Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[N:54]=[C:55]([CH:57]([NH2:65])[CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[NH:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([NH:65][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: NC(Cc1ccccc1)c1nc2ccc(Cl)cc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(Cc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 85 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chlorobenzimidazol-2-yl)-2-phenylethylamine in tetrahydrofuran. Yield: 85% (over 2 steps); Rf value: 0.52 (silica gel; dichloromethane/ethanol=9:1); C28H27ClN4O2 (487.01); mass spectrum: (M−H)−=485/487 (chlorine isotope).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:8]=1[F:16])C>[Pd].CO>[C:20]([O:19][C:17]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[F:16])[NH:13][C:4](=[O:3])[CH2:5]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)c1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(=O)Nc2cccc(F)c21
Reaction time: 1 h

Procedure:
A mixture of 2.06 g of N-(tert-butyloxycarbonyl)-N-(2-fluoro-6-nitrophenyl)glycine ethyl ester (XX, EXAMPLE 22, 2.06 g) and palladium on carbon (10%, 0.19 g) in methanol (150 ml) is shaken under hydrogen on a Parr apparatus at 37 psi for 1 hr. The catalyst is then filtered off and p-toluenesulfonic acid 0.016 g) is added. The solution is stirred at 80° for 1 hr and then at 20°-25° overnight The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel (200 ml) eluting with ethyl acetate/dichloromethane (5/95). The appropriate fractions are pooled and concentrated to give the title compound, mp 155°-156°; MS (m/z) at 266; NMR (CDCl3) 1.48, 6.70, 6.84, 7.12 and 8.61 δ.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+].FC(F)(F)C(O)=O>CO>[CH2:32]([O:31][C:29]([NH:28][C@@H:4]([CH2:5][NH:6][C:7]([CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:13][CH2:14]1)=[O:8])[C:3]([OH:39])=[O:2])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)[C@H](CNC(=O)C1CCN(c2cccc(NC3=NCCCN3)c2)CC1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H](CNC(=O)C1CCN(c2cccc(NC3=NCCCN3)c2)CC1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product obtained in Example 1 in methanol (100 ml) is added 2M aqueous sodium hydroxide solution (100 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is neutralized with trifluoroacetic acid, and purified by CHP-20 (manufactured by Mitsubishi Chemical Corporation, highporous styrene resin: 75–150 μm) (eluent: gradient, 30% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound (6.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[OH:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:26]3[CH2:27][CH2:28][CH2:29][CH:24]([OH:23])[CH2:25]3)=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reactant: OC1CCCNC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCN3CCCC(O)C3)ccc21
Yield: 66.9 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (50 mg, 0.17 mmol) and 3-hydroxypiperidine (300 mg, 2.67 mmol) are reacted to provide the title compound (45 mg, 67%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1.[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:17][CH2:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCCc1cccnc1
Agent: [H-]
Agent: [Na+]
Product: Clc1cncc(OCCc2cccnc2)n1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol) and 2-(3-pyridyl)ethanol (405 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). The crude product, obtained as an oil (0.62 g, 88% yield), was used directly in the next step. MS m/z 235 (M)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[CH2:16][C:15]3[N:14]=[C:13]([CH3:17])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:31])=CC=1>C1COCC1.O>[CH3:17][C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:4]3[NH:3][C:2](=[S:31])[NH:1][CH:5]=3)[CH2:16][C:15]=2[N:14]=1
Reactant: Cc1ccc2c(n1)CC(Cc1c[nH]cn1)CC2
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)CC(Cc1c[nH]c(=S)[nH]1)CC2
Reaction time: 5 h

Procedure:
A solution of 7-(1H-imidazol-4-ylmethyl)-2-methyl-5,6,7,8-tetrahydro-quinoline (Intermediate 200A5) (5.16 g, 22.7 mmol) in THF (20 mL) and water (20 mL) was treated with NaHCO3 (11.5 g, 136 mmol) and phenyl chlorothionoformate (7.9 mL, 57 mmol). Stirring was continued for 5 h at rt. The mixture was diluted with water and extracted with ethyl acetate (2×). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (10 mL) and treated with NEt3 (140 mL) for 18 h. The mixture was evaporated to dryness, diluted with water and extracted with chloroform:isopropanol (3:1). The organic portions were combined, dried over MgSO4, filtered and concentrated onto SiO2. The solvent was removed under vacuum and the product was purified on a column of SiO2 with a gradient elution of 60% acetone:hexanes to 100% acetone to give enantiomeric 4-(2-methyl-5,6,7,8-tetrahydro-quinolin-7-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 201, racemic mixture) as a white solid, 3.0 g (51%). Individual enatiomers can be obtained from the racemic mixture as described below.