Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][CH:14]([Cl:18])[C:15]([OH:17])=[O:16].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.Cl>C1COCC1.CCCCCC.O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:14]([Cl:18])([Cl:13])[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C(Cl)Cl
Reactant: BrCCCCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Cl)(Cl)CCCCCBr
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 58.5 %

Procedure:
24.3 g (33.6 ml, 0.240 mol) diisopropylamine was dissolved in 100 ml THF while stirring in a nitrogen atmosphere and it was added dropwise at -50° C. to 100 ml (0.240 mol) of a 2.40 M solution of butyllithium in hexane. It was allowed to reach -10° C. for 10 minutes, a solution of 15.5 g (0.120 mol) dichloroacetic acid in 20 ml THF was then added dropwise at -75° C., it was stirred for 25 minutes at -75° C. and subsequently 93.5 g (55.0 ml, 0.41 mol) 1,5-dibromopentane in 50 ml THF was added in such a way that the temperature increased to -40° C. After 2.5 hours at -40° C. it was hydrolyzed with 10 ml 6 N HCl and the precipitate that formed was dissolved with 20 ml water. The organic phase was washed twice with a small amount of water, dried over magnesium sulfate and the solvent was removed in a vacuum. Flash chromatography of the residue on silica gel (mobile solvent: ethyl acetate/heptane 1:10) yielded 19.5 g (59%) 7-bromo-2,2-dichloroheptanoic acid 5 as a colourless oil.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CCC[CH2-].[F:18][C:19]([F:32])([F:31])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](Cl)=[O:29])=[CH:22][CH:21]=1>C1COCC1>[C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:31])([F:32])[F:18])=[CH:25][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C
Yield: 100.2 %

Procedure:
To a 500 mL round-bottomed flask was added (R)-4-phenyloxazolidin-2-one (19 g, 116.00 mmol) and THF (464 mL, 116 mmol). The solution was cooled to −78° C. N-butyllithium (46 mL, 116 mmol) was then added slowly, and the reaction was stirred for about 15 minutes before the addition of a THF solution of (E)-3-(4-(trifluoromethyl)phenyl)acryloyl chloride (27 g, 116 mmol). The cold bath was removed, the reaction was allowed to warm to room temperature, and the progress of the reaction was checked by LCMS. After LCMS indicated that the reaction was complete, the reaction was quenched with water, and the organics were washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and reduced to give an orange solid, (R,E)-4-phenyl-3-(3-(4-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one (42 g, 100% yield).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:15]([OH:17])=O)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][CH3:3].[Na].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O[N:43]=[C:44]([C:46]1[CH:63]=[CH:62][C:49]([CH2:50][N:51]2[CH2:54][CH:53]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:52]2)=[CH:48][CH:47]=1)[NH2:45].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C:4]1[C:5]([C:15]2[O:17][N:45]=[C:44]([C:46]3[CH:47]=[CH:48][C:49]([CH2:50][N:51]4[CH2:52][CH:53]([C:55]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[O:56])[CH2:54]4)=[CH:62][CH:63]=3)[N:43]=2)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][CH3:3]
Reactant: CCCc1c(C(=O)O)noc1-c1ccccn1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Agent: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Agent: On1nnc2ccccc21
Agent: [Na]
Solvent: CC#N
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 4-propyl-5-(pyridin-2-yl)isoxazole-3-carboxylic acid, sodium salt (13.5 mg, approx 0.053 mmol), HOBt (16.0 mg, 0.105 mmol), and diisopropylethylamine (0.041 mL, 0.233 mmol) in acetonitrile (1 mL) was added EDC (26.1 mg, 0.136 mmol) and tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (17.8 mg, 0.058 mmol). The reaction mixture was stirred at 80° C. for 2 h, cooled to room temperature, and concentrated to yield the crude product. The residue was dissolved in ethyl acetate (3 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by preparative HPLC afforded tert-butyl 1-(4-(5-(4-propyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate. [Prep HPLC: Column: PHENOMENEX® S10 30×100 mm; Gradient time: 10 min; Flow rate=40 ml/min; Solvent A=10% MeOH—90% Water—0.1% TFA; Solvent B=90% MeOH—10% water—0.1% TFA; Start % B=20; Final % B=100.]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][F:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(#N)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][F:15])[N:11]([CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN[C@@H](CF)CN1C(=O)OC(C)(C)C
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CF)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A mixture of (2R,5R)-5-fluoromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.371 g, 1.27 mmol), potassium carbonate (0.70 g, 5.1 mmol), benzyl bromoacetate (0.38 g, 1.65 mmol) and acetonitrile (10 mL) was stirred at 20° C. for 18 h. Mixture was poured into water (50 mL) and extracted with DCM (3×30 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-100% Et2O in 40-60 petroleum ether) gave the title compound (0.424 g, 87%) as an oil. MS [M+H]+=381.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][OH:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.S(Cl)(Cl)=O.CO.[C:39]([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][O:31][CH3:39])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C([O-])O
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1CO
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a mixture of hemiaminal A1 (2.0 g, 4.2 mmol) in dichloromethane (20 mL) was added thionyl chloride (1.5 mL, 12.6 mmol) and stirred for 2 h at room temperature. To the reaction mixture was added methanol (10 mL) and stirred a further 2 h. The reaction poured into NaHCO3 (aq) and extracted with dichloromethane. The organic phase dried over MgSO4, evaporated and the residue purified on silica eluting with 1:1:0.1 dichloromethane/ethyl acetate/methanol to give the title compound as a cream solid (1.3 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[N:7]=1.Br[CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:20]=2)[N:7]=1
Reactant: CC(C)=CCCC(C)CCBr
Reactant: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1O
Product: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1OCCC(C)CCC=C(C)C
Yield: 74.2 %

