Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[Si:27]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[O-]S([O-])=O.[Na+].[Na+]>C(#N)C.C1(C)C=CC=CC=1>[Si:27]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][I:25])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCCI
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a mixture of imidazole (1.13 g, 16.6 mmol), triphenyl phosphine (2.16 g, 8.24 mmol), and iodine (1.92 g, 7.56 mmol) in a mixed solvent of toluene (40 mL) and acetonitrile (4 mL) was added 5-t-butyldimethylsilyloxy-1-pentanol (1.5 g, 6.87 mmol). The mixture was stirred for 1 h at room temperature and aqueous Na2SO3 was added. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 10:1 hexane/ethyl acetate to give the title compound (1.55 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][CH:18]1[O:22][CH:21]([CH3:23])[CH2:20][O:19]1>>[CH3:23][CH:21]1[CH2:20][O:19][CH:18]([CH2:17][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[O:22]1
Reactant: COc1ccccc1N
Reactant: CC1COC(CBr)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1NCC1OCC(C)O1
Temperature: 100 °C

Procedure:
2-Methoxyaniline (99 grams; 0.6 moles) and sodium carbonate (31.6 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4-methyl-1,3-dioxolane (25 ml) was added and the reaction mixture was heated at a temperature of about 100° C. for a period of about 4 hours. After this time the reaction mixture was filtered and additional sodium carbonate (5.0 grams) was added to the filtrate. The mixture was then vacuum distilled and the fraction boiling at 120° C. and 0.07 mm of Hg pressure was collected to yield the desired product N-(4-methyl-1,3-dioxolan-2-ylmethyl)-2-methoxyaniline.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:1]([NH:8][C:9]1[S:10][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:12][C:13]=1[N+:17]([O-:19])=[O:18])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(C(C)C)s1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1sc(C(C)C)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
2-Ethoxalylamino-5-isopropylthiophene (6.9 g, 28.5 mol) was dissolved in 50 ml of acetic anhydride, cooled to -10° C., and treated with a solution of fuming nitric acid (1.8 g, 28.5 mmol) in 15 ml of acetic acid. After 20 minutes, the mixture was evaporated in vacuo to yield 8.4 g of crude product which was purified by chromatography on silica gel (toluene:acetone 95:5), to yield 4.8 g (57%) of 2-ethoxalylamino-5-isopropyl-3-nitrothiophene. 1H-NMR (CDCl3, δ): 1.3 (d, 6H), 1.5 (t, 3H), 3.1 (m, 1H), 4.5 (q, 2H), 12.0 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.[C:16]1([CH2:22][SH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:22]([S:23][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cncc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a solution of 5-chloropyridin-3-yl trifluoromethanesulfonate (1.73 g) in toluene (15 mL) were added phenylmethanethiol (861 mg), N,N-diisopropylethylamine (1.88 g), tris(dibenzylideneacetone)dipalladium(0) (121 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 3 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-hexane-ethyl acetate=19:1) to give the title compound as a yellow oil (yield 1.63 g, quantitative).
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][CH:7]=[O:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.CO/[CH:17]=[CH:18]/[C:19]([O:21][Si](C)(C)C)=[CH2:20].ClCCl.O>C1C=CC=CC=1.CCOCC.Cl[Zn]Cl>[O:21]=[C:19]1[CH:18]=[CH:17][O:8][CH:7]([CH2:6][N:5]2[C:4](=[O:9])[C:3]3[C:2](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:1]2=[O:14])[CH2:20]1
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: Cl[Zn]Cl
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C1C=COC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
To a mixture of phthalimidoacetaldehyde (64 g, 0.34 mol) and trans-1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (81.5 g, 0.38 mol) in benzene (600 ml) stirred for 15 min. under nitrogen was added dropwise a 45% solution of zinc chloride diethyl ether complex in dichloromethane (55.5 ml, 0.17 mol) at 0° C. The reaction was allowed warm up to room temperature overnight. To the reaction mixture was added water (500 ml) and the resulting mixture was extracted with ethyl acetate (200 ml). The organic extract was washed successively with 1.0 N hydrochloric acid (2×200 ml) and brine (200 ml). The organic phase was dried (Na2SO4), filtered and the solvent evaporated in vacuo which afforded a slowly crystallising oil (98 g). To the solid was added a mixture of ethyl acetate and diethyl ether (400 ml, 1:1) and the resulting precipitate was filtered off, washed with a small portion of diethyl ether and dried at 50° C. for 1 h affording 59.8 g (69%) of 2-(4-oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid. The filtrate was evaporated in vacuo and the residue purified by column chromatography on silica gel (1 L) using a mixture of ethyl acetate and heptane (1:2) as eluent. Pure fractions were collected and the solvent evaporated in vacuo to almost dryness, the solid was filtered off and dried in vacuo at 50° C. for 16 h affording an additional 15 g (17%) of 2-(4oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C1COCC1>[I:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(I)ccc1CO
Temperature: -78 °C
Yield: 31.2 %

