Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].CI.[C:19](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:12][C:11]([O:10][C:8]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][O:4][CH3:19])=[O:9])([CH3:14])[CH3:13]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
In a DMF solution containing 2.00 g of Boc-Ser-OH, 0.86 g of sodium hydride (60% oily suspension) was added under ice cooling and the resultant mixture was stirred for 30 min. To the resultant solution, 0.72 ml of methyl iodide was added and the resultant solution was stirred for 3 hr. The reaction mixture was neutralized with citric acid and evaporated under reduced pressure. The obtained residue was redissolved in ethyl acetate, and the solution was washed with 5% aqueous citric acid solution and saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography (chloroform:methanol=10:1) and crystallized as its DCHA salt from n-hexane to give 0.79 g of the title compound.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:21])[NH:12][C:13]2[S:14][CH:15]=[C:16]([S:18]([CH3:20])=[O:19])[N:17]=2)=[CH:7][CH:6]=1)(=O)C.[C:22]([O:25]C1C=CC=C(C(=O)NC2SC=C(SC)N=2)C=1)(=[O:24])[CH3:23]>>[C:22]([O:25][C:6]1[CH:5]=[CH:10][CH:9]=[C:8]([C:11](=[O:21])[NH:12][C:13]2[S:14][CH:15]=[C:16]([S:18]([CH3:20])=[O:19])[N:17]=2)[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Oc1ccc(C(=O)Nc2nc(S(C)=O)cs2)cc1
Reactant: CSc1csc(NC(=O)c2cccc(OC(C)=O)c2)n1
Product: CC(=O)Oc1cccc(C(=O)Nc2nc(S(C)=O)cs2)c1

Procedure:
Using the above procedure for compound (3), 513 (0.61 g, 2.0 mmol) gives crude 5 as a white solid. The crude product is stirred in diethyl ether (30 mL) for 30 minutes, filtered and air dried to give 5 as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19][CH2:20]I.O>CN(C=O)C>[Cl:17][CH2:18][CH2:19][CH2:20][NH:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)(C)N
Reactant: ClCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NCCCCl
Reaction time: 8 h
Yield: 102.5 %

Procedure:
A solution of ethyl aminoisobutyrate hydrochloride (10 g) in DMF (50 mL) was cooled to 0° C. To the solution were added potassium carbonate (18 g) and 1-chloro-3-iodopropane (12 g), and the mixture was stirred overnight at 0° C. to room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 12.5 g of crude ethyl 2-(3-chloropropylamino)isobutyrate.
Reaction SMILES: CC([O-])(C)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>COCCOC.CCOCC.CCCCCCCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH:19]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: COc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: CCCCCCCCCCCC
Solvent: COCCOC
Product: COC(=O)c1cccc(Nc2ccc(OC)cc2)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 4.7 %

Procedure:
A solution of Pd2(dba)3 [92 mg, 0.1 mmol (4.6 mg, 0.005 mmol, 2 mol % Pd per reaction)], ligand 1 (see FIG. 1) [168 mg, 0.4 mmol (8.4 mg, 0.02 mmol, 4 mol % per reaction)] and NaOt-Bu [40 mg, 0.4 mmol (2 mg, 0.02 mmol, 4 mol % per reaction)] were stirred in 10 mL DME (anhy). After 10 minutes, 0.5 mL of the solution was added via syringe to a test tube containing (under an Argon atmosphere) K3PO4 (148 mg, 0.7 mmol), methyl-3-bromo-benzoate (107 mg, 0.5 mmol), and p-anisidine (74 mg, 0.6 mmol). The test tube was capped (with a proper cap-no rubber septa) and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with ether and dodecane was added as an internal standard. The reaction mixture was purified by preparatory TLC (EtOAc/hexanes as the eluent) to yield 6 mg of the desired product (which was used for calibration with the internal standard). The GC yield was calculated to be 12%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18](OCC3C=CC=CC=3)=[O:19])=[N:9]2)=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([CH2:18][OH:19])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)nc1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(Cl)cc2)nc1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
To a solution of 3-benzyl 4-ethyl 1-(4-chlorophenyl)-1H-pyrazole-3,4-dicarboxylate (Example 1C, 3.57 g, 9.28 mmol) in THF (100 mL) was added LiBH4 solution (7.89 mL, 15.77 mmol, 2M in THF). The reaction mixture was stirred at room temperature for 5 h. The resulting mixture was quenched with aqueous sat. NH4Cl solution (10 mL). Solvent was evaporated and the crude product was diluted with H2O (30 mL), extracted with EtOAc (150 mL). The organic layer was separated, dried over MgSO4 and concentrated to give a crude product which was further purified by ISCO automated chromatography (42 g, Hexane/EtOAc, 100:0 to 60:40 gradient) to give the product as a white solid (1.5 g, 58% yield). 1H NMR (CDCl3) δ 1.40 (t, J=7.2 Hz, 3H), 4.38 (q, J=7.2 Hz, 2H), 3.98 (t, J=7.1 Hz, 1H). 4.88 (d, 7.1 Hz, 2H), 7.40-7.48 (m, 2H), 7.60-7.67 (m, 2H), 8.32 (s, 1H). LC-MS, [M+H]+=281.0.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C(OC)=CC=C2C=1C=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Reactant: COc1c(Br)ccc2cc[nH]c12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2cc[nH]c2c1OC

