Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)([CH3:5])=[CH2:4].[CH2:14](Br)[CH3:15]>CS(C)=O>[CH2:14]([O:13][CH2:12][C@H:9]1[CH2:10][CH2:11][C@@H:6]([C:3]([CH3:5])=[CH2:4])[CH2:7][CH2:8]1)[CH3:15]
Reactant: C=C(C)[C@H]1CC[C@@H](CO)CC1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=C(C)[C@H]1CC[C@@H](COCC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 g of sodium hydride -- 50% in mineral oil -- were allowed to react with 100 ml of dimethyl-sulfoxide, at 55° - 60° for 90 min. 7.5 g of cis-4-isopropenyl-cyclohexylmethanol were then added to the resulting solution, followed by a dropwise addition of 20 g of ethyl bromide. The reaction mixture was stirred overnight at room temperature, then poured onto crushed ice and finally extracted with hexane. After the usual treatments of washing, drying and evaporation, the fractional distillation of the obtained residue yielded cis-4-isopropenyl-cyclohexylmethyl ethyl ether, bp 96° - 97°/10 Torr.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH2:20][C@@H:21]([CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23]>>[CH2:41]([O:40][CH2:39][C@H:21]([NH:20][C:17](=[O:19])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc(N2CCN(CC(=O)O)CC2)cc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: COc1ccc(N2CCN(CC(=O)N[C@@H](COCc3ccccc3)C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)CC2)cc1
Yield: 35.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(4-methoxyphenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 224, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(4-methoxyphenyl)piperazin-1-yl)acetamido)propanamide (17.2 g, 35.1%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 8.00 (d, 1H), 7.60 (d, 2H), 7.30-7.65 (m, 5H), 7.19-7.25 (m, 2H), 6.98-7.04 (m, 4H), 6.87-6.90 (d, 2H), 6.81-6.84 (d, 2H), 4.71 (m, 1H), 4.52 (s, 2H), 3.70-3.80 (m, 2H), 3.69 (s, 3H), 3.06 (s, 2H), 3.02 (m, 4H), 2.59-2.67 (m, 4H). MS (EI) for C35H37FN4O5. found 613.6 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][CH2:18][NH2:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:21]1([C:24]2[C:29]([CH2:30][C:31](O)=[O:32])=[CH:28][N:27]=[C:26]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[N:25]=2)[CH2:23][CH2:22]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][CH2:18][NH:19][C:31](=[O:32])[CH2:30][C:29]2[C:24]([CH:21]3[CH2:22][CH2:23]3)=[N:25][C:26]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=3)=[N:27][CH:28]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(CCN)cc(OC)c1
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1cc(CCNC(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc(OC)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester (example 93A]) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-(2-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-ethyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]2[C:3]([N:4]=1)=[C:2]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: CN1CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CCS(C)(=O)=O)c2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCS(C)(=O)=O)c2n1
Yield: 76.4 %

Procedure:
Heat a solution of 6-chloro-8-(2-chlorophenyl)-2-methyl-9-(2-methylsulfonylethyl)purine (0.3 g, 0.0007 mol), N-methylpiperazine (0.08 g, 0.0008 mol) and triethylamine (0.08 g, 0.0008 mol) in ethanol (15 mL) at 90° C. for 16 h. Cool and concentrate the reaction mixture under reduced pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column using dichloromethane:methanol (96:4) as eluent to afford a 8-(2-chlorophenyl)-6-(4-methylpiperazin-1-yl)-2-methyl-9-(2-methylsulfonylethyl)purine (0.24 g). ES/MS m/z 449 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[S:13][CH:14]=[CH:15][C:7]1=2)=[O:5].C(N(CC)CC)C.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]([C:34](Cl)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>ClCCl>[S:13]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:6]([C:4]([C:3]3[CH:16]=[CH:17][C:18]([NH:20][C:34]([C:29]4[C:28]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:35])=[CH:19][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:15]=[CH:14]1
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCCCc3sccc32)c(Cl)c1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 1, a solution of 2 mmol of 4-(2-chloro-4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 5 mmol of triethylamine in 10 ml of dichloromethane under argon is reacted with [1,1'-biphenyl]-2-carbonyl chloride for 16 hours at room temperature to give the product as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=1[CH3:20].[OH-].[Na+]>CCO.O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[CH3:20]
Reactant: COCc1ccccc1-c1ccc(C(=O)OC)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCc1ccccc1-c1ccc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2′-(methoxymethyl)-2-methylbiphenyl-4-carboxylate (3 g; 11.10 mmol; 1 eq.) in EtOH (90 mL) at RT was treated with NaOH (6.66 mL; 5 M; 33.29 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a brown solid which was taken up in water (100 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2 and it was extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.95 (br s, 1H), 7.92-7.91 (m, 1H), 7.84-7.81 (dd, J=7.83 Hz, 1.91 Hz, 1H), 7.55-7.52 (m, 1H), 7.47-7.38 (m, 2H), 7.25-7.22 (d, J=7.86 Hz, 1H), 7.15-7.14 (m, 1H), 4.09 (m, 2H), 3.17 (s, 3H), 2.07 (s, 3H). LC/MS (Method B): 255.2 (M−H)−. HPLC (Method A) Rt 4.35 min (Purity: 96.8%).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12]C)=[O:11].O[Li].O.Cl>CO.O>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc2cnccc2s1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cnccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl thieno[3,2-c]pyridine-2-carboxylate (D-2) (12 g, 62.1 mmol) in MeOH (150 mL) and H2O (15 mL) was added LiOH.H2O (5.2 g, 124.2 mmol). The solution was stirred at room temperature overnight, and then acidified with 1N aqueous HCl. The resulting white precipitate was collected by filtration and air-dried to afford the title compound. MS (m/z): 179 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([OH:16])[CH:8]=1)[CH3:2].[NH4+].[Cl-].CCO>[Fe].O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([OH:16])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=Cc1ccc(N)c(O)c1

