Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([N:5]([CH3:37])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[C:14]([NH:22][C:23]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:30]=2)=[O:24])[CH:13]=1)[CH3:4].Cl>O1CCOCC1>[CH2:3]([N:5]([CH3:37])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O-:18])=[O:17])=[C:14]([NH:22][C:23]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:30]=2)=[O:24])[CH:13]=1)[CH3:4].[Na+:2]
Reactant: CCN(C)c1ccccc1-c1ccc(C(=O)OC)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(C)c1ccccc1-c1ccc(C(=O)[O-])c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 mol/L aqueous solution of sodium hydroxide (0.67 mL) was added to a dioxane (3.0 mL) solution of the obtained methyl 4-(2-((ethyl)(methyl)amino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g) at room temperature, followed by stirring at the same temperature for 1 hour and then at 55° C. for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature and adjusting the pH to 7.3 with 1 mol/L hydrochloric acid, the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid substance was collected by filtration. Ethanol (1.5 mL) and a 1 mol/L aqueous solution of sodium hydroxide (0.091 mL) were sequentially added to the obtained solid substance, followed by stirring at room temperature for 1 hour. Then, the solvent was evaporated under reduced pressure, and water was added to the obtained residue. The solid substance was collected by filtration to obtain 2.5 mg of sodium 4-(2-((ethyl)(methyl)amino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:9][OH:10])[CH2:7][CH3:8].[Li+].CC([N-]C(C)C)C.[C:19]([O:26][CH2:27][CH3:28])(=[O:25])[C:20]([O:22]CC)=O>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:9][OH:10])[CH:7]([CH3:8])[C:20](=[O:22])[C:19]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCC(=NO)c1ccco1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=NO)c1ccco1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
1-(Furan-2-yl)propan-1-one oxime (6.1 g, 43.9 mmol) was dissolved in 100 mL of THF and cooled to 0° C. LDA solution (55 mL, 110 mmol, 2M in heptane/THF/ethyl benzene) was added dropwise, and the reaction mixture was stirred at 0° C. for 1 hour and then warmed to room temperature. The mixture was then transferred to an addition funnel and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (30 mL, 219 mmol) and THF (100 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 150 mL of 10% hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The aqueous layer was then neutralized with solid sodium bicarbonate and extracted further with CH2Cl2. The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-40% EtOAc/hexanes) to give 10 g of the title compound. MS: (+) m/z 240.42 (M+1).
Reaction SMILES: CO.[BH4-].[Na+].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]>O>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10]
Reactant: COc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 201.6 %

Procedure:
Five milliliters of a methanol solution containing 0.6 g (16.0 mmol) of NaBH4 is added dropwise to 10 ml of a methanol solution containing 2.0 g (14 7 mmol) of 2-methoxybenzaldehyde, followed by stirring at room temperature for about 1 hour. After the progress of reaction has been confirmed by thin-layer chromatography, 100 ml of water is poured into the reaction solution to decompose excess NaBH4, followed by extraction with three 30 ml portions of ether. The ether layer is dried over anhydrous Na2SO4, and then filtered. When the solvent is removed by distillation, 1.95 g (yield: 96.1%) of 2-methoxybenzyl alcohol is obtained as an oily colorless product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:36])[C:19](=[O:35])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>>[ClH:37].[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:35])[C@H:18]3[CH3:36])=[CH:15][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: Cl
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4CCNCC4)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To HCl (1 M in EtOAc, 10 mL) was added 4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.20 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo to give (R)-7-(2-fluoro-phenyl)-4-methyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride (0.65 g, 81%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ 7.51-7.41 (m, 1H), 7.32-7.27 (m, 2H), 7.23 (t, J=9.0 Hz, 1H), 7.03 (s, 1H), 6.87 (s, 1H), 5.01-4.95 (m, 1H), 4.70-4.60 (m, 2H), 3.50-3.38 (m, 2H), 3.01-2.69 (m, 3H), 2.05 (m, 2H), 1.90 (m, 2H), 1.52 (m, 3H). LCMS (Table 1, Method 5) Rt=2.351 min; MS m/z: 395[M+H]+.
