Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:4](=[O:6])[C:3]2[CH:2]=[CH:10][C:9]([CH:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:12])=[CH:8][CH:7]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C(C)c2ccccc2)ccc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)c3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
2-methyl-4-(1-phenylethyl)benzoic acid (150 mg, 0.6 mmol) was dissolved in 20 mL dichloromethane, and then N-hydroxybenzotriazole (0.9 mmol, 100 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9 mmol, 200 mg), triethylamine (10.48 mmol, 3 mL) was added to the mixture. After the mixture was stirred at room temperature for 10 minute, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.6 mmol, 90 mg) was added. The mixture was stirred at room temperature for 18 hours. Then washed with water (30 mL), extracted with dichloromethane (40 mL). The organic layer were concentrated and subjected to column chromatography (silica gel, dichloromethane/menthol=15/1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenylethyl)benzamide (150 mg, 90%). 1H NMR (300 MHz, CD3OD): δ 7.25-7.05 (m, 8H), 6.08 (s, 1H), 4.44 (s, 2H), 4.09 (m, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H) 1.59 (d, J=8.4 Hz, 3H); LRMS (M+H+) m/z: calcd 374.20. found 374.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[Br:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH:17]=[O:18])[CH:12]=[CH:13][C:14]=1[F:15].C(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:17]=2[OH:18])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CNN=CC(C)=O
Reactant: O=CC(=O)c1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(=O)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 4.8 %

Procedure:
2-Oxopropanal methylhydrazone (10.5.6 mmol, 1.06 g) and (3-bromo-4-fluorophenyl)(oxo)acetaldehyde (10.56 mmol, 2.44 g) synthesized in Reference Synthetic Example 9 were dissolved in acetic acid (37 mL) and stirred at 100° C. for 4.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1), then by silica gel thin layer chromatography (chloroform) and by silica gel thin layer chromatography (n-hexane/ethyl acetate=3/1) to give the desired product as a brown solid (160 mg, yield 5%).
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].Cl[C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.CS(C)=O>O>[Cl:12][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([O:4][CH2:2][CH3:3])[CH:11]=1
Reactant: CCO
Reactant: Clc1cncc(Cl)c1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cncc(Cl)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium (8.1 g, 338 mmol) was added to ethanol (200 ml). After complete reaction, the excess of ethanol was evaporated. 3,5-Dichloropyridine (40.0 g, 270 mmol) and dimethyl sulfoxide (300 ml) were added to the crude mixture. The mixture was stirred at 70° C. for 1 h. Water (500 ml) was added, followed by extraction twice with ethyl acetate (300 ml). The product was isolated in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:11][N:10]=1)=[O:7])([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)=[CH:11][N:10]=1)=[O:7]
Reactant: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide (140 mg, 0.30 mmol, 1.00 equiv) in methanol/tetrahydrofuran (5 mL/2 mL). The mixture was treated with Pd/C and stirred under a hydrogen atmosphere for 1 h at room temperature. The solids were filtered out. The resulting solution was diluted with 50 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 100 mg (76%) of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(C)(=O)=O)c1

Procedure:
A solution of ({3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (0.045 g, 0.109 mmol), triethylamine (16.8 mL, 0.120 mmol) and methanesulfonyl chloride (8.6 ml, 0.11 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 2 hours. The reaction was quenched with water. The aqueous solution was washed with CH2Cl2 and the organic solution was dried over Na2SO4, filtered, and concentrated. The product was purified via flash chromatography on silica gel (1/1 EtOAc/Hexanes) to afford the title compound of Step B as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.85 (s, 1H), 7.35 (m, 3H), 7.32 (m, 1H), 6.80-6.90 (m, 3H), 4.48 (s, 2H), 4.36 (s, 2H), 4.29 (s, 2H), 2.79 (s, 3H), 1.47 (s, 9H); MS 489 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:20]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:19]=2)=[CH:12][CH:11]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[OH-].[Na+]>C1COCC1.O>[CH3:7][NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:20]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:19]=2)=[CH:14][CH:15]=1
Reactant: O=CNc1ccc(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69 %

