCCC(OC)=N1

Procedure:
The product of Example 82 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)([CH:11]([CH3:13])[CH3:12])C(OCC)=O)C.[OH-].[Na+].S(=O)(=O)(O)O>CS(C)=O>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH:5]([CH:11]([CH3:13])[CH3:12])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(C(=O)OCC)(c1ccco1)C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)C(C(=O)O)c1ccco1
Yield: 98.2 %

Procedure:
240.6 g (0.9 mol) of 2-furyl-2-isopropylmalonic acid diethyl ester were dissolved in 500 ml of dimethyl sulfoxide, treated with 2000 ml of 2N sodium hydroxide solution and heated to reflux for 2 hours. After cooling, o the reaction mixture was poured into dilute sulfuric acid and extracted exhaustively with ether. The organic extracts were thereafter dried and the solvent was evaporated under reduced pressure, to obtain 148.7 g (98%) of (±) 2-(2-furyl)-3-methyl- butyric acid in the form of a thick yellowish oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C@H:10]([CH3:18])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[CH2:1]([N:8]1[CH2:13][C@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C@H:10]([CH3:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1O[C@@H](C(F)(F)F)CN(Cc2ccccc2)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one (4-4) was added 1M LAH (48 ml, 48.0 mmol) in THF slowly at rt. After the addition was complete the mixture was heated to reflux. After 1 hr the mixture was cooled to rt then 0° C. The mixture was slowly quenched with 2M NaOH until gas evolution had ceased and a fine white precipitate formed. Anhydrous MgSO4 was added and the mixture stirred for 15 minutes The slurry was filtered through a pad of celite washing with EtOAc then concentrated. The crude product was subjected to silica gel chromatography (120 g, 0-10% EtOAc/hexanes, 15 minute gradient) to give a afford (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholine (4-5, 4.1 g, 66% over 3 steps) as clear oil. 1H NMR (400 MHz, CDCl3): δ 7.35-7.26 (m, 5H); 4.02 (dqd, J=10.7, 6.4, 2.5 Hz, 1H); 3.76-3.69 (m, 1H); 3.60-3.48 (m, 2H); 2.89 (d, J=11.1 Hz, 1H); 2.73-2.68 (m, 1H); 2.16-2.04 (m, 1H); 1.91-1.79 (m, 1H); 1.19 (d, J=6.3 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][N:20]=2)[CH2:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[N:20]=[CH:21][C:22]([C:3]3[C:4]4[C:9](=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:23][N:24]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=Cc1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CN1CCN(c2ncc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1
Temperature: 125 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 1H-indazole-6-carbaldehyde (50 mg, 0.18 mmol), 2-(4-Methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (70 mg, 0.22 mmol), Pd(PPh3)4 (13 mg, 0.018 mmol) and 2M Na2CO3 (0.10 mL, 0.22 mmol) in DME/H2O/EtOH (1.4 mL/0.4 mL/0.2 mL) was sealed and heated with stirring under microwave irradiation at 125° C. for 120 min. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using MeOH (5% to 10%) in DCM as the eluent to provide the title compound as a pale yellow solid (47 mg, 80%). 1H NMR (400 MHz, CD3OD) δ ppm 10.12 (s, 1H), 8.91 (s, 2H), 8.14 (s, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 3.94 (t, J=4.5 Hz, 4H), 2.56 (t, J=4.9 Hz, 4H), 2.37 (s, 3H); MS ESI 323.1 (100) [M+H]+, calcd for [C17H18N6O+H]+ 323.2.
Reaction SMILES: [CH2:1]1[CH:3]2[C:4](=[O:25])[CH:5]=[C:6]3[C@@:21]([CH3:22])([CH:2]12)[C@H:20]1[C@H:9]([C@H:10]2[C@:17]([CH3:23])([CH2:18][CH2:19]1)[C@@:13]([OH:24])([C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3>C1(C)C=CC=CC=1.[Pd]>[CH2:1]1[CH:3]2[C:4](=[O:25])[CH:5]=[C:6]3[C@@:21]([CH3:22])([CH:2]12)[C@H:20]1[C@H:9]([C@H:10]2[C@:17]([CH3:23])([CH2:18][CH2:19]1)[C@@:13]([OH:24])([C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)C5CC5[C@@]4(C)[C@@H]3CC[C@@]21C
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C5CC5[C@@]4(C)[C@@H]3CC[C@@]21C
Yield: 95 %