Reaction SMILES: C(C1C=C[C:6]([C@:9]23[CH2:35][C:25]4([NH:29][C@H:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][S:26]4)[CH2:24][N:10]2[C:11](=[O:23])[N:12]([C:15]2C=C(Cl)C=C(Cl)C=2)[C:13]3=[O:14])=[CH:5]C=1)#N.[C:36](Cl)(=[O:38])[CH3:37]>C(#N)C>[C:36]([N:29]1[C@@H:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][S:26][C:25]21[CH2:24][N:10]1[C:11](=[O:23])[N:12]([CH3:15])[C:13](=[O:14])[C@:9]1([CH2:6][CH3:5])[CH2:35]2)(=[O:38])[CH3:37]
Reactant: CCOC(=O)[C@@H]1CSC2(CN3C(=O)N(c4cc(Cl)cc(Cl)c4)C(=O)[C@@]3(c3ccc(C#N)cc3)C2)N1
Reactant: CC(=O)Cl
Solvent: CC#N
Product: CCOC(=O)[C@H]1CSC2(CN3C(=O)N(C)C(=O)[C@]3(CC)C2)N1C(C)=O
Temperature: 25 °C

Procedure:
To a solution of ethyl (4′R,7aS)-7a-(4-cyanophenyl)-2-(3,5-dichlorophenyl)-1,3-dioxotetrahydro-1H-spiro[pyrrolo[1,2-c]imidazole-6,2′-[1,3]thiazolidine]-4′-carboxylate (examples 12–13, crude mixture of isomers, 0.30 g, 0.58 mmol) and ET3N (0.10 ml, 0.6 mmol)) in acetonitrile (3 mL) was added acetyl chloride (0.05 ml) and the contents stirred one night at RT. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (25 mL) and 1N Hydrochloric acid (10 mL). The dichloromethane layer was washed with 1N Sodium Bicarbonate, water then dried over sodium sulfate, concentrated and purified by silica gel chromatography using cyclohexane/ethyl acetate as the eluent, diluted with t-butyl methyl ether, washed with water, NaHCO3 solution, water then dried over sodium sulfate, concentrated and purified by silica gel chromatography using dichloromethane/acetone as the eluent. yield: 0.016 g. 1H NMR (CDCl3): 7.6 (2H, d), 7.35 (2H, d), 7.3 (1H, m), 6.8 (2H, m), 4.9 (1H, m), 4.75 (1H, d), 4.3 (2H, q), 4.05 (1H, d), 3.5–3.2 (5H, m), 2.65 (1H, d), 2.15 (3H, s), 1.3 (3H, t).
Reaction SMILES: C1COCC1.[NH:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.C1C=CC2N(O)N=NC=2C=1.[NH:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:33]([C:35](O)=[O:36])[CH3:34]>CN(C=O)C>[NH:32]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C@H:33]([C:35]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:36])[CH3:34]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
THF (200 ml), H-Pro-OBzl.HCl (48.3 g, 0.2 M) and HOBT (27.0 g, 0.2 M) were added to BOC-Ala-OH (37.8 g, 0.2 M); DMF (100 ml) was added, and WSCI (36.6 ml, 0.2 M) was added dropwise at 0° C. After stirring at 0° C. for one hour and at room temperature overnight, the solvent was distilled off in vacuo. The residue was dissolved in ethyl acetate (500 ml), washed three times with 5% sodium bicarbonate solution, three times with 1 N HCl and three times with water, in that order, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in a small amount of benzene and charged on a column of silica gel (250 g) packed with benzene. Elution was carried out with benzene (1 l.), benzene-ethyl acetate (10:1) (1 l.) and benzene-ethyl acetate (1:1) (1 l.), and the corresponding fractions were collected and checked by TLC and concentrated in vacuo to obtain the oily substance [24] (75.55 g, yield: 100%).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][O:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[O:9][CH2:10][CH:11]([OH:18])[CH2:12][NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:4].[CH2:23]=O>C(O)C>[CH3:1][NH:2][C:3]([CH2:5][O:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[O:9][CH2:10][CH:11]1[O:18][CH2:23][N:13]([C:14]([CH3:17])([CH3:15])[CH3:16])[CH2:12]1)=[O:4]
Reactant: CNC(=O)COc1ccccc1OCC(O)CNC(C)(C)C
Reactant: C=O
Solvent: CCO
Product: CNC(=O)COc1ccccc1OCC1CN(C(C)(C)C)CO1

Procedure:
