Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[C:13]([C@:22]([C@@H:30]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]2)([OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[N+](C1C=CC([O:50][C:51]([NH:53][C@H:54]2[CH2:59][CH2:58][CH2:57][N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:55]2)=O)=CC=1)([O-])=O>C(Cl)Cl>[F:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[C:13]([C@:22]([C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:51]([NH:53][C@H:54]3[CH2:59][CH2:58][CH2:57][N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:55]3)=[O:50])[CH2:31]2)([OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)C1
Reaction time: 0.5 h

Procedure:
A solution of (S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol TFA salt (62.7 mg, 0.13 mmol) in anhydrous CH2Cl2 (0.5 mL) containing triethyl amine (0.1 mL) was added to above solution of (S)-tert-butyl 3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate within 1 min. The mixture was stirred for 30 min. The reaction mixture was evaporated and the residue was purified by preparative HPLC to afford (S)-tert-Butyl 3-((R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)piperidine-1-carboxylate (35 mg). MS m/z 612 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].C(O)C.[CH2:8]([CH:15](C(C)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:24]N1C(=O)CCC1=O>>[Br:24][C:14]1[C:9]([CH2:8][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1Br
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a 2 L 4-necked round bottom flask that was equipped with an overhead stirrer, an addition funnel, a condenser and a temperature-probe, was added the solution of sodium ethoxide/ethanol (21% wt. %, 161.8 g) at 20–25° C. under nitrogen. Ethyl 2-benzylacetoacetate (103.1 g, 0.454 mole) was added dropwise. The resulting solution was stirred at 20–25° C. for 30 minutes. The reaction mixture was then cooled to −35° C. with a dry ice/acetone bath. N-Bromosuccinimide (NBS; 97.95 g, 0.545 mole) was added portion-wise over 30 minutes. After the addition was over, the reaction mixture was stirred at −35° C. for 1 hr before warming up to 20–25° C. and it was stirred for an additional 2 hrs. The reaction was then quenched with water (400 mL) and ethyl acetate (600 mL) was added. The layers were separated and the product was extracted from aqueous layer with ethyl acetate (400 mL×3). The combined organic layers was washed with saturated sodium bicarbonate twice (400 mL×2), water twice (400 mL×2) and brine (500 mL). After the removal of solvent, the product (crude, 132 g) was distilled under reduced pressure. Ethyl 2-bromo-3-benzenepropanoate (97.7 g) was obtained at yield 83.7%.
Reaction SMILES: [CH2:1]([N:8]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=2)[C:10]=1[N+:30]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].CO.O>C1COCC1.[Fe]>[NH2:30][C:10]1[C:11]([NH:15][C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:19]=[CH:20][CH:21]=2)=[N:12][CH:13]=[N:14][C:9]=1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)c1
Temperature: 50 °C
Yield: 46 %

Procedure:
To a solution of tert-butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenylcarbamate (2) (9.2 g, 17.5 mmol) in 100 mL THF were added Fe powder (9.8 g, 175 mmol), NH4Cl (18.7 g, 350 mmol), 100 mL MeOH and 20 mL H2O. The reaction mixture was heated at 50° C. for 7 hrs under N2. After cooling to rt, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to 100 mL, and extracted with EtOAc (80 mL×3). The combined organic layer was washed with water (100 mL×2) and brine (100 mL×1), dried over Na2SO4, then concentrated to dryness in vacuo. The residual was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenylcarbamate (3) (4.0 g, 46.1%) as a brown solid. LC-MS (ESI): m/z (M+1) 497.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][CH2:5][N:4]([C:7]2[C:11]([N+:12]([O-])=O)=[CH:10][N:9]([CH3:15])[N:8]=2)[C:3]1=[O:16].C1COCC1>[C].[Pd].CO>[NH2:12][C:11]1[C:7]([N:4]2[CH2:5][CH2:6][C:2]([CH3:1])([CH3:17])[C:3]2=[O:16])=[N:8][N:9]([CH3:15])[CH:10]=1
Reactant: Cn1cc([N+](=O)[O-])c(N2CCC(C)(C)C2=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(N)c(N2CCC(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A mixture of 3,3-dimethyl-1-(1-methyl-4-nitro-1H-pyrazol-3-yl)pyrrolidin-2-one (170 mg), 10% palladium-carbon (76 mg), THF (2 mL) and methanol (2 mL) was stirred at room temperature for 2 hr under hydrogen atmosphere. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure to give the title compound (140 mg).
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O>[CH3:21][NH:20][C:16]1[N:15]=[C:14]([O:13][C:12]2[CH:22]=[CH:23][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: CNc1nccc(Oc2ccc(OCc3ccccc3)cc2)n1
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1nccc(Oc2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
[4-(4-Benzyloxy-phenoxy)-pyrimidin-2-yl]-methyl-amine (Step B, 0.75 g, 2.44 mmol) was dissolved in 5 mL MeOH and 10 mL EtOAc. To the argon-degassed solution was added 10% by weight Pd/C (0.15 g). The reaction was stirred vigorously at RT under 1 atm H2 gas for 4 days. The reaction was filtered through Celite® and concentrated in vacuo to yield the title compound. MS (MH+)=218.1; Calc'd 217.23 for C11H11N3O2.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH3:20])[C:7]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:29])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:29])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH3:20])[C:7]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: COCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.7 %