Procedure:
A solution of methyl 4-iodo-2-methoxybenzoate (840 mg, 2.88 mmol) in THF was purged with nitrogen and cooled to −78° C. DIBALH (6 mL, 5.75 mmol, 1M in toluene) was added slowly. The mixture was then stirred at the same temperature for an hour. Saturated aqueous NH4Cl solution was added, followed by extraction with ethyl acetate twice. The organic phase was then washed with brine and dried with anhydrous Na2SO4. Solvent was removed and the resulting residue purified by flash column chromatograph to give 237 mg of the title compound (31%). 1H NMR (400 MHz, CDCl3): δ 2.17 (1H, s), 3.84 (3H, s), 4.62 (2H, d, J=4.0 Hz), 7.01 (1H, d, J=7.6 Hz), 7.18 (1H, s), 7.29 (1H, d, J=8.0 Hz).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(OCc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ccn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methoxy)pyridin-4-yl)propanoate (28 mg) in THF (1.0 mL) and methanol (0.50 ml) was added 1N aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (21 mg) as a yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH:13]=[CH:14][C:15]([O:17]C)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[CH:37][CH:36]=2)=[O:34])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[CH:39][CH:40]=2)([OH:34])[CH:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:15][OH:17])=[CH:31][CH:30]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)CCOc1ccc(C(=O)c2ccc(OCc3ccccc3)cc2)cc1
Reactant: COC(=O)C=Cc1ccc(OCc2ccccc2)cc1
Product: CN(C)CCOc1ccc(C(O)(c2ccc(OCc3ccccc3)cc2)C(CCO)c2ccc(OCc3ccccc3)cc2)cc1
Yield: 64 %

Procedure:
1,2-bis (4-benzyloxyphenyl)-1-[4-[2-(N,N-dimethylamino) -ethoxy]phenyl]butan-1,4-diol is prepared according to the procedure described in Example 2 using methyl 4-benzyloxy-cinnamate and 4-benzyloxy-4'-dimethylaminoethoxybenzophenone as starting materials. The product is recrystallized from toluene. Yield is 64%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][C:42]([CH3:45])([OH:44])[CH3:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][C:42]([OH:44])([CH3:45])[CH3:43])=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CC(C)(O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCC(C)(C)O)cc2)c2ccccc21
Temperature: 80 °C
Yield: 78.8 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.1 g, 0.23 mmol) was dissolved in DMF (5 mL) at room temperature. K2CO3 (0.317 g, 2.3 mmol) was added. 5-Bromo-2-methyl-pentan-2-ol (0.092 g, 0.51 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (70% EtOAc/30% Hexane) to afford the product (0.097 g, 79%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[O:17])[CH:11]=[CH:12]2)=[N:7]1.Cl>CC(C)=O>[O:2]=[CH:3][CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[O:17])[CH:11]=[CH:12]2)=[N:7]1
Reactant: COC(CCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1