Procedure:
Under the conditions of example 1 D, 500 mg of 3-{3-hydroxy-6-[2-(4-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is reacted with 354 mg of 1-bromo-(3RS)-3,7-dimethyl-6-octene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 522 mg of 3-{6-[2-(4-methoxycarbonylphenyl)-ethinyl]-3-[(3RS)-3,7-dimethyl-6-octenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as yellow oil.
Reaction SMILES: C1COCC1.CO.C[Si]([C:12]#[C:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[C:13]([C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1)#[CH:12]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of THF (1 mL) and methanol (1 mL) of 5-trimethylsilanylethynyl-pyridin-2-ylamine (26 mg) described in Manufacturing Example 3-2 was added potassium carbonate (38 mg) at room temperature, which was stirred for 1 hour at room temperature. Water was added at 0° C. to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (16 mg).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([NH:24][C:25](=[O:37])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:28])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:19])[C:12]([C:14](OCC)=[O:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:23]=[C:22]([NH:24][C:25](=[O:37])[CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[O:28])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:19])[C:12]([CH2:14][OH:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)c1cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c2c1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1c(CO)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of ethyl 4-(2-fluoro-4-(3-(4-fluorophenylamino)-3-oxopropanamido)phenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (66 mg, 0.13 mmol, Example 40) in 20 mL of THF at −78° C. was added DIBAL-H (1 M, 1.65 mL). The reaction mixture was allowed to stir at −78° C. for 1 h and then at room temperature for 2 h. At that time, HPLC analysis indicated the completion of the reaction. The reaction was quenched with 4 mL of MeOH, followed by addition of 4 mL of H2O. The mixture was allowed to stir for 0.5 h and then Na2SO4 was added. The stirring was continued for 1 h. Filtration and concentration gave rise to the title compound (50 mg, 82%). 1H NMR (CD3OD) δ 7.70 (m, 3H), 7.50 (m, 2H), 7.25 (m, 2H), 7.00 (m, 2H), 4.60 (s, 2H), 3.45 (s, 2H), 2.50 (s, 3H); MS(ESI+) m/z 468.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.C(=O)C1C=C[C:19]([O:22]C)=CC=1.C[O-].[Na+]>CN(C)C=O>[CH3:19][O:22][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(-c2nsnc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nsnc2OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a dry nitrogen atmosphere 3.0 g (0.0013 mole) of 3-chloro-4-(4-methoxyphenyl)-1,2,5-thiadiazole (prepared by the method of Example 2 from p-anisaldehyde) was added to a stirred suspension of 0.78 g (0.0015 mole) of anhydrous sodium methoxide in 30 ml of N,N-dimethylformamide. The reaction mixture became exothermic. The mixture was allowed to cool slowly to room temperature and stir for approximately 18 hours. Approximately 0.1 g of anhydrous sodium methoxide was added and the mixture stirred an additional three hours. The reaction mixture was poured into 250 ml of ice water and the total extracted with diethyl ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to leave a beige solid. The solid was chromatographed on silica gel, eluted with methylene chloride to give a yellow solid. The yellow solid was purified by column chromatography on silica gel, eluted with n-hexane:ethyl acetate (7:1) to yield 0.7 g of 3-methoxy-4-(4-methoxyphenyl)-1,2,5 -thiadiazole, Compound 32 of Table I.
Reaction SMILES: [OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][O:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1
Reactant: CI
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate in DMF (2 mL) was added dropwise to a suspension of NaH (50 mg, 1.98 mmol) in DMF (5 mL) at 0° C. A solution of methyl iodide (700 mg, 5 mmol) in DMF (1 mL) was then added dropwise. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was quenched with ice/saturated NH4Cl, extracted with DCM (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated to afford tert-butyl 4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as an oil, which was used without purification. MS (APCI+) [M+H]+ 349.0. This material was used to prepare the title compound as described analogously in Example 3, Steps 12-14, substituting the appropriate starting materials. m/z 504.3; 1H NMR (400 MHz, D2O) d ppm 8.49 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 5.16 (t, J=7.6 Hz, 1H), 4.49-3.61 (m, 10H), 3.47 (s, 3H), 3.38-3.33 (m, 3H), 2.37-1.78 (m, 6H), 1.36-1.32 (m, 2H), 1.08 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:30])[C:13]2[C:14]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1.[H][H]>CC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:30])[C:13]2[C:14]([NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/C(=O)c2ccc(C(F)(F)F)nc2Nc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CCC(=O)c2ccc(C(F)(F)F)nc2Nc2ccccc2)cc1
Yield: 65.3 %

