Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1.[SH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CN(C)C=O>[N:23]1[CH:24]=[CH:25][C:20]([S:19][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[CH2:6][CH2:5]2)=[CH:21][CH:22]=1
Reactant: O=C(Oc1ccccc1)N1CCC(Cl)CC1
Reactant: Sc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)N1CCC(Sc2ccncc2)CC1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 81.8 %

Procedure:
60% Sodium hydride dispersion in a mineral oil (2.40 g) was slowly added to an ice-cooled solution of phenyl 4-chloro-1-piperidine-carboxylate (15.2 g) and 4-mercaptopyridine (6.66 g) in dry N,N-dimethylformamide (150 ml) with stirring under nitrogen gas. The mixture was stirred at the same temperature for 30 minutes and then at 80° C. for 4.5 hours. The resultant reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, and concentrated to dryness in vacuo. The crystalline residue was recrystallized from a mixture of n-hexane and isopropanol to give phenyl 4-[(4-pyridyl)thio]-1-piperidine-carboxylate (15.4 g) as colourless crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH:18][C:13]=3[O:12][C:11]2([CH3:28])[CH3:27])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([N:19]([CH3:31])[C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH:18][C:13]=3[O:12][C:11]2([CH3:28])[CH3:27])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)c1ccc(C2c3cc(NC(=O)CC(C)(C)C)ccc3OC2(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(C2c3cc(N(C)C(=O)CC(C)(C)C)ccc3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (110 mg, 290 mmol) obtained in Example 320 in DMF (3 mL) was added sodium hydride (a 60% dispersion in liquid paraffin, 12.8 mg, 319 mmol) at 0° C. and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (8.0 g, 319 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the product was extracted with diisopropyl ether. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 47 mg (yield: 41%) of the title compound. Melting point: 78-79° C. (ethyl acetate-hexane).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.Br[CH2:13][C:14]([O:19][CH3:20])([O:17][CH3:18])[CH2:15]Br.O>CN(C=O)C>[CH3:18][O:17][C:14]1([O:19][CH3:20])[CH2:15][C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)([C:10]#[N:11])[CH2:13]1
Reactant: N#CCc1cccnc1
Reactant: COC(CBr)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(OC)CC(C#N)(c2cccnc2)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a stirred suspension of NaH (1.466 g, 36.6 mmol, 60% in mineral oil) in DMF (25 mL) was added 2-(pyridin-3-yl)acetonitrile (1.954 mL, 18.32 mmol) followed by 1,3-dibromo-2,2-dimethoxypropane (4 g, 15.27 mmol) and the reaction mixture was warmed to 60° C. and stirred for 12 h. The reaction mixture was cooled to RT, poured into water (250 mL) and extracted with EtOAc (3×50 mL). The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 50% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 311A as a white solid (2 g, 60%). MS(ES): m/z=219.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.71 (dd, J=0.8, 2.6 Hz, 1H), 8.58 (dd, J=1.7, 4.7 Hz, 1H), 7.89 (s, 1H), 7.51-7.45 (m, 1H), 3.19 (s, 3H), 3.08 (s, 3H), 2.89 (s, 1H), 2.83 (s, 1H), 2.78 (s, 1H), 2.73 (d, J=0.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH3:14])[CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:13][CH3:14])[CH2:9][CH2:10][C:11]([OH:17])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(CCCO)c1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(CCC(=O)O)c1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chloro-phenyl)-4-methoxy-butan-1-ol (120.0 mg, 0.56 mmol) in 6 mL acetone was added dropwise at room temperature 0.6 mL of Jones reagent. After stirring an additional 30 min water was added and the mixture extracted with DCM (3×20 mL). The combined DCM layers were washed with water (2×10 mL) and dried over Na2SO4. The solvent was evaporated under reduce pressure and the crude product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOCCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) solution of N-benzyloxycarbonyl-ethanolamine (12.03 g, 61.6 mmol) in dry dichloromethane (50 ml) was added diisopropylethylamine (32.2 ml, 184.9 mmol) and 2-methoxyethoxymethyl chloride (16.9 ml, 147.9 mmol) with stirring. The mixture was allowed to warm to room temperature then stirred for a further 3 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and washed successively with 1M hydrochloric acid, sat. aq. sodiumhydrogen carbonate and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to porvide the title compound as a orange/yellow oil which was used without further purification. 1H--NMR; δ(CDCI3), 7.35 (5H, m), 5.45 (1H, m), 5.11 (2H, s), 4.72 (2H, s), 3.67 (4H, m), 3.55 (2H, m) and 3.38 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([OH:13])=O.[Cl-].[CH2:19]([O:21][C:22](=[O:34])[CH:23]([OH:33])[CH:24]([NH3+:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20]>>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:32][CH:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:23]([OH:33])[C:22]([O:21][CH2:19][CH3:20])=[O:34])=[O:13]
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1F
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting (R)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxylic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+=443.2.