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19]([NH:21][CH2:22][CH2:23][OH:24])[CH3:20]>C(Cl)Cl>[CH2:19]([N:21]([CH2:22][CH2:23][OH:24])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Benzylchloroformate (5.91 g, 34.67 mmol) and triethylamine (5.2 ml) were added sequentially to a solution of 2-(ethylamino)ethanol (3.0 g, 33.66 mmol) in DCM (180 ml) at 0° C. The ice bath was removed and the reaction mixture was allowed to stir overnight at ambient temperature. The solution was washed with 10% citric acid (100 ml) and H2O (2×100 ml) and concentrated in vacuo. The organic phase was dried (MgSO4), concentrated under reduced pressure, and the concentrate was purified by column chromatography (ISCO, silica gel column, eluting with 60→100% EtOAc/hexanes for 14 minutes) to give the title compound (7.29 g, yield: 97%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][NH2:37])=[CH:28][N:27]=1>>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)=[CH:28][N:27]=1
Reactant: NNc1cncc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cncc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and isoquinolin-4-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:7]2=[N:6][N:5]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1C=CC=CC=1>[NH2:1][C:2]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:7]2=[N:6][N:5]=1)=[S:29]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2C(N)=O)C1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2c(nnc2C(N)=S)C1
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethylethyl 3-(aminocarbonyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I111) (0.2 g, 0.748 mmol) and Lawesson's reagent (0.151 g, 0.374 mmol) in benzene (7.48 ml) was heated at 80° C. for 2 h, left to stand over the weekend at RT and then heated for a further 6 h at 80° C. The mixture was cooled, concentrated and then chromatographed (0-5% MeOH in DCM) to give the desired product as a yellow solid in 99 mg.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>ClCCl>[CH2:13]([Cl:1])/[CH:14]=[C:15](\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])/[CH3:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)=CCC/C(C)=C\CO
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C\CCl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of N-chlorosuccinimide (10.0 g) and dimethylsulfide (6.56 ml) in dichloromethane (200 ml) was added nerol (7.71 g) while being cooled with ice. The mixture was stirred at 0° C. for 4 hours. The reaction solution was washed with brine and dried over sodium sulfate anhydride. Then, the solvent was evaporated, thereby yielding a raw product of neryl chloride. In a manner similar to Reference Example 1, this raw product was reacted with methyl 4- hydroxybenzoate (7.61 g) and then hydrolyzed to yield 7.47 g (55%) of 4- neryloxybenzoic acid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH3:14].[Si:24]([N:31]1[CH:34]([CH2:35][CH:36]=[O:37])[CH2:33][C:32]1=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CCCCCC.O1CCCC1>[Si:24]([N:31]1[CH:34]([CH2:35][CH:36]([OH:37])[CH2:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:33][C:32]1=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Reactant: CC(=O)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
To a flame dried, 50 ml, 3-neck flask fitted with a N2 inlet, magnetic stirrer, addition funnel, and serum cap are added anhydrous tetrahydrofuran (THF) (10.5 ml) and diisopropyl amine (0.579 ml, 4.13 mmol). The solution is cooled in an ice-methanol bath under N2 and treated with 2.4 N n-butyl lithium in hexane (1.72 ml). After being stirred at -10° for 15 mins, the solution is cooled to -78° and treated dropwise over 9 mins with a solution of benzyl acetate (0.620 g, 4.13 mmol) in anhydrous THF (3.5 ml). After stirring 15 more mins at -78° C. the reaction mixture is treated dropwise over 13 mins with a solution of N-(t-butyldimethylsilyl)-4-(2-oxoethyl)-azetidin-2-one (0.894 g, 3.93 mmol) in anhydrous THF (6 ml). The reaction mixture is stirred at -78° an additional 15 mins and then quenched with 2.5 N HCl (6 ml). EtOAc (100 ml) is added and the organic phase is separated, washed with H2O (2×20 ml), 5% NaHCO3 (20 ml) and brine, dried with MgSO4, and filtered. The filtrate is evaporated i.v. and the residue stripped with φH (benzene) to yield N-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one (1.432 g) as an oil: ir (neat) 2.87, 5.73, 5.79, 7.57, 7.96, 8.39, 11.92, and 12.16 cm-1 ; mass spectrum m/e 362, 320, 278, 170 and 128.