Procedure:
3-(7-Methoxy-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester CXXXVIII was prepared from 6-bromo-7-methoxy-1H-indole using the procedure described above for preparation of 3-(5-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester XLVIII (Example 12).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[OH:15][B:12]1[C:11]2[CH:16]=[CH:17][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][NH:1][C:27]([NH:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:28])=[CH:4][CH:5]=3)=[CH:9][C:10]=2[CH2:14][O:13]1
Reactant: O=C=Nc1ccccc1
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccc(Oc2ccc3c(c2)COB3O)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (150 mg, 0.59 mmol, 1.0 eq.) in DCM (5.0 mL) was added phenylisocyanate (71 μL, 0.65 mmol, 1.1 eq.). The mixture was stirred at room temperature overnight. The mixture was treated with H2O (5 mL). The precipitate was collected by filtration and washed with H2O to give 1-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-phenyl-urea as a white solid. LCMS (m/z) 375 (M+H); 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.51 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.37 (dd, J=8.6, 1.0 Hz, 2H), 7.30-7.35 (m, J=8.6 Hz, 2H), 7.19 (t, J=8.0 Hz, 2H), 6.99-7.04 (m, 2H), 6.88-6.95 (m, 3H), 6.58 (s, 1H), 4.89 (s, 2H), 4.27 (d, J=5.9 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.C(O)(=O)C1C=CC=CC=1.[O-:27][C:28]#[N:29].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[C:17]([C:28]([NH2:29])=[O:27])[C:5]=2[CH:4]=1
Reactant: N#C[O-]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: O=C(O)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC1=Cc2c(cccc2C(N)=O)Nc2ccccc21

Procedure:
An especially preferred method according to this invention comprises reaction of 10-methoxy-5H-dibenz[b,f]azepine with benzoic acid and sodium cyanate in toluene at reflux temperature to give 10-methoxy-5H-dibenz[b,f]azepine carboxamide as a major product (such as about 75%), along with 10-oxo-iminodibenzyl and other impurities. The reaction mixture is thereafter filtered and washed with water, and the toluene layer taken as such for hydrolysis in a biphasic system (aqueous hydrochloric acid/toluene) to furnish oxcarbazepine, which is purified just once (whereas twice at least is needed when the prior art process is carried out) in a mixture of methanol and dichloromethane (Scheme-5).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[O:21][CH3:22])[CH2:5][CH2:4]1>ClCCl.CO>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(OC)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)ccc1OCCN1CCC(OC)CC1

