Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]O.[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C(Cl)=CC=C(Cl)C=1.C(OCC1OC1)(=O)C(C)=C.[C:30]1([C:36]([CH2:38]C(C2C=CC=CC=2)(C)C)=[CH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:11][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[CH2:10].[CH3:38][C:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH2:37]
Reactant: CC(C)c1ccccc1
Reactant: C=C(CC(C)(C)c1ccccc1)c1ccccc1
Agent: C=C(C)C(=O)OCC1CO1
Agent: [O-]O
Solvent: Clc1ccc(Cl)cc1
Product: C=C(C)c1ccccc1
Temperature: 90 °C
Reaction time: 0.71 h

Procedure:
A high temperature initiator, cumene hydroperoxide, was included in this run to drive the polymerization further towards completion and to reduce residual monomer. The flask was charged with brominated styrene monomer (1002.6), dichlorobenzene (497 g), glycidyl methacrylate (5.13 g, 0.0360 mol), 2,4-diphenyl-4-methyl-1-pentene (20.26 g, 0.08571 mol), VAZO-52™ azo type initiator (1.05 g, 4.22 mmol) and cumene hydroperoxide (1.06 g, 6.96 mmol). The solution was then heated to about 90° C. until exotherm. Peak temperature reached was 163° C. after which the mixture was heated to 190° C. over 5-10 min and held at 190° C. for 40-45 min. Heating was halted; the solution (1513.7 g) was transferred to a 2-liter bottle, and cooled to room temperature. The material was split into four parts. Each part was precipitated into a 5-liter flask of 3400 mL acetone and 400 mL methanol. The precipitate was filtered over frit, dried at ambient temperature for about 14 h and oven dried at 110° C. for 8 h. A white powder (883 g) was isolated.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[C:18]([O-])([O-])=O.[K+].[K+].[CH:24]1(CBr)[CH2:26][CH2:25]1>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH:24]2[CH2:26][CH2:25]2)[CH:5]=[C:6]([CH3:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: BrCC1CC1
Reactant: O=c1[nH]ccc(OCc2ccc(F)cc2)c1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(C2CC2)c(=O)c(Br)c1OCc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a solution of 3-bromo-4-(4-fluorobenzyloxy)-1H-pyridin-2-one (0.25 g, 0.84 mmol) in DMF (13 mL) was added K2CO3 (0.33 g, 1.7 mmol) and cyclopropylmethyl bromide (0.14 g, 1.0 mmol), and the reaction mixture was stirred at 110° C. for 2 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with a 50% aqueous solution of brine, and extracted with CHCl3 (3×50 mL). The combined organics were washed with water and then brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 EtOAc/hexanes) afforded 3-bromo-1-cyclopropyl-methyl-4-(4-fluorobenzyloxy)-1H-pyridin-2-one as a yellow solid (0.12 g, 39%): mp 139-141° C.; 1H NMR (300 MHz, CDCl3) δ 7.43-7.34 (m, 3H), 7.07 (t, J=9 Hz, 2H), 6.06 (d, J=6 Hz, 1H), 5.19 (s, 2H), 3.82 (d, J=9 Hz, 2H), 1.26-1.23 (m, 1H), 0.62-0.57 (m, 2H), 0.40-0.36 (m, 2H). ES HRMS m/z 352.0368 (M+H C16H16BrFNO2 requires 352.0343).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:20]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:20]=1
Reactant: Cc1c(OCC(=O)OC(C)C)ccc(F)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(OCC(=O)O)ccc(F)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[3-(3-fluorophenyl)-5-hydroxy-phenyl]methylamino]-2-methyl-phenoxy]acetate (90 mg, 0.2 mmol, 1 eq) in a mixture of MeOH (3 mL) and THF (3 mL) was added NaOH (1 M aqueous solution, 3 mL, 3 mmol) and the reaction was stirred at room temperature for 3 h. The MeOH and THF were removed under reduced pressure and the aqueous phase was acidified to pH 3-6 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as yellow oil (30 mg, 37%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([CH2:20][C:21]([O:23][C:24]1[CH:45]=[CH:44][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:26][CH:25]=1)=[O:22])=[O:19]>ClCCl>[Cl:4][CH:20]([C:18](=[O:19])[NH:17][C:8]1[CH:9]=[C:10]([C:13]([F:15])([F:16])[F:14])[CH:11]=[CH:12][C:7]=1[Cl:6])[C:21]([O:23][C:24]1[CH:45]=[CH:44][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:26][CH:25]=1)=[O:22]
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)C(Cl)C(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.5 %