Reaction SMILES: Br[CH2:2][CH3:3].[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:3]
Reactant: CCBr
Reactant: CCOC(=O)c1c(C(=O)OCC)c(O)c2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(=O)OCC)c(OCC)c2ccccc2c1O
Yield: 60.5 %

Procedure:
Bromoethane (0.359 g, 3.29 mmol) was added to a stirred solution of diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate (1 g, 3.29 mmol) and potassium carbonate (0.454 g, 3.29 mmol) in acetone (25 ml). The reaction mixture was refluxed for 24 hours under an atmosphere of argon. The resulting mixture was evaporated and the residue was partitioned between 2× ethylacetate and water. The combined organics were washed with water and dried over magnesium sulphate. The orange oil was purified by chromatography on silica gel, eluting with ethyl acetate (0-10%) in hexane to give the title compound as a clear oil (0.661 g, 1.99 mmol). LC/MS: Rt=3.63, [MH]− 331.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:27][CH2:28][CH3:29])[NH:14][C:15]=1[C:16]([O:18][CH2:19][C:20]1[O:21][C:22](=[O:26])[O:23][C:24]=1[CH3:25])=[O:17])([CH3:10])[CH3:9].[C:30]([N:49]1[C:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:60]2[CH:67]=[CH:66][C:63]([CH2:64]Br)=[CH:62][CH:61]=2)=[N:52][N:51]=[N:50]1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C.C(OCC)(=O)C>[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]([CH2:64][C:63]2[CH:62]=[CH:61][C:60]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[C:53]3[N:49]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:50]=[N:51][N:52]=3)=[CH:67][CH:66]=2)[C:15]=1[C:16]([O:18][CH2:19][C:20]1[O:21][C:22](=[O:26])[O:23][C:24]=1[CH3:25])=[O:17])([CH3:9])[CH3:10]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Yield: 49.7 %

Procedure:
A suspension of 0.97 g of potassium carbonate in 100 ml of N,N-dimethylacetamide was warmed at 60° C., and then a solution of 1.14 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 31) and 2.35 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 50 ml of N,N-dimethylacetamide was added dropwise to the warm suspension, whilst stirring. The reaction mixture was stirred at 60° C. for 3.5 hours, and it was then diluted with ethyl acetate. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.4 g of the title compound as an amorphous solid. This product was crystallized from diisopropyl ether, to give pure title compound, melting at 98°-99° C. (with decomposition).
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[CH:5]1>C(Cl)Cl>[NH2:29][CH:14]([CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][CH:5]=1)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClCCl
Product: COc1ccccc1CCC(=O)NCC(N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid (9.0 ml, 238.540 mmoles) was added to a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane (14.11 g, 23.763 mmoles) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10](Br)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[CH:41]=2)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1Br
Reactant: OB(O)c1cccc(Cl)c1
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(Cl)c1
Yield: 55 %

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-bromo-isoxazole-3-carboxylic acid ethylamide (60 mg, 0.11 mmol), and 3-chlorobenzene boronic acid (23 mg, 1.3 equiv.) were coupled together using the suzuki method previously described to provide 35 mg (55% yield) of the crude as a brown powder which was taken on to the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][O:32][CH2:33][C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:35]4[C@H:34]([CH2:33][O:32][CH3:31])[CH2:38][O:37][C:36]4=[O:39])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COC[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 71.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 118 and (R)-4-methoxymethyloxazolidin-2-one (65.6 mg) described in Preparation Example 38, the title compound (194.2 mg) was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]/[O:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)([CH3:29])([CH3:28])[CH3:27]>[N+](C)([O-])=O.O>[CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a solution of (E)-N-methyl-2-(2-phenoxyphenyl)2-methoxyiminoacetamide (300 mg) in nitromethane (3 ml), aluminium chloride (423 mg) and t-butyl chloride (147 mg) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with diethyl ether. The solvent was dried and evaporated, and the residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate to give 375 mg of the objective compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7].[C:34]([N:37]1[CH2:42][CH2:41][CH:40](C(O)=O)[CH2:39][CH2:38]1)(=[O:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([N:37]1[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]2)=[O:7])[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(NCCCNC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)CC1
