Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Li+].[OH-].[Cl:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[CH2:20][CH2:19][CH2:18][CH:12]([C:13]([O:15]CC)=[O:14])[CH2:11]2)=[CH:7][CH:6]=1>C1COCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:20][CH2:19][CH2:18][CH:12]([C:13]([OH:15])=[O:14])[CH2:11]2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
An H2O (25 mL) solution of LiOH (1.66 g) was added to a THF (60 mL) solution of ethyl 1-(4-chlorobenzyl)nipecotate. The resulting reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to provide an amorphous solid. The obtained crude product was purified by column chromatography (SiO2, 50% methanol-dichloromethane) to afford 1-(4-chlorobenzyl)nipecotic acid (9.75 g, 98.2%) as an off-while amorphous solid. The purity was determined by RPLC/MS (>95%). ESI/MS m/e 254.0 (M++H, C13H17ClNO2).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:36](OCC)[O:37]CC)=[C:5]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:36]=[O:37])=[C:5]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 91.7 %

Procedure:
To a solution of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (7.25 g) in acetone (70 ml) was added 6 N-hydrochloric acid (7 ml) and the resultant mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. Water was added to the residue, where an oily substance appeared. The aqueous mixture was adjusted to an alkaline medium by addition of power of sodium bicarbonate, and then extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off under reduced pressure to give a reddish oil (5.8 g) of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[C:7](OCC)(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10].C[O-].[Na+].C(O)=O>C1(C)C(C)=CC=CC=1.C(O)C.CO>[CH2:1]([N:4]1[C:7](=[O:15])[C:8]2[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:10][C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CCCN=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: Cc1ccccc1C
Product: CCCn1c(=O)[nH]c2ccccc2c1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A solution of propyl isocyanate (34.0 g, 0.40 mol) in xylene (100 ml) is metered, at room temperature, into a solution of ethyl anthranilate (66.1 g, 0.40 mol) in xylene (200 ml). After the addition has ended, the batch is stirred at 110° C. for 2 hours. 7.20 ml of a 30% solution of methanolic sodium methylate (0.040 ml) are metered in and the mixture is stirred at 90° C. for a further 2 hours, during which process methanol and ethanol are distilled off. 3.6 ml of 85% formic acid (0.080 mol) are subsequently added and the mixture is stirred at 90° C. for a further hour. After cooling, the product is filtered off with suction, washed with 3×25 ml of xylene, 3×25 ml of ethanol and 3×25 ml of water, and dried. 67.3 g of 3-(propyl)-2,4(1H,3H)-quinazolinedione (yield: 82.4% of theory) of melting point 190° to 191° C. (lit. 187° to 188° C.) are obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:14]1>>[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(=O)Cl)cc1
Reactant: CCN1CCCC(N)C1
Agent: Cl
Product: CCN1CCCC(NC(=O)c2ccc(N)cc2)C1

Procedure:
4-Aminobenzoyl chloride hydrochloride is reacted with 3-amino-1-ethylpiperidine to afford 4-amino-N-(1-ethyl-3-piperidyl)benzamide which is reacted with 4-chloro-8-trifluoromethylquinoline to afford the title compound, melting point 177°-178° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15]Br)=[CH:11][CH:10]=1)C1C=CC=CC=1.[ClH:19].[F:20][C:21]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:22]=1[CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:19].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:27]2[CH2:26][CH2:25][CH:24]([CH2:23][C:22]3[C:21]([F:20])=[CH:33][CH:32]=[CH:31][C:30]=3[F:34])[CH2:29][CH2:28]2)=[CH:17][CH:18]=1
Reactant: Fc1cccc(F)c1CC1CCNCC1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccc(OCCN2CCC(Cc3c(F)cccc3F)CC2)cc1