Procedure:
Sulphuryl chloride (9.5 g, 70.2 m mol) in dichloromethane (15 ml) was slowly added to a solution of the 4-equivalent coupler from (d) (40 g, 70.2 m mol) in dichloromethane (250 ml). After stirring at room temperature for 20 h, the volatiles were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (elutant 10% ethyl acetate in petrol (b.p. 60°-80° C.)) followed by recrystallization from methanol to give a white solid (25.2 g, 60%).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:31][NH:30][S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:33])=[O:32]
Reactant: C1COCCN1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 40 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-methylsulfamoyl-benzoic acid and morpholine and obtained in 40% yield. MS (m/e): 299.2 (MH−, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:16][O:17][NH:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:18]([O:17][CH3:16])[CH3:19])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (5.34 g, 20 mmol) in DCM (120 mL) was added O,N-dimethylhydroxylamine hydrochloride (2.9 g, 30 mmol), HATU (9.2 g, 30 mmol) and Et3N (8.0 g, 80 mmol). The mixture was stirred at rt overnight, concentrated and purified by CC (hexane) to afford compound P30a (5.1 g, 83%) as a solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:27][C:28]2[N:29]=[CH:30][N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:44]=[O:45])C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:27][C:28]2[N:29]=[C:30]([CH:44]=[O:45])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)cn1)C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)c(C=O)n1)C1CCN(Cc2ccccc2)CC1
Yield: 61 %

Procedure:
A solution of n-butyllithium in hexane (1.5 M, 5.7 ml) was added dropwise a solution of tert-butyl (1-benzyl-4-piperidinyl)((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)carbamate (3.9 g) obtained in Example 83c) in THF (50 ml) at −40° C. under argon atmosphere. The reaction solution was mixed at −40° C. for 15 minutes, and then DMF (72 ml) was mixed, and mixed at room temperature for 15 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column (ethyl acetate:ethanol=10:1) to obtain the title compound as a pale yellow oil (2.5 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1Br.[CH3:17][C:18]1([CH3:33])[CH2:23][CH2:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:21]1[CH2:22][CH2:23][C:18]([CH3:33])([CH3:17])[CH2:19][CH:20]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(S(=O)(=O)NC(C)(C)C)ccc2N)CC1
Temperature: 80 °C
Yield: 48.1 %

Procedure:
A solution of 300 mg (0.976 mmol) of 4-amino-3-bromo-N-tert-butyl-benzenesulfonamide (as prepared in Example 48, step (a)) in toluene (8 mL) and EtOH (4 mL) was treated with 253 mg (1.07 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 3.90 mL (7.81 mmol) of 2.0 M Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 113 mg (0.0976 mmol) of Pd(PPh3)4, and heated to 80° C. for 6 h. The mixture was diluted with EtOAc (30 mL) and washed with water (2×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1-4% MeOH—CH2Cl2 afforded 158 mg (48%) of 4-amino-N-tert-butyl-3-(4,4-dimethyl-cyclohex-1-enyl)-benzenesulfonamide as a colorless glassy solid. A suspension of 215 mg (0.704 mmol) 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)) in CH2Cl2 (10 mL) was treated with 60.0 μL (0.704 mmol) of pyridine for 5 min. The mixture was then treated with 51.4 μL (0.704 mmol) of SOCl2 at RT for 30 min. A solution of 158 mg (0.0470 mmol) of 4-amino-N-tert-butyl-3-(4,4-dimethyl-cyclohex-1-enyl)-benzenesulfonamide (as prepared earlier in this step) in CH2Cl2 (5 mL) was treated with the acid chloride solution and stirred at RT for 17 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1% MeOH—CH2Cl2 afforded 100.0 mg (17%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.95 (br s, 1H), 8.55 (d, 1H, J=8.8 Hz), 7.78 (dd, 1H, J=8.8, 2.4 Hz), 7.78 (s, 1H), 7.69 (d, 1H, J=2.4 Hz), 5.92 (s, 2H), 5.84-5.80 (m, 1H), 4.55 (br s, 1H), 3.68-3.62 (m, 2H), 2.32-2.24 (m, 2H), 2.14-2.08 (m, 2H), 1.63-1.56 (m, 2H), 1.23 (s, 9H), 1.11 (s, 6H), 1.00-0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1Br.[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO.CCOC(C)=O>[Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:13]=[CH2:14]
Reactant: O=C1OCc2c1ccc(Br)c2Br
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1Br)COC2=O

