Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.C[O-].[Na+].[Na].[CH2:21]([N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:24][CH3:25])[CH3:22]>CO.C1(C)C=CC=CC=1>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCN(CC)CCCCl
Reactant: Oc1ccc(-c2cc3ccccc3o2)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN(CC)CCCOc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
A solution of 4.9 g. (0.023 mol.) of 2-p-hydroxyphenylbenzofuran in 75 ml. of toluene and 5 ml. of methanol was added to a sodium methoxide solution prepared by dissolving 0.54 g. (0.023 g.-atom) of sodium in 25 ml. of methanol. The mixture was refluxed for 15 minutes, then the methanol was removed by distillation and 3.48 g. (0.023 mol.) of diethylaminopropyl chloride was added and the resulting reaction mixture was refluxed for four hours. The mixture was filtered and the filtrate concentrated under reduced pressure to give 2-[4'-(3-diethylaminopropoxy)phenyl]benzofuran, m.p. 86°-88°.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])=[CH2:5].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl>CN(C)C=O>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([C:4]([CH3:3])=[CH2:5])[C:7]1=[O:15]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: ClCCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCCCCCl)c2ccccc21
Reaction time: 8 h

Procedure:
To a stirred mixture of 3.2 parts of a sodium hydride dispersion 70% in 9 parts of N,N-dimethylformamide is added dropwise (slowly), during a 2 hours-period, a mixture of 17.4 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, 77.5 parts of 1,6-dichlorohexane and 36 parts of N,N-dimethylformamide. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is filtered over hyflo and the N,N-dimethylformamide is evaporated in vacuo. The excess of 1,6-dichlorohexane is distilled off in an oil-bath with water-jet. The residue is dissolved in methylbenzene and the solution is stirred with activated charcoal. The latter is filtered off over hyflo and the filtrate is evaporated, yielding 1-(6-chlorohexyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: C.CC.FC(F)(F)S(O)(=O)=[O:7].[N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>FC(F)(F)C(O)=O>[N+:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:7])=[O:13]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=Nc1ccccc1
Agent: C
Agent: CC
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccccc1

Procedure:
Para-nitroso-diphenylhydroxylamine is a compound which may be readily obtained by means of the catalytic dimerization of nitrosobenzene. According to a recent, especially advantageous process, the foregoing compound may be obtained with practically quantitative yield, if a sulfonic acid with a pKa ≤1, for example methane-, ethane-, or trifluoromethanesulfonic acid, or perchloric or trifluoroacetic acid is used as a catalyst (German Patent Application No. P 27 03 919). The nitrosobenzene required for the preparation of para-nitroso-diphenylhydroxylamine is likewise easily accessible and may be obtained by the catalytic reduction of nitrobenzene. The reduction will proceed with a high conversion rate and high selectivity if, pursuant to another recent process, an aliphatic, cycloaliphatic, olefinic, or aromatic hydrocarbon is used as the reducing agent (German Patent Application No. P 27 13 602).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O.O>[Cl:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1Cl)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 62 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 mL) under nitrogen was added potassium carbonate (19.76 g, 143 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g) along with some less pure material (2.7 g). The pure material is an off-white crystalline solid, which is used as such in the next step.
Reaction SMILES: [IH:1].CS[C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[F:9][C:10]([F:15])([F:14])[CH2:11][NH:12][NH2:13]>C(O)C>[IH:1].[F:9][C:10]([F:15])([F:14])[CH2:11][NH:12][NH:13][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1
Reactant: NNCC(F)(F)F
Reactant: CSC1=NCCN1
Agent: I
Solvent: CCO
Product: FC(F)(F)CNNC1=NCCN1
Reaction time: 0.5 h