Procedure:
A solution of 4-[(E)-3-oxo-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (4.02 g, 9.43 mmol) in acetone (150 mL) at 25° C. was treated with 10% palladium on activated carbon (402 mg, 3.78 μmol). The reaction was stirred under a balloon of hydrogen gas for 18 h. At this time, the reaction was filtered through a pad of Celite® and was rinsed with a solution of 10% methanol/methylene chloride (3×75 mL). The filtrate was concentrated in vacuo to afford 4-[3-oxo-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-propyl]-benzoic acid methyl ester (2.64 g, 65.4%) as a yellow solid. The material was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([C:18]([CH3:47])([CH3:46])[CH2:19][CH:20]1[NH:24][CH:23]([C:25]([OH:27])=O)[CH:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[C:21]1([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=1[F:45])[C:36]#[N:37])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC1(C)[O:53][C@@H:52]([CH2:54][CH2:55][NH2:56])[CH2:51][O:50]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:53][C@H:52]([CH2:51][OH:50])[CH2:54][CH2:55][NH:56][C:25]([CH:23]1[CH:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[C:21]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[F:45])([C:36]#[N:37])[CH:20]([CH2:19][C:18]([C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])([CH3:47])[CH3:46])[NH:24]1)=[O:27]
Reactant: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C(=O)OCc1ccccc1
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C(=O)OCc1ccccc1
Yield: 22.1 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 103c (0.94 g, 1.34 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.58 g, 4.0 mmol), HATU (0.92 g, 2.41 mmol) and iPr2NEt (1.17 mL, 6.7 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.2 g, 22%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CCO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: CCOC(=O)c1cnc2cc(OCCOC)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOc1ccn2c(C(=O)O)cnc2c1
Reaction time: 8 h

