Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]([O:31]CC)=[O:30])[CH:25]=4)[CH:20]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO>[CH3:1][C:2]1([CH3:34])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]([OH:31])=[O:30])[CH:25]=4)[CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc2cc(-c3ccc4c(c3)C(c3ccc(C)cc3)=CCC4(C)C)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(-c4ccc5cc(C(=O)O)ccc5c4)cc32)cc1
Temperature: 0 °C
Yield: 19.4 %

Procedure:
A solution of ethyl 5',6'-dihydro-5',5'-dimethyl-8'-(4-methylphenyl)-[2,2'-binaphthalene]-6-carboxylate (Compound 64) 0.19 g, 0.43 mmol), EtOH (8 ml) and 1N aqueous NaOH (2 ml) was heated to 60° C. for 3 hours. The solution was cooled to 0° C. and acidified with 1N aqueous HCl. The product was extracted into ethyl acetate, and the organic layers combined, washed with water, brine, dried (MgSO4), filtered and the solvent removed in-vacuo. The residue was recrystalized from THF/ethyl acetate at 0° C. to give 35 mg of pure material. The mother liquor was concentrated under reduced pressure and the residue purified by silica gel chromatography (100% ethyl acetate) to give an additional 125 mg of the title compound (overall yield=160 mg, 90%) as a colorless solid. 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 8.11 (d, 1H, J=8.7 Hz), 7.96-7.82 (overlapping d's, 3H),7.65 (d, 2H, J=7.6 Hz), 7.50 (d, 1H, J=7.9 Hz), 7.28 (s, 1H), 7.26 (d, 2H, J=8.3 Hz), 7.21 (d, 2H, J=8.3 Hz), 6.01 (t, 1H, J=4.5 Hz), 3.34 (br s, 1H), 2.31 (s, 3H), 2.31 (d, 2H, J=4.5 Hz), 1.31 (s, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=1.[N:25]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:28]2[CH2:29][CH2:30][CH2:31][N:25]([CH2:32][CH2:33][OH:34])[CH2:26][CH2:27]2)=[O:24])[CH:17]=1
Reactant: OCCN1CCCNCC1
Reactant: Cn1nc(C(=O)O)cc1-c1ccccc1-c1cc2ccccc2o1
Product: Cn1nc(C(=O)N2CCCN(CCO)CC2)cc1-c1ccccc1-c1cc2ccccc2o1
Yield: 5 %

Procedure:
In analogy to the procedure described in Example 12D], 5-(3-benzofuran-2-yl-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid and 2-(1,4-diazepan-1-yl)ethan-1-ol gave [5-(3-benzofuran-2-yl-phenyl)-1-methyl-1H-pyrazol-3-yl]-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]-methanone in 5% yield as light yellow oil. MS: 445.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1

Procedure:
The phenyl bromide (106) (100 mg, 0.25 mmol) was coupled to 3-fluoro-phenylboronic acid (39 mg, 0.28 mmol) using Method E. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](=[O:12])[CH3:11].[BH4-].[Na+]>CO.CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH:10]([OH:12])[CH3:11]
Reactant: CC(=O)Cc1c(Cl)cccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
General Procedure GG: To a solution of 2,6-dichlorophenylacetone (500.00 mg, 2.46 mmol) in MeOH (5.0 mL) was added sodium borohydride (112 mg, 2.96 mmol) in small portions. The reaction mixture was allowed to stir overnight at rt. The reaction was monitored by TLC analysis on silica gel plates using Hexane/EtOAc (70:30) as eluent. The reaction mixture was quenched with aq. sat. NH4Cl (15 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to give a colorless oil. The crude material was purified by silica gel chromatography using Hexane/EtOAc (70:30) as eluent to obtain the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.33 (d, J=6.1 Hz, 3H), 1.49 (d, J=5.3 Hz, 1H), 3.08-3.22 (m, 2H), 4.18-4.29 (m, 1H), 7.09-7.14 (m, 1H), 7.31 (s, 1H), 7.33 (s, 1H).
Reaction SMILES: [N:1]1([C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H]1[BH2][H][BH2]1.Cl>C1COCC1>[N:1]1([CH2:6][C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([C@H]1CCCN1)N1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: C1CN[C@@H](CN2CCCC2)C1
Yield: 73 %