Procedure:
The title compound was prepared from 2-(4-benzyloxyphenoxy)ethyl bromide (0.393 g, 1.28 mmol), 4-(2,6-difluorobenzyl)piperidine hydrochloride (0.317 g, 1.28 mmol) and potassium carbonate (0.444 g, 3.2 mmol) in two steps as off white solid (0.240 g). mp 198-200° C. 1H NMR (CD3OD) 1.595 (m, 2 H), 1.906 (m, 3 H), 2.705 (d, J=5.7 Hz, 2 H), 3.029 (t, J=12.3 Hz, 2 H), 3.303 (m, 2 H), 3.629 (d, J=12.6 Hz, 2 H), 4.238 (t, J=4.5 Hz, 2 H), 6.702 (d, J=9.0 Hz, 2 H), 6.825 (d, J=9.0 Hz, 2 H), 6.953 (m, 2 H), 7.277 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][OH:9])[S:4][N:3]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:10]([O:9][CH2:8][C:5]1[S:4][N:3]=[C:2]([Cl:1])[C:6]=1[Cl:7])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCc1snc(Cl)c1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1snc(Cl)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
3.0 g (16.3 mmol) of the above-produced (3,4-dichloroisothiazol-5-yl)methanol and 2.52 g (17.9 mmol) of benzoyl chloride were dissolved in 70 ml of toluene. Thereto was dropwise added, under ice-cooling, 1.98 g (19.6 mmol) of triethylamine. The mixture was stirred at room temperature for 3 hours. Water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The resulting crystals were washed with hexane to obtain 4.1 g (yield: 87%) of (3,4-dichloroisothiazol-5-yl)methyl benzoate as colorless crystals (melting point: 79 to 80° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:23][N:24]([CH3:26])[CH3:25]
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Temperature: 140 °C
Yield: 90.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3,4-dihydro-quinazolin-4-one (1.0 g, 3.46 mmol) and dimethylformamide dimethyl acetal (0.92 mL, 6.92 mmol) in dimethylformamide (4 mL) was heated to 140° C. for 24 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure. The dark residue was triturated with methanol and the bright yellow crystalline solid which formed was collected and dried to give 1.075 g (90%) of 3-(2-chloro-phenyl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one which had: mp 210-211° C.; 1H NMR δ 7.86 (d, J=12.3 Hz, 1H), 7.79 (dd, J=3, 8.5 Hz, 1H), 7.61-7.54 (m, 1H), 7.51-7.29 (m, 5H), 4.06 (d, J=12.3 Hz, 1H), 2.80 (br s, 6H). Analysis calculated for C18H15ClFN3O: C, 62.89; H, 4.40; N, 12.22. Found: C, 62.75; H, 4.28; N, 12.29.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[N:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[N:13]([CH3:14])[CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1cc(-c2ncc[nH]2)nc(Cl)n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1ccnc1-c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 2,4-Dichloro-6-(1-dimethylsulfamoylimidazole-2-yl)pyrimidine 83 (246 mg, 0.76 mmol) in 10 mL of 1.5 N HCl was refluxed for 1 h. After cooling to RT, the pH was adjusted to 8.5 with aq NaHCO3 and the product was extracted into CH2Cl2. After drying the CH2Cl2 layer was evaporated to give 110 mg of 2,4-dichloro-6-(imidazole-2-yl)pyrimidine. A mixture of 2,4-dichloro-6-(imidazole-2-yl)pyrimidine (121 mg, 0.56 mmol), K2CO3 (100 mg, 0.72 mmol) and CH3I (2.280 g, 1 mL, 16 mmol) in 15 mL of dry acetone was refluxed for 48 h. After cooling to RT, the solvent was evaporated and the residue was partitioned between water and CH2Cl2. The CH2Cl2 layer was washed successively with water and brine, and then the solvent was evaporated to give 75 mg of 2,4-dichloro-6-(1-methylimidazole-2-yl)pyrimidine 86.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:41]=[CH:40][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[CH2:30][NH:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH2:30][NH:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=3)=[CH:40][CH:41]=2)=[O:10])=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CNC(=O)c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CNC(=O)c2cccnc2)c1
Temperature: 25 °C
Yield: 114.9 %