Reaction SMILES: [OH:1][CH:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([O:5]CC)=[O:4].[OH-].[K+].O1CC[CH2:28][CH2:27]1.CO>O>[CH2:27]([O:1][CH:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:3]([OH:5])=[O:4])[CH3:28]
Reactant: CCOC(=O)C(O)c1c(-c2ccccc2)n(C)c2ccccc12
Reactant: C1CCOC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(C(=O)O)c1c(-c2ccccc2)n(C)c2ccccc12
Temperature: 60 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
A solution of ethyl hydroxy-(1-methyl-2-phenyl-1H-indol-3-yl)-acetate (8b) (20 mg, 0.055 mmol) and potassium hydroxide (50 mg, 0.89 mmol) in a mixture of water (2 mL), tetrahydrofuran (2 mL) and methanol (0.5 mL) was stirred at 60° C. for 12 hours. Water (10 mL) was added to the reaction mixture which was washed with diethyl ether (10 mL). The aqueous layer was acidified to pH 2 with an aqueous solution of hydrochloric acid 0.5N and extracted with dichloromethane. The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (dichloromethane/ethanol) to afford unexpected ethoxy-(1-methyl-2-phenyl-1H-indol-3-yl)-acetic acid (example 8) (5.3 mg, 0.017 mmol, 31%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:33][C:34](O)=[O:35])[CH:29]=[CH:30][C:31]=4[F:32])=[CH:24][CH:23]=[C:22]([CH:37]4[CH2:39][CH2:38]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C1COCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:33][CH2:34][OH:35])[CH:29]=[CH:30][C:31]=4[F:32])=[CH:24][CH:23]=[C:22]([CH:37]4[CH2:39][CH2:38]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(C2CC2)ccc1-c1cc(CC(=O)O)ccc1F
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(C2CC2)ccc1-c1cc(CCO)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-cyclopropylpyridin-3-yl]-4-fluorophenyl}acetic acid (32.8 mg, 0.055 mmol) in THF (2 mL) was added BH3 (0.22 mL of a 1M solution in THF, 0.22 mmol). The reaction was stirred at room temperature for 1 hour and then quenched with water (2 mL). The reaction was diluted with EtOAc (35 mL) and washed with water and brine (10 mL each). The organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 100% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({6-cyclopropyl-3-[2-fluoro-5-(2-hydroxyethyl)phenyl]pyridin-2-yl}methyl)-4-methyl-1,3-oxazolidin-2-one. Rf=0.44 (25% EtOAc/hexanes). LCMS=583.4 (M+H)+ 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H), 7.69 (s, 2H), 7.48 (d, J=7.8 Hz, 1H), 7.08-7.27 (m, 4H), 5.55 (d, J=7.8 Hz, 1H), 4.93 (bs, 1H), 3.82-4.10 (m, 4H), 2.85 (t, J=5.8 Hz, 2H), 2.08 (m, 1H), 1.02-1.06 (m, 4H), 0.71 (d, J=6.7 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=O)(C)(C)C.C(OC([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27]O)=O)(C)(C)C.N.[ClH:30]>>[ClH:30].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:25]1[CH:26]=[N:22][C:27]([Cl:30])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: Cl
Agent: N
Product: Clc1ccc(OC[C@H]2CCCN2)cn1

Procedure:
Following the procedures described in Example 45 steps a-c, substituting (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol for the (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol of step 45a thereof, the title compound was prepared. mp 157-159° C. MS (DCI/NH3) m/e: 213/215 (M+H)+ and 230/232 (M+NH4)+. 1H NMR (D2O, 300 MHz) d: 8.10 (d, J=3.0 Hz, 1H), 7.53-7.43 (m, 2H), 4.45 (dd, J=10.7, 7.7 Hz, 1H), 4.15-4.08 (m, 1H), 3.41 (t, J=7.2 Hz, 2H), 2.34-1.88 (m, 4H). Anal. Calc. for C10H14Cl2N2O.0.3 HCl: C, 46.18; H, 5.54; N, 10.77; Found C, 46.35; H, 5.51; N, 10.66.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C1(C)C(S(O)(=O)=O)=CC=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13]
Reactant: C1=COCCC1
Reactant: OCCOCCOCCOCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: OCCOCCOCCOCCOC1CCCCO1
Reaction time: 3.5 h

Procedure:
To a 20 mL solution of methylene chloride containing tetraethylene glycol (15 mmol, 2.91 g) and toluenesulfonic acid (20 mg) was added dropwise via syringe 3,4-dihydro-2H-pyran (12 mmol, 1.0 g, 1.1 mL). The reaction mixture was stirred for 3.5 h, and the solvent was removed by rotary evaporation. Mono-tetrahydropyran 1 was isolated by flash chromatography on silica eluting with 1:1 tetrahydrofuran/methylene chloride, affording 1.82 g of a clear, colorless oil (44% yield). 1H NMR (400 MHz, CDCl3): δ4.61 (dd, 1H, J1 =J2 =4 Hz), 4.6-4.8 (m, 2H), 3.69 (t, 2H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:10][C:9]([CH:7]1[CH2:6][C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[C:3]([Cl:14])[C:4]=2[O:8]1)=[O:11])[CH3:21]
Reactant: CCO
Reactant: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1

Procedure:
A solution of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (70 g.) conc. sulfuric acid (2 ml.) and ethanol (250 ml.) is refluxed for 2 hours. The ethanol is distilled at reduced pressure and the residue is suspended in saturated sodium bicarbonate and extracted with ether. The ether solution is washed with brine, dried over magnesium sulfate and the ether distilled at reduced pressure. The 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester is used without further purification in the following synthesis.
