Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH3:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#N.Cl.C([O:19]CC)C>O>[Cl:7][C:8]1[CH:9]=[C:10]([C:11](=[O:19])[CH2:4][CH3:5])[CH:13]=[CH:14][CH:15]=1
Reactant: CCBr
Reactant: CCOCC
Reactant: N#Cc1cccc(Cl)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Product: CCC(=O)c1cccc(Cl)c1
Reaction time: 8 h

Procedure:
4.86 g (0.2 mol) of magnesium turnings, 30 ml of dry diethyl ether and a grain of iodine are placed in a one liter three-necked round-bottomed flask equipped with a condenser, a calcium chloride drying tube, a pressure equalizing funnel and a magnetic stirrer; the flask is purged with nitrogen, and 21.8 g (0.2 mol) of ethyl bromide in 30 ml of dry diethyl ether are then added. The mixture is then heated under reflux for one hour and left to cool. At ambient temperature, 16.51 g (0.12 mol) of 3-chlorobenzonitrile in 70 ml of dry diethyl ether are then added. A copious precipitate forms. The mixture is stirred overnight at ambient temperture and then cooled in an ice bath and hydrolysed by slowly adding 50 ml of water and then about 100 ml of 6N hydrochloric acid until the pH is acid. The mixture is stirred for one and a half hours and then extracted with ethyl acetate. The organic extract is then washed twice with water, dried and concentrated on a rotary evaporator. This gives 26 g of an orange oil, which is concentrated in vacuo to give about 18.2 g of ochre crystals of 3'-chloropropiophenone melting at about 40° C.
Reaction SMILES: [Mg].II.[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[B:21](OC)([O:24]C)[O:22]C>C1COCC1.C(OCC)C.CCCCCC>[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[B:21]([OH:24])[OH:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1ccc(Br)c(OCc2ccccc2)c1
Reactant: COB(OC)OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(B(O)O)c(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a stirred and gently refluxing suspension of magnesium powder (382 mg, 15.7 mmol) in THF (10 ml) containing a few crystals of iodine, was added dropwise, a solution of 2-benzyloxy-1-bromo-4-methoxybenzene (WO 93/08799, 4.39 g, 15.0 mmol) in THF (40 ml). After completion of the addition, the mixture was refluxed for 1.25 hours, cooled and then transferred via a canula to a stirred solution of trimethyl borate (3.11 g, 3.40 ml, 30.0 mmol) in THF (25 ml) at -78° C. The mixture was stirred at -78° C. for 30 minutes and then the cooling bath was removed and stirring was continued at room temperature for a further 2 hours. The mixture was partitioned between diethyl ether and 1 N HCl (200 ml) and the product was extracted into diethyl ether. The extracts were washed with water, dried (MgSO4) and concentrated to give a yellow solid. Trituration with warm diethyl ether/n-hexane gave after drying the title compound as a cream solid. Yield 2.159 g (56%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.[CH2:31]([N:33]=[C:34]=S)[CH3:32].[OH2:36].[Cl-].[Na+]>CN(C)C=O>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[C:9](=[CH:10][C:11]([NH:12][CH2:13][CH3:14])=[C:2]([NH:1][C:34]([NH:33][CH2:31][CH3:32])=[O:36])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: CCN=C=S
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc2c(N3CCN(C(=S)NCc4ccccc4)CC3)ncnc2cc1NCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 502.5 mg (1.19 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 10 ml of dimethylformamide was added 0.10 ml (1.19 mmol) of ethyl isothiocyanate, followed by overnight stirring at room temperature. To the resulting mixture was added 0.10 ml (1.19 mmol) of ethyl isothiocyanate, followed by heating at 80° C. with stirring for 4 hours. The reaction mixture was allowed to cool to room temperature, and then poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]([OH:27])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:43]1[CH2:48][CH2:47][CH:46]([O:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:45][CH2:44]1>C(OCC)(=O)C.ON1C(=O)CCC1=O>[C:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:25]([N:43]2[CH2:44][CH2:45][CH:46]([O:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:48]2)=[O:27])=[CH:15][CH:16]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