Procedure:
Prepared analogously to Example 3.1.b. from 1 g (3.22 mmol) of 4-methoxy-1-[2-(2-methoxy-4-nitrophenoxy)ethyl]piperidine. Yield: 0.85 g (94% of theory); C15H24N2O3 (M=280.36); calc.: molecular ion peak (M+H)+: 281; found: molecular ion peak (M+H)+: 281; Rf value: 0.6 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH:1]([CH:3]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)[C:4]([O:6]C)=O)=O.CC(C)([O-])C.[K+].[N+:23]([NH:26][C:27]([NH2:29])=[NH:28])([O-:25])=[O:24]>C(O)C>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][C:3]2[C:4](=[O:6])[N:28]=[C:27]([NH:26][N+:23]([O-:25])=[O:24])[NH:29][CH:1]=2)=[CH:14][N:13]=1
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To the solution of methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (2 g, 8.92 mmol) and potassium tert-butoxide (3.00 g, 26.8 mmol) in ethanol (15 mL) was added neat N-nitroguanidine (1.857 g, 17.84 mmol). The reaction mixture was stirred at 120° C. for 1 h. After removing the solvent, 5 mL water was added to dissolve the solid, and HCl (conc.) was used to adjust pH ˜3. The precipitate was collected to provide the title compound (1.8 g, 72.5% yield). LCMS: rt=0.96 min, [M+1-H+]=279.1
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))i soindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, isobutyryl chloride (0.24 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the solid was purified from ether (10 mL) and hexane (10 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-methylpropanamide (0.48 g, 73%) as a white solid: mp 218-220° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.39 (t, J=5.8 Hz, 1H), 7.87-7.78 (m, 2H), 7.66-7.63 (m, 1H), 5.19-5.12 (dd, J=6.9 and 12.5 Hz, 1H), 4.71 (d, J=5.8 Hz, 2H), 2.97-2.83 (m, 1H), 2.63-2.43 (m, 3H), 2.08-2.04 (m, 1H), 1.07 (d, J=6.9 Hz, 6H); 13C NMR (DMSO-d6) δ 176.52, 172.75, 169.82, 167.49, 166.95, 139.54, 134.77, 132.85, 131.50, 127.02, 121.77, 48.83, 37.48, 33.98, 30.92, 21.96, 19.53; Anal. Calcd. For C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.48; H, 5.33; N, 11.64.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:32])[NH:33][CH2:34][CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCCCN1CCOCC1
Product: O=C(NCCCN1CCOCC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 63.9 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with N-(3-aminopropyl)morpholine (available from Aldrich Chemical Company, Inc.; 89 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-morpholin-4-yl-propylcarbamoyl)-biphenyl-2-carboxylic acid (80 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br s, 1H), 9.60 (br s, 1H), 8.67 (br t, 1H), 8.47 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 6H), 3.60-4.00 (m, 4H), 3.34-3.42 (m, 3H), 2.93-3.21 (m, 4H), 1.87-1.97 (m, 2H).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[C:5](Cl)=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1.Cl>C1COCC1>[Cl:10][C:7]1[NH:6][C:5](=[O:1])[C:4]([F:3])=[CH:9][N:8]=1
Reactant: [OH-]
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(Cl)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Example 30A was also prepared as follows. Dimethylaniline (195 mL, 1.54 mol) was added to a slurry of 5-fluorouracil (99.73 g, 0.77 mol) in phosphorus oxychloride (215 mL, 2.31 mol) at 95° C. under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 3.5 h, cooled to room temperature and then slowly added to a stirred mixture of ice (200 g) and 6 M HCl (200 mL). The resulting slurry was extracted with dichloromethane (2×400 mL) and the combined organic extracts were washed with DI water (4×275 mL), dried over MgSO4 and concentrated under reduced pressure to afford 111.77 g (87%, 98.1% AUC by HPLC) of 5-fluoro-2,4-dichloro-pyrimidine as an amber oil. A molar solution of sodium hydroxide (1.34 L) was slowly added to a solution of the 5-fluoro-2,4-dichloro-pyrimidine (111.77 g, 0.67 mol) in THF (377 mL) at 0° C. After the reaction mixture was stirred for about 30 min at room temperature, the pH was adjusted to 6 by a slow addition of 1.0 M HCl. The aqueous solution was extracted with ethyl acetate (440 mL) to remove impurities following which the pH was adjusted to 1 with 1.0 M HCl. The acidic aqueous solution was extracted with ethyl acetate (4×555 mL) and the combined organic extracts were washed with brine (111 mL), dried over MgSO4 and concentrated under reduced pressure to produce 88.35 g (89%, 99.2% AUC by HPLC) of 2-chloro-5-fluoro-3H-pyrimidin-4-one as an off-white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:46]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCO)cc2)cc2ccccc12
Product: COc1ccccc1COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCOC(=O)c3ccccc3)cc2)cc2ccccc12

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-methoxy-benzyloxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzoyloxy-ethoxy)-phenyl]-3-[4-(2-methoxy-benzyloxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil; MS: 736 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([CH3:22])[CH3:21])=[N:7][CH:6]1[CH3:31])=[O:4].C([O-])([O-])=O.[K+].[K+].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH:20]([CH3:22])[CH3:21])=[N:7][C:6]=1[CH3:31])=[O:4]
Reactant: COC(=O)C1C(=O)N(Cc2ccccc2)C(C(NC(=O)OC(C)(C)C)C(C)C)=NC1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)nc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 40.3 %

