Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(C(C(OC)=O)C(OC)=O)(=O)C(C)(C)C>C(OCC)C>[C:1]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)C
Agent: COC(=O)C(C(=O)OC)C(=O)C(C)(C)C
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C(C)(C)C
Reaction time: 7 h
Yield: 83 %

Procedure:
The experiment of Example 1 was repeated using diethyl pivaloylmalonate as the starting material, instead of dimethyl pivaloylmalonate, and using diethyl ether as the solvent. The reaction was carried out at 35° C. for 7 hours. From GLC-analysis it appeared that conversion of starting material was essentially complete and that ethyl pivaloylacetate had been obtained in a yield of 83%. A small amount of ethyl pivalate had been formed, together with diethyl malonate and pivalic acid.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:17][CH3:18])[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]([OH:16])=O)[CH2:8]1)=[O:6])[CH3:3].[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:14](=[O:16])[CH2:13][N:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:5]([N:4]([CH2:2][CH3:3])[CH2:17][CH3:18])=[O:6])[CH2:8]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCN(CC)C(=O)C1CCCN(CC(=O)O)C1
Agent: Cl
Product: CCN(CC)C(=O)C1CCCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Yield: 41.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-(diethylcarbamoyl)piperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 231, 1-(2-((S)-3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-ylamino)-2-oxoethyl)-N,N-diethylpiperidine-3-carboxamide (20.2 mg, 41.8%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 8.01 (t, 1H), 7.61 (d, 2H), 7.27 (m, 6H), 7.00 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 3.71 (m, 2H), 3.27 (m, 4H), 3.02 (m, 6H), 2.15 (m, 2H), 1.63 (m, 3H), 1.35 (m, 1H), 1.06 (m, 3H), 0.93 (m, 3H). MS (EI) for C34H41FN4O5: 605.8 (MH+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([N:18]3[CH2:22][CH:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH2:20][C:19]3=[O:33])[S:17][C:13]=2[C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-:44].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C@H:6]([C:7]([OH:9])=[O:8])[C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([NH:18][CH2:22][CH:21]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([CH3:32])[N:27]=[CH:26]4)[CH2:20][C:19]([OH:33])=[O:44])[S:17][C:13]=2[C:12]=1[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CC(c4ccc5c(cnn5C)c4)CC3=O)sc2c1-c1ccc(Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(NCC(CC(=O)O)c3ccc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-(1-methyl-1H-indazol-5-yl)-2-oxopyrrolidin-1-yl)benzo[d]thiazol-6-yl)acetate (5 mg) in THF/MeOH (0.5 mL/0.5 mL) was added sodium hydroxide solution (1.0 N, 0.5 mL). The mixture was stirred at 25° C. for 2 hours and heated at 50° C. for 16 hours. The mixture was cooled and neutralized with 0.1 N hydrochloric acid until pH=5. The reaction mixture was freeze-dried and used for next step without further purification. LCMS-ESI+: calc'd for C32H33ClN4O5S: 621.2 (M+H+); Found: 621.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([CH:6]=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CO.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.O>[OH:3][CH2:4][CH:6]=[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=CCO)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 19.901 g (73.888 mM) of tert-butyl 4-(ethoxycarbonylmethylene)piperidine-1-carboxylate in 100 ml of toluene was added 123 ml (185 mM) of 1.5 M diisobutylaluminum hydride-toluene at −78° C. and the mixture was stirred at −78° C. for 1 hour. Then, methanol was added at −78° C. and the mixture was stirred for 0.5 hour to decompose the excess diisobutylaluminum hydride. Then, water was added under ice-cooling and the mixture was stirred for 2 hours. The resulting precipitate was filtered off with the aid of celite and the celite was washed with ethyl acetate. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to provide the title compound.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@H:14]([N:25]([CH2:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)[C:26]([O:28][CH3:29])=[O:27])[CH2:13][C@@H:12]1[CH3:45])=O)C1C=CC=CC=1.N1C=CC=CC=1.Cl[C:53]([O:55][CH:56]([CH3:58])[CH3:57])=[O:54].[OH-].[K+]>ClCCl.C1(C)C=CC=CC=1.O>[CH:56]([O:55][C:53]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=2)[C@H:14]([N:25]([CH2:30][C:31]2[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:32]=2)[C:26]([O:28][CH3:29])=[O:27])[CH2:13][C@@H:12]1[CH3:45])=[O:54])([CH3:58])[CH3:57]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2ccc(C(F)(F)F)cc21
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of cis-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (Example 70) (95 mg, 0.185 mmol) and anhydrous pyridine (0.5 mL) in anhydrous dichloromethane (2 mL) was added isopropyl chloroformate (1.9 mL of a 1M solution in toluene, 1.85 mmol). After stirring at room temperature overnight, water (5 mL) and an aqueous 10% KOH solution (5 mL) were added, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were then washed with 1 N HCl (3×10 mL), then a saturated sodium bicarbonate solution, and then brine (10 mL of each). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 117 mg crude product. Purification by silica gel chromatography using 0-10% ethyl acetate/hexanes as eluent afforded 90 mg of the title compound (81%): MS m/z 602 (M++2), 619 (M++19); 1H NMR (CDCl3) δ 1.20 (Me, d, 3H, J=6.1 Hz), 1.28 (d, 3H), 1.31 (d, 3H), 3.83 (OMe, s, 3H), 5.04 (septet, 1H), 7.12 (C5, s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][OH:15])[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][O:15][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](CO)O1
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4S,5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one (695 mg, 3.0 mmol) in dry dichloromethane (30 mL) was added 2,3-dihydropyran (0.3 mL, 3.6 mmol) and 10-camphorsulfonic acid (70 mg, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate solution (2×100 ml), brine (1×100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting solid was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S,5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyl)-oxazolidin-2-one as a colorless oil.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.6 %