Procedure:
3.7 G of 1,2-methylene-17α-hydroxy-9β ,10α-pregna-4,6-diene-3,20-dione is added to a hydrogenation mixture of 370 mg of palladium on CaCO3 in 37 ml of toluene. After the absorption of the theoretical quantity of hydrogen the reaction mixture is filtered and the solvent is subsequently evaporated. The residue is recrystallized, yield 95% of pure 1,2-methylene-17α-hydroxy-9β ,10α-pregn-4-ene-3,20-dione.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([NH:23][C:24]1[CH:36]=[C:35]([CH:37]=[CH2:38])[CH:34]=[CH:33][C:25]=1[C:26]([O:28]C(C)(C)C)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(P([Pd+])C2CCCCC2)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:15]([NH:23][C:24]1[CH:36]=[C:35](/[CH:37]=[CH:38]/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])[CH:34]=[CH:33][C:25]=1[C:26]([OH:28])=[O:27])(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccccc1I
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Agent: [Pd+]P(C1CCCCC1)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccccc1/C=C/c1ccc(C(=O)O)c(NC(=O)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
0.031 mL of 2-iodotoluene, 81 g of cesium carbonate, 12 mg of tetrabutylammonium bromide and 19 mg of polymer supported di(acetato) dicyclohexylphosphino palladium(II) were added to 1.0 mL of toluene solution containing 40 mg of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added, the organic layer was separated, and the solvent was evaporated under reduced pressure after washed with 10% citric acid aqueous solution, 5 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 65-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 2.8 mg of 2-(benzamido)-4-((E)-2-(2-methylphenyl)vinyl)benzoic acid as while solid.
Reaction SMILES: BrBr.C[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13]C)[CH:8]=[O:9].S([O-])([O-])(=O)=S.[Na+].[Na+].[C:22](=[O:25])(O)[O-].[Na+]>C(O)(=O)C>[OH:13][C:12]1[C:5]([OH:4])=[CH:6][C:7]2[C:8](=[O:9])[CH2:10][C:11]3[CH:12]=[CH:5][CH:6]=[CH:7][C:22]=3[O:25][C:10]=2[CH:11]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(C=O)cc1OC
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2Oc2cc(O)c(O)cc21
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of bromine (0.96 g) in acetic acid (10 ml) was dropped into a solution of 3,4-dimethoxybenzaldehyde (1.0 g) in acetic acid (4 ml) and the mixture was stirred for three hours. Sodium thiosulfate was added to the reaction mixture, then sodium bicarbonate was added thereto and the mixture was filtered. The crude crystals collected by the filtration were recrystallized from chloroform-ether to give the title compound (0.83 g, 56%). The peaks of this compound in 1H-NMR (400 MHz, CDCl3) were as follows.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=O)[C:18]([C:36]([F:39])([F:38])[F:37])=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.O[N:48]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([NH2:48])=[O:28])[C:18]([C:36]([F:39])([F:37])[F:38])=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)OC(C)(C)C)c4)n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)cc2)CC1
Temperature: 35 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
tert-Butyl 3-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzoate (I21) (0.025 g, 0.046 mmol) was dissolved in dry DCM (3 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.177 mL, 2.31 mmol) was added to the solution and the reaction was stirred at 35° C. for 2 hours. The mixture was concentrated to dryness, toluene (˜2 mL) was added to the residue and the solvent was removed in vacuo to give a yellow solid. This material was dissolved in dry THF (3 mL) and dry DMF (0.2 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.009 g, 0.064 mmol) and EDCl (0.012 g, 0.064 mmol) and N,N-diisopropylethylamine (0.048 mL, 0.276 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.018 g, 0.18 mmol) was added in one portion, and the reaction was stirred room temperature for 20 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (20 mL) and saturated aq. NaHCO3 (10 mL). The layers were separated and the organic layer was washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow solid. The product was dissolved in DCM (˜4 mL) and MeOH (˜1 mL) and the solvents were removed in vacuo. The process was repeated 3 times with DCM only and to give the title compound (2) (0.017 g, 76% yield over 2 steps) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.95 (br s, 1H), 7.79 (s, 1H), 7.75-7.66 (m, 1H), 7.57-7.47 (m, 2H), 7.40-7.30 (m, 3H), 6.94-6.86 (m, 2H), 3.14-3.01 (m, 8H), 2.47-2.42 (m, 4H), 2.21 (s, 3H). LCMS Method C: rt 4.75 min; m/z 485.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:26]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Reactant: CCCCCCCBr
Product: CCCCCCCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 65.7 %

Procedure:
In a similar manner to Example 10b), by reaction of 2 g (9.3 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) benzaldehyde [prepared in Example 16(a)] with 1.1 ml (6.8 mmol) of 1-bromoheptane, 1.88 g (72%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:27])[C:15](=[O:26])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[F:25])=[CH:17][C:7]2=1)(=[O:3])[CH3:2].CC(O[CH:33](N(C)C)[N:34]([CH3:36])[CH3:35])(C)C>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[C:15](=[O:26])[N:14]([CH3:27])[C:8]3[N:9]([CH3:13])[C:10]4[C:6]([C:7]=3[CH:17]=2)=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:33][N:34]([CH3:36])[CH3:35])=[CH:12][CH:11]=4)=[C:19]([F:25])[CH:20]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3F)c(=O)n(C)c1n2C
Product: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3F)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in preparation 1.9C above, with compound B 6-acetyl-3-(4-chloro-2-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and Bredereck's reagent.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[CH:21]([O:23][C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si](C(C)(C)C)(C)C)[CH2:36]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:32])[CH:21]([O:23][C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:50])[C@@H:15]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([OH:42])[CH2:36]2)=[CH:10]1
Reactant: Cc1cccc(C)c1OC(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OC(C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 60.3 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.21 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2,6-dimethylphenoxy)propionyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 103, above] and 23.8 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.50 g of the title compound as white crystals, melting at between 85° and 88° C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]C1C=CC=CC=1.[K+].[PH2](O)=O.F[B-](F)(F)F.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]#[N:34])=[CH:29][CH:28]=1>ClCCl.C(Cl)(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[N:34][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:9])[CH3:1])=[CH:4][CH:5]=2)=[CH:29][CH:28]=1
Reactant: N#[N+]c1ccc(Cl)cc1
Reactant: CN(C)c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=[PH2]O
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(N=Nc2ccc(Cl)cc2)cc1
Reaction time: 24 h
Yield: 95 %

