Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:12][N:13]([C@@H:20]2[CH2:22][C@H:21]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C(=O)C(F)(F)F)([C:8]([O:10]C)=[O:9])[CH2:4][CH2:3]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:12][NH:13][C@@H:20]2[CH2:22][C@H:21]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 69.9 %

Procedure:
To a solution of methyl 1-methyl-4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (160 mg, 0.402 mmol) in methanol (2 mL) was added sodium hydroxide (6M, 0.3 mL, 1.800 mmol), and the mixture was stirred at room temperature for 30 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 81 mg of product (HCl salt) as white solid. MS: (M+H)+=289.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.37 (m, 1H), 1.59-1.74 (m, 1H), 1.84-2.09 (m, 2H), 2.11-2.33 (m, 2H), 2.59-2.80 (m, 3H), 2.86-3.08 (m, 2H), 3.25 (d, J=7.58 Hz, 3H), 3.35-3.60 (m, 3H), 7.12-7.40 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([C:27]1[CH:35]=[CH:34][C:30]2[CH2:31][CH2:32][O:33][C:29]=2[CH:28]=1)[N:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][NH:19][C:18]=3[N:17]=2)[C:8]1=[O:26])C.[OH-].[Na+]>CCO>[O:33]1[C:29]2[CH:28]=[C:27]([C@@H:6]([N:7]3[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[CH2:22][CH2:21][CH2:20][NH:19][C:18]=5[N:17]=4)[C:8]3=[O:26])[CH2:5][C:4]([OH:36])=[O:3])[CH:35]=[CH:34][C:30]=2[CH2:31][CH2:32]1
Reactant: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCCN(CCCc2ccc3c(n2)NCCC3)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@@H](c1ccc2c(c1)OCC2)N1CCCN(CCCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 2 h

Procedure:
To a solution of 4-12 (0.20 g, 0.41 mmol) in EtOH (5 mL) was added 1N NaOH (0.5 ml, 0.5 mmol). After stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 followed by 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 4-13 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)(O)[O-].[Na+].Br[CH2:17][C:18](Br)=[O:19]>C(Cl)(Cl)Cl>[O:19]=[C:18]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10][CH2:17]1
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The title compound was prepared similarly to literature procedure (Caliendo, G; et. al.; Bioorg. Med Chem. Lett., 2002, 10, 2663), but in one step. Commercially available 3-amino-4-hydroxybenzonitrile (2.5 g, 18.6 mmol) was dissolved in chloroform (300 mL) and saturated sodium bicarbonate (90 mL). The biphasic reaction mixture was cooled to 0° C. and bromoacetyl bromide (2.4 mL, 28 mmol) was added dropwise. The reaction was stirred overnight at room temperature. The layers were separated and the aqueous layer was filtered to yield the desired product as a tan solid, 2.3 g (69%).
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:13]1[CH:18]=[C:17]([O:19][C@H:20]([CH3:42])[CH2:21][O:22][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=[C:15]([S:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=2[F:52])[N:14]=1>>[C:1]([C:3]1[O:7][C:6]([S:8]([NH:11][C:13]2[CH:18]=[C:17]([O:19][C@H:20]([CH3:42])[CH2:21][O:22][C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:16]=[C:15]([S:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[F:52])[N:14]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(N)(=O)=O)o1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C#N)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared from 5-cyanofuran-2-sulfonamide (the product of step i) (0.29 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-pyrimidine (the product of Example 13, step ii) (0.15 g) according to the procedure outlined in Example 1, step iv). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:4 to 2:3 gradient) to give the subtitle compound as a pale yellow solid. Yield: 0.25 g
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10]([C:8]1[S:7][C:6]2[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:9]=1)=[O:12])[CH3:18]
Reactant: COc1cc2cc(C(=O)O)sc2cc1OC
Reactant: CCO
Product: CCOC(=O)c1cc2cc(OC)c(OC)cc2s1