Procedure:
A mixture of (+)-carbobenzyloxy-D-proline (1.5 g, 6 mmol), EDC (2.3 g, 12 mmol), HOBt (800 mg, 6 mmol), TEA (1.5 mL) and pyrrolidine (853 mg, 12 mmol) in DMF (20 mL) was stirred at rt for 18 hr. The reaction was diluted with water and sodium bicarbonate, extracted with dichloromethane (3×). The combined DCM was concentrated and purified on a silica gel column to give (R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester. (R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester was hydrogenated using Pd/C in methanol at ambient temperature for 20 hr to provide pyrrolidin-1-yl-(R)-pyrrolidin-2-yl-methanone. To a solution of pyrrolidin-1-yl-(R)-pyrrolidin-2-yl-methanone (1.2 g, 7.1 mmol) in THF (10 mL) at 0° C. was added B2H6 (10 mL, 10 mmol). The mixture was heated to reflux for 16 hr. The reaction was acidified with HCl and concentrated. The residue was basified to pH 10 with 2N NaOH and extracted with 5% methanol in DCM. The organic layer was concentrated and purified on a silica gel column to give 800 mg (73%) of (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine.
Reaction SMILES: [OH-:1].[K+].Br.[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][C@@H:17]([C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16]3)=[CH:12][C:7]=2[CH2:6][CH2:5]1.O>CC(O)(CC)C>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][C@@H:17]([C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]([NH2:22])=[O:1])[CH2:16]3)=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: [OH-]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3c(c2)CCO3)C1
Agent: Br
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3c(c2)CCO3)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A slurry of potassium hydroxide (48.7 g, 0.87 moles) in 2-methylbutan-2-ol (175 mL) is heated at 50-60° C. After 1 hour (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile hydrobromide (VI) (25.0 g, 0.051 moles) is added and the resulting mixture is heated at reflux for 20 hours. The reaction mixture is cooled to ambient temperature and water (125 mL) is added maintaining the temperature below 30° C. The mixture is stirred for 15 minutes, then allowed to settle and the organic phase is separated. The organic phase is washed with aqueous sodium chloride (125 mL of 5% w/w solution) to provide a solution of (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide as a solution in 2-methylbutan-2-ol (VII). The solution is heated at reflux in the presence of Amberlite® resin (37.5 g) for 22 hours then cooled to ambient temperature. The Amberlite® resin is removed by filtration and washed with 2-methylbutan-2-ol (25 mL). The combined 2-methylbutan-2-ol phases are concentrated and essentially replaced by toluene to a final volume of approximately 140 mL. The toluene solution is cooled to 0° C. during which time crystallisation occurs. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide toluene solvate (VIII) is collected by filtration, washed with chilled toluene (25 mL) and dried at 35° C. under vacuum. Yield (22.2 g, 84%).
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.C(OC([NH:18][CH2:19][C@:20]1([CH2:28][C:29]([OH:31])=[O:30])[CH2:26][C@@H:25]2[C@H:21]1[CH:22]=[C:23]([CH3:27])[CH2:24]2)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:18][CH2:19][C@:20]1([CH2:28][C:29]([OH:31])=[O:30])[CH2:26][C@@H:25]2[C@H:21]1[CH:22]=[C:23]([CH3:27])[CH2:24]2
Reactant: CC1=C[C@@H]2[C@H](C1)C[C@]2(CNC(=O)OC(C)(C)C)CC(=O)O
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C[C@@H]2[C@H](C1)C[C@]2(CN)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
[(1R,5S,6S)-6-tert-butoxycarbonylaminomethyl-3-methylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid benzenesulfonic acid (5.6 g, 15.8 mmol) was suspended in methylene chloride (50 mL). To the suspension, triethylamine (4.4 ml, 31.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration and washed with isopropanol to obtain the compound of interest as a white solid (2.4 g, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11](C([Sn])=C(CCCC)CCCC)[CH2:12]CC.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:11]=[CH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 90 %