Procedure:
8-Cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido [2,3-d]pyrimidin-7-one (4.44 g, 14.54 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (4.94 g, 18.90 mmol) were dissolved in dichloromethane (100 mL) and stirred at ambient temperature for 12 hours. The solvent volume was reduced to approximately 50 mL and was then purified by silica gel chromatography to give 8-cyclopentyl-2-methanesulfinyl-6-methoxymethyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (2.51 g, 53.7%). 1H NMR δ (400 MHz, CDCl3) 8.93 (s, 1H), 7.78 (t, J=1.7 Hz, 1H), 5.99 (m, 1H), 4.46 (d, J=1.7 Hz, 1H), 3.53 (s, 3H), 2.96 (s, 3H), 2.23 (m, 2H), 2.12 (m, 2H), 1.93 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[NH:16][N:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[O:20])[CH2:11]1.[C:21]1([CH2:27][CH2:28]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[N:16]([CH2:28][CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[O:20])[CH2:11]1.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:18][C:17]2[C:13](=[C:14]([CH3:19])[N:15]([CH2:28][CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:16]=2)[C:12](=[O:20])[CH2:11]1
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2c(nn1CCc1ccccc1)CC(c1ccccc1Cl)CC2=O
Product: Cc1nn(CCc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 60% sodium hydride (0.041 g, washed with hexane thrice) in dimethylformamide (10 ml) was added a solution of 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.4 g) in dimethylformamide (2 ml), and the mixture was stirred at room temperature for 40 minutes. To the mixture was added 2-phenylethyl bromide (0.30 g), and the mixture was stirred at the same temperature for 18 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (ethyl acetate-hexane) to give 6-(2-chlorophenyl)-3-methyl-1-(2-phenylethyl)-4,5,6,7-tetrahydroindazol-4-one (0.22 g) as colorless crystals and 6-(2-chlorophenyl)-3-methyl-2-(2-phenylethyl)-4,5,6,7-tetrahydroindazol-4-one (0.2 g) as oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:23](=[O:24])[N:22]([CH3:25])[C:14]3[N:15]=[C:16](S(C)=O)[N:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29]C=1>>[CH:25]1([N:22]2[C:14]3[N:15]=[C:16]([NH:31][CH:30]4[CH2:29][CH2:27][CH2:33][CH2:32]4)[N:17]=[CH:18][C:13]=3[CH:12]=[C:11]([S:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:23]2=[O:24])[CH2:4][CH2:3][CH2:2][CH2:7]1
Reactant: Cn1c(=O)c(S(=O)(=O)c2ccc(Cl)cc2)cc2cnc(S(C)=O)nc21
Reactant: Nc1ccc(Cl)cc1
Product: O=c1c(S(=O)(=O)c2ccccc2)cc2cnc(NC3CCCC3)nc2n1C1CCCC1

Procedure:
The title compound was prepared according to the procedure of Example 3, substituting 8-cyclopentyl-2-(methylsulfinyl)-6-(phenylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one for 6-(4-chlorophenylsulfonyl)-8-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one, and substituting cyclopentylamine for 4-chloroaniline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([OH:38])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14](C(OC(C)(C)C)=O)[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([OH:38])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of Compound (48a) (30 mg, 0.051 mmol) in 2.0 ml of dry dichloromethane were added 17 μl (0.156 mmol) of anisole and 40 μl (0.51 mmol) of trifluoroacetic acid under ice-cooling, and the mixture stirred for 1 hours at room temperature. Under ice-cooling, an aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, which was followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=10:1) to give 24 mg (96%) of Compound (49a).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)N.[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C.O>[CH2:17]([C:16]1[C:14]2[C:4](=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:13]=2)[NH:2][CH:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)c1ccc(NN)cc1
Reactant: CCCCCC=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCc1c[nH]c2ccc(C(=O)OCC)cc12
Temperature: 100 °C
Yield: 7.1 %