Procedure:
4,5-Dibromo-2-benzofuran-1(3H)-one (3.00 g, 10.3 mmol), potassium vinyltrifluoroborate (12.7 g, 20.6 mmol) and Pd (dppf)Cl2 (839 mg, 1.03 mmol) in TEA (2.7 mL) and EtOH (15 mL) were heated at 60° C. for 2 h. Analysis by TLC showed clean and complete reaction. The reaction mixture was diluted with EtOAc (500 mL), washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was subjected to purification over silica gel to give 4-bromo-5-ethenyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([CH:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])(=O)[CH3:12]>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[C:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1ccc2c(c1)CCC2
Product: COC(=O)CC(C(=O)OC)=C(C)Nc1ccc2c(c1)CCC2
Reaction time: 72 h
Yield: 53.8 %

Procedure:
2,3-dihydro-1H-inden-5-amine (10 g; 75 mmol) and dimethyl acetylsuccinate (12.82 g; 68 mmol) were mixed in a flask placed in a dessicator and the homogeneous mixture was stirred under vacuum (3 mbars) for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 20%) in heptane furnished 11.1 g (48%) of dimethyl 2-(1-(2,3-dihydro-1H-inden-5-ylamino)ethylidene)succinate as a deep orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:17]=O)=[C:12]3[C:16]=2[S:15][CH:14]=[CH:13]3)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].N1C=CC=CC=1>CO.CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:17]=[N:20][OH:21])=[C:12]3[C:16]=2[S:15][CH:14]=[CH:13]3)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(-c2ccc(O)cc2)c2sccc12
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CO
Product: ON=Cc1ccc(-c2ccc(O)cc2)c2sccc12
Yield: 77.4 %

Procedure:
To a 10 ml round bottom flask was added 7-(4-hydroxyphenyl)-1-benzothiophene-4-carbaldehyde (61.7 mg, 0.24 mmol), hydroxylamine hydrochloride (34 mg, 0.49 mmol), and anhydrous pyridine (0.04 ml, 0.49 mmol) in MeOH (1.5 ml) was heated to reflux for 1 h and then allowed to cool. The mixture was then diluted with ether, washed with water and the organic layer was dried over anhydrous Na2SO4 then passed through a silica plug. Concentration under reduced pressure produced 60 mg of a slightly yellow solid and purification by column chromatography (40% EtOAc-hexanes) afforded 50 mg (92%) product as a slightly yellow solid: mp 230–231° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.93 (2H, d, J=8.55 Hz), 7.38 (1H, d, J=7.63), 7.57 (2H, d, J=8.53 Hz), 7.68 (1H, d, J=7.71 Hz), 7.91 (1H, d, J=5.61 Hz), 8.12 (1H, d, J=5.64 Hz), 8.57 (1H, s), 9.77 (1H, s), 11.41 (1H, s); MS (ESI) m/z 270 ([M+H]+).
Reaction SMILES: CC(C)C[O:4][C:5](=[O:34])[CH2:6][NH:7][C:8](=[O:33])[C@H:9]([CH2:17][N:18]1[CH2:23][CH2:22][C@:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)([CH3:24])[C@@H:20]([CH3:32])[CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([OH:38])C.[OH-:39].[Na+]>O>[OH2:4].[OH2:38].[OH:31][C:27]1[CH:26]=[C:25]([C@:21]2([CH3:24])[CH2:22][CH2:23][N:18]([CH2:17][C@H:9]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:8]([NH:7][CH2:6][C:5]([OH:34])=[O:4])=[O:33])[CH2:19][C@@H:20]2[CH3:32])[CH:30]=[CH:29][CH:28]=1.[OH2:39].[OH:31][C:27]1[CH:26]=[C:25]([C@:21]2([CH3:24])[CH2:22][CH2:23][N:18]([CH2:17][C@H:9]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:8]([OH:33])=[O:38])[CH2:19][C@@H:20]2[CH3:32])[CH:30]=[CH:29][CH:28]=1
Reactant: [OH-]
Reactant: CC(C)COC(=O)CNC(=O)[C@@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: C[C@H]1CN(C[C@H](Cc2ccccc2)C(=O)NCC(=O)O)CC[C@@]1(C)c1cccc(O)c1
Product: C[C@H]1CN(C[C@H](Cc2ccccc2)C(=O)O)CC[C@@]1(C)c1cccc(O)c1

