Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=O)[C:10]([CH3:16])([CH3:15])[C:11](OC)=[O:12])=[C:4]([CH3:18])[CH:3]=1.[NH2:19][NH2:20]>O1CCCC1.C(O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[C:10]([CH3:16])([CH3:15])[C:11](=[O:12])[NH:20][N:19]=2)=[C:4]([CH3:18])[CH:3]=1
Reactant: COC(=O)C(C)(C)C(=O)c1cc(C)c(Br)cc1C
Reactant: NN
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C2=NNC(=O)C2(C)C)c(C)cc1Br

Procedure:
3.5 g (11.7 mmol) of methyl 3-(4-bromo-2,5-dimethyl-phenyl)-2,2-dimethyl-3-oxo-propionate and 28 ml (28 mmol) of 1 molar hydrazine solution in tetrahydrofuran are refluxed in 50 ml of ethanol for 24 hours. The solvent is distilled off and the residue is recrystallised from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:10][C:11]1[CH:31]=[CH:30][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[CH:20][CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:41]([O:45][C:46]1[CH:61]=[CH:60][C:49]([CH2:50][C@@H:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[NH2:52])=[CH:48][CH:47]=1)([CH3:44])([CH3:43])[CH3:42].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[C:36]([O:35][C:33]([NH:32][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH:52][C@H:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:50][C:49]3[CH:60]=[CH:61][C:46]([O:45][C:41]([CH3:43])([CH3:42])[CH3:44])=[CH:47][CH:48]=3)=[O:28])=[CH:22][CH:23]=2)=[O:16])=[CH:30][CH:31]=1)=[O:34])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CCCC(=O)N[C@@H](Cc3ccc(OC(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of 4-[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)phenyl]butanoic acid (250 mg) in N,N-dimethylformamide (5.00 mL) were added tert-butyl O-tert-butyl-L-tyrosinate hydrochloride (152 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (88.5 mg), 1H-benzotriazol-1-ol (62.4 mg), and triethylamine (0.0643 mL), followed by stirring at room temperature overnight. To a reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-{4-[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)phenyl]butanoyl}-O-tert-butyl-L-tyrosinate (327 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CCOC(C)=O.[Cu]>[Br:1][C:2]1[C:3](=[O:9])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Oc1ncc(Br)cc1Br
Reactant: Cc1ccc(Br)nc1
Agent: [Cu]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2cc(Br)cc(Br)c2=O)nc1

Procedure:
3,5,-Dibromo -2-pyridinol (1.47 g, 5.81 mmol), 2-bromo-5-methylpyridine (1.00 g, 5.81 mmol), copper (0.008 g, 0.116 mmol) and K2CO3 (0.883 g, 6.39 mmol) were heated at 180° C. for 18 hrs. The brown reaction mixture was cooled, diluted with EtOAc and stirred with saturated NaHCO3 for 1 hr. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 10:90 to 30:70 gradient elution) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1F)=O.O.[NH2:22][NH2:23]>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:13]2[C:14](=[C:15]([F:19])[CH:16]=[CH:17][CH:18]=2)[NH:23][N:22]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Yield: 105.1 %

Procedure:
Prepared according to Method D Step A from (2,4-dimethoxyphenyl)[2,3-difluorophenyl]-methanone (1.60 g, 5.8 mmol), hydrazine hydrate (1.79 mL, 5702 mmol) and DMAP (0.632 g, 57.5 mmol) to give the product (1.66 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)=[CH:6][C:5]([C:13]2[CH:14]=[N:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[N:17][CH:18]=2)=[CH:4][C:3]=1[N+:23]([O-])=O.C1COCC1.CCN(CC)CC>[Pd].CO>[NH2:23][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[N:17][C:16]([C:19]([OH:22])([CH3:20])[CH3:21])=[N:15][CH:14]=2)[CH:6]=[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[C:2]=1[NH2:1]
Reactant: CC(C)(O)c1ncc(-c2cc(C3CCCO3)c(N)c([N+](=O)[O-])c2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2)cn1
Yield: 105.4 %