Procedure:
5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid (10 g) was suspended in ethanol (80 ml) and the mixture was stirred and heated at reflux for 5 hours. The resultant solution was evaporated to dryness and then crystallised from dichlolormethane:methanol to give 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester as a white solid (9.5 g), m.p. 84°-85° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH2:25][C:26](=[CH2:30])[C:27]([O-])=[O:28])[CH3:24].[Na+].Cl.O1CCOCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[CH3:22][N:23]([CH2:25][C:26](=[CH2:30])[C:27]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:28])[CH3:24]
Reactant: C=C(CN(C)C)C(=O)[O-]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C=C(CN(C)C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Reaction time: 8 h

Procedure:
To methyl 2-[(dimethylamino)methyl]prop-2-enoate (314 mg, 2.19 mmol) in tetrahydrofuran (1.4 mL) and water (1.4 mL) was added LiOH (52.5 mg, 2.19 mmol). The solution was stirred at 40° C. for 4 hours, before being frozen and lyophilized to afford sodium 2-[(dimethylamino)methyl]prop-2-enoate which was used as is in the next step as is. To a solution of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (100 mg, 0.354 mmol) in DMF (886 μL) was added sequentially sodium 2-[(dimethylamino)methyl]prop-2-enoate (96 mg, 0.71 mmol), 4 M solution of HCl in dioxane (177 μL, 0.708 mmol), TEA (197 μL, 1.42 mmol), and 1-propanephosphonic acid cyclic anhydride (422 μL, 0.708 mmol) at room temperature. The reaction was stirred overnight before being purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained and the water layer was neutralized with saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-[3-({2-[(dimethylamino)methyl]acryloyl}amino)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C21H24N5O3 [M+H]+: 394, found 394. 1H NMR (600 MHz, DMSO-D6) δ 12.9 (s, 1H), 11.1 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.77 (d, 1H, J=8.21 Hz), 7.42 (t, 1H, J=8.21 Hz), 7.35 (d, 1H, J=7.63 Hz), 6.01 (s, 1H), 5.58 (s, 1H), 3.87 (q, 2H, J=7.04 Hz), 3.23 (s, 2H), 2.24 (s, 6H), 0.86 (t, 3H, J=7.04 Hz).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)[CH:2]=C.C[OH:13]>C(Cl)Cl>[O:13]=[CH:2][CH2:1][C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1
Reactant: C=CCc1ccc(C#N)cn1
Reactant: CO
Solvent: ClCCl
Product: N#Cc1ccc(CC=O)nc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
A mixture of 6-(Prop-2-en-1-yl)pyridine-3-carbonitrile (4.8 g, 33 mmol) in 80 mL of DCM and 20 mL of MeOH was cooled to −70° C. Ozone was bubbled through the mixture until the mixture turned blue (about 20 minutes). The excess of ozone was removed by flush with N2 flow until the mixture turned colorless. 5 mL of Me2S was added to the mixture which was then warmed slowly to room temperature and stirred for 2 hours. The solvent was removed under vacuum below 30° C. to afford the title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][C:13]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH2:16][OH:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:17][CH2:16][C:13]1([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:11][N:10]([CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1
Reactant: Oc1ccccc1F
Reactant: COc1ncccc1CN1CCC(CO)(CCc2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ncccc1CN1CCC(CCc2ccccc2)(COc2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
After dissolving 55 mg of 1-(2-methoxy-3-pyridinylmethyl)-4-(2-phenylethyl)piperidine-4-methanol, 51 mg of triphenylphosphine and 20 mg of 2-fluorophenol in 10 ml of tetrahydrofuran, the solution was cooled to 0° C. 0.13 ml of diethyl azodicarboxylate (40% toluene solution) was then added dropwise and the mixture was stirred overnight at room temperature. After stirring for 5 hours at 70° C. and cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (5 mg, 7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=2[CH3:26])=[C:4]([O:27][CH3:28])[CH:3]=1.[OH-].[Na+].OO.CC[O:35]C(C)=O>CS(C)=O.CO>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[O:27][CH3:28])[CH:12]=[CH:11][C:10]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:19]([CH3:26])[CH:20]=1)(=[O:35])[NH2:25]
Reactant: CCOC(=O)c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C#N)cc1C
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.1 %

