Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]([C:12]1[CH:29]=[C:28]([CH2:30][CH2:31][CH3:32])[C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([N+]([O-])=O)=[C:21]([CH:24]=2)[CH:22]=[O:23])=[C:14]([CH2:33][CH2:34][CH3:35])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:59].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.O.[Fe].O.C(O)(=O)C>[I:59][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:15]2[C:28]([CH2:30][CH2:31][CH3:32])=[CH:29][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:37])([F:36])[F:1])=[CH:13][C:14]=2[CH2:33][CH2:34][CH3:35])=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: [I-]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1Oc1ccc([N+](=O)[O-])c(C=O)c1
Agent: [Fe]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1Oc1ccc(I)c(C=O)c1
Reaction time: 0.08 h
Yield: 7 %

Procedure:
To a solution of 5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2,6-dipropylphenoxy)-2-nitrobenzaldehyde (100 mg, 0.186 mmol) in dioxane/water (2:1, 1.7 mL), iron powder (26 mg, 0.465 mmol) and acetic acid (290 μL) were added sequentially under ice-cold conditions, and the resultant mixture was stirred at room temperature overnight. After completion of the reaction, water and a saturated aqueous solution of sodium hydrogen carbonate were added under ice-cold conditions, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. A solution of the obtained crude product (98 mg) in acetonitrile (0.744 mL) was added with p-toluene sulfonic acid monohydrate (106 mg, 0.558 mmol), added with a mixed aqueous solution (water 100 μL) of sodium nitrite (26 mg, 0.372 mmol) and potassium iodide (77 mg, 0.465 mmol) under ice-cold conditions, and stirred at the same temperature for 5 minutes. Subsequently, the resultant mixture was stirred at room temperature overnight. The reaction solution was added with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and (2-iodo-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2,6-dipropylphenoxy) benzaldehyde (8.0 mg, yield 7.0%) was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]2=[N:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][C:14]=1[C:28]1[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:15][C:14]=1[C:28]1[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: Cc1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-methylimidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-methylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile. Purification by high performance liquid chromatography afforded the trifluoroacetate salt as a white powder: δH (400 MHz, DMSO) 2.60 (3H, s), 7.11 (1H, d, J 7), 7.59-7.70 (2H, m), 7.76 (1H, d, J 8), 7.84-7.89 (3H, m), 8.00-8.04 (2H, m), 9.00 (1H, d, J 7); m/z (ES+) 329 (M++H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:28]=[N:29][N:30]([Sn](CCCC)(CCCC)CCCC)[N:31]=3)=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].C(C1C=C(OCC2C=CC(C3C(C#N)=CC=CC=3)=CC=2)C2C(=CC=CC=2)N=1)C.C([Sn](N=[N+]=[N-])(CCCC)CCCC)CCC.C([Sn]([Cl:102])(CCCC)CCCC)CCC.[N-]=[N+]=[N-].[Na+].N([O-])=O.[Na+].Cl.S(=O)(=O)(O)N>C1(C)C=CC=CC=1.O>[ClH:102].[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)n1nnc(-c2ccccc2-c2ccc(COc3cc(CC)nc4ccccc34)cc2)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: CCc1cc(OCc2ccc(-c3ccccc3C#N)cc2)c2ccccc2n1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2ccccc2n1
Reaction time: 1 h

Procedure:
A solution of 2-ethyl-4-[(2'-(2-tributylstannyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline in toluene (15 ml), prepared in situ by refluxing for 90 hours a mixture of 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carbonitrile (0.9 g) and a solution of tributyltin azide in toluene (15 ml) [the latter prepared by reaction of tributyltin chloride (3.3 g) and sodium azide (1.13 g) in water (22.5 ml) at ambient temperature for 4 hours, followed by extraction with toluene and azeotropic removal of water from the extract to leave a volume of 15 ml], was added slowly over 1 hour to a solution of sodium nitrite (2.5 g) in water (10 ml) containing 12% w/v hydrochloric acid (10 ml), maintaining the temperature of the mixture below 5° C. A solution of sulphamic acid (1.43 g) in water (10 ml) was then added, maintaining the temperature below 5° C., and the mixture stirred for 1 hour. The resultant suspended semi-solid was collected by filtration and washed with water (3×10 ml), followed by toluene (10 ml). The semi-solid was then added to tetrahydrofuran (THF) (40 ml), which caused the product to dissolve and then crystallise as a white solid. After cooling for one hour the solid was collected by filtration, washed with THF (5 ml) and dried to give 2-ethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-quinoline hydrochloride; NMR similar to the product obtained from Example 10.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=1.O.[NH2:21][NH2:22]>C(O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(N2CCCC2=O)cc1
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(N3CCCC3=O)cc2)=NN1