Procedure:
To a mixture of ethyl 4-hydrazinobenzoate hydrochloride (10 gm) in ethanol:water (5:1 100 mL) was added hexanal (4.62 gm). The mixture was refluxed at 100° C. for 3 h. The solvents were removed and toluene (100 mL) and p-toluene sulfonic acid (0.1 g) were added. The mixture was refluxed at 120° C. for 18 h, cooled to room temperature and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 90:9:1 (hexanes: methylene chloride: ethyl acetate) as eluent to give 0.8 g of the title compound: 1H NMR (CDCl3) δ 0.957, 1.44, 1.72, 2.78, 4.40, 7.02, 7.34, 7.90, 8.13, 8.38.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39][C:40](OC(C)(C)C)=[O:41])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[CH2:73]([O:75][C@H:76]([CH2:82][CH2:83][CH:84]=[CH2:85])[C@@H:77](C)[C:78](O)=O)[CH3:74].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39][C:40](=[O:41])[C@H:77]([CH3:78])[C@H:76]([O:75][CH2:73][CH3:74])[CH2:82][CH2:83][CH:84]=[CH2:85])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2]
Reactant: C=CCC[C@@H](OCC)[C@@H](C)C(=O)O
Reactant: C=Cc1cccc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC[C@@H](OCC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCc2cccc(C=C)c2)N1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.2 %

Procedure:
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 3-vinyl-benzyl ester (300 mg, 0.42 mmol) in anhydrous dichloromethane (9 mL) was treated with trimethylsilyl trifluoromethanesulfonate (114 μL, 0.63 mmol). The reaction mixture was stirred at room temperature for 1.5 hours then N,N-diisopropylethylamine (293 μL, 1.68 mmol) was added. The reaction mixture was evaporated to give the crude amine as a colourless solid. A solution of (2R,3R)-3-ethoxy-2-methyl-hept-6-enoic acid (78 mg, 0.42 mmol) in anhydrous dichloromethane (8 mL) was cooled to 0° C. before adding N,N-diisopropylethylamine (293 μL, 1.68 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (160 mg, 0.42 mmol). The mixture was stirred at 0° C. for 20 minutes before adding a solution of the crude amine in dichloromethane (8 mL). The reaction mixture was allowed to warm to room temperature and was stirred under a nitrogen atmosphere for 16 hours. The reaction mixture was evaporated and purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 to yield the title compound (200 mg, 60%) as a colourless solid. 1H NMR (300 MHz, CDCl3) δ0.17 (s, 6H), 0.88-0.99 (m, 6H), 0.97 (s, 9H), 1.08-1.30 (m, 8H), 1.34-1.60 (m, 3H), 1.61-1.87 (m, 4H), 2.09-2.26 (m, 3H), 2.38-2.55 (m, 2H), 3.39-3.72 (m, 4H), 4.24-4.36 (m, 2H), 4.91-5.19 (m, 4H), 5.30 (d, J=10.9 Hz, 1H), 5.70-5.90 (m, 3H), 6.53-6.84 (m, 6H), 6.97-7.50 (m, 1H), 7.21-7.44 (m, 4H). LCMS (m/z) 791.4 [M+H] Tr=6.01 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[C-:20]#[N:21].[Na+]>CCO>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[N:7]=[CH:8][C:3]([CH2:2][C:20]#[N:21])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(Oc2ccc(CCl)cn2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Oc2ccc(C(F)(F)F)cc2)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a solution of 5-chloromethyl-2-(4-trifluoromethylphenoxy)-pyridine (1.8 g, 6.27 mmol) in EtOH (12 mL) was added NaCN (1.23 g, 25 mmol). The reaction mixture was heated to 50° C. for 16 h. More ethanol (6 mL) was added, and the reaction mixture clarified. After an additional 3 h, the solvent was removed in vacuo, the residue taken up in Et2O and washed with H2O. The organic layer was dried with Na2SO4, suction filtered and concentrated in vacuo. The residue was purified by flash chromatography (50% Et2O in petroleum ether over SiO2) to yield [6-(4-trifluoromethylphenoxy)-pyridin-3-yl]-acetonitrile (1.3 g) as a pink solid; 1H NMR (300 MHz, CDCl3) δ 8.17-8.09 (m, 1H), 7.81-7.71 (m, 1H), 7.70-7.61 (m, 2H), 7.29-7.19 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 3.73 (s, 2H); EIMS m/z 278 ([M]+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17].[C:21]([O:27][CH2:28][CH2:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31])(=[O:26])[CH2:22][C:23]([CH3:25])=O>CC(O)C>[CH3:25][C:23]1[NH:13][C:14]([CH3:20])=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:4]([C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[F:1])[C:22]=1[C:21]([O:27][CH2:28][CH2:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31])=[O:26]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN(C)Cc1ccccc1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cc([N+](=O)[O-])ccc1F
Yield: 40 %