Procedure:
To a solution of 12.2 g of 2-methylthioimidazoline, hydroiodide in 30 ml of ethanol was slowly added 12.6 g of 2,2,2-trifluoroethyl hydrazine, dropwise over 30 minutes. This mixture was refluxed overnight, then evaporated to an oil which crystallized on standing, giving 4,5-dihydro-2-[2-(2,2,2-trifluoroethyl)hydrazino]-1H-imidazole, hydroiodide, a one gram portion of which was reacted as described in Example 33, giving 1.0 g of the desired product, mp>290° C.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([C:8](=[C:22]([S:29][C:30](=[O:32])[CH3:31])[S:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:33])[CH2:5]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)Cl>[CH2:1]([S:3]([CH:4]1[N:7]([C:8](=[C:22]([S:29][C:30](=[O:32])[CH3:31])[S:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[O:10])[C:6](=[O:33])[CH2:5]1)=[O:42])[CH3:2]
Reactant: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1S(=O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.4 g p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-3-acetylthio-3-(2-ethoxyethylthio)acrylate in 75 ml. methylene chloride was cooled to 0° C. under a nitrogen atmosphere. A solution of 0.551 g m-chloroperbenzoic acid in 25 ml methylene chloride was added dropwise, then the reaction mixture was stirred at 0° C. for 1 hour. The methylene chloride solution was then washed with two 25 ml portions of saturated aqueous sodium bicarbonate solution and two 25 ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. The crude title compound (1.25 g) was used without further purification. The NMR spectrum of a deuterochloroform solution showed peaks at 1.24(m,6H); 2.27-3.74(c,13H); 4.7-5.46(c,3H); 7.75(m,2H); and 8.23(m,2H) ppm. The infrared spectrum of a dichloromethane solution has absorption bands at 5.6 and 5.79 microns.
Reaction SMILES: Br[C:2]1[C:3](=[O:48])[N:4]([CH3:47])[C:5](=[O:46])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[NH:29][C:30]2[C:35]([C:36]=1[C:37]1[C:38](=[O:45])[N:39]([CH3:44])[C:40](=[O:43])[C:41]=1Br)=[CH:34][CH:33]=[CH:32][CH:31]=2.CN(C=O)C.[NH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CCN(CC)CC>[CH3:47][N:4]1[C:5](=[O:46])[C:6]2[C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[NH:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=4[C:36]=3[C:37]3[C:38](=[O:45])[N:39]([CH3:44])[C:40](=[O:43])[C:41]=3[N:57]3[CH2:58][CH2:59][N:54]([CH2:55][CH2:56]3)[C:2]=2[C:3]1=[O:48]
Reactant: C1CNCCN1
Reactant: CN1C(=O)C(Br)=C(c2c(CCCCCCCCCCCCc3[nH]c4ccccc4c3C3=C(Br)C(=O)N(C)C3=O)[nH]c3ccccc23)C1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)C2=C(C1=O)N1CCN(CC1)C1=C(C(=O)N(C)C1=O)c1c([nH]c3ccccc13)CCCCCCCCCCCCc1[nH]c3ccccc3c12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
0.75 mmol of 3-bromo-4-(2-(12-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)dodecyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione is dissolved in 200 ml of absol. DMF, treated with 0.5 ml of abs. NEt3 and heated to 80° C. The solution of 0.75 mmol of piperazine in 100 ml of absol. DMF and 0.5 ml of NEt3 is then slowly added dropwise to the warm solution and the mixture is then stirred at 80° C. for 48 h. The solvent is then removed in vacuo to the greatest possible extent and the residue is treated with 100 ml of 1N HCl. This solution is then extracted with ethyl acetate (in total about 600 ml), the combined extracts are dried over Na2SO4 and the solvent is stripped off in vacuo. Purification is carried out by column chromatography (SiO2, CH2Cl2/EA9.5:0.5) orange crystals, yield: 0.267 g (52%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:27])=[N-].C(OCC)C>C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]([O:24][CH3:27])=[O:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(=O)O)c12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1c(F)ccc2onc(OCCNC(=O)OC(C)(C)C)c12
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carboxy-5-fluoro-1,2-benzisoxazole (0.31 g) in diethylether (20 ml) was added diazomethane/diethylether solution at 5° C. until the reaction mixture became yellow, and the mixture was then stirred for 15 minutes. The reaction mixture was evaporated under reduced pressure to give the title compound (0.32 g, 100% yield) as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([NH:31][C@H:32]3[CH2:37][CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)=[O:30])[CH2:24]2)([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.ClCCl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]3)=[O:30])[CH2:24]2)([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: 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
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)NC2CCCNC2)C1
Reaction time: 0.33 h
Yield: 55.6 %