Procedure:
A solution of a compound of Example 1 (12.5 g, 0.026 mol, 1.0 equiv) in 315 mL of 3A ethanol was charged to round bottom flask. Water (74.0 mL) was added to the mixture. Aqueous solution of sodium hydroxide ((1.0 M) 0.077 mol, 3.0 equiv) was added dropwise over 10-15 minutes at 25°-30° C. The solution was stirred and then filtered. The pH of the solution was adjusted from 12.50 to 6.00 by addition of concentrated hydrochloric acid. The solution was seeded and (2S,3R,4R)[[2-[[4-(3-hydroxyphenyl)-3,4-dimethYl-1-piperidinyl]methyl]-1-oxo -3-phenylpropyl]amino]acetic acid began to precipitate within 10-15 minutes. The crystallization was stirred at 25° C. for two hours and then (2S,3R,4R)[[2-[[4-(3-hydroxyphenyl)-3,4-dimethYl-1-piperidinyl]methyl]-1-oxo -3-phenylpropyl] amino]acetic acid was filtered under slight suction to a wet cake. The crystals were slurried with 60 mL of water and filtered to a hard cake under suction. The crystals were dried to the dihydrate overnight (16 hours) under open air at 33% relative humidity at 25° C. by pulling air over the product in the filter funnel under slight suction. The title compound was isolated in 85% yield (10.2 g), from (αS,3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl -α-(phenylmethyl)-1-piperidine propanoic acid monohydrate, as white crystals with a sharp melting point of 208° C. The sample was analyzed using x-ray powder diffraction.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH:31]1([O:30][C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OC4CCCCC4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(OC3CCCCC3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Yield: 95 %

Procedure:
A solution of 2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.339 g, 0.667 mmol) in ethanol (40 mL) was treated with 5 N NaOH (0.8 mL) and the reaction heated to reflux for 1 h. The reaction mixture was cooled and the solvent removed in vacuo. The resultant oil was acidified with 1 N HCl and extracted with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 0.304 g (95%) of 2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. 1H NMR (500 MHz, CDCl3) δ 7.94-7.85 (m, 2H), 6.89-6.73 (m, 4H), 6.71 (d, 2H, J=9.28 Hz), 4.30-4.23 (m, 1H), 4.14-4.05 (m, 2H), 2.95-2.85 (m, 2H), 2.29 (s, 3H), 1.98-1.85 (m, 2H), 1.80-1.75 (m, 2H), 1.58-1.40 (m, 8H), 1.38-1.20 (m, 4H); HRMS (ES+) m/z exact mass calcd for C28H34NO6 480.2386, found 480.2381The following compound was prepared using tetrahydro-2H-pyran-4-ol:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[C-:10]#[N:11].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]#[N:11])=[CH:4][N:3]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.2 %

Procedure:
The 476 g of crude 2-bromo-5-bromomethylpyridine from step 4 was dissolved in 4000 mL of dimethylformamide (DMF)/water (7:1) and treated with 168 g (2.58 mol) of potassium cyanide. The reaction was allowed to stir at ambient temperature for 72 h, concentrated in vacuo, and partitioned between ethyl acetate and water; the organic layer was washed with water, washed with brine, dried (MgSO4), and reconcentrated in vacuo to provide the crude nitrile. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (25:75) gave 109 g (32% from 2-bromo-5-picoline) of 2-bromo-5-cyanomethylpyridine as a yellowish orange solid: mp 55.5°-57.5° C.; NMR (CDCl3) δ3.74 (s, 2H), 7.54 (d, J=8Hz, 1H), 7.59 (dd, J=8 and 2 HZ, 1H), 8.35 (d, J=2Hz, 1H); MS (FAB) m/e (rel intensity) 199 (85 ), 197 (100).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[C:35](Cl)(=[O:37])[CH3:36]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:35](=[O:37])[CH3:36])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=1)([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1cccc(Br)c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 38.1 %

Procedure:
3-(4-Benzyloxy-phenyl)-2-(3-bromo-phenoxy)-3-hydroxy-2-methyl-propionic acid ethyl ester (10.0 g, 20.7 mmol) was added slowly to a −20° C. solution of triethylsilane (9.9 mL, 62.0 mmol, d=0.728) and boron trifluoride etherate (15.3 mL, 124.0 mmol, d=1.154) in anhydrous CH2Cl2 (370 mL). The mixture was stirred for 6 h, gradually warming to 0° C. The reaction mixture was quenched with a saturated solution of aqueous sodium carbonate and extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography to provide the titled compound (3.7 g, 38%). 1H NMR (400 MHz, CDCl3): δ 7.46-7.33 (m, 5H), 7.18 (d, 2H, J=8.60 Hz), 7.15-7.05 (m, 3H), 6.94 (dt, 2H, J=8.60 Hz), 6.78 (dt, 1H, J=7.82 Hz, 2.35 Hz), 4.23 (q, 2H, J=7.04 Hz), 3.28 (d, 1H, J=13.69 Hz), 3.19 (d, 1H, J=13.69 Hz), 1.45 (s, 3H), 1.23 (t, 3H, J=7.04 Hz). Rf=0.46 in 25% ethyl acetate in hexanes.