Procedure:
To a suspension of 2-[5-(4-amino-3-nitro-5-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (8) (30.10 g, 87.41 mmol) and THF (90 mL) in a Parr bottle under nitrogen was added a slurry of 5% palladium on carbon (3.01 g, 50% wet, 0.707 mmol, Aldrich 330116) in MeOH (90 mL, JT-Baker 909333), followed by NEt3 (24.37 mL, 174.8 mmol, Sigma-Aldrich 471283). The vessel was placed on a Parr shaker and saturated with H2. After adding 45 psi H2, the vessel was shaken until consumption was complete (HPLC showed complete conversion). The reaction mixture was purged with nitrogen, filtered through Celite™ and rinsed with EtOAc. The filtrate was re-filtered through a 0.5 micron glass fiber filter paper sandwiched between two P5 papers, and concentrated under reduced pressure giving (9) as a light brown foam (28.96 g, 98% yield; 93% NMR purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 315.32 (1.54 min). 1H NMR (300 MHz, CDCl3) δ 8.83 (s, 2H), 6.92 (d, J=1.8 Hz, 1H), 6.88 (d, J=1.8 Hz, 1H), 4.90 (dd, J=7.9, 6.2 Hz, 1H), 4.72 (s, 1H), 4.18 (s, 2H), 4.17-4.08 (m, 1H), 3.99-3.89 (m, 1H), 3.46 (s, 2H), 2.34-2.19 (m, 1H), 2.17-2.05 (m, 3H), 1.63 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].C1COCC1.[H-].[Na+].[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])[C:10]#[N:11]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C(=O)C(F)(F)F)c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
Slurry 2,4-dichlorophenylacetonitrile (I) (5.0 g, 26.9 mmol, 186.04 g/mol) in ethyl trifluoroacetate (6.4 mL, 7.6 g, 142.08 g/mol) and add 20 mL anhydrous THF. Portionwise at ambient temperature add NaH (1.88 g, 47.1 mmol, 60% in mineral oil) over 5 min. Heat reaction to reflux (90° C. bath temperature) overnight. Evaporate to thick red-brown oil and partition between Et2O (100 mL) and H2O (60 mL). Separate layers and extract H2 O with Et2O (2×75 mL). Acidify the aqueous layer with 1.0 N HCl to pH 1 (becomes cloudy white suspension) and extract aqueous layer with CH2Cl2 (3×100 mL). Dry pooled CH2Cl2 layers over Na2SO4, filter and concentrate to yellow oil (7.5 g, 26.5 mmol). Use without further purification. LCMS=281.9 (MH+); 279.8 (M−).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].Cl.[F:9][C:10]1([F:15])[CH2:14][CH2:13][NH:12][CH2:11]1.C(N(CC)CC)C>CO>[F:9][C:10]1([F:15])[CH2:14][CH2:13][N:12]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:11]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: [C-]#[N+]CC(=O)N1CCC(F)(F)C1
Yield: 60 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 345 mg, 3.48 mmol) was slowly added 3,3-difluoropyrrolidine hydrochloride (500 mg, 3.48 mmol), triethylamine (487 μL, 3.48 mmol) and MeOH (1 mL). The mixture was stirred for 15 h at RT and then concentrated. The resulting oil was coevaporated twice from EtOAc. 1-(3,3-Difluoropyrrolidin-1-yl)-2-isocyanoethanone VIB 01158 was obtained as a yellow oil (305 mg, 60% yield) and used in the next step without purification.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]OS(C)(=O)=O)[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:34]=[N+:35]=[N-:36])[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](c2nc(COS(C)(=O)=O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](c2nc(CN=[N+]=[N-])cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-[4-(methanesulfonyloxymethyl)thiazol-2-yl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.5 g) in dimethylformamide (20 ml) was added sodium azide (0.15 g) at ambient temperature. After stirring at 70° C. for 2 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated to give a syrup. The syrup was subjected to a column chromatography on silica gel and eluted with a mixture of acetone and dichloromethane (1:9, V/V) to give (2S,4S) 4 acetylthio-2-(4-azidomethylthiazol-2-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (500 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:8](=[O:10])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH2:27][CH2:26]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](NC(=O)c2cccc(Br)n2)CC1
Temperature: 50 °C

Procedure:
A solution of 6-bromopicolinic acid acid (3 g, 14.85 mmol), and 1,1′-carbonyldiimidazole (2.41 g, 14.85 mmol) in dimethylformamide (30 mL) was heated at 50° C. for 2 hours. After this time, trans-4-methylcyclohexylamine hydrochloride (2.2 g, 14.85 mmol), and N,N-diisopropylethylamine (3.88 mL, 22.3 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with ethyl acetate (300 mL). The organic solution was washed with water (4×300 mL). The aqueous extracts were washed with ethyl acetate (2×250 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated. Chromatography of the crude product through a Biotage silica cartridge (15×4 cm i.d.) using ethyl acetate-hexane (1:3, containing 1% diethylamine) afforded 3.84 g (87%) of 409:
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[S:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([NH:20][CH2:2][C:3]2[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[S:5][C:4]=2[C:12]([O:14][CH3:15])=[O:13])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(N)cccc1Br
Reactant: COC(=O)c1sc(C(C)(C)C)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1sc(C(C)(C)C)cc1CNc1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
A 250-mL single-necked round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 101c (1.09 g, 4.68 mmol), 3-bromo-2-methyl-aniline (2.61 g, 14.0 mmol) and acetonitrile (25 mL). Cesium carbonate (1.67 g, 5.15 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated under reduced pressure. Purification of the resulting residue by column chromatography afforded a 70% yield (1.30 g) of 101d as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 6.92 (m, 2H), 6.85 (s, 1H), 6.57 (dd, 1H, J=4.8, 2.1 Hz), 4.60 (s, 2H), 3.86 (s, 3H), 2.29 (s, 3H), 1.37 (s, 9H); MS (ESI+) m/z 396.2 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](O)[CH3:18].S(=O)(=O)(O)O.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:15]=[C:11]([C:12]([O:14][CH2:17][CH3:18])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)ccc1O
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccccc2)ccc1O
Yield: 55 %