Procedure:
To a stirred suspension of 11-2 (4.64 g, 19.6 mmol), NH4Cl (524 mg, 9.8 mmol), EtOH (140 mL) and H2O (70 mL) was added iron dust (2.72 g, 48.9 mmol). The resulting yellow suspension was refluxed for 1.5 h., and then the solution was filtered while hot through celite. The filtrate was concentrated and the residue was partitioned between EtOAc and brine. The layers were separated and the EtOAc layer dried (Na2SO4) and concentrated to give 11-3 which was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=2)/[CH:33]=[CH:34]/[C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=3)/[CH:33]=[CH:34]/[C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)c1ccc(/C=C/c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Yield: 37.3 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (150 mg, 0.46 mmol) and (E)-methyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)styryl)benzoate (200 mg, 0.55 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (100 mg, 0.94 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (40 mg, 0.035 mmol) was added in one portion and the reaction mixture was stirred at reflux for 18 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate=1:1) to give (E)-methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)styryl)benzoate (90 mg, 37%) as a yellow sold. LC-MS: 525 [M+H]+, tR=1.89 min.
Reaction SMILES: C1(C)C=CC=C(CC[O:9][C:10](=[O:29])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[C:13]([CH:27]=[O:28])[CH:12]=2)C=1.[Li+].[OH-].O>C1COCC1>[CH:27]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)[C:10]([OH:29])=[O:9])=[O:28]
Reactant: Cc1cccc(CCOC(=O)c2ccc(OCCc3cccc(C)c3)c(C=O)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(CCOc2ccc(C(=O)O)cc2C=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.2 %

Procedure:
8.0 g of 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid 2-m-tolyl-ethyl ester and 1.7 g of LiOH (Monohydrate) were stirred in 30 ml of THF and 2 ml of water at room temperature for 16 h. Then, an additional 1 g of LiOH (monohydrate) was added and the mixture stirred at room temperature for 4 h. Then, 100 ml of water were added, the THF evaporated and the aqueous layer was washed twice with diisopropylether, 100 ml each. The aqueous layer was then acidified to pH=3 using aqueous HCl-solution and the crude product collected by filtration. Chromatography on silica gel using a gradient EA/HEP to EA yielded 1.2 g of the title compound that was used without further purification.
Reaction SMILES: [OH:1][C@H:2]([CH2:9][OH:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C@H:2]([CH2:9][O:10][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[C@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 30.1 %

Procedure:
To (S)-ethyl 3,4-dihydroxybutanoate (1.40 g, 9.45 mmol) in methylene chloride (20 ml) were added triethylamine (1.15 g, 11.36 mmol) and DMAP (17 mg, 0.139 mmol) and the solution was cooled in ice bath. Trityl chloride (2.90 g, 10.4 mol) in methylene chloride (15 ml) was dropped to the solution under stirring and then stirred at room temperature over night. The reaction mixture was washed with saturated ammonium chloride and then saturated brine, dried on magnesium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-ethyl 3-hydroxy-4-trityloxybutanoate (1.11 g, yield 31%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I>O1CCCC1.C(OCC)(=O)C>[CH3:22][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of methyl 4-[[(tert-butoxycarbonyl)amino]methyl]benzoate (compound obtained in Reference Example 81(1), 2.0 g) in tetrahydrofuran (20 mL) is added sodium hydride (60% dispersion in mineral oil, 0.9 g) under ice-cooling. The mixture is stirred at room temperature for 30 minutes and then to the reaction mixture is added dropwise methyl iodide (2.3 mL). The mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with ethyl acetate, washed with water, and concentrated in vacuo to give methyl 4-[[N-methyl-N-(tert-butoxycarbonyl)amino]-methyl]benzoate (1.9 g, yield; 94%) as a yellow oil. MS (APCI) m/z: 280 [M+H]+
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH:14]([C:16]2[C:17]([CH3:28])=[N:18][O:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:38]=[CH:39][C:40]([C:24]3[CH:23]=[CH:22][C:21]([C:20]4[O:19][N:18]=[C:17]([CH3:28])[C:16]=4[CH:14]([C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[N:13]=4)[OH:15])=[CH:26][CH:25]=3)=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(Cc2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(Cc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using (6-benzyl-pyridin-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1](C(O)C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([OH:17])(=[O:16])[CH2:14][OH:15].C(N(CC1C=CC=CC=1)C(=NC(C)C)O)(C)C>C1COCC1>[C:13]([O:17][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:16])[CH2:14][OH:15]
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: O=C(O)CO
Agent: CC(C)N=C(O)N(Cc1ccccc1)C(C)C
Solvent: C1CCOC1
Product: O=C(CO)OCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
Construction of Benzyl-glycolic Acid. Glycolic acid (5.89,100 mmol) is added to N,N'-diisopropylbenzylisourea (23.3 g, 100 mmol) with stirring for 1 hour. The volume is then increased to 200 mL with THF, and the mixture stirred for 48 h at room temperature. After cooling the mixture to -15° C., the diisopropylurea is removed by filtration and the THF evaporated under reduced pressure. The resulting product is pumped under high vacuum for 24 h to give benzyl glycolate which may be used without further purification.