Procedure:
To a stirred solution of 0.68 g (2 mmol) of 2-(4-benzyl-piperidin-1-yl)-N-(4-methoxy-phenyl)-acetamide (Example 190) and in 30 ml of dichloromethane 0.95 ml (10 mmol) of boron tribromide in 9 ml of dichloromethane is added dropwise at −20° C., and the reaction mixture is stirred at room temperature for 10 hours. The reaction mixture is concentrated. Then 30 ml of 8% sodium hydrogenecarbonate solution and 20 ml of chloroform are added to the mixture. The organic layer is separated and the water phase is extracted three times with 20 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and chloroform:methanol=9:1 as eluent to yield 0.4 g (62%) of the title compound. Melting Point: 66-70° C. (hexane)
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:11]=2)([CH3:6])[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.CC(=O)OCC>C1COCC1>[NH2:1][C:2]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:11]=2)([CH3:6])[CH2:3][OH:4]
Reactant: CCCCCCCOc1ccc2cc(C(C)(N)C(=O)O)cnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCOc1ccc2cc(C(C)(N)CO)cnc2c1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a solution of crude 2-amino-2-(7-(heptyloxy)quinolin-3-yl)propanoic acid (600 mg, 1.8 mmol) in dry THF (30 mL) was added LAH (138 mg, 3.6 mmol, 2 eq.) at 0° C. under N2. The mixture was warmed to room temperature for 3 h. Then to the reaction mixture was added water (1 mL), diluted (EA), filtered and dried (Na2SO4), evaporated to dryness to give the crude product, which was purified by prep-HPLC to give desired compound as white solid (200 mg, yield 35%). ESI-MS: 317 (M+H)+. 1H NMR (300 MHz, CDCl3) δ: 0.90 (t, 3H), 1.32-1.42 (m, 6H), 1.48-1.52 (m, 2H), 1.53 (s, 3H), 1.82-1.89 (m, 2H), 2.34 (brs, 3H), 3.66-3.69 (d, 1H), 3.81-3.84 (d, 1H), 4.08 (t, 2H), 7.11-7.14 (m, 1H), 7.26 (s, 1H), 7.57-7.59 (d, 1H), 8.10 (s, 1H), 8.83 (s, 1H). HPLC: 214nm: 98.948%, 254nm: 99.526%.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O-:24])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:34])=[O:35])=[CH:31][CH:32]=1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-fluorobenzenesulfonamide. MS (ESI) m/z 493 [M+H]+, 491 [M−H]−, 1H-NMR (CDCl3) δ 1.23 (3H, t, J=7.5 Hz), 2.68 (2H, q, J=7.7 Hz), 2.87 (2H, t, J=7.0 Hz), 3.42-3.60 (2H, m), 6.46 (1H, br), 7.16-7.28 (7H, m), 7.37 (2H, t, J=7.3 Hz), 7.76 2H, d, J=7.1 Hz), 7.85-7.91 (2H, m).
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=C=O.O.O.[OH-].[Li+].C(OCC)(=O)C>O1CCOCC1.C(O)(=O)C>[NH2:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2
Reactant: COC(=O)CC/C(C)=C/Cc1c(N=C=O)c2c(c(C)c1OC)COC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.0 g (5.5 mmol) of methyl (B)-6-(4-carboxy-1,3-dihydro-6-methoxy-7methyl-3-oxoisobenzofuran-5-yl)-4-methyl -4-hexenoate, a compound of Formula 5, was converted to crude methyl E-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, a compound of Formula 6, as described in Preparation 6 above without purification. The resulting 4-isocyanate was redissolved in 50 ml of 1,4-dioxane and treated with 16 ml of water and 2.0 g (47.7 mmol) of lithium hydroxide monohydrate. The mixture was stirred at room temperature for 2 hours and then partitioned between aqueous 1N sodium hydrogen sulfate and ethyl acetate. The organic phase was washed twice with water, once with brine, and was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, using 50:40:1 hexane:ethyl acetate:acetic acid as eluant to give 1.28 g (4.0 mmol) of (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid as a white solid, mp 130°-131° C.
Reaction SMILES: [OH-].[Na+].N1CCC[C@H]1C(O)=O.[CH3:11][O:12][N:13]=[C:14]1[CH2:18][N:17]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:23][CH:22]=2)=[O:20])[C@H:16]([C:34]([O:36]C)=[O:35])[CH2:15]1.O1CCOCC1>O>[CH3:11][O:12][N:13]=[C:14]1[CH2:18][N:17]([C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[CH:25][CH:26]=2)=[O:20])[C@H:16]([C:34]([OH:36])=[O:35])[CH2:15]1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CON=C1C[C@@H](C(=O)O)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1
Yield: 91 %