A mixture of 1.3 g. of 3-(o-N-methylcarbamoylmethoxyphenoxy)-1-t-butylaminopropan-2-ol, 20 ml. of absolute ethanol and 2 ml. of aqueous 36% w/v formaldehyde solution is heated under reflux for 24 hours. The solution is evaporated to dryness under reduced pressure and there is thus obtained as the residual oil 5-(o-N-methylcarbamoylmethoxyphenoxymethyl)-3-t-butyloxazolidine which is characterised by its proton magnetic resonance spectrum.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH:27]([F:29])[F:28])[N:20]=1>>[F:29][CH:27]([F:28])[O:26][CH2:25][C:21]1[N:20]=[C:19]([CH2:18][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Reactant: FC(F)OCc1cccc(CBr)n1
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(COC(F)F)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2-bromomethyl-6-difluoromethoxymethylpyridine by the alkylation method described in Example 36.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:22]=4[O:23][CH:24]([CH3:28])[C:25]([OH:27])=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:36]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:22]=4[O:23][CH:24]([CH3:28])[C:25]([O-:27])=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4].[Na+:36]
Reactant: COc1cccc(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c1OC(C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c1OC(C)C(=O)[O-]

Procedure:
To a solution of 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-6-methoxyphenoxy}propionic acid (583 mg) in methanol (5 ml) was added 1N sodium hydroxide solution (1.21 ml). The solution was concentrated under reduced pressure and the residue was dissolved in water (5 ml) and lyophilized to give sodium 2-{2-{[2-(tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-6-methoxyphenoxy}propionate (580 mg) as an amorphous solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:11][C:12]1[CH:24]=[CH:23][C:22]2[C:21]3[C:16](=[CH:17][C:18]([Br:25])=[CH:19][CH:20]=3)[C:15](=[C:26](Br)Br)[C:14]=2[CH:13]=1>C(COC)OC.[Ni](Cl)Cl.N1C=CC=CC=1C1C=CC=CN=1.C1(C)C=CC=CC=1>[Br:25][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[C:14](=[CH:13][C:12]([Br:11])=[CH:24][CH:23]=3)[C:15](=[C:26]([S:10][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[S:10][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:16]=2[CH:17]=1
Reactant: CCCCCCCS
Reactant: BrC(Br)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl[Ni]Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CCCCCCCSC(SCCCCCCC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (3.45 g, 86.25 mmol) was added under a heavy flow of nitrogen to anhydrous toluene (1 L). 1-Heptanethiol (14.65 g, 17.0 mL, 110.7 mmol) was added via syringe. Once effervescence stopped, 2,7-dibromo-9-dibromomethylene-fluorene (2) (18.50 g, 37.46 mmol) was added followed by 2,2′-bipyridyl (0.29 g, 1.87 mmol) and nickel(II) chloride dimethoxyethane adduct (0.41 g, 1.87 mmol). The reaction was stirred overnight at reflux. After cooling to room temperature, the reaction mixture was washed with 2M aqueous sodium hydroxide (2×100 mL), 5% aqueous hydrochloric acid (2×100 mL), water (200 mL), and brine (200 ml) before being dried over sodium sulphate and evaporated to dryness. Excess 1-heptanethiol was removed via Kugelrohr distillation. The crude product was purified by flash chromatography (eluent: petrol 40-60) followed by recrystallisation from iso-hexane to afford 2,7-dibromo-9-(bis-heptylsulfanyl-methylene)-fluorene (3) (16.76 g, 75%) as a bright yellow solid, purity 100% (GC): υmax (KBr, cm−1) 3068, 2949, 2920, 2851, 1588, 1559, 1513, 1443, 1396, 1330; δH(CDCl3, 300 MHz) 9.09 (2H, s), 7.53 (2H, d, 3JHH=6.0 Hz), 7.43 (2H, d, 3JHH=6.0 Hz), 3.04 (4H, t, 3JHH=7.5 Hz) 1.70 (4H, m), 1.43 (4H, m), 1.26 (12H, m), 0.86 (6H, m); δc(CDCl3, 75 MHz) 145.5, 139.7, 137.6, 136.1, 130.3, 129.5, 121.1, 120.3, 36.4, 31.7, 30.1, 28.9, 22.6, 14.1; M+=596 (t).