Procedure:
To ethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate (5.01 g, 19.0 mmol) in THF/EtOH (32/6 mL) was added lithium hydroxide (37.9 ml, 37.9 mmol), and the reaction was stirred overnight. HCl (57 mmol, 2M in ether) was added to the mixture, followed by concentration to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+]([C:18]1[CH:19]=[C:20]([CH3:25])[N+:21]([O-:24])=[CH:22][CH:23]=1)([O-])=O>CN(C)C(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:19]=[C:20]([CH3:25])[N+:21]([O-:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(Oc2ccc(F)cc2)cc[n+]1[O-]
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6.2 g (55 mmol) of 4-fluorophenol are dissolved in 75 ml of N,N-dimethylacetamide and 20.7 g (150 mmol) of finely powdered potassium carbonate was added. 7.7 g (50 mmol) of 4-nitro-2-picoline-N-oxide are added to this suspension and the mixture is warmed at 80° C. for 3 hours. A further 7 g (50 mmol) of potassium carbonate are subsequently added and the mixture is stirred for one hour at 100° C. After cooling, it is freed from N,N-dimethylacetamide in vacuo, and the residue is taken up in water, extracted a number of times using dichloromethane, dried over MgSO4 and concentrated, and the residue is brought to crystallization using diisopropyl ether, m.p. 122°-124° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].C([O-])(=O)C.[Na+].[N+:20](CC)([O-])=O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[C:6]#[N:20])[CH3:2]
Reactant: CC[N+](=O)[O-]
Reactant: CCOc1ccc(C=O)c(OCC)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ccc(C#N)c(OCC)c1
Yield: 37.8 %

Procedure:
A mixture of 2,4-diethoxybenzaldehyde (5.0 g, 25.7 mmol), sodium acetate (4.23 g, 51.6 mmol), nitroethane (3.86 g, 51.4 mmol) in acetic acid (7 mL) was heated at reflux for 6 h. The mixture was then cooled and poured onto ice-water. The solids were filtered off, washed with water and dried. Chromatography of the residue over silica gel using 2-5% ethyl acetate in hexanes followed recrystallization in ethyl acetate gave 2,4-diethoxybenzonitrile (1.86 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:22][CH2:13][C:12]1[C:11]([F:14])=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: CCOC(=O)c1cc(F)c(C)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(F)c(CBr)c(Cl)c1
Temperature: 80 °C
Yield: 48.8 %

Procedure:
To a solution of ethyl 3-chloro-5-fluoro-4-methylbenzoate (5.3 g, 24.46 mmol) in CCl4 (100 mL) was added NBS (4.79 g, 26.91 mmol) followed by AIBN (0.4 g, 2.45 mmol). The reaction mixture was heated at 80° C. overnight. After cooling, the reaction mixture was diluted with H2O and washed with DCM (2×). The combined extracts were dried (Na2SO4), concentrated and purified by flash chromatography (12% EtOAc/Hex) to yield ethyl 4-(bromomethyl)-3-chloro-5-fluorobenzoate (3.53 g, 49%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.96-7.85 (m, 1H), 7.83 (dd, J=9.6, 1.5 Hz, 1H), 4.80 (t, J=5.7 Hz, 2H), 4.41 (q, J=7.1 Hz, 2H), 3.47 (s, 1H), 1.47-1.30 (m, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][NH:20][NH2:21])=[CH:17][CH:16]=1>>[NH2:10][C:6]1[NH:21][N:20]([CH2:19][C:18]2[CH:22]=[CH:23][C:15]([O:14][C:13]([F:24])([F:25])[F:12])=[CH:16][CH:17]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C=C(N)OCC
Product: Nc1cc(=O)n(Cc2ccc(OC(F)(F)F)cc2)[nH]1

Procedure:
From 17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 20.6 g of 4-trifluoromethoxybenzylhydrazine, analogously to the procedure described in Example 1. 8.7 g of the compound identified above as colorless crystals of melting point 99°, corresponding to 32% of theory, are obtained.