Procedure:
A solution of sodium hydroxide (73 mg, 1.81 mmol) in water (1.2 ml) was added to a proline oximether methyl ester derivative, e.g. methyl (2S,4 EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate (391 mg, 1.1 mmol) in 3:1 dioxane:water (12 ml) and the reaction stirred for 3 h. The reaction mixture was then washed with diethyl ether (2×10 ml), and the aqueous phase acidified to pH 2 (0.1N HCl) and extracted into ethyl acetate. The ethyl acetate layer was then dried over magnesium sulfate, filtered and the solvent was then removed in vacuo to give the desired product, e.g. (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylic acid in 91% yield as an oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]([O:16]C)=[O:15])[N:8]([CH3:18])[CH:7]=[C:6]2[C:19]1[N:27]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1>[OH-].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]([OH:16])=[O:15])[N:8]([CH3:18])[CH:7]=[C:6]2[C:19]1[N:27]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)(=[O:29])=[O:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1
Reactant: COC(=O)COc1cc2c(cc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCC(=O)O
Yield: 98 %

Procedure:
A solution of methyl {5-methoxy-1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-6-yloxy}acetate, (0.91 g; 1.751 mmol) in methanolic potassium hydroxide (74 ml at 1 g/ml) is placed in a 100 ml round-bottomed flask, at 20° C. for 16 hours with agitation. After reaction, the precipitate formed is filtered off, and rinsed with methanol (20 ml). A suspension of the above solid in water (30 ml) is placed in a 250 ml Erlenmeyer flask and the pH is then adjusted to 4 with 2N aqueous hydrochloric acid. The yellow solid formed is triturated in the reaction mixture and is then filtered, rinsed with water and dried under reduced pressure. {5-Methoxy-1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-6-yloxy}acetic acid (0.666 g; 98%) is isolated, the characteristics of which are as follows:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:35])[F:36])[CH:27]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(OC(F)(F)F)c3)c2o1
Temperature: 70 °C

Procedure:
200 mg (0.52 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 106.8 mg (0.52 mmol) of 3-(trifluoromethoxy)phenylboronic acid are introduced into 2.0 ml of DMF. Addition of 0.78 ml of 2 M sodium carbonate solution and 21.2 mg (0.03 mmol) of PdCl2(dppf) is followed by heating at 70° C. for 17 h. After cooling, the reaction mixture is filtered through kieselguhr and purified by preparative HPLC. The product fractions are combined and concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 48.8 mg (20% of theory) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:77]1([O:83][C:84]([N:86]2[CH2:91][CH2:90][NH:89][CH2:88][CH2:87]2)=[O:85])[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>CN(C=O)C>[C:77]1([O:83][C:84]([N:86]2[CH2:91][CH2:90][N:89]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]3[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[C:30](=[O:36])[NH:31][CH:32]4[CH2:33][CH2:34][CH2:35]4)=[O:24])[N:18]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:17]=3)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:88][CH2:87]2)=[O:85])[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: O=C(Oc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)Oc2ccccc2)CC1
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 55 μl DIPEA, 64 mg HATU and 54 mg piperazine-1-carboxylic acid phenyl ester hydrotrifluoroacetate. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 190 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 40 mg MS (ES+): m/e=730.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[C:5]=1[O:22][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCc2ccc(S(N)(=O)=O)cc2)c1OC(F)F
Temperature: 70 °C
Yield: 16.3 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.75 mmol) and 4-bromomethyl-benzenesulfonamide (94 mg, 0.375 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 16%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][Zn+].[CH2:12]([N:19]1[CH2:24][CH:23]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)[O:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.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>[CH2:12]([N:19]1[CH2:20][CH2:21][O:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([CH2:5][C:4]3[C:3]([Cl:2])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])=[CH:27][CH:26]=2)[CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1cccc(Cl)c1C[Zn+]
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a mixture of 2,6-dichlorobenzylzinc chloride (7.95 mL; 0.50 mol/l in THF; 3.97 mmol) and tetrakis(triphenylphosphine)palladium(0) (83.48 mg; 0.07 mmol) in THF (25 mL) was added 4-benzyl-6-(4-bromo-phenyl)-morpholine (1.20 g; 3.61 mmol). The resulting mixture was stirred at RT for 2 hours, and subsequently heated under reflux, for 2 h. After cooling to RT the mixture was concentrated in vacuo. The residue was partitioned between 5% aqueous NaHCO3 and EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-benzyl-2-[4-(2,6-dichloro-benzyl)-phenyl]-morpholine (1.40 g).