Procedure:
(S)-tert-Butyl 3-((R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)piperidine-1-carboxylate (20 mg, 0.033 mmol) was dissolved in TFA/dichloromethane (1 mL, 1:3, v/v), stirred 20 min, evaporated, and purified by preparative HPLC to give the (3R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide (9.39 mg) as its TFA salt. 1H NMR (400 MHz, CD3OD): 6 ppm 7.57 (d, J=8.4 Hz, 1H), 7.36-7.20 (m, 3H), 7.04-7.02 (m, 2H), 6.92 (m, 1H), 4.03 (m, 1H), 3.85-3.75 (m, 2H), 3.39-3.32 (m, 3H), 3.29 (s, 3H), 2.86 (m, 1H), 2.71-2.56 (m, 3H), 2.37, 2.35 (two s, 3H, rotamer), 1.99 (m, 2H), 1.88-1.26 (m, 13H), 0.92 (m, 1H). MS m/z 512 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14](C(C)(C)C)[C:13]([OH:20])=[C:12](C(C)(C)C)[CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C[N+](=O)[O-]
Product: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.2 %

Procedure:
To a solution of 5.0 g (15 mmol) of 4-(4'nitrophenyl)-2,6-di-tert-butylphenol in 50 mL of toluene was added a solution of 9.2 g (69 mmol) of aluminum chloride in 10 mL of nitromethane. This mixture was stirred at ambient temperature for 4 hours and poured into 100 mL of 1N HC1 mixed with ice. The resulting aqueous mixture was extracted with two 100-mL portions of ethyl acetate. Combination, drying (MgSO4), and concentration of the organic layers resulted in crystallization of 2.3 g (69% yield) of yellow 4-(4'-nitrophenyl)phenol, which may also be named as 4'-nitro-(1,1'-biphenyl)-4-ol: 1H NMR (DMSO-d6) 6.93 (d, 2H, J=9Hz), 7.64 (d, 2H, J=9Hz), 7.82 (d, 2H, J=9Hz), 8.25 (d, 2H, J=9Hz), 9.98 (broad s, 1H).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC=C(Cl)C=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1cccc(Cl)c1)c1cc(Br)ccc1OCc1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (384 mg, 9.16 mmol) in water (20 ml) was added dropwise to a stirred solution of (3-chlorophenyl)methyl 5-bromo-2-([(3-chlorophenyl)methyl]oxy)benzoate (may be prepared as described in Description 21; 427 mg, 0.92 mmol) in THF (20 ml) over 1 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as a white solid. 200 mg.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+]=[N-].[H-].[CH3:19][O:20]CCO[Al+]OCCOC.[Na+].[H-].C(OC=O)(=O)C>>[CH2:11]([N:7]1[CH2:8][C@H:9]([F:10])[C@H:5]([CH2:4][NH:1][CH:19]=[O:20])[CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COCCO[Al+]OCCOC
Reactant: [N-]=[N+]=NC[C@@H]1CN(Cc2ccccc2)C[C@@H]1F
Agent: CC(=O)OC=O
Agent: [H-]
Agent: [Na+]
Product: O=CNC[C@@H]1CN(Cc2ccccc2)C[C@@H]1F