Procedure:
To an ethanol solution (3 ml) containing 4-nitroiodobenzene (125 mg), tributylvinyltin (174 mg), and potassium carbonate (138 mg) the mesh catalyst precursor (12 mm by 14 mm, wire diameter of 0.1 mm, opening of 0.154 mm) prepared in Example 3 was added to be heated for 12 hours at 80° C. The reaction mixture was cooled to room temperature, and the mesh catalyst precursor was washed with ethanol to be taken off from the reaction mixture. The solvent was distilled from the reaction mixture under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give an intended product, 4-nitrostyrene with 90% yield. The mesh catalyst precursor taken off from the mixture was again used in the same reaction to again give the intended product, 4-nitrostyrene with 88% yield. The mesh catalyst precursor could be recycled at least ten times.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23](I)=[CH:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3=[N:19][CH:20]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:45][C:46]1[CH:47]=[C:48]([CH:66]=[CH:67][CH:68]=1)[CH2:49][N:50]1[C:54]([CH3:55])=[C:53](B2OC(C)(C)C(C)(C)O2)[C:52]([CH3:65])=[N:51]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]([CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:53]4[C:52]([CH3:65])=[N:51][N:50]([CH2:49][C:48]5[CH:66]=[CH:67][CH:68]=[C:46]([F:45])[CH:47]=5)[C:54]=4[CH3:55])=[CH:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3=[N:19][CH:20]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(-c3cnc4c(c3)c(I)cn4C(=O)OC(C)(C)C)cc2)CC1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2ncc(-c3ccc(N(C(=O)OC(C)(C)C)C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 25.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 5-(4-((tert-butoxycarbonyl)(1-(tert-butoxycarbonyl)piperidin-4-yl)amino)phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 66H) (150 mg, 0.20 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (89 mg, 0.27 mmol) using Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (63 mg, 0.6 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 40 mg (25.3% yield) of the titled compound after column purification using 35% ethyl acetate in hexane as eluent. MS: m/z=694.9 (M-Boc+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:9][C:10](=O)[C@H:11]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:12][CH:13]=[CH2:14])[CH3:8].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC.C(Cl)Cl.O>[CH2:7]([NH:9][CH2:10][C@H:11]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:12][CH:13]=[CH2:14])[CH3:8]
Reactant: C=CC[C@H](C(=O)NCC)c1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: C=CC[C@H](CNCC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
LiAlH4 (36 mg, 0.95 mmol) was added to ether (5 mL) at 0° C. under nitrogen. (2S)-N-Ethyl-2-(4-fluorophenyl)pent-4-enamide (140 mg, 0.63 mmol), dissolved in ether (2 mL) was added and the mixture was stirred overnight at room temperature. Water (0.04 mL) was added followed by an aqueous solution of NaOH (0.16 mL, 1M) and the mixture stirred for 30 min. Celite®, MgSO4 and CH2Cl2 was added and the solid material removed by filtration. The solvent was removed by evaporation and there was obtained 0.13 g (100%) of (2S)-N-ethyl-2-(4-fluorophenyl)pent-4-en-1-amine. 1H NMR (500 MHz, CDCl3): 1.0 (m, 3H), 2.2-2.9 (m, 5H), 3.2-3.4 (m, 2H), 4.9-5.1 (m, 2H), 5.6-5.7 (m, 1H), 7.0-7.4 (m, 4H). LCMS: m/z 208 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][C:32]1([CH2:36][OH:37])[CH2:35][CH2:34]C1.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>[OH:37][CH2:36][C:32]1([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:28])[CH2:35][CH2:34]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCC1(CO)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC2(CO)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 10.9 %

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 (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with (1-aminomethyl-cyclobutyl)-methanol (34.5 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight 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 (1-hydroxymethyl-cyclopropylmethyl)-amide (11.2 mg, 10.6%).
Reaction SMILES: Br[CH2:2][C:3]([CH3:13])([CH3:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[C-:14]#[N:15].[Na+].C(Cl)(Cl)Cl>CS(C)=O.[Cl-].[Na+].O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]([CH3:13])([CH3:12])[CH2:2][C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CC(C)(CBr)Oc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(CC#N)Oc1ccc(Cl)cc1