Procedure:
To a solution of tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(nicotinamidomethyl)phenyl)acetate (0.005 g, 0.008 mmol) in dichloromethane (1.0 ml) was added TFA (1.0 ml) and the reaction was stirred at ambient temperature. After 1 hour the reaction was concentrated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(nicotinamidomethyl)phenyl)acetic acid (0.005 g). MS −449.1 [M—CO2H].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])=[CH:17][C:16]=2[NH:29][C:30]2[C:31]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[N:36][C:32]=3[N:33]=[CH:34][N:35]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])=[CH:17][C:16]=2[NH:29][C:30]2[C:31]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:41])[CH3:42])=[N:36][C:32]=3[N:33]=[CH:34][N:35]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(NC(=O)c4cccs4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(NC(=O)c4cccs4)ccc3Oc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 256d (276 mg, 0.462 mmol) was dissolved in a 1:1 mixture of TFA in CH2Cl2 and stirred at room temperature for 2 hrs. The solvent was removed under vacuum and the crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (33 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.27-1.35 (m, 6 H), 6.80-6.91 (m, 5 H), 6.99 (d, J=9.19 Hz, 1 H), 7.21-7.25 (m, 1 H), 7.63 (dd, J=8.82, 2.57 Hz, 1 H), 7.81 (d, J=8.46 Hz, 1 H), 7.87 (d, J=4.04 Hz, 1 H), 8.01-8.03 (m, 2 H), 8.82 (s, 1 H), 8.91 (d, J=8.46 Hz, 1 H), 10.39 (s, 1 H) MS (ESI+) m/z 497 (M+TFA+H)+; (ESI−) m/z 495 (M+TFA−H)−.
Reaction SMILES: [C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([O:12]CC)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+].O.C(OCC)(=O)C>C(O)C>[C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)CC1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C2(C#N)CCC(CC(=O)O)CC2)c2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of Compound 20 (0.41 g, 1.1 mmol) obtained in Example 19 in ethanol (4.1 mL) was added a 2 mol/L aqueous solution of sodium hydroxide (1.1 mL), and the mixture was stirred at room temperature for 1 hour and then stirred at 60° C. for 20 minutes. The mixture was allowed to cool, and water and ethyl acetate were added to the mixture, followed by separating into an organic layer and an aqueous layer. The aqueous layer was acidified with 6 mol/L aqueous hydrochloric acid and extracted with ethyl acetate, and the extract was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, toluene was added to the residue, and the mixture was evaporated in vacuo. To the residue was added diisopropyl ether, and the precipitated solid was collected by filtration and recrystallized from ethanol to give Compound 21 (0.13 g, 36%) as a mixture of isomers in white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]([C:18](=[NH:21])[NH:19][OH:20])([CH3:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](N(CC)CC)[CH3:24].C(Cl)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]([CH3:17])([C:18]1[N:21]=[C:23]([CH3:24])[O:20][N:19]=1)[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CS(C)(=O)=O)(NC(=O)OCc1ccccc1)C(=N)NO
Reactant: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of [1-(N-Hydroxycarbamimidoyl)-2-methanesulfonyl-1-methyl-ethyl]-carbamic acid benzyl ester (Example 109b, 2.04 g, 6.19 mmol) in dry DMF (30 mL) were added triethylamine (1.73 mL, 12.4 mmol) and acetyl chloride (572 μL, 8.05 mmol). the reaction was stirred 30 minutes at room temperature. Reaction was then stirred at 130° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.21 g, 55%) as yellow oil. MS (ESI, m/z): 354.5 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:6]=[C:5]([CH3:16])[CH:4]=1)=[O:2].[Cl-].[CH2:18]([O:22][NH3+:23])[CH2:19][CH2:20][CH3:21]>>[CH:1]([C:3]1[C:4](=[N:23][O:22][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]([CH3:16])[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:8]=1)=[O:2]
Reactant: CCCCO[NH3+]
Reactant: Cc1cccc(-c2nc(C)cc(C=O)n2)n1
Agent: [Cl-]
Product: CCCCON=C1C(C=O)=NC(c2cccc(C)n2)=NC1C

Procedure:
If 6-formyl-4-methyl-2-(6-methyl-2-pyridyl)pyrimidine is used instead of 4-formyl-2-(2-pyridyl)pyrimidine and O-n-butylhydroxylammonium chloride instead of hydroxylammonium chloride, 6-formyl-O-n-butyloximino-4-methyl-2-(6-methyl-2-pyridyl)-pyrimidine (compound 133c) is obtained in a corresponding manner.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1Br.[C:29]1(OB(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1-c1ccccc1
Yield: 120.9 %

Procedure:
In a solution of 0.70 g of 2-bromo-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzoic acid methyl ester synthesized similarly to Step 1 of Synthetic Example 10 in 20 ml of tetrahydrofuran and 10 ml of water, 0.18 g of phenyl boric acid, 0.39 g of potassium carbonate and 0.05 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under reflux with heat for 1.5 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was poured in 30 ml of water, then extracted with ethyl acetate (50 ml×1). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate, and 0.78 g of the aimed product was obtained as brown resinous substance.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:19](=[O:36])[NH:20][C@@H:21]([CH3:35])[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1>[Pd].CO>[NH2:10][C@@H:11]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[C:19]([NH:20][C@@H:21]([CH3:35])[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=1)=[O:36]
Reactant: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@@H](N)CC1CCCCC1
Reaction time: 5 h