Procedure:
cis-3-Azidomethyl-1-benzyl-4-fluoropyrrolidine was reduced with sodium bis-(2-methoxyethoxy)aluminium hydride and formylated with formic acid-acetic anhydride to yield cis-1-benzyl-4-fluoro-3-formylaminomethylpyrrolidine.
Reaction SMILES: N[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[I:12]I.N(OC(C)(C)C)=O>C(Cl)(Cl)Cl>[I:12][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1
Reactant: II
Reactant: Nc1cncc(C(F)(F)F)n1
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cncc(I)n1
Reaction time: 0.67 h

Procedure:
A three liter flask was charged with a solution of 2-amino-6-trifluoromethylpyrazine (obtained by the method of J. L. Miesel, U.S. Pat. No. 4,293,552, 95% pure by HPLC analysis, 32.6 g, 0.20 mol) in chloroform (1000 mL). Freshly ground iodine (101 g. 0.40 mol) was added to give a dark purple solution. After 40 min, a solution of t-butyl nitrite (22.9 g, 0.20 mol) in chloroform (300 mL) was added dropwise over 1 h. During the addition, slow gas evolution was observed together with a mild exotherm (<10° C.) which was moderated with a cold water bath. After an additional 1 h at room temperature the reaction mixture was washed with saturated aqueous sodium sulfite (3×500 mL) to remove the excess iodine. The chloroform solution was dried over magnesium sulphate, filtered and concentrated on a Buchi to give 23 g of an orange oil. The crude product was purified by distillation from copper (40-80 mesh, 200 mg) to give 19.5 g of the title compound as a yellow oil; b.p. 50°-56° C./0.6 mmHg; δ (360 MHz, CDCl3) 9.06 (1H, s, pyrazine-H), 8.86 (1H, s, pyrazine-H); m/e 274 (M+).
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]([C:9]([OH:11])=[O:10])=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C@H:46]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)[CH2:47][C:48]1([C:51]([OH:53])=[O:52])[CH2:50][CH2:49]1>C(Cl)Cl>[C:58]1([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:57]=[CH:56][C:55]([CH2:54][C@@H:46]([NH:45][C:6]([C:5]2[CH:4]=[C:3]([C:9]([OH:11])=[O:10])[NH:2][N:1]=2)=[O:8])[CH2:47][C:48]2([C:51]([OH:53])=[O:52])[CH2:50][CH2:49]2)=[CH:60][CH:59]=1
Reactant: N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C(=O)O)CC1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C(=O)O)CC1)c1cc(C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
3,5-Pyrazoledicarboxylic acid (35.2 mg, 226 μmol, 1.0 eq.), DIPEA (126 μL) and HATU (85.9 mg, 226 μmol, 1.0 eq.) and DCM (5 mL) were combined and stirred for 5 minutes at room temperature. 1-((R)-2-Amino-3-biphenyl-4-yl-propyl)-cyclopropanecarboxylic acid (86.7 mg, 294 μmol, 2.3 eq,) and DIPEA (0.5 mL) in DCM (5 mL) was added, and the resulting mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and the product was extracted with DCM, dried and evaporated. The resulting product was combined with AcOH (1.5 mL) and purified with preparative HPLC to yield the title compound (21.4 mg; 93% purity). MS m/z [M+H]+ calc'd for C24H23N3O5, 434.16; found 433.5.
Reaction SMILES: [O-]Cl.[Na+].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH:8]=[N:9][OH:10].[CH3:15][O:16][C:17]([C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([C:29]([NH:31][CH:32]([CH2:40][C:41]#[CH:42])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:18]>C(Cl)(Cl)Cl.CCN(CC)CC>[CH3:15][O:16][C:17]([C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([C:29]([NH:31][CH:32]([CH2:40][C:41]4[O:10][N:9]=[C:8]([C:7]5[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=5[O:5][CH3:4])[CH:42]=4)[C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:30])([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:18]
Reactant: COc1ccccc1C=NO
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(CC(C(=O)NC(Cc4cc(-c5ccccc5OC)no4)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.25% aqueous NaOCl (1.33 g, 0.77 mmol) in CHCl3 at 0° C. was added a solution of 2-methoxybenzaldehyde oxime (0.77 mmol, 0.116 g) dropwise and tert-butyl 2-(3-methoxycarbonyladamant-1-ylcarbonylamino)pent4-ynoate (300 mg, 0.77 mmol) and one drop of Et3N. After addition, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the crude product was purified on a prep plate (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[OH:10])C=NC=1.[Br:27][C:28]1[N:33]=C(/C=C/C2C=C(F)C=CC=2F)C=C[N:29]=1>>[Br:27][C:28]1[N:33]=[C:4]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C@@H:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[OH:10])[CH:3]=[CH:2][N:29]=1
Reactant: Fc1ccc(F)c(/C=C/c2ccnc(Br)n2)c1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cncc(Br)c1)[C@H](O)c1cc(F)ccc1F
Product: CC(C)(C)OC(=O)N[C@H](c1ccnc(Br)n1)[C@H](O)c1cc(F)ccc1F