Procedure:
To a stirred solution of 1-[2-(3,3-dimethoxypropyl)-2H-indazol-6-yl]-3-(4-phenoxyphenyl)urea (832 mg, 1.87 mmol) in acetone (15 mL) was added 2N aqueous HCl (7.5 mL) and the reaction was heated to 50 C for 3h. The heating bath was removed and the reaction was concentrated under reduced pressure to a volume of ˜5 mL. Et2O was added to the slurry with stirring and the mixture was filtered. The solid was washed with additional Et2O (10 mL) and air-dried to give 1-[2-(3-oxopropyl)-2H-indazol-6-yl]-3-(4-phenoxyphenyl)urea as a beige solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.11 (t, J=6.27 Hz, 2 H), 4.67 (t, J=6.61 Hz, 2 H), 6.97 (m, 5 H), 7.10 (m, 1 H), 7.36 (m, 2 H), 7.48 (m, 2 H), 7.59 (m, 1 H), 7.82 (s, 1 H), 8.26 (s, 1 H), 8.70 (m, 2 H) and 9.75 (s, 1 H); MS (ESI) 399 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:24])[CH2:19][C:20](=[O:23])[CH2:21][CH3:22]>>[CH3:16][O:17][C:18](=[O:24])[CH:19]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:12][C:11](=[O:14])[CH2:10][C@@H:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: C[C@@H](CC(=O)CBr)OCc1ccccc1
Reactant: CCC(=O)CC(=O)OC
Product: CCC(=O)C(CC(=O)C[C@H](C)OCc1ccccc1)C(=O)OC
Yield: 46.8 %

Procedure:
After (4S)-4-(benzyloxy)-1-bromopentan-2-one (15 g, 52 mmol) was prepared from the compound of Comparative Example 1 in the process similar to Comparative Example 2, it was reacted with 3-oxopentanoic acid methyl ester (6.5 mL, 52 mmol) to give the title compound (7.8 g, 47%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[N:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[S:20][CH:21]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3]C)=[O:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[N:18]=[C:19]([C:22]([F:24])([F:23])[F:25])[S:20][CH:21]=2)[CH3:13])=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared analogously to Example 2 by reaction of N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1N sodium hydroxide solution. After neutralisation with hydrochloric acid, the mixture is evaporated to dryness and the residue is treated with a mixture of ethyl acetate/ethanol=6:1. The extract is evaporated to dryness and the residue is triturated with 5 ml of water. The water is decanted off and the remaining residue is taken up in methanol, the solution is evaporated to dryness, and the residue is triturated with ether and filtered off with suction.
Reaction SMILES: [NH2:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]([CH3:37])[C:8]([O:10][C@H:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:23]=2)[CH2:12][C:13]2[C:18]([Cl:19])=[CH:17][N+:16]([O-:20])=[CH:15][C:14]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1.C(Cl)Cl.[NH4+].[Cl-]>[Cl:19][C:18]1[CH:17]=[N+:16]([O-:20])[CH:15]=[C:14]([Cl:21])[C:13]=1[CH2:12][C@@H:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[C:24]([O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[CH:23]=1)[O:10][C:8](=[O:9])[N:7]([CH3:37])[CH2:6][C:5]1[CH:38]=[CH:39][C:2]([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccc(N)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(Cc1ccc(NS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
(S)-4-(2-((4-aminobenzyl)(methyl)carbamoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (for reference procedure see Example 3, Table 5) (73.2 mg, 0.126 mmol) was dissolved in pyridine (3 ml) and cooled at 0° C. Methanesulfonyl chloride (13.71 μl, 0.176 mmol) was added, and the reaction was stirred RT for 1 hour. The reaction was diluted with DCM and aqueous sat. NH4Cl. The aqueous phase was extracted twice with DCM, the combined organic layers were dried and evaporated. The residue was purified by flash chromatography on silica gel cartridge (DCM/AcOEt=80/20 to 50/50) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(methyl(4-(methylsulfonamido)benzyl)carbamoyloxy)ethyl)pyridine 1-oxide (69 mg, 0.104 mmol, 83% yield, MS/ESI+ 660.0 [MH]+.
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].C(S(N1CCC2(C(=O)N(C3C=CC(C(O)C(F)(F)F)=CC=3)CC2)CC1)(=O)=O)C(C)C.[F:49][C:50]([F:62])([F:61])[C:51]([C:54]1[CH:59]=[CH:58][C:57](I)=[CH:56][CH:55]=1)([OH:53])[CH3:52]>>[CH2:1]([S:5]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[N:14]([C:57]3[CH:58]=[CH:59][C:54]([C:51]([OH:53])([CH3:52])[C:50]([F:61])([F:62])[F:49])=[CH:55][CH:56]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CS(=O)(=O)N1CCC2(CCNC2=O)CC1
Reactant: CC(O)(c1ccc(I)cc1)C(F)(F)F
Agent: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(C(O)C(F)(F)F)cc3)C2=O)CC1
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(C(C)(O)C(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared in analogy to example 162 step B) from 8-(isobutylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one, product of example 167 A) and 1,1,1-trifluoro-2-(4-iodo-phenyl)-propan-2-ol (synthesis: H. Urata et al, Tetrahedron Letters; 1991; p 91). White crystalline solid. MS (ESI): 463.2 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])C=C>ClCCl>[C:11]1([CH3:14])[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH:1]=[CH:17][CH2:16][CH2:15]2)(=[O:6])=[O:7])=[CH:13][CH:12]=1
Reactant: C=CCN(CC=C)S(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C=CCC2)cc1
Reaction time: 24 h
Yield: 0.5 %