11.14 g (30 mmol) of N-(benzyloxycarbonyl)-O-(1,1-dimethylethyl)-L-tyrosine were dissolved in 65 ml of ethyl acetate while warming to 40°. The solution was treated at 20° with 0.1 g (0.9 mmol) of N-hydroxysuccinimide. Subsequently, a solution of 7.5 g (36 mmol) of dicyclohexylcarbodiimide in 40 ml of ethyl acetate was added dropwise at 22° within 25 minutes. A white suspension formed during the addition and this was stirred for 30 minutes. A solution of 7.8 g (36 mmol) of t-butyl (4-piperidinyloxy)acetate in 100 ml of ethyl acetate was then added dropwise to the suspension within 30 minutes. A suspension formed and this was stirred at 22° for 3 hours. The precipitated dicyclohexylurea was filtered off and the filtrate was washed with 2N hydrochloric acid, water and semi-saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and, after removing the drying agent, evaporated. The residue was a viscous oil and weighed 18.5 g. The oil was diluted with a mixture of 10 ml of ethyl acetate and 60 ml of hexane and warmed to 50°. The insoluble solid was filtered off under suction and the filtrate was treated with 20 ml of hexane and seeded with a small amount of crystalline product at 30°. The mixture was cooled to 0° within one hour and stirred at this temperature for 30 minutes. The crystals were then filtered off under suction and washed on the filter with 20 ml of hexane. 14.5 g (85%) of benzyl [(S)-p-t-butoxy-α-[[4-[(t-butoxycarbonyl)methoxy]-piperidino] carbonyl]phenethyl]carbamate were obtained in this manner. Its content was 96% according to HPLC.
Reaction SMILES: F[C:2](F)(F)[C:3]([O-])=[O:4].[C:8]([C:11]1[C:12]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13][N:14]([C:16]2([CH2:20][C:21]#[N:22])[CH2:19][NH2+:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:3]([N:18]1[CH2:17][C:16]([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:13]2)([CH2:20][C:21]#[N:22])[CH2:19]1)(=[O:4])[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)C[NH2+]C1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)C1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (50 mg, 0.17 mmol) in DCM (2 mL) was added pyridine (0.050 mL, 0.62 mmol), followed by acetic anhydride (0.030 mL, 0.32 mmol). The reaction mixture was allowed to stir for 30 minutes before the solvent was removed in vacuo. Saturated aqueous NaHCO3 solution was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 50-100% EtOAc/hexanes followed by 10% MeOH/EtOAc) to afford the title compound, Example #32.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>C(Cl)(Cl)Cl>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:25]3[C:24](=[O:26])[C:23]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]4[C:21]3=[O:31])[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CN3C(=O)c4ccccc4C3=O)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (881 mg) in chloroform (10 mL) was added potassium phthalimide (556 mg). The mixture was stirred at room temperature overnight and water was added. After separating the organic layer, the aqueous layer was extracted with chloroform. Organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to give the title compound as white powder.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Cl:18][C:19]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#N.[OH2:35]>C1COCC1>[Cl:18][C:19]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:35]
Reactant: O
Reactant: N#Cc1ccccc1Oc1ccc(Cl)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., a 1.2 M solution of diisobutylaluminum hydride in toluene (12.3 ml, 14.8 mmol) was added dropwise to a solution of 2-(2,4-dichlorophenoxy)benzonitrile (3.0 g, 11.3 mmol) in THF (30 ml). The reaction mixture was warmed to room temperature and stirred for 16 hours. It was cooled to 0° C. Water (10 ml) was added dropwise. It was warmed to room temperature. The solid was removed by filtration through a plug of celite. The solvent was removed from the filtrate in vacuo. The crude product was purified by flash chromatography on silica (130 g), using ethyl acetate/heptane 1:3 as eluent, to give 800 mg of 2-(2,4-dichlorophenoxy)benzaldehyde.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]([F:25])([F:24])[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.Br[CH2:27][C:28]([CH2:30][CH2:31][Cl:32])=[CH2:29]>C1COCC1.CCOC(C)=O.C(Cl)(Cl)Cl>[Cl:32][CH2:31][CH2:30][C:28](=[CH2:27])[CH2:29][CH:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]([F:24])([F:25])[F:11])=[CH:19][CH:18]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: C=C(CBr)CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C=C(CCCl)CC(C(=O)O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.4 %