Procedure:
10.4 g (0.04 mole) of 4-(4-(2-oxo-pyrrolidin-1-yl)-phenyl)-4-oxo-butyric acid and 2 g (0.04 mole) of hydrazine hydrate are stirred under reflux in 100 ml of ethanol for 1 hour, the mixture is cooled and the product is filtered off with suction. The solid which has precipitated is stirred with sodium bicarbonate solution, filtered off with suction, washed and dried.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1([C@@H](N)C([NH:22][C@H:23]2[C:30](=[O:31])[N:29]3[C@@H:24]2[CH2:25][CH2:26][CH:27]=[C:28]3[C:32]([OH:34])=[O:33])=O)C=CC=CC=1>>[NH2:22][CH:23]1[C:30](=[O:31])[N:29]2[CH:24]1[CH2:25][CH2:26][CH:27]=[C:28]2[C:32]([OH:34])=[O:33]
Reactant: N[C@@H](C(=O)N[C@H]1C(=O)N2C(C(=O)O)=CCC[C@H]12)c1ccccc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: NC1C(=O)N2C(C(=O)O)=CCCC12
Reaction time: 48 h

Procedure:
Clostridium acetobutylicum IFO 3346 is inoculated in 100 ml of Potato Dextrose Broth (product of DIFCO Lab.). Air in the fermentor is replaced with sterilized nitrogen gas and the fermentor is sealed. Culturing is carried out at a temperature of 30° C. for 48 hours. After the cultivation, cells are recovered, washed with physiological saline solution and suspended in 2 ml of 1/30 M potassium phosphate buffer (pH 7.0). 0.5 ml of the substrate solution prepared as in Example 5 and the cell suspension are combined and allowed to react at a temperature of 30° C. for 20 hours. The reaction is monitored as in Example 5. (-)-cis-7-[(R)-2-phenyl-2-aminoacetamido]-1-azabicyclo[4,2,0]oct-2-en-8-on-2-carboxylic acid is remained unchanged and only (+)-cis-7-[(R)-2-phenyl-2-aminoacetamido]-1-azabicyclo[4,2,0]oct-2-en-8-on-2-carboxylic acid is decreased. The amount of the decrease is 1.0 mg, producing 0.2 mg of (+)-7-amino-1-azabicyclo[4,2,0]oct-2-en-8-on-2-carboxylic acid.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)([O:3][CH3:4])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([CH2:15][C@@H:16]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mechanically stirred solution of 17β-carbomethoxy-3β-hydroxy-5-androstene (100 g, 0.30 mol), prepared as described in Rasmusson et al., Journal of Medicinal Chemistry 1984, 27, 1690, incorporated herein by reference, in pyridine (750 mL) in a 2 L 4-necked round bottom flask equipped with an addition funnel at ambient temperature is added acetic anhydride (130 mL, 1.38 mol). The resulting dark solution is stirred at ambient temperature for 18 h, transferred to an addition funnel, and added drop wise to 3 L of ice-water. The resulting precipitate is collected by filtration, washed with 2×1 L H2O, and dried under vacuum to afford 17β-carbomethoxy-3β-acetoxy-5-androstene; 1H NMR (400 MHz, CDCl3) δ5.36 (br d, J=5.1 Hz, 1H), 4.59 (m, 1H), 3.67 (s, 3H), 2.37-2.29 (m, 3H), 2.20-2.08 (m, 1H), 2.03 (s, 3H), 2.02-1.97 (m, 2H), 1.90-1.38 (m, 10H), 1.34-1.21 (m, 2H), 1.18-1.05 m, 2H), 1.02 (s, 3H), 1.00-0.96 (m, 1H), 0.66 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[C:10]=1[CH:15]([CH3:17])[CH3:16].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:14][C:11]1[C:10]([CH:15]([CH3:17])[CH3:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[O:13][N:12]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(C)c1c(O)noc1-c1ccc(F)cc1F
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(F)cc1F
Yield: 78.2 %