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1)/[CH:5]=[CH:6]/[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=1.CO.CC(O)=O.[K+].[Br-]>O.C1COCC1>[O:3]=[C:4]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1)/[CH:5]=[CH:6]/[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(C(=O)/C=C/C(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1
Agent: [Br-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)/C=C/C(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.24 g (10.0 mmol) of lithium hydroxide in 20 ml of water was added to a solution of 1.2 g (2.6 mmol) of (E)-3,4-dihydro-3-{1-[1,4-dioxo-4-(4-ethoxycarbonylphenyl)-2-buten-1-yl]-4-piperidinyl}-2(1H)-quinazolinone (Item no. 169) in 20 ml of THF. After stirring for 4 hours at ambient temperature the mixture was diluted with 200 ml of water and extracted once with 100 ml of tert.butylmethylether. The aqueous phase was acidified with 1N hydrochloric acid and extracted five times with a mixture of dichloromethane and methanol (9/1 v/v). The combined organic extracts were dried over sodium sulphate and concentrated by evaporation in vacuo. The residue remaining was triturated with diethylether and suction filtered. After drying in a circulating air dryer 0.5 g (44% of theoretical) of colourless crystals were obtained. Rf 0.72 (EE/MeOH/AcOH 80/20/5 v/v/v) or 0.43 (El D). IR (KBr): 1689 (C═O) MS: no M+
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C[O-].[Na+:14]>CO>[CH3:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O-:11].[Na+:14]
Reactant: CCCCCCCCCCO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCC[O-]

Procedure:
Into a 500 ml eggplant type flask, 1-decanol (180 g) and a methanol solution of sodium methylate (28%) were charged, stirred and heated under reduced pressure to distill off methanol. By GC, it was confirmed that no methanol remained in the reaction solution. Into a 1 l four-necked flask, N,N-dimethylformamide (150 ml) and CH3CHClCOO(CH2)9CH3 (27.1 g) obtained in Example 19 were charged and stirred, and a solution of sodium decylate obtained in the above operation was added dropwise at an internal temperature of not higher than 25° C. The mixture was heated to an internal temperature of 70° C. and stirred for 30 minutes.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[CH3:2][O:3][C:4]([C:6]1([NH:12][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2ccc(OC)cc2)CCCCC1
Yield: 70.8 %

Procedure:
581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 512 mg (3 mmol) of 4-methoxybenzoyl chloride was used instead of phenylacetyl chloride in the process according to Reference example 1 to obtain 619 mg (71%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:17]=[C:16]([NH2:18])[O:15][N:14]=1>N1C=CC=CC=1>[CH3:12][C:13]1[CH:17]=[C:16]([NH:18][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[O:15][N:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1cc(N)on1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
4-brombenzenesulfonyl chloride (solid) was added, in five portions, to a solution of 3-methyl-5-aminoisoxazole (3.82 g, 40 mmol) in dry pyridine (30 ml). This was stirred at room temperature for 3 h and the pyridine was removed under reduced pressure. The residue was dissolved in THF (300 ml) and a 5% NaOH solution (100 ml) was added. Stirring continued for 1 h at room temperature. The THF was removed under reduced pressure and the resultant residue was neutralized to pH 2 using concentrated hydrochloric acid. This was extracted with ethyl acetate (3×200 ml) and the combined organic layer was dried over MgSO4 and concentrated. The crude product was recrystallized using hexane/ethyl acetate giving N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (9.2 g, 72% yield).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[O:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>C(O)C>[CH2:17]([CH:14]1[CH2:13][O:12][CH:11]([CH:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[O:16][CH2:15]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC1COC(C2CCC(C(=O)OC)CC2)OC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC1COC(C2CCC(C(=O)O)CC2)OC1