Procedure:
The ability of the cyclic ethers to solubilize salts were determined as follows. The cyclic ether (~90 mg) was dissolved in 0.4 ml. of chloroform and its 100 MHz pmr spectrum recorded. Excess salt (3 to 4 moles per mole of cyclic ether) was shaken with this solution which was then filtered, and the pmr spectrum again taken. The relative number of moles of the cyclic ether to the dissolved salt were determined (±5%) by integrating the appropriate signals of the protons of the cycle vs those of the salt. After the spectra were run, all solutions were returned to contact with the excess salt, and the mixtures were shaken intermittently for 24 hours without spectral change. With each salt, a parallel experiment was performed in which the cyclic ether was absent. Unless noted otherwise, no signal was observed for the salt in the absence of the cyclic ether, indicating the salt alone to be too insoluble to be detected. Run 23 involved benzoyl hexafluorophosphate as the guest salt. This material both complexed with and more slowly reacted with (benzoylated) the host cycle. Within 5 minutes, the nmr spectrum of the mixture indicated that 80% of the benzoyl salt originally complexed had reacted. The aryl-diazonium salts were stabilized by complexation, as shown by the decreased rate of nitrogen evolution upon complexation of the more unstable of them. Reactions other than complexation of the diazonium salts with the cyclic ethers were very slow. However, reactions of the complexed diazonium salts with compounds with which they ordinarily react rapidly (e.g., N,N-dimethylaniline, potassium phenoxide, Sandmeyer reaction reagents, hypophosphorous acid) were not inhibited by complexation. For example, when 2.25 g. (10 mmol) of 4-chlorobenzenediazonium tetrafluoroborate was dissolved at 25° in a solution of 4.88 g. (10 mmol) of a cyclic ether 6 in 50 ml. of dichloromethane, cooled to -75°, and N,N-dimethylaniline added, a 95% yield of 4-chloro-4'-(N,N-dimethylamino)-azobenzene was produced.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:30])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1.Cl[CH2:32][C:33](Cl)=[O:34].[OH-].[Na+].Cl>C(O)C.O>[CH3:30][N:21]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][CH2:5][N:4]3[CH2:3][CH2:2][O:1][CH2:32][C:33]3=[O:34])[CH2:8][N:9]=1)=[CH:20]2)[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: CN(c1cccc2cc(C3=NCC(CCNCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(CCN4CCOCC4=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of N-[2-(5-{2-[(2-hydroxyethyl)amino]ethyl}-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (220 mg) in ethanol (2 mL) and water (1 mL) were added chloroacetyl chloride (95 μL) and 8M aqueous sodium hydroxide solution (310 μL), and the mixture was stirred at the inside temperature of 20° C. or less for 3 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (100 mg, yield 41%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (10:1, volume ratio). MS:505(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13](OC)=[O:14].[BH4-].[Li+]>C1COCC1.CCOCC>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14]
Reactant: COC(=O)Cc1ccc(C#N)c(OC)c1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(C#N)ccc(CCO)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl (2-chloro-4-cyano-3-methoxyphenyl)acetate (700 mg, 2.92 mmol) in THF (30 mL) was added 2M lithium borohydride (1.46 mL, 2.92 mmol) and the reaction was stirred at RT for 16 hours. The reaction was diluted with ether and quenched into water containing 2N HCl. The mixture was extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product mixture was separated by flash chromatography (10-40% ethyl acetate/hexanes) to afford the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 3.10 (t, J=6.4 Hz, 2H), 3.94 (t, J=6.4 Hz, 2H), 4.08 (s, 3H), 7.175 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[OH:18])=[C:4]([F:20])[CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:21])=[C:4]([F:20])[CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of compound 2a (0.59 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and iodomethane (0.28 mL, 4.4 mmole) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N+:18]([O-])=[C:17]([CH3:24])[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:42][NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([CH2:24][N:43]([CH3:42])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1-c1ccc(Cl)cc1
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CN(C)c3ccccc3)ccc2c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide (13 mg, 0.029 mmol) in toluene (2 mL) was added benzenesulfonyl chloride (0.2 mL, excess). The mixture was stirred at 80° C. for 1 hour, then cooled to room temperature. N-methylaniline (0.2 mL, excess) and K2CO3 (250 mg, excess) were added. The mixture was stirred at 60° C. for 16 h, then diluted in ethyl acetate (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (12 mg, 78%). LCMS-ESI+ (m/z): 531.3, 533.2 (M+H)+.