Procedure:
LAH (0.25 g, 6.5 mmole) is added to dry THF (20 ml) under an inert atmosphere, then cooled to ~4° C. (ice/water bath). N-formyl-4-[2-(3,4-dibenzyloxyphenyl)ethyl]benzeneamine (2.9 g, 6.5 mmole) is dissolved in dry THF (20 ml) and added via cannula dropwise to the LAH/THF suspension. The reaction is stirred for 20 hours at ambient temperature under an inert atmosphere. Water (0.25 ml) followed by 15% NaOH (0.25 ml) and finally water (0.75 ml) is added to the reaction mixture. The mixture is filtered, diluted with 0.5 volume of ether, and the organics are washed with brine and then dried (Na2SO4). Concentration affords 1.9 g (70% g) of N-methyl-4-[2-(3,4-dibenzyloxyphenyl)ethyl]benzeneamine, mp 61°-65° C., of sufficient purity for further use.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH:9]([OH:15])[C:10]([O:12]CC)=[O:11])=[CH:3][CH:2]=1.O.O1CCCC1.Cl>[OH-].[Na+]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH:9]([OH:15])[C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(O)CSc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(O)CSc1ccc(-c2ccccc2)cc1
Yield: 76.4 %

Procedure:
A mixture of ethyl 3-(4-biphenylylthio)lactate (0.093 g, 0.31 mmole), in NaOH (0.5 ml), water (2 ml) and tetrahydrofuran (1 ml) was stirred overnight at 25° C. The mixture was acidified (1 N HCl, 0.5 ml) and then extracted with methylene chloride (3×5 ml). The residue from evaporation of the methylene chloride was recrystallized from acetonitrile to yield 0.065 g of 3-(4-biphenylylthio)-2-hydroxypropionic acid, m.p. 175.5°-176° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.O1CCOCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:27]([OH:29])=[O:28])[N:25]=1)([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)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=NOCc1cccnc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C(=NOCc1cccnc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A mixture of 7 g of the product of Step A, 35 ml of dioxane, 35 ml of ethanol and 21 ml of aqueous N sodium hydroxide was stirred at 35°-40° C. for one hour and after cooling, the pH was adjusted to 2 by addition of aqueous N hydrochloric acid. 250 ml of water were added and the mixture was vacuum filtered. The product was washed and dried to obtain 4.9 g of 2-(2-tritylamino-thiazol-4-yl)-2-(3-pyridinylmethoxyimino)-acetic acid. mp=192° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[F:30][C:2]([F:1])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[C:24]([OH:26])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.9 %

Procedure:
To ethyl 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-cyclopropane-carboxylate (C19) (1.50 g, 3.59 mmol) in methanol (24 mL) was added sodium hydroxide (2 N, 7.20 mL, 14.4 mmol) and stirred at room temperature for 4 hours. The reaction was acidified with hydrogen chloride (2 N) and the methanol was evaporated off under vacuum. The aqueous solution was extracted with ethyl acetate (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound as a yellow oil (1.62 g, 98%): 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.13-8.08 (m, 2H), 7.83-7.77 (m, 3H), 7.40 (t, J=5.9 Hz, 4H), 7.22 (d, J=8.3 Hz, 2H), 2.65 (ddd, J=6.7, 5.3, 2.8 Hz, 2H), 2.03-1.95 (m, 1H), 1.76-1.66 (m, 2H), 1.47 (ddd, J=8.4, 6.6, 4.7 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 390 ([M+H]+).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.ClC1[S:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:29][N:30]=1>>[CH3:22][C:14]1([CH3:21])[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]([C@H:10]2[CH2:11][C@H:8]([NH:7][C:6]3[S:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][N:30]=3)[CH2:9]2)[C:13]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Reactant: Clc1ncc(-c2ccccc2)s1
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3ncc(-c4ccccc4)s3)C2)c2ncccc21

Procedure:
3,3-Dimethyl-1-(trans-3-((5-phenylthiazol-2-yl)amino)cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-2(3h)-one was prepared by Method B7 using starting materials 1-(trans-3-aminocyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (intermediate 26, 0.100 g, 0.329 mmol) and 2-chloro-5-phenylthiazole (0.0643 g, 0.329 mmol) at 120° C. for 96 h. M+1: 391.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (s, 6 H) 2.31-2.40 (m, 2 H) 3.21-3.31 (m, 2 H) 4.34-4.43 (m, 1 H) 5.17 (quin, J=8.46 Hz, 1 H) 7.08 (dd, J=7.24, 5.09 Hz, 1 H) 7.17-7.22 (m, 1 H) 7.35 (br. t, J=7.70, 7.70 Hz, 2 H) 7.45 (br. d, J=7.20 Hz, 2 H) 7.52 (s, 1 H) 7.76 (dd, J=7.24, 1.56 Hz, 1 H) 8.21 (dd, J=5.28, 1.56 Hz, 1 H) 8.30 (d, J=6.20 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([C:7](Cl)=[O:8])[CH2:4][O:3]1.Cl.[S:12]1[N:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]2[O:23][C:22](=[O:24])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH:32]=4)=[C:27]([F:37])[CH:26]=3)[CH2:20]2)=[N:13]1.N1C=CC=CC=1>ClCCl>[S:12]1[N:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]2[O:23][C:22](=[O:24])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:36][CH2:35][N:34]([C:7]([C@H:5]5[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]5)=[O:8])[CH2:33][CH:32]=4)=[C:27]([F:37])[CH:26]=3)[CH2:20]2)=[N:13]1
Reactant: CC1(C)OC[C@H](C(=O)Cl)O1
Reactant: O=C1O[C@@H](COc2cnsn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC[C@H](C(=O)N2CC=C(c3ccc(N4C[C@H](COc5cnsn5)OC4=O)cc3F)CC2)O1
Yield: 92.5 %