Yield: 70.6 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide prepared in Example 29 (0.18 g, 0.37 mmol) was reacted with 1-acetylpiperidine-4-carboxylic acid (Lancaster) (0.7 g, 0.58 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propyl]-amide as a white solid (0.16 g, 67%).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].O>N1C=CC=CC=1>[C:1]1([NH:7][NH:8][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: NNc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NNc1ccccc1)c1ccccc1F
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred solution of 50.0 g of phenylhydrazine in 280 ml of dry pyridine, cooled to about 5° was added, dropwise, 80.0 g of o-fluorobenzoyl chloride. After coming to ambient temperature, the reaction mixture was stirred for about 2 hours, and then poured into water. The resultant precipitate was recrystallized from toluene to yield 82 g (77.5%) of 2-fluorobenzoic acid, 2-phenylhydrazide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:24](=[O:31])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH3:2]
Reactant: O=C(O)c1cccnc1
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)c1cccnc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Temperature: -30 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To solution of 12.7 ml (1 M in THF, 13 mmol) of lithium hexamethyldisilylazide cooled to −78° C. under Ar was added, drop wise, a solution of 3.8 g (12 mmol) of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) in 20 ml of THF. The mixture was brought to −30° C. and stirred for 1 h. Separately, 0.6 g (5 mmol) of nicotinic acid was added to 0.8 g (5 mmol) of 1,1-carbonyl diimidazole in 10 ml of CH2Cl2 and the mixture stirred for 1 h after which time it was concentrated to dryness. The crude residue was re-dissolved in 10 ml of THF under Ar and cooled to −30° C. The enolate solution of intermediate 7B (described above) was then added by cannula to the crude imidazolide solution and the mixture was allowed to reach room temperature. After 2 h the reaction was diluted with EtOAc, washed with saturated ammonium chloride solution, the organic phase dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:1] afforded 1.2 g (58%) of the title compound as an orange oil. MS: 437.2 (MH+).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:17]=1.[CH3:36][NH:37][C:38]1[N:43]=[C:42]([CH:44](O)[CH3:45])[CH:41]=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:36][NH:37][C:38]1[N:43]=[C:42]([CH2:44][CH2:45][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C@H:23]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CNc1cccc(C(C)O)n1
Reactant: CCOC(=O)C[C@H](Cc1ccc(O)cc1)c1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](Cc1ccc(OCCc2cccc(NC)n2)cc1)c1cccnc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Diisopropyl azodicarboxylate (7.8 mL, 39.8 mmole) was added dropwise to a solution of ethyl (S)-4-(4-hydroxyphenyl)-3-(pyridin-3-yl)butanoate (9.455 g, 33.1 mmole), 6-(methylamino)-2-pyridylethanol (6.06 g, 39.8 mmole), and triphenylphosphine (10.44 g, 39.8 mmole) in anhydrous THF (150 mL) at 0° C. The mixture was allowed to warm to RT as the bath warmed. After 18 hr the reaction was concentrated and the residue was flash chromatographed on silica gel (3% MeOH in 1:1 EtOAc/CHCl3) to afford the title compound (9.2 g, 66%) as a viscous yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J=4.8, 1.6 Hz, 1 H). 8.39 (d, J=1.9 Hz, 1 H), 7.31-7.45 (m, 2 H), 7.13-7.21 (m, 1 H), 6.91 (d, J=8.6 Hz, 2 H), 6.77 (d, 3=8.6 Hz, 2 H), 6.53 (d, J=7.3 Hz, 1 H), 6.24 (d, J=8.2 Hz, 1 H), 4.43-4.58 (m, 1 H), 4.26 (t, J=7.0 Hz, 2 H), 3.92-4.05 (m, 2 H), 3.32-3.45 (m, 1 H), 3.04 (t, J=7.0 Hz, 2 H), 2.89 (d, J=5.3 Hz, 3 H), 2.88 (dd, J=13.7, 7.2 Hz, 1 H), 2.82 (dd, J=13.7, 7.8 Hz, 1 H), 2.70 (dd, J=15.6, 6.3 Hz, 1 H), 2.59 (dd, J=15.6, 9.0 Hz, 1 H), 1.11 (t, J=7.1 Hz, 3 H); MS (ES) m/e 420 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][C:23]=1[C:37]([OH:40])([CH3:39])[CH3:38].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)=[CH:24][C:23]=1[C:37]([OH:40])([CH3:38])[CH3:39]
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: CC(C)(O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2ccc(Cl)c(C(C)(C)O)c2)n1
Yield: 19.9 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0.58 g), 2-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-ol (0.63 g), Cs2CO3 (1.36 g) and tetrakis(triphenylphosphine)palladium (0) (50 mg) in water (8 mL)/DME (32 mL) is heated at 90° C. for 16 h. The solution is poured into water and extracted with EtOAc (2×200 mL). The organic layer is dried over sodium sulfate, filtered, evaporated in vacuo. The residue is chromatographed on silica gel eluting with EtOAc to afford 2-(2-chloro-5-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-propan-2-ol (162 mg, Example 98). MS: 466 (M+H); 1H NMR (300 MHz, DMSO) □8.2 (m, 1H); 7.8, (d, 1H, J=0.3 Hz); 7.5-7.7 (m, 2H); 7.4 (d, 2H, J=0.4 Hz); 7.3 (m, 1H); 7.3 (s, 1H); 6.6 (s, 1H); 4.2 (s, 3H); 4 (s,3H); 3.8 (m, 2H); 3.05 (t, 2H); 1.55 (s, 6H). IC50=110 nM