Reaction SMILES: Br[C:2]1[C:28]([F:29])=[CH:27][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:8]2=[O:26])=[C:4]([F:30])[CH:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+].[C@H]1(N)CCCC[C@@H]1N>CS(C)=O.CCOC(C)=O>[F:30][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[C:28]([F:29])=[CH:27][C:5]=1[O:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)[C:8]1=[O:26]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Oc3cc(F)c(Br)cc3F)C2=O)CC1
Agent: N[C@H]1CCCC[C@@H]1N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Oc3cc(F)c(S(C)(=O)=O)cc3F)C2=O)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
A suspension of (S)-tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (700 mg, 1.39 mmol), and sodium methanesulfinate (219 mg, 2.08 mmol) in DMSO (5.55 mL), was deoxygenated and purged with nitrogen. Cu(I) triflate benzene complex (77.6 mg, 0.139 mmol) and (1S,2S)-cyclohexane-1,2-diamine (63.4 mg, 0.555 mmol) were introduced and the heterogeneous mixture was sealed and heated to 110° C. in an oil bath and stirred for 18 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (75 mL), washed with water (30 mL) and brine (three 50 mL washes), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified over silica gel (EtOAc) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (305 mg, 0.606 mmol, 44% yield) as a light yellow oil that solidified. Mass spectrum (apci) m/z=389.1 (M+H-Boc).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:37])[C@H:24]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:37])=[O:22])[CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc3ccccc3c2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-(2-naphthyl)-L-alanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>ClCCl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:17](=[O:20])[CH:18]=[CH2:19])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: C=C(C)C(=O)OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOC(=O)C(=C)C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
5.0 g of hydroxyethyl methacrylate was weighed into a 250 ml r.b. flask fitted with stirrer, thermometer and nitrogen blanket. 3.88 g of triethylamine was then added followed by 80 ml of dichloromethane. The mixture was cooled and 4.15 g of acryloylchloride was added dropwise. The reaction mixture turned yellow and after 10 min a precipitate formed. Stirring was continued for 90 minutes. The precipitated material (TMEDA.HCl) was then filtered off and the organic solution extracted with sodium bicarbonate solution. The solution was then dried over anhydrous magnesium sulphate and after filtration the solvent evaporated to give a pale yellow oil (yield˜90%).
Reaction SMILES: [Si:1]([O:18][C@H:19]([CH3:23])[C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCCCCCC.[C:43]([O:49][CH2:50][CH3:51])(=[O:48])[CH2:44]C(O)=O>C1COCC1>[Si:1]([O:18][C@H:19]([CH3:23])[C:20](=[O:22])[CH2:44][C:43]([O:49][CH2:50][CH3:51])=[O:48])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: CCOC(=O)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2R)-2-{[tert-Butyl(diphenyl)silyl]oxy}propanoic acid (the product from step i, 7.85 g) in THF (300 ml) was added CDI (4.26 g) and the reaction was stirred at room temperature for approximately 15 mins. In a separate flask (71.7 ml) of a 1M heptane solution was added to a solution of ethyl hydrogen malonate (9.47 g) in THF (300 ml) at 0° C. This solution was then allowed to warm to RT. The acyl imidazole solution was then transferred to the flask which contained the magnesium salt and the reaction was monitored for the next 2 d. When the reaction was complete it was quenched by the addition of 250 ml of sat. aq NH4Cl solution. The reaction mixture was then extracted with Et2O (3×200 ml). The combined organics were dried (MgSO4), filtered and reduced to yield a clear oil which was purified by column chromatography on silica gel 4% EtOAc/96% iso-hexane. This gave the subtitle compound as a colourless oil. Yield: 2.0 g