Procedure:
5-(2,4-Difluorophenyl)-3-hydroxy-4-isopropylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.16 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.25 g, 78%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].I[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: ICCCc1ccc(CCCCCOc2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(CCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(3-iodopropyl)-4-(5-phenoxypentyl)benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2.[Br:23]Br>C(Cl)Cl>[Br:23][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[N:9]2
Reactant: BrBr
Reactant: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3n2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc3c(Br)c(OC)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 4-(6-methoxyquinolin-2-yl)benzoate (630 mg, 2.15 mmol) in DCM (9 mL) was added Br2 (0.3 mL, 6.45 mmol). The reaction mixture was stirred at room temperature overnight. Then the mixture was partitioned with brine and DCM. The precipitate was filtered and dried to give the product as a solid (800 mg, 100%). MS (ESI): m/z=373.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:12]([N:32]=1)=[N:13][CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)[CH:16]=2.[C:33]([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH3:33])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:12]([N:32]=1)=[N:13][CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)[CH:16]=2
Reactant: Nc1ccc(F)c(-c2nc3ncc(-c4ccc(OCCN5CCOCC5)cc4)cc3o2)c1
Reactant: CC(=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNc1ccc(F)c(-c2nc3ncc(-c4ccc(OCCN5CCOCC5)cc4)cc3o2)c1
Temperature: 80 °C

Procedure:
In a 40 ml vial 4-fluoro-3-(6-(4-(2-morpholinoethoxy)phenyl)oxazolo[4,5-b]pyridin-2-yl)aniline I-23 (15 mg, 0.032 mmol, 1.0 eq.) was dissolved in DCE. Paraformadelhyde (30 mg) followed by sodium acetate (2.62 mg, 0.032 mmol, 1.0 eq) was added and reaction was heated for one hour. Sodium triacetoxy borohydride (16 mg, 0.08 mmol, 2.5 eq) was added and the reaction was heated to 80° C. for 4 hours. LCMS indicated that the reaction was complete with a formation of new peak of desired mass 449.2 (M+1). The reaction was concentrated under reduced pressure. The crude reaction was dissolved in DMF and filtered through a frit funnel to remove the insoluble matter. The clear filtrate by purified by HPLC to get the desired product 4-fluoro-N-methyl-3-(6-(4-(2-morpholinoethoxy)phenyl)oxazolo[4,5-b]pyridin-2-yl)aniline (Example 421). The TFA salt was neutralized by passing a methanolic solution of the compound through a bicarbonate resin. MS M/Z=449.2 (M+1). RT=1.33: Method B.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH3:15])[CH2:8][C:9]1[N:13]=[C:12]([CH3:14])[NH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].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]>CC#N>[C:1]([O:5][C:6]([N:7]([CH2:8][C:9]1[N:13]=[C:12]([CH3:14])[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])[N:10]=1)[CH3:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(CN(C)C(=O)OC(C)(C)C)n[nH]1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nc(CN(C)C(=O)OC(C)(C)C)nn1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl-(5-methyl-1H-[1,2,4]triazol-3-ylmethyl)-carbamic acid tert-butyl ester (470 mg) in MeCN (20 mL) was added Cs2CO3 (677 mg) followed by benzyl bromoacetate (0.343 mL). The reaction mixture was stirred at RT overnight and evaporated to dryness. The residue was taken up in DCM and washed with water. The aq. layers were extracted with DCM, the combined org. layers were dried (Na2SO4), filtered off and evaporated in vacuo. The residue was purified by CC (silica gel, Hept/EA 1/1 then DCM/MeOH 9/1) to afford benzyl 2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methyl-1H-1,2,4-triazol-1-yl)acetate (290 mg, yellow oil). LC-MS (B): tR=0.83 min; [M+H]+: 375.14. 1H-NMR (CD3OD): 7.39-7.35 (m, 5H); 5.24 (s, 2H); 5.09 (s, 2H); 4.43 (m, 2H); 2.89 (m, 3H); 2.41 (s, 3H); 1.44 (d, 9H). Roesy signal seen between CH2 at 5.09 ppm and CH3 at 2.41 ppm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:39]=[C:40]=[O:41])(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][N:11]1[C:40]([NH2:39])=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: NC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1ccccc1
Yield: 46.9 %