Procedure:
According to Barbasiewicz et al. (Organometallics, published on Web Jun. 17, 2006), a solution of 88 mg (0.35 mmol) N,N-diallyl 4-methylbenzenesulfonamide and 11.2 mg (0.018 mmol) [RuCl2(ImH2Mes)(8-quinolinylmethylene)] in 17.5 ml dichloromethane was stirred at room temperature. To monitor the conversion and selectivity, 0.2-ml samples were taken were after 4 h and 24 h. Each sample was filtered over a silica gel pad, the filtrate was evaporated to dryness and analyzed by GC as described in Example 12. After 4 h (2% conversion), 0.6% of the title compound and 0.3% of 1-(toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole and after 24 h (3% conversion) 1.5% of the title compound and 0.5% of 1-(toluene-4-sulfonyl)-2,3-dihydro-1H-pyrrole were formed.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[N+:18]([C:21]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])=[CH:29][C:22]=1[O:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])([O-:20])=[O:19]>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH:24]([O:23][C:22]1[CH:29]=[C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])[CH:31]=[CH:32][C:21]=1[N+:18]([O-:20])=[O:19])[CH3:28])[CH:2]=[CH2:3]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: C=CCNCC1OCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN(CC1OCCO1)C(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
N-Allyl-N-(1,3-dioxolan-2-ylmethyl)amine (1.32 grams; 0.0092 mole), dry toluene (70 ml) and triethylamine (3.0 ml) were charged into a glass reaction vessel equipped with a magnetic stirrer, thermometer, gas inlet tube and addition funnel. The mixture was blanketed with nitrogen gas, cooled to 10° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (3.9 grams; 0.0092 mole) in toluene (40 ml) was added dropwise with stirring. After the addition was completed the mixture was allowed to warm to room temperature and stirring was continued for a period of about 1.5 hours. After this time the reaction mixture was transferred to a separatory funnel and was washed with water and with aqueous sodium bicarbonate. The washed solution was dried by passing it through phase separation paper. The dried solution was then chromatographed through a clay column using mixtures of ethyl acetate and hexane as the eluant. Nine fractions were collected. Fraction five was stripped of solvents and thereafter further dried by letting the residue stand under vacuum at 110° C. for a period of four hours to yield the desired product N-allyl-N-(1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as an amber gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:23][C:6]2[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1.[C:34](=O)(O)[O-].[K+]>CO.S(=O)(=O)(O)O.O>[CH3:34][O:32][C:31](=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:9][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1
Reactant: COc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1OCCCCCC(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CCCCCOc1cc2c(cc1OC)NC(c1ccccc1)N2c1ccc(C)cc1
Reaction time: 2 h

Procedure:
40 mg of 6-[[5-methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid was dissolved in 2 ml of methanol, mixed with 1 drop of concentrated sulfuric acid, and the mixture was stirred for 2 hours. It was mixed with saturated potassium bicarbonate solution, diluted with water, extracted with ethyl acetate, the extracts were dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was crystallized from diisopropyl ether.