Procedure:
A mixture of 170 mg of 2-fluoro-5-nitrobenzaldehyde, 126 mg of methyl 3-aminocrotonate and 253 mg of 2-(N-benzyl-N-methylamino)ethyl acetoacetate in 1 ml of 2-propanol was reacted and then purified in the same way as in Example 9 to yield 200 mg of the desired compound (144).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31].Cl>C(Cl)Cl.CC(OC)(C)C>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccc(F)cc2F)C1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a solution of methyl 2-(2,4-difluorobenzyl)piperidine-4-carboxylate (7.1 g, 26.37 mmol) in DCM (100 mL) was added DIPEA (6.5 mL, 37.32 mmol) followed by methyl carbonochloridate (2.3 mL, 29.21 mmol) dropwise. After completed addition the reaction mixture was stirred at room temperature for 4 h, then 2 M HCl was added. The organic layer was diluted with MTBE, the biphasic mixture was filtered to remove insolubles and after phase separation the organic layer was washed with brine and satd NaHCO3, dried over MgSO4 and evaporated to give dimethyl 2-(2,4-difluorobenzyl)piperidine-1,4-dicarboxylate (8.51 g, 99%) as a dark oil. MS m/z 328 (M+H)+
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[OH:25][C:26]1[CH:27]=[C:28]([CH:43]=[CH:44][CH:45]=1)[CH2:29][NH:30][C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([CH3:42])[CH:34]=1)=[O:32].[CH3:46][O:47][C:48](=[O:57])[CH:49]([P:51]([O:55][CH3:56])([O:53][CH3:54])=[O:52])[NH2:50].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:46][O:47][C:48](=[O:57])[CH:49]([P:51]([O:53][CH3:54])([O:55][CH3:56])=[O:52])[NH:50][C:37](=[O:39])[C:36]1[CH:40]=[CH:41][C:33]([C:31]([NH:30][CH2:29][C:28]2[CH:43]=[CH:44][CH:45]=[C:26]([OH:25])[CH:27]=2)=[O:32])=[CH:34][C:35]=1[CH3:42]
Reactant: Cc1cc(C(=O)NCc2cccc(O)c2)ccc1C(=O)O
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1C)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.50 g, 9.2 mmol) was added to a solution of 4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoic acid (Example 90; 2.40 g, 8.4 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 1.80 g, 9.1 mmol) and diisopropylethylamine (1.50 g, 11.6 mmol) in N,N-dimethylformamide (50 mL). The solution was stirred overnight at room temperature. Ethyl acetate (200 mL) was added and the solution was washed with 1N hydrochloric acid solution, water and brine (200 mL each), dried (MgSO4), filtered and evaporated to give crude rac.-2-(dimethoxyphosphinyl)-N-[4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoyl]glycine methyl ester (2.47 g, 63% yield). This material was used in subsequent reactions without flrther purification.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:25]([OH:27])=O)[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])([CH3:15])([CH3:14])[CH3:13].[NH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[NH2:39])[C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>CN(C)C=O.O>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:36]=[CH:37][C:38]([NH2:39])=[C:29]([NH:28][C:25](=[O:27])[CH:20]([NH:19][C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])[CH2:21][CH:22]([CH3:23])[CH3:24])[CH:30]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N)c(NC(=O)C(CC(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
Hydroxybenzotriazole monohydrate (760 mg, 5.62 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (973 mg, 5.07 mmol) were added to a dimethyl formamide (30 mL) solution of N-tert-butoxycarbonyl-L-leucine (1.06 g, 4.57 mmol). The mixture was stirred until all 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride had dissolved. Methyl 3,4-diaminobenzoate (759 mg, 4.57 mmol) in dimethyl formamide (10 mL) and triethyl amine (0.68 mL, 4.89 mmol) were added sequentially. The reaction was stirred at room temperature over night and poured into water. This mixture was extracted with ethyl acetate three times. The organic portion was extracted with a saturated solution of sodium bicarbonate, water (2×) and brine. The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with ethyl acetate/hexanes (2:3) which yielded the title compound (690 mg, 40%). MS (CI) m/z 380.0 (M+1), 378.2 (M−1).