Procedure:
A solution of 400 mg (0.86 mmol) (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine in 15 ml CH2Cl2 with 0.3 ml (2.2 mmol) trimethylsilylisocyanate and a catalytic amount of DMAP was stirred over night. The reaction was extracted with aqueous 10% KHSO4/EtOAc (3×) and the organic phase was dried over Na2SO4. Crystallization (CH2Cl2/MeOH/Et2O) gave 205 mg (47%) (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid amide, MS: 509 (MH+).
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]([N:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][CH3:12])([CH3:9])[CH3:8]>>[Cl:1][C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[CH:7]([N:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][CH3:12])([CH3:9])[CH3:8]
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)Cl

Procedure:
In Scheme 2, 2-bromobenzenesulfonyl chloride (25) and 2-phenyl allyl amine (33) are reacted in the presence of pyridine to generate intermediate (34) which, upon treatment with TBTH and AIBN in toluene gives the radical derived adduct (35) which, when reacted with (2S,3S)-1,2-epoxy-3-(boc-amino)-4-phenylbutane (29) in the presence of Cs2CO3 gives compound (36), as mixture of two diastereomers. The mixture of two diastereomers is treated with TFA:DCM (1:1) to produce compound (37) as a mixture of diastereomers. Treatment of (37) with substituted chloroformates for example ethyl chloroformate in the presence of di-isopropyl-N-ethylamine yielded a mixture of diastereomers which could be separated into pure diastereomers (10) and (11) using preparative TLC. Similarly, compound (37) on treatment with allyl chloroformate in the presence of di-isopropyl-N-ethylamine yielded a mixture of diastereomers which could be separated by preparative TLC into pure diastereomers (8) and (9).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][C:24]([OH:26])=O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:52]([O:59][NH2:60])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>O1CCCC1>[C:53]1([CH2:52][O:59][NH:60][C:24](=[O:26])[CH2:23][NH:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)(=[O:20])=[O:21])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)NOCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In a separate flask containing a cool (5° C.), stirred solution of [4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid (0.2307 g, 0.0006161 mol) and 1-hydroxy-benzo-1,2,3-triazole (0.0842 g, 0.000623 mol) in anhydrous tetrahydrofuran (10 mL) was added in one portion 1,3-dicyclohexylcarbodiimide (0.1449 g, 0.000702 mol). The mixture was stirred for 30 minutes at 5° C. then allowed to warm to room temperature. After 3 hours at room temperature, the mixture was added in one portion to the filtrate containing O-benzylhydroxylamine. The mixture was stirred at room temperature for 16 hours, then refluxed (74° C.) for 1 hour. The volatiles were rotary evaporated off, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 0.1 M NaOH, water, 0.1 M HCl, water, and saturated sodium chloride. The organic layer was dried (MgSO4) and rotary evaporated. The residue was dissolved in chloroform, and chromatographed on silica gel (34 g, 230-400 mesh) eluting with dichloromethane-acetone (9:1, 10×30 mL). Fractions containing product were rotary evaporated to give a white solid. The solid was dried in vacuo; yield 0.1448 g (49%), mp=163-165° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1>>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1nccc(Cl)n1
Product: COC(=O)[C@H](Cc1ccnc(C(F)(F)F)n1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in a manner analogous to that described Example 475, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 4-chloro-2-(trifluoromethyl)pyrimidine.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])=O)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccc(OCCN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.41 g of 3-[2-(t-butoxycarbonylamino)ethoxy]benzonitrile was dissolved in 20 ml of 4 N solution of hydrogen chloride in dioxane, and the obtained solution was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was suspended in dichloromethane. The obtained suspension was filtered to obtain hydrochloride of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20]C(=O)C)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:24]2[CH2:26][CH2:25]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:24]2[CH2:26][CH2:25]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCCN1CCN(c2cc(C3CC3)nc(C(C)(C)C)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCO)CC2)n1
Yield: 30.8 %

Procedure:
3.7 g of acetic acid 3-[4-(2-tert-butyl-6-cyclopropyl-pyrimidin-4-yl)-piperazin-1-yl]-propyl ester (10.2 mmol) and 0.4 g of lithium hydroxide (16.7 mmol) were stirred overnight in 20 ml of tetrahydrofuran and 20 ml of water. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (0-8%) as eluent to yield 1.0 g of the title compound.