Procedure:
Prepared according to the same procedure as tert-butyl (1R,2R)-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate, starting with (E)-2-bromo-4-(2,5-difluorostyryl)pyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=5.2 Hz, 1H), 7.65 (d, J=5.2 Hz, 1H), 7.45 (d, J=9.8 Hz, 1H), 7.29 (ddd, J=9.0, 5.3, 3.4 Hz, 1H), 7.22-7.10 (m, 2H), 5.82 (d, J=5.2 Hz, 1H), 5.46-5.30 (m, 1H), 4.85 (dd, J=9.8, 3.1 Hz, 1H), 1.29-1.03 (m, 9H), Mass spec.: 432.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[C-]#N.[CH3:18][N:19](C=O)C>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1COCC1>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:18]#[N:19])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 110 °C
Reaction time: 21 h
Yield: 84 %

Procedure:
Under an inert atmosphere a flask is charged with [2-(5-bromo-1H-indol-3-yl)ethyl]-dimethyl-amine (Example 3) (1.0 g, 3.74 mmol), zink cyanide (0.235 g, 2 mmol), Pd2(dba)3xCHCl3 (0.194 mg, 5 mol %), dppf (bis-diphenylphosphino ferrocene) (0.207 g, 0.374 mmol, 10 mol %), and DMF (12 mL). The orange slurry is heated to 110° C. and stirred for 21 hours. To the black suspension which has formed, THF (100 mL) is added, and this is extracted with 1 N NaOH (100 mL). The organic layer is washed with water twice (50 mL each), dried and removal of the solvent gives the title product (0.67 g, 84%) as brown solid. 1H-NMR (CDCl3, 300 MHz) δ 2.35 (s, 6H, 2 CH3); 2.67 (m, 2H, CH2NMe2); 2.91 (m, 2H, CH2); 7.01 (s, 1H, H-2); 7.13 (d, 1H, 3J=8.3 Hz, H-7); 7.26 (dd, 1H, 4J=1.6 Hz, H-6); 7.87 (d, 1H, H-4); 9.80 (br s, 1H, NH). 13C-NMR (CDCl3, 75 MHz) δ 23.48 (CH2); 45.42 (CH3); 60.06 (CH2N); 101.75 (C-5); 112.24 (C-7); 114.74 (C-3); 121.41 (CN); 124.49 (C-4); 124.62 (C-6); 124.75 (C-2); 127.31 (C-9); 138.47 (C-8).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)#[N:26].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][CH:31]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(C#N)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Cyanophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 7.44 (d, 2H), 6.77 (d, 2H), 4.90 (s, 2H), 3.67 (m, 4H), 3.29 (m, 4H), 2.22 (s, 3H) ppm; MS (ES) M+Na expected=434.0, found 434.0.