Procedure:
To a solution of ethyl 1-(4-chloro-2-methoxyphenyl)-2-(4-cyano-2-methylphenyl)-1H-pyrrole-3-carboxylate (5.0 g, 12.7 mmol) in DMSO (10 mL) was added aqueous NaOH solution (2 mol/L, 1.0 mL) and 30% aqueous solution of H2O2 (1.0 mL), the reaction mixture was stirred at room temperature for four hours. TLC (EtOAc: MeOH=10:1) indicated that the starting material was consumed. Saturated aqueous Na2SO3 solution was added to quench the reaction, and the aqueous layer was extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatograph to afford the titled compound as a yellow oil (1.2 g, yield: 23.1%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]([CH:29]=[CH:30][N:31]=3)[C:24]([O:26]CC)=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>CO.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]([CH:29]=[CH:30][N:31]=3)[C:24]([OH:26])=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccnc(-c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(-c2cc(C(=O)O)ccn2)no1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.9 %

Procedure:
To a solution of the title compound of Example 24 (0.44 g, 1.0 mmol) in methanol (20 mL) was added a solution of lithium hydroxide (0.09 g, 2.0 mmol) in water (7 mL) and the reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was diluted with water (20 mL) and dichloromethane (20 mL). The layers were separated, the organic layer was discarded and the aqueous layer was acidified to pH 4 with 2M aqueous hydrochloric acid and then extracted with dichloromethane (2×20 mL). The combined organic layers were dried (MgSO4) and the solvent was removed in vacuo to give the title compound as a white solid (0.04 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C=O)cc3)c2)CC1
Yield: 60 %

Procedure:
Using 3.0 g (6.6 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester and 4-fluorobenzaldehyde (1.66 g, 13.3 mmol) and following the procedure of Example 42(b) afforded 2.2 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.18 (1H, m), 3.68 (1H, m), 6.75 (1H, d), 7.25 (4H, m), 7.50 (2H, s), 7.82 (2H, d), 7.95 (2H, d), 8.38 (1H, d), 9.94 (1H, s).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:18][CH:17]=1.O.[H-].[Na+]>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:13][C@:11]3([CH3:14])[O:12][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:10]3)[CH2:30][CH2:31]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(CCCOC2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CCC(OCCCc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C
Reaction time: 4 h
Yield: 19.2 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.103 g, 0.473 mmol) and 4-[3-(4-chlorophenyl)propoxy]piperidine (0.109 g, 0.430 mmol) were dissolved in DMF (10 ml), and the solution was stirred at 60° C. for 4 hours. The reaction mixture was added water and extracted with ethyl acetate. The organic phase was combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/3) to afford an oil. The oil was dissolved in DMF (2 ml). To the solution, sodium hydride (15 mg, 0.375 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 3 hours. To the reaction mixture, water was added, and the precipitates were filtered off, purified by silica gel column chromatography (methylene chloride/ethyl acetate=6/1) and then recrystallized from ethyl acetate/n-hexane=1/3 (6 ml) to afford (S)-2-{4-[3-(4-chlorophenyl)propoxy]-piperidin-1-ylmethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (36 mg, yield 19%) as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:38])(=[O:37])[N:22]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:23]([N:22]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1)(=[O:38])=[O:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)CC1
Product: O=S(=O)(c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Using general procedure H with the above aniline (970 mg, 1.81 mmol) and benzyl bromide (0.66 mL, 5.52 mmol) followed by general procedure C afforded N,N-dibenzyl-4-(benzyl-piperidin-4-yl-amino)-benzenesulfonamide as a white solid (679 mg, 72% over 2 steps).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=O)=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:20])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)N3CCOCC3)s2)cc1

Procedure:
The title compound was prepared from (R)-{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid and morpholine as described in Example 12. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.48 (s, 1H), 3.96 (t, 1H), 3.64 (s, 2H), 3.63-3.46 (m, 8H), 3.09 (s, 3H), 2.25-2.18 (m, 1H), 1.88-1.75 (m, 3H), 1.64 (m, 3H), 1.50 (m, 2H), 1.17 (m, 2H); HPLC-MS: m/z: 538 (M+1).
Reaction SMILES: CSC.COS([O:9][CH3:10])(=O)=O.[C:11]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19](=O)[C:20]([CH3:24])([CH3:23])[CH:21]=[CH2:22])=[CH:13][CH:12]=1.C[O-].[Na+]>C(#N)C>[C:11]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2([C:20]([CH3:24])([CH3:23])[CH:21]=[CH2:22])[CH2:10][O:9]2)=[CH:15][CH:16]=1
Reactant: COS(=O)(=O)OC
Reactant: C=CC(C)(C)C(=O)COc1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Reaction time: 96 h
Yield: 80.4 %