Temperature: 7 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
4-(5-Pentyl-1,3-dioxane-2-yl)cyclohexanecarboxylic acid methylester 28.2 g (94.5 mmol) was added in ethanol 100 ml, and cooled to 7° C., and 2N-sodium hydroxide 70 ml was added dropwise. The mixture was heated to room temperature, and stirred for one hour, and 2N-sodium hydroxide 70 ml was added dropwise. After st g the mixture father one hour at room temperature, 2N-sodium hydroxide 50 ml was added dropwise, and the mixture was stirred further one hour at room temperature. 6N-Hydrochloric acid 65 ml was added to the reactant, and the product was extracted with diethylether. The extract was washed with water, a saturated sodium bicarbonate aqueous solution and then water, and dried over magnesium sulfate, and the solvent was distilled off. The residue 27.3 g was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=1/1), and recrystallized from a mixed solvent of heptane/ethanol =20/1 to obtain 4-(5-pentyl-1,3-dioxane-2-yl)cyclohexanecarboxylic acid 2.3 g (8.1 mmol). The yield was 8.6% from 4-(5-pentyl-1,3-dioxane-2-yl)cyclohexane carboxylic acid methylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N+:19]([O-])=O)[CH:12]=2)[CH:6]=[C:5]([O:22][CH3:23])[C:4]=1[O:24][CH3:25]>C(O)(=O)C.ClCCl.C(OCC)(=O)C.[Zn]>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][S:9][C:7]2[CH:6]=[C:5]([O:22][CH3:23])[C:4]([O:24][CH3:25])=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:12][C:13]=1[NH2:19]
Reactant: COc1ccc(CSc2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CSc2cc(OC)c(OC)c(OC)c2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A room temperature suspension of zinc dust (2.35 g) in acetic acid (20 mL) was treated dropwise with a solution of Example 89A (100 mg, 0.27 mmol) and acetic acid (0.40 mL) in dichloromethane (1 mL), stirred at room temperature for 30 minutes, diluted with ethyl acetate (100 mL), filtered, and concentrated. The concentrate was dissolved in ethyl acetate, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/dichloromethane to provide the desired product.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14]COC)=[CH:10][C:9]=2[O:18]COC)[CH2:3]1>CO>[F:1][C:2]1([F:22])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:18])[CH2:3]1
Reactant: COCOc1ccc(C2CCCC(F)(F)C2)c(OCOC)c1
Solvent: CO
Product: Oc1ccc(C2CCCC(F)(F)C2)c(O)c1
Yield: 23.1 %

Procedure:
A mixture of (±)-1-(3,3-difluorocyclohexyl)-2,4-bis(methoxymethoxy)benzene (30 mg), methanol (2 ml) and acidic ion exchange resin (200 mg) was heated under reflux for 4 h. The reaction mixture was filtered and the resin was washed with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to give the title compound as a solid (5 mg, 23%). δH (CD3OD) 1.2-2.2 (8H, m), 3.08 (1H, m), 6.23-6.27 (2H, m), 6.87 (1H, d); m/z (ES−) 287 (M−1+AcOH)−.
Reaction SMILES: [NH2:1][C:2]([CH2:21]O)([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].[Li].C([Li])CCC.[F:29][CH:30]([P:32](=[O:39])([O:36]CC)[O:33]CC)[F:31].CP(=O)(OC)OC>>[F:29][C:30]([P:32](=[O:33])([OH:39])[OH:36])([F:31])[CH2:21][C:2]([NH2:1])([CH2:3][OH:4])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Reactant: CCOP(=O)(OCC)C(F)F
Agent: COP(C)(=O)OC
Agent: [Li]
Agent: [Li]CCCC
Product: CCCCCCCCc1ccc(CCC(N)(CO)CC(F)(F)P(=O)(O)O)cc1

Procedure:
The title compound was prepared from 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol (FrY 720) using procedures analogous to those described in EXAMPLE 2, except that lithium dilsopropylamide was substituted for n-butyllithium in Step C and diethyl difluoromethylphosphonate was substituted for dimethyl methylphosphonate in Step C: Mass spectrum (NH3—CI) 422 (M+H).