Procedure:
A solution of (R)-2,2-dimethyl-1,3-dioxolan-4-ylcarbonyl chloride (S Handa et al, Synth. Commun. (1995), 25, 2837) [0.597 g, 3.63 mmol ] in dichloromethane (5 ml) was added dropwise to a stirred mixture of 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one hydrochloride (1 g, 2.42 mmol) and pyridine (0.49 ml, 6.06 mmol) in dichloromethane (30 ml) under nitrogen at −10° C. After 10 minutes the cooling bath was removed and the mixture stirred for a further hour. Water (30 ml) was added and the organic layer washed with brine, dried (Na2SO4) and evaporated. The residue was triturated with ether and filtered to give 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one as a solid (1.13 g, 93%) MS: 504 (MH+); NMR: 1.32 (6H, s); 2.42 (2H+DMSO); 3.7 (2H, m); 4.0 (1H, m); 4.11 (2H, m); 4.25 (2H, m); 4.8 (2H, m); 4.91 (1H, m); 5.12 (1H, m); 6.02 (1H, s); 7.29-7.43 (2H, m); 7.5 (1H, d); 8.42 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:17][C:18]([F:36])([F:35])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][N:28]=[CH:27][C:26]=2[CH2:30][CH2:31][C:32](O)=[O:33])=[CH:21][CH:20]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:26]2[CH:27]=[N:28][O:29][C:25]=2[C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:35])([F:17])[F:36])=[CH:20][CH:21]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(C(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (72.9 mg), 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (57 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (40 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (45 mg) and N,N-dimethylformamide (0.3 ml) was stirred at room temperature overnight. The reaction mixture was directly introduced into preparative HPLC and purified to give N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(C)c3)CC2)c(C)c1
Yield: 100.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-3-methylbenzoic acid (25 g) and 1-(2,4-dimethylphenyl)piperazine (22 g), the title compound (45 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:14]([CH2:16][C:17](=[O:19])[OH:18])[OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:19][C:17](=[O:18])[CH2:16][C@H:14]([OH:15])[C@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)OCc1ccccc1
Yield: 81 %

Procedure:
N-(t-butyloxycarbonyl)-statine (1141 mg., 5.12 mmol) were dissolved in 20 ml of dimethylformamide. 708 mg. of potassium carbonate and 0.609 ml of benzyl bromide was then added. After the reaction was complete, the reaction mixture was concentrated, taken up in ethyl acetate, washed twice with 5 ml of H2O, dried over MgSO4, filtered and concentrated to yield 1510 mg of a yellow oil (81% yield). 1H NMR, 90 mHz, CDCl3, partial, 0.92 (d, J=7 Hz, 6H), 1.42 (s, 9H, Boc), 2.58 (m, 2H), 4.05 (m, 1H), 4.72 (d, BocNH, 1H), 5.13 (s, CH20, 2H), 7.3 (s, 5H, aromatic).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12](=[O:25])[O:11][C@@H:10]([CH3:26])[C@@H:9]1[O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:34][N:35](C(C)C)[CH:36](C)C.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.Cl.CNC>CN(C)C=O.CCOC(C)=O>[CH2:1]([C@@H:8]1[C@@H:9]([O:27][CH2:28][CH2:29][C:30]([N:35]([CH3:36])[CH3:34])=[O:32])[C@H:10]([CH3:26])[O:11][C:12](=[O:25])[C@@H:13]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][O:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1OCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1OCCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.5 %