Procedure:
Step AAJ (1): NaHMDS 2.0 M in THF (10.2 mL, 20.4 mmol) was added to a solution of 2-(4-(trifluoromethoxy)phenyl)acetic acid (2.00 g, 9.08 mmol) in THF (18.2 mL) at 0° C. The resulting mixture was stirred for 20 min at 0° C., then neat 2-(bromomethyl)-4-chlorobut-1-ene (1.83 g, 9.99 mmol, from Step AAI (3)) was added. The mixture was quenched at 0° C. after 10 min with water (5 mL) and concentrated in vacuo. The mixture was diluted with EtOAc and the organic layer was extracted with 1N HCl, then brine, dried over sodium sulfate, and concentrated in vacuo to afford after purification by silica gel column chromatography (60-100% EtOAc/chloroform), 6-chloro-4-methylene-2-(4-(trifluoromethoxy)phenyl)hexanoic acid (2.21 g, 6.85 mmol, 75% yield) as a pale-yellow oil. LC-MS (M−H)− 321.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.35-7.44 (2 H, m), 7.20 (2 H, d, J=8.5 Hz), 4.89-4.97 (2 H, m), 3.81-3.93 (1 H, m), 3.55-3.66 (2 H, m), 2.86 (1 H, dd, J=15.3, 8.9 Hz), 2.39-2.57 (3 H, m).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CCO.[Pd]>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCN2CCOCC2)cc1N
Reaction time: 18 h

Procedure:
To a solution 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine (1.0 eq) in EtOH was added Pd/C (0.1 eq). The reaction vessel was repeatedly purged with nitrogen, then stirred under a hydrogen atmosphere (1 atm) for 18 hours. The product was filter ed through a Celite plug, and the plug washed with EtOH. The diamine was used without purification. LC/MS m/z 238.3 (MH+), Rf 0.295 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:11]([SH:14])[NH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:22][CH:23]=[O:24]>C1COCC1.O.C(OC(=O)C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:11]3[S:14][CH2:22][CH:23]([OH:24])[N:12]3[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Reactant: O=CCCl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2nn3c(c2-c2ccncc2)SCC3O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
5-(3-Methoxy-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol prepared as described in Example 8 (115 mg, 0.406 mmol) was dissolved in a 1:1 THF/water mixture (3 mL). A 55% aqueous solution of chloroacetaldehyde (0.071 mL, 0.609 mmol, 1.5 eq) was added and the mixture was stirred at room temperature for 2 hours. It was then diluted with ethylacetate and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness to give 123 mg (93%) of crude product, which was used without further purification in the following step.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(Cl)Cl>[NH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:6][O:7][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:19]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCNC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the Wang resin (12 g, 1.1 mmol/g) in a 250 mL peptide synthesis vessel was added 120 mL of 0.4 N CDI in anhydrous THF, and shaken at room temperature for 17 hours. The resin was thoroughly washed with CH2Cl2 (3×100 mL ) and THF (3×100 mL) to remove the excess CDI and then treated with 120 mL of 0.4 N 3-piperidinemethanol in THF at room temperature for 17 hours. The resulting resin 1 was washed with DMF (3×100 mL), MeOH (4×100 mL), and CH2Cl2 (4×100 mL) and dried in vacuo. To the alcohol resin 1 was added methanesulfonyl chloride (5.11 ml, 66 mmol) in 100 mL CH2Cl2 followed by 20 mL of pyridine, and the resulting slurry was shaken at room temperature for 17 hours. The resulting mesylate resin 2 was washed with DMF (3×100 mL), MeOH (4×100 mL), and CH2Cl2 (4×100 mL) and dried in vacuo.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]([C:9]1[CH:10]=[C:11]([C:15](=O)[CH3:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].[C:18](=[O:21])(O)[O-].