Procedure:
A solution of 41.9 ml (0.567 mol) of dimethyl sulphide in 50 ml of acetonitrile was added dropwise to a solution of 49.4 ml (0.518 mol) of dimethylsulphate in 250 ml of acetonitrile at 25° C., in the course of 2 hours, with external cooling. After the mixture had stood for 4 days at room temperature, 87.4 g (0.31 mol) of 5-(biphenyl-4-yloxy)-3,3-dimethylpent-1-en-4-one, dissolved in 90 ml of acetonitrile, were stirred in in the course of 1 hour. Thereafter, 31.6 g (0.58 mol) of sodium methylate were introduced at 25° C. After the mixture had been stirred for twelve hours at room temperature, the precipitated salt was filtered off, and the filtrate was concentrated. The oily residue was taken up in 500 ml of ethyl acetate, and the solution was washed with twice 500 ml of water and dried over anhydrous sodium sulphate. After the solution had been concentrated in vacuo, 73.4 g (80.4% of theory) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane were obtained as a colorless waxy mass. ##STR23##
Reaction SMILES: [N:1]1([C:10]2[O:11][C:12]([CH2:22][CH2:23][C:24]([N:26]3[CH2:30][CH2:29][S:28][CH2:27]3)=[O:25])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:31]1CCCC1.ClC1C=CC=C(C(OO)=O)C=1>O>[N:1]1([C:10]2[O:11][C:12]([CH2:22][CH2:23][C:24]([N:26]3[CH2:30][CH2:29][S:28](=[O:31])[CH2:27]3)=[O:25])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1)N1CCSC1
Reactant: C1CCOC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: O=C(CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1)N1CCS(=O)C1
Yield: 28 %

Procedure:
To a mixture of 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propanoyl}thiazolidine (25 mg) and tetrahydrofuran (10 mL) was added m-chloroperbenzoic acid (14.4 mg) with stirring under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, dried (MgSO4) and concentrated. The residue was introduced into preparative HPLC and purified to give 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propanoyl}thiazolidine-1-oxide (7.3 mg, yield 28%).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[O:9]1)(=O)=O.C([Mg]Br)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.O.[Cl-].[NH4+]>O1CCCC1.C(Cl)Cl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:7][C@H:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)=[CH:22][CH:23]=1
Reactant: O=S(=O)(OC[C@H]1CCc2ccccc2O1)C(F)(F)F
Reactant: COc1ccc(C[Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
(R)-(-)-3,4-Dihydro-2-trifluoromethanesulfonyloxymethyl-2H-benzopyran (23.0 g, 78 mmol) and copper (I) bromide dimethyl sulfide complex (2.8 g, 13 mmol) were dissolved in tetrahydrofuran (400 ml) under a nitrogen atmosphere and cooled to -10° C., 4-Anisylmagnesium bromide (215 ml of a 1M solution in tetrahydrofuran, 0.215 mol) was added dropwise over 30 minutes, keeping the temperature below -5° C. The solution was stirred for 3 hours at 0° C. and then slowly poured into a mixture of water (800 ml) containing ammonium chloride (96 g, 1.8 mol) and methylene chloride (400 ml). The layers were separated and the aqueous portion was extracted with methylene chloride (400 ml). The combined organics were washed with 10% ammonium chloride (2×400 ml), water (250 ml), and brine (250 ml). The methylene chloride layer was dried (MgSC4), filtered and concentrated in vacuo. The residue was purified on silica gel using hexanes/methylene chloride (1:1) as eluent to afford 18.5 g (92% yield) of the title product as an oil. [α]D -99.2° (c 1.7, MeOH); 1H NMR (300 MHz, CDCl3) δ1.6-1.7 (m, 1H), 1.9-2.0 (m, 1H), 2.7-2.8 (m, 3H), 3.1 (dd, 1H), 3.8 (s, 3H), 4.1 (m, 1H), 6.8 (m, 3H), 7.0 (m, 2H), 7.2 (m, 2H) .