Procedure:
A solution of 3-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)propanoic acid (250 mg, 0.554 mmol, 1.00 equiv), Hünig's base (0.484 mL, 2.77 mmol, 5.00 equiv), hydroxybenzotriazole (HOBT; 85 mg, 0.55 mmol, 1.00 equiv), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC; 159 mg, 0.831 mmol, 1.50 equiv) in N,N-dimethylformamide (DMF; 5.5 mL, 0.1 M) were stirred at room temperature for 10 min, and then dimethylamine hydrochloride (54 mg, 0.66 mmol, 1.2 equiv) was added. The resulting solution was stirred at room temperature for 3 days (d). The reaction was diluted with EtOAc (20 mL) and washed with ½ sat'd NaCl (20 mL), and the phases separated. The aqueous phase was extracted with EtOAc (10 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated to provide a yellow oil. The product was purified by automated silica gel column chromatography (5-35% acetone in hexanes) to provide an oily solid that by TLC still had a large amount of DMF. The oily solid was taken up in 20 mL EtOAc and washed with ½ sat'd NaCl (2×10 mL), dried over MgSO4, filtered and concentrated to provide tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-(dimethylamino)-3-oxopropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (208 mg, 78%) as an off-white solid: mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.23-7.14 (m, 3H), 5.12 (d, J=7.6 Hz, 1H), 4.94 (dq, J=9.2, 6.3 Hz, 1H), 4.60 (d, J=7.4 Hz, 1H), 4.02 (dd, J=15.5, 6.8 Hz, 1H), 3.93-3.81 (m, 2H), 3.49 (d, J=10.8 Hz, 1H), 3.42-3.33 (m, 1H), 3.34-3.25 (m, 1H), 3.21-3.08 (m, 2H), 3.02 (s, 3H), 2.94 (s, 3H), 2.71-2.51 (m, 2H), 2.31 (t, J=12.7 Hz, 1H), 1.92 (s, 1H), 1.50 (d, J=6.4 Hz, 3H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.15, 170.50, 154.97, 139.88, 129.11, 128.42, 126.09, 85.45, 80.09, 77.22, 75.43, 73.11, 72.81, 68.77, 53.07, 47.17, 37.35, 35.37, 35.12, 33.77, 28.26, 18.77; HRMS-ESI (m/z) [M+H]+ calc'd for C25H39N2O7, 480.2784. found, 480.2785.
Reaction SMILES: [N:1]([CH:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:6]2[CH2:5][NH:4]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1>[NH2:1][CH:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:6]2[CH2:5][NH:4]1
Reactant: O=NC1CN2CCCCC2CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC1CN2CCCCC2CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.7 %

Procedure:
A solution of 6.76 g of crude 3-nitrosoperhydro-1H-pyrido[1,2-a]pyrazine (prepared according to stage (a)) in 30 ml of tetrahydrofuran is added dropwise at reflux temperature to a stirred suspension of 1.71 g of lithium aluminium hydride in 150 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for a further 3 hours; while cooling with ice 10 ml of aqueous 2N sodium hydroxide solution and then 10 ml of water are added and the whole is stirred at room temperature for a further 2 hours. The precipitate is filtered off with suction and then washed on the suction-filter with hot isopropyl alcohol. The filtrate (including the isopropyl alcohol portions) is concentrated by evaporation in vacuo and yields the desired 3-aminoperhydro-1H-pyrido[1,2-a]pyrazine (6.68 g) in the form of a slightly yellow-coloured oil of a purity that is sufficient for the hydrazone formation described above.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[C:15]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[S:30][C:29](N)=[N:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:12])[CH3:9].O.[ClH:37]>C(#N)C.C(Cl)(Cl)Cl>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[C:15]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[S:30][C:29]([Cl:37])=[N:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:12])[CH3:9]
Reactant: Cl
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3sc(N)nc3C(F)(F)F)n2)c1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)c1cccc(Nc2nccc(-c3sc(Cl)nc3C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
t-Butyl nitrite (0.87 mL, 6.54 mmol) is added drop-wise to a suspension of N-[3-ethoxycarbonyl-phenyl]-4-(2-amino-4-trifluoromethyl-5-thiazolyl)-2-pyrimidineamine (1.34g, 3.27 mmol) and anhydrous cupric chloride (925 mg, 6.55 mmol) in acetonitrile (15 mL) over 0.5 hours. After stirring at room temperature for 3 hours, water and chloroform are added and the mixture is made acidic with 12N hydrochloric acid. The layers are separated and the aqueous layer is extracted with chloroform. The combined organic extracts are dried over MgSO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give N-[3-ethoxycarbonyl-phenyl]-4-[2-chloro-4-trifluoromethyl-5-thiazolyl]-2-pyrimidineamine (1.1 g); ESI-MS (m/z): 429 (M++H).