Procedure:
A crude solution of 1-(2-bromo-1,1-dimethylethoxy)-4-chlorobenzene (60.3 mmol) in dimethyl sulfoxide (60 mL) is treated with sodium cyanide (180.7 mmol). The reaction mixture is heated to 95 degrees Celsius overnight under nitrogen. The reaction mixture is transferred into a separatory funnel using brine (150 mL) and chloroform (300 mL). The reaction mixture is equilibrated and the aqueous layer is removed. The aqueous layer is extracted an additional two times with chloroform (2×300 mL). The combined organic extracts are dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford 3-(4-chlorophenoxy)-3-methylbutyronitrile. This crude material is used in the next step (hydrolysis of the nitrile into the corresponding amide) without further purification. [Alternatively, the corresponding carboxylic acid can be obtained from this material by acid hydrolysis (e.g., using sulfuric acid).]
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([Br:9])[CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[NH2:1][C:2]1[CH:3]=[C:4]([Br:9])[N:5]=[CH:6][C:7]=1/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=CC(=O)OCC
Reactant: Nc1cc(Br)ncc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnc(Br)cc1N
Temperature: 100 °C
Yield: 89.6 %

Procedure:
4-Amino-2-bromo-5-iodopyridine (9.0 g 30.0 mmole) was dissolved in DMF (90 mL) and ethyl acrylate (6.5 mL, 60 mmole), triethylamine (6.1 mL, 43.2 mmole), tri-o-tolylphosphine (728 mg 2.4 mmole) and palladium acetate (270 mg 1.2 mmole) were added. The reaction was placed under nitrogen and heated at 100° C. for 3 hours. The reaction was concentrated in vacuo and diluted with EtOAc (250 mL). Water (100 mL) was added and the biphasic mixture filtered through celite. The filter cake was washed with EtOAc and the organic layers collected. The combined organic layers were washed with water (2×100 mL), brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a gradient of 10-40% EtOAc in DCM to afford the title compound (7.29 g, 89%).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>>[CH2:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COP(OC)OC
Product: COP(=O)(OC)C(=O)OCc1ccccc1

Procedure:
From 50 ml (0.4 mole) of trimethylphosphite and 56.9 g (0.3 mole) of benzyl chloroformate (Sigma 90-95%) (100° C., 2 hours). Yield 73 g (90%). Bp0.02 135°-6° C. nD25 1,4997.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:13]([CH3:25])([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17])[CH3:14])#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]([CH3:25])([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)=[O:17])[CH3:14])#[N:12]
Reactant: CC(C)(C#N)OC(=O)N1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C#N)OC(=O)N1CCC(=O)CC1
Reaction time: 1 h
Yield: 78 %

Procedure:
5.06 ml of dimethylsulfoxide was gradually dropped at -78° C. into a solution of 4.15 ml of oxalyl chloride in dichloromethane (50 ml), into which a dichloromethane solution of 5.05 g of 1-(1-cyano-1-methylethoxycarbonyl)-4-hydroxypiperidine was dropped. After agitation at the temperature for 1 hour, 16.57 ml of triethylamine was added, followed by agitation at room temperature for 1 hour. The reaction solution was filtered, washed with water, and dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant residue was purified by silica gel column chromatography (elution solvent: ethyl acetate:n-hexane=1:9), thereby obtaining 3.9 g of the intended compound.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)(C)(C)C.[NH2:16][C:17]1[C:22]([C:23]([C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[O:24])=[CH:21][N:20]=C(S(CC)(=O)=O)[N:18]=1>>[NH2:18][C:17]1[C:22]([C:23]([C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[O:24])=[CH:21][N:20]=[C:6]([NH:7][C@H:8]2[CH2:9][CH2:10][C@H:11]([NH2:14])[CH2:12][CH2:13]2)[N:16]=1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N

Procedure:
The title compound was prepared as in Example 113 and Example 114 using (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (Altech) and (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone Example 103. MS (M+H)+=378.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[Cl:36].C(=O)([O-])[O-].[K+].[K+]>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[C:27]([Cl:36])[CH:28]=1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 1, step 6) was reacted with methyl 4-(bromomethyl)-3-chlorobenzoate and potassium carbonate to give the title compound as a colorless waxy solid. MS (m/e, ISP neg. ion)=526.9 [M−H+].
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=[O:37])/C/2=C\C1NC=CC=1)#C.IC1C=C(O)C=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[OH:37][C:7]1[CH:6]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Oc1cccc(I)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#Cc3cccc(O)c3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner to analogous to the preparation of (Z)-I,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.43 mmol) (from Example 82) was coupled with 3-iodophenol (110 mg, 0.50 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (15 mg, 0.021 mmol) (Aldrich) as catalyst in 1 mL DMF and 3 mL triethylamine at 70° C. for 13 hours to give (Z)-1,3-dihydro-5-(3-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 100 mg, 71%).