Procedure:
The product from step C (138 mg, 0.265 mmol) and 5 mol % of 10% palladium on carbon (14 mg) was dissolved in 20 mL of methanol and purged with nitrogen. Balloon pressure of hydrogen was added and the resulting slurry was stirred for 5 hours. The septum was removed and the slurry was filtered through celite and concentrated. Yield 98 mg, quantitative.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[OH:5][C:6]1[CH:11]=[C:10]([OH:12])[N:9]=[C:8]([SH:13])[N:7]=1.[OH-].[Na+]>O>[CH2:1]([S:13][C:8]1[NH:9][C:10](=[O:12])[CH2:11][C:6](=[O:5])[N:7]=1)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: Oc1cc(O)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCSC1=NC(=O)CC(=O)N1

Procedure:
Propyl iodide (136 ml) was added to a suspension of 4,6-dihydroxy-2-mercaptopyrimidine (200 g) in water (800 ml), containing sodium hydroxide (55.6 g). The reaction mixture was stirred for 2 weeks then concentrated to half volume, 2N hydrochloric acid added and the product isolated by filtration (167 g).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].CO[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1>C(OCC)C>[CH3:7][C:6]([CH3:8])=[CH:5][CH2:4][CH2:3][C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1
Reactant: COC1=CC(=O)CC1
Reactant: CC(C)=CCCBr
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)=CCCC1=CC(=O)CC1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Magnesium turnings 2.1 g (0.086 mole) were added to 50 ml diethyl ether with stirring. 1-Bromo-4-methyl-3-pentene 10 g (0.061 mole) was added dropwise over 30 minutes. The reaction was allowed to warm from 25° C. to 40° C. during the addition and aged for 30 minutes. A solution of 3-Methoxy-2-cyclopenten-1-one, 10 g (0.089 mole) in diethyl ether was added at 25° C. The resulting mixture was aged 30 minutes then quenched with 20% aqueous acetic acid (50 ml). The organic layer was dried over sodium sulfate, filtered and distilled to give 6.6 g (65% yield) of 3-(4-methyl-3-pentenyl)-2-cyclopenten-1-one. The 3-(4-methyl-3-pentenyl)-2-cyclopenten-1-one had a boiling point (Bp) of 117° C. at 5 mmHg.
Reaction SMILES: O[C@@:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].C(O)C>[Ni].O>[CH3:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[CH2:25][N:26]([CH3:36])[C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])=[O:22])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: COCCCC[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A 100-mL round bottom flask was charged with of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropyl-methylcarbamate (0.9806 g, 1.59 mol, 1.0 equiv), absolute ethanol (6 mL), and Raney nickel (2.15 g, ca. 20 equiv) (Aldrich Raney® 2800 nickel, slurry in water, washed with distilled water prior to use until the washings were neutral, then washed three times with absolute ethanol and stored under ethanol until needed.) The reaction mixture was heated to 100° C. for 3 h and then stirred at rt overnight. LC-MS showed about 60% conversion. The ethanolic solution was decanted from the catalyst. The catalyst was washed with absolute ethanol three times, the solvent being removed by decanting in each case. The organic solutions were combined and concentrated in vacuo. The residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 16 min, flow rate 25 mL/min) to give of 2-(trimethylsilyl)ethyl (S)-2-((S)-3-((R)-5-methoxy-1-phenylpentyl)-piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate (0.5422 g, 57%). LC-MS (3 min) tR=2.61 min, m/z 624 (M+Na+), 602 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.28 (br s, 2H), 7.29-7.25 (m, 2H), 7.21-7.17 (m, 1H), 7.09-7.06 (m, 2H), 5.46 (m, 1H), 4.21-4.06 (m, 4H), 3.68-3.59 (m, 2H), 3.33-3.27 (m, 2H), 3.28 (s, 3H), 2.92 (s, 3H), 2.68-2.63 (m, 1H), 2.43-2.29 (m, 2H), 1.80-0.83 (m, 25H), 0.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.5, 158.0, 142.8, 128.4, 128.2, 126.2, 72.7, 64.3, 58.3, 52.8, 49.4, 49.1, 47.9, 45.1, 41.2, 41.1, 34.7, 34.3, 33.4, 33.3, 32.4, 29.2, 28.7, 26.4, 26.2, 26.1, 25.1, 24.1, 17.7, −1.5.