[Na+]>CN(C)C=O>[N+:6]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([Cl:3])=[CH:16][CH:18]=[O:21])([O-:8])=[O:7]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CC=C(Cl)c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To 400 ml of anhydrous dimethylformamide was added with stirring 455 g. (3.01 moles) of phosphorus oxychloride. The mixture was kept at 20° to 25° throughout the addition by external cooling. After standing overnight, a solution of 330 g. (2 moles) of m-nitroacetophenone in 400 ml anhydrous dimethylformamide was added dropwise, keeping the pot temperature at 20° to 25° by external cooling. Addition required about 1/2 hour. Stirring was continued without external cooling, during which time the temperature rose to 55° C. and then dropped to ambient temperature. The mixture was poured into cold sodium bicarbonate solution, keeping the pH at least 7, and the crude product was filtered. This product was taken up in ca. 1 liter of benzene and separated from residual water entrained by the crystals by drying with anhydrous potassium carbonate. The benzene solution was concentrated on a rotary evaporator to approximately one-third of its volume, and hexane was added until the hot solution just began to cloud. A small amount of benzene dissolved some material that oiled out, and the solution was cooled to yield crystals m.p. 83°. A second crop was obtained by evaporation of the filtrate and cooling. Total yield 195.7 g. (46.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:29])[N:11]([C@H:22]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]2)[C:12]2[N:13]([N:18]=[C:19]([CH3:21])[N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].C([O:40]C(=O)C(C)C[N+]#N)C.[C:48]1([CH3:54])[CH:53]=CC=[CH:50][CH:49]=1>C([O-])(=O)C.[Rh+]>[F:1][C:2]1[CH:3]=[C:4]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:29])[N:11]([C@H:22]2[CH2:23][CH2:24][C@H:25]([O:28][CH:49]([CH3:50])[C:48]([OH:40])([CH3:54])[CH3:53])[CH2:26][CH2:27]2)[C:12]2[N:13]([N:18]=[C:19]([CH3:21])[N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)C(C)C[N+]#N
Reactant: Cc1ccccc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Agent: [Rh+]
Agent: CC(=O)[O-]
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Reaction time: 1 h

Procedure:
To a mixture of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.46 g), rhodium(I) acetate (0.004 g) and toluene (10 mL) was added dropwise 3-ethoxy-2-methyl-3-oxopropane-1-diazonium (0.69 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography. The obtained residue was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.5 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 50%).
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[Cl:9])[OH:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:10]([OH:17])(=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]1=[N:1][OH:2]
Reactant: O=C(Cl)c1ccccc1
Agent: ON=C1CCCCC1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1

Procedure:
The procedure of Example II is repeated except that 7.4 grams (0.05M) of 1-oximino-2-chlorocyclohexane, 7.0 gm. (0.05M) of benzoyl chloride, 5.1 grams (0.051M) of triethylamine, and 130 ml. of benzene are employed.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.CCCCCC>C1COCC1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH:5]([CH2:3][OH:2])[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2C(CO)CCC2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and crystallization from diethyl ether/hexane yielded the title compound, white solid, m.p. 82° C. and MS: m/e=350 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][C:6]([CH3:17])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[F:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:14]=2)=[CH:7][C:6]([CH3:17])=[CH:5][N:4]=1
Reactant: COC(CCBr)OC
Reactant: Cc1cnc(F)c(-c2c[nH]c(=O)[nH]c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cc(C)cnc2F)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A mixture of 5-(2-fluoro-5-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep99, 300 mg, 1.16 mmol), and K2CO3 (241 mg, 1.7 mmol) in DMF (5 ml) was stirred for one hour at room temperature. 3-Bromo-1,1dimethoxy-propane (234 mg, 1.3 mmol) was added and stirring was continued for three days. Water was added and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (95:5:0.5) to give 200 mg of the final compound as oil (53% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][N:22](C)[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.[CH:33](N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:19]([CH3:33])[CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: CN(CCN)c1ccc([N+](=O)[O-])cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCNc1ccc([N+](=O)[O-])cn1)c1cnc([N+](=O)[O-])c(-c2ccc(Cl)cc2Cl)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), (2-aminoethyl)methyl(5-nitro(2-pyridyl))amine (12.0 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.