Procedure:
To a stirred solution of 1-Benzyl-2-(1-t-butoxycarbonylamino-2-methyl-propyl)-4-methyl-6-oxo-1,4,5,6-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (6.37 g, 14.8 mMol) in CCl4 (150 mL) was added K2CO3 (4.0 g, 29 mMol), N-Bromosuccinimde (2.63 g, 14.8 mMol) and Benzoyl peroxide (0.18 g, 0.74 mMol). The reaction was refluxed for 0.5 h, cooled to RT, filtered through a pad of Celite®, and rinsed with CH2Cl2. The filtrate was concentrated tinder vacuum and purified by flash chromatography (step gradient of 0 to 5% EtOAc in CH2Cl2). The semi-purified product obtained was taken up in a solution of 20% EtOAc in hexane (10 mL) at which point the product began to crystallize out. The mixture was diluted with a solution of 10% Et2O in pet. Et2O (50 mL), triturated, filtered and dried under vacuum to give the title compound (2.56 g, 40%) as a white solid: MS (ES) m/e 432.2 and 430.2 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C)=[O:8])(=O)C.[OH-].[Na+]>Br>[NH2:4][C:5]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:8]
Reactant: COc1ccccc1C(=O)c1cc(Cl)ccc1NC(C)=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Cl)cc1C(=O)c1ccccc1O
Yield: 98.1 %

Procedure:
A mixture of 10 g of 2-acetylamino-5-chloro-2'-methoxybenzophenone and 100 ml of 47% hydrogen bromide was heated for 2 hours under reflux. The solution was rendered neutral with sodium hydroxide, and was subjected to extraction with 200 ml of ethyl acetate. The extract solution was washed with water and dried over anhydrous magnesium sulfate; the solvent was then distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (eluent, hexane:ethyl acetate=5:1) to yield 8.0 g of 2-amino-5-chloro-2'-hydroxybenzophenone as needles.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]([Cl:12])=[N:9][C:10]=1[CH3:11])=[O:4].C[O-].[Na+].C[C:18](O)=[O:19]>CO>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:19][CH3:18])=[N:7][C:8]([Cl:12])=[N:9][C:10]=1[CH3:11])=[O:4]
Reactant: CC(=O)O
Reactant: COC(=O)c1c(C)nc(Cl)nc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(C)nc(Cl)nc1OC

Procedure:
To a solution of 2,4-dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester (15.3 g, 69.6 mmol) in methanol (150 mL) at 0° C. under nitrogen with magnetic stirring is added 0.5 M NaOMe in MeOH (139 mL, 69.6 mmol) in dropwise fashion over 1 h. HOAc (2 mL) is added and the reaction mixture is evaporated at reduced pressure. The resulting residue is treated with sat. NaHCO3 (100 mL) and extracted with EtOAc (120 mL×3). The combined organic layers are washed with water (75 mL) and brine (75 mL), dried over magnesium sulfate, filtered and evaporated at reduced pressure to obtain a cream-colored solid. Purification by chromatography on silica gel (1:3 ether/hexanes) affords the title compound a s a white solid (less polar of two isomeric addition products formed) and 4-chloro-2-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester. 2-Chloro-4-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester 1H NMR (CDCl3) δ=4.03 (s, 3H), 3.92 (s, 3H), 2.48 (s, 3H). 4-Chloro-2-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester 1H NMR (CDCl3) δ=4.03 (s, 3H), 3.95 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.OS(O)(=O)=O.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O>O>[Br:20][C:3]1[C:2]([F:1])=[C:7]([C:6]([CH3:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1)[C:8]([OH:10])=[O:9]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(Br)c(F)c1C(=O)O
Reaction time: 6 h
Yield: 158 %

Procedure:
To a solution of 6-fluoro-2-methyl-3-nitrobenzoic acid (100 mg, 0.5 mmol) in concentrated H2SO4 (0.5 ml, 9.38 mmol) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (79 mg, 0.28 mmol) at room temperature and under nitrogen. The reaction mixture was stirred for 6 hours during which time a precipitate formed. The reaction mixture was added slowly to deionized water (3 ml) and the resulting precipitate was filtered. The solid was washed with deionized water (2 ml) and air dried for 2 hours to give 123 mg (88%) of 3-bromo-2-fluoro-6-methyl-5-nitrobenzoic acid as a pale yellow solid. LC-MS 94%, 1.61 min (3 minute LC-MS method), m/z=275.9/277.9 (ES−), 1H NMR (500 MHz, Chloroform-d) δ ppm 8.25 (d, J=6.2 Hz, 1H), 2.58 (s, 3H).