Procedure:
To 18.58 g of 5-phenylsalicylic acid, 350 ml of ethanol, 100 ml of toluene and 42 ml of concentrated sulfuric acid were added. The mixture was heated under reflux for 14 hours. After it was confirmed with TLC that the starting materials were almost disappeared, the reaction liquid was poured into a mixed medium of diluted hydrochloric acid-ethyl acetate. The mixture was extracted, and the organic phase was collected and washed with saturated sodium chloride aqueous solution. After dried with magnesium sulfate, the liquid was concentrated to form a crude product. The product was recrystallized from ethanol to obtain 11.53 g of ethyl 5-phenylsalicylate in the form of colorless crystallites. The yield was 55%. The product was confirmed with NMR and mass spectroscopy.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:16])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[N:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([O:27][CH2:2][C:3]2[O:4][C:5](=[O:16])[N:6]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[N:7]=2)=[O:26])=[CH:22][CH:23]=1
Reactant: Cc1ccccc1Cn1nc(CCl)oc1=O
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Cc1ccccc1Cn1nc(COC(=O)C(c2ccc(Cl)cc2)C(C)C)oc1=O
Temperature: 110 °C
Yield: 48.4 %

Procedure:
A solution of 2-chloromethyl-4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-one (13.3 g) in xylene (35 cc) is added in the course of 20 minutes to a solution of 2-(4-chlorophenyl)-3-methyl-butyric acid (19 g) and triethylamine (11.7 cc) in xylene (175 cc) heated to 110° C. The reaction mixture is heated at the reflux temperature for 4 hours and, after cooling, is washed successively with water (100 cc), a 3.5% strength aqueous hydrochloric acid solution (100 cc), a 4% strength aqueous sodium carbonate solution (100 cc) and water (100 cc). After drying, decolorizing over animal charcoal and concentrating under reduced pressure, the residue obtained is purified by chromatography on a silica column and gives [4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-on-2-yl]-methyl 2-(4-chlorophenyl)-3-methylbutyrate (11.2 g) in the form of an oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]=[CH2:15].C(N(CC)CC)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>ClCCl.C(OCC)(=O)C>[Si:23]([O:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]=[CH2:15])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCc1cc(C(=O)OC)cc(C)c1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCc1cc(C(=O)OC)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of methyl 4-hydroxy-3-allyl-5-methylbenzoate (157 mg, 0.762 mmol) in dichloromethane (5 mL) was treated with triethylamine (0.21 mL, 2 equivalents) and tert-butyldimethylsilyl chloride (172 mg, 1.5 equivalents). The reaction was stirred at room temperature under a nitrogen atmosphere for 3 days by which time TLC analysis showed complete conversion. The reaction was diluted with ethyl acetate (30 mL) and washed with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to afford the product as a brown oil. Yield=0.239 g (98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoate (Novabiochem), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.2 in 95:5 CHCl3/MeOH) and the product was purified by flash column chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:28])[N:17]([CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22][CH2:21]1)[CH3:18])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:28])[N:17]([CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH:26]=[O:27])[CH2:22][CH2:21]1)[CH3:18])([CH3:12])([CH3:14])[CH3:13]
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(C[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