Reaction SMILES: Cl.N[C@@H]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[OH:9].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].IC1CCOCC1>C(O)(C)C.[Ni](I)I>[O:9]1[CH2:8][CH2:7][CH:6]([C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[CH2:5][CH2:4]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: I[Ni]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: N#Cc1ccc(C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
186 mg (0.594 mmol) of nickel(II) iodide, 90 mg (0.594 mmol) of trans-2-aminocyclohexanol hydrochloride and 3.63 g (19.8 mmol) of sodium hexamethyldisilazide were added to a solution of 2.91 g (19.8 mmol) of 4-cyanophenylboronic acid [M. Nishimura et al., Tetrahedron 2002, 58 (29), 5779-5788] in 20 ml of isopropanol. The suspension thus obtained was stirred at RT under an argon atmosphere for 5 min. Then 2.1 g (9.90 mmol) of 4-iodotetrahydropyran [Heuberger et al., J. Chem. Soc. 1952, 910] were added. After the reaction mixture had been stirred at a temperature of 75° C. for 15 h, it was cooled to RT and substantially freed of inorganic salts with dichloromethane by filtration through approx. 50 g of silica gel. The crude product was purified by MPLC (silica gel, eluent: dichloromethane). 986 mg (53% of theory) of the title compound were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:9]([O:30][CH3:31])=[CH:10][C:11]([O:28][CH3:29])=[C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:13]=1)=[O:7].Cl.[NH:33]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[C:36](=[O:43])[NH:35][C:34]1=[O:44].[I-].[Na+].C(N(CC)CC)C>CN(C=O)C>[O:44]=[C:34]1[NH:35][C:36](=[O:43])[C:37]2([CH2:42][CH2:41][N:40]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]3[C:9]([O:30][CH3:31])=[CH:10][C:11]([O:28][CH3:29])=[C:12]([NH:14][S:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[CH:13]=3)=[O:7])[CH2:39][CH2:38]2)[NH:33]1
Reactant: O=C1NC(=O)C2(CCNCC2)N1
Reactant: COc1cc(OC)c(C(=O)CCCCCl)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)CCCCN2CCC3(CC2)NC(=O)NC3=O)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 115 °C
Yield: 38.2 %

Procedure:
A mixture of N-[5-(5-chloropentanoyl)-2,4-dimethoxyphenyl]-4-trifluoromethylbenzenesulfonamide (0.8 g, 1.7 mmol), prepared as in Example 14, 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (0.55 g, 2.7 mmol), prepared as in Example 16, sodium iodide (0.4 g, 2.7 mmol), triethylamine (0.5 g, 5 mmol) in DMF (approximately 5 mL) was heated 16 hours at 115° C. The mixture was concentrated and the residue was stirred with water and the solids were collected, dried and purified by column chromatography eluting with methylene chloride/methanol+ammonium hydroxide (95:5) to give N-{5-[5-(2,4-dioxo -1,3,8-triazaspiro[4.5]dec-8-yl)pentanoyl]-2,4-dimethoxyphenyl}-4-trifluoromethylbenzenesulfonamide (0.4 g, 0.65 mmol), m.p. 226° C. The free base was recrystallized from a solution of hydrogen chloride in ethanol to give N-{5-[5-(2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl)pentanoyl]-2,4-dimethoxyphenyl}-4-trifluoromethylbenzenesulfonamide hydrochloride (0.37 g, 0.57 mmol), m.p. 277°-278° C. (dec).