0.45 ml of oxalyl chloride in 5.0 ml of dichloromethane were cooled to −78° C.; then, 0.41 g of dimethylsulfoxide in 2.0 ml of dichloromethane were slowly added and the reaction mixture stirred at −78° C. for 10 minutes. Then, 0.680 g (2.64 mmol) trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester dissolved in 5.0 ml of dichloromethane were added and the reaction mixture stirred at −78° C. for 10 minutes. Subsequently, 1.84 ml of triethylamine were added at the same temperature, the reaction mixture stirred 30 minutes at −78° C., warmed to room temperature and stirred for 1 hour. It was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 4:1 v/v mixture of dichloromethane and ether as the eluent giving 0.615 g (91.1%) trans-(4-formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester as colorless amorphous solid, MS: 273 (MNH4+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([CH:17]=O)[N:5]([S:7]([C:10]2[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=1.C([O-])(=O)C.[K+].Cl.CN.[N+:28]([CH3:31])([O-:30])=[O:29].[Li+].[BH4-]>C(O)C.O.C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([CH2:17][CH2:31][N+:28]([O-:30])=[O:29])[N:5]([S:7]([C:10]2[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c(C)c2C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c(C)c2CC[N+](=O)[O-])cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Following a general procedure,50 a stirred mixture of 3-Ts (7.73 g, 28.5 mmol) in the form of a finely ground powder, potassium acetate (2.24 g, 22.8 mmol), methylamine hydrochloride (1.54 g, 22.8 mmol), and acetic acid (0.1 mL) in absolute ethanol (10 mL) was treated with nitromethane (4.0 mL, 78 mmol). The mixture was stirred for 2 h, whereupon water was added (100 mL) and the resulting yellow precipitate was filtered by vacuum filtration. The solid filtered material was washed with water (200 mL) followed by cold ethanol (˜100 mL, 0° C.) until the eluant was clear. The yellow filtered solid was dried overnight under high vacuum. The crude solid material was dissolved in dry THF (117 mL, distilled). The solution was cooled to −10° C. (internal temperature, using an acetone bath with a few pieces of dry ice) under argon. The solution was treated with 95% LiBH4 (0.64 g, 28 mmol) all at once under vigorous stirring. The reaction mixture was stirred for ˜15 min at −10° C., until all of the starting material disappeared (starting material: CH═CHNO2: d, J=13.6 Hz, 8.56 ppm; product: CH2CH2NO2: t, J=7.3 Hz, 4.54 ppm and 3.36 ppm), whereupon the reaction mixture was quenched by slowly adding a cold saturated aqueous NH4Cl solution (200 mL, 0° C.). The mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated to a solid. The solid was dried under high vacuum for 2 h. The crude solid material was dissolved in 100 mL of 2-propanol by refluxing in a hot water bath. Upon cooling the solution to −10° C. the product crystallized. The mixture was vacuum-filtered, and the resulting light brown crystals were dried under high vacuum (9.03 g, 82%): mp 85° C.; 1H NMR δ 1.92 (s, 3H), 2.43 (s, 3H), 3.36 (t, J=7.3 Hz, 2H), 4.54 (t, J=7.3 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.34 (s, 1H), 7.66 (d, J=8.4 Hz, 2H); 13C NMR δ 10.5, 21.9, 24.3, 74.3, 105.2, 121.7, 124.3, 124.9, 126.9, 130.6, 135.6, 146.0; ESI-MS obsd 387.0024, calcd 387.0009 [(M+H)+, M=C14H15BrN2O4S];
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+]>CS(C)=O.[NH4+].[Cl-]>[NH2:16][C:15]1[C:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])=[C:9]2[N:8]([C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10]2
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C)c(C(C#N)c2ccccn2)c(C)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(N)c(-c2c(C)cc(C)cc2C)c2ccccn12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Slowly add dropwise ethyl bromoacetate (23 mL; 0.21 mol) over a 3-hour period to a mixture of 2-(2-pyridinyl)-2-(2,4,6-trimethylphenyl)-ethanenitrile (22.3 g; 0.094 mol) and potassium carbonate (78 g; 0.57 mol) suspended in DMSO (100 mL). Stir the mixture for 1 day, pour into an aqueous NH4Cl solution (ca. 1 L), and extract with 3×200 mL of Et2O. Wash the combined extracts with saturated brine, dry over Na2SO4, filter, and concentrate in vacuo. Dissolve the residue in THF (200 mL), cool to 0° C., and add slowly in portions potassium t-butoxide (12 g; 0.11 mol) over a 10-minute period. After 30 minutes at 0° C., dilute the mixture with aqueous NH4Cl and extract with 2×150 mL of 50% Et2O in hexane. Wash the combined extracts with saturated brine, dry over Na2SO4, filter, concentrate in vacuo, and purify by column chromatography on silica gel (eluent: 5 to 10% EtOAc in hexane) to obtain the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ 1.47 (t, 3H), 2.06 (s, 6H), 2.35 (s, 3H), 4.46 (br q, 2H), 6.6 (br t, 1H), 6.75 (d, 1H), 6.9 (br t, 1H), 7.00 (s, 2H), 9.4 (1H).