Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C:8]3[CH:19]=[CH:20][C:21](Br)=[CH:22][C:7]2=3)[N:6]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C:8]3[CH:19]=[CH:20][C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][C:7]2=3)[N:6]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2c(c1)CCc1ccc(Br)cc1C21N=C(N)N(C)C1=O
Product: COc1ccc2c(c1)CCc1ccc(-c3ccccc3)cc1C21N=C(N)N(C)C1=O

Procedure:
Using essentially the same procedure described in Example 3 and employing 2′-amino-2-methoxy-1′-methyl-7-bromo-10,11-dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol]-5′(1′H)-one and phenylboronic acid, the title compound was obtained as an off-white powder, mp 167-171° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[C:4]([CH2:10][Br:11])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1F
Yield: 100.7 %

Procedure:
To a stirred solution of 5-bromo-2-fluoro-1,3-dimethylbenzene (5.0 g, 25 mmol) in carbon tetrachloride (100.0 mL) was added N-bromosuccinimide (4.11 g, 23.1 mmol) and benzoyl peroxide (100.0 mg, 0.017 mmol). The reaction was heated at reflux for 7 hours. The reaction was filtered and the filtrate washed with 2N HCl, saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was flash chromatographed (5% EtoAc/Haptanes) to obtain 6.56 g of 5-bromo-1-(bromomethyl)-2-fluoro-3-methylbenzene as an oil product. 1H NMR (400 MHz, CDCl3) δ ppm 2.22-2.36 (s, 3 H) 4.42 (d, J=0.98 Hz, 2 H) 7.21-7.37 (m, 2 H)
Reaction SMILES: O1CCOCC1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17](=[O:47])[O:18][C:19]([O:42][CH2:43][CH2:44][CH2:45]Br)([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[C:20]=3[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.[S:48]([O-:51])([O-:50])=[O:49].[Na+:52].[Na+].[Na]>O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17](=[O:47])[O:18][C:19]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)([O:42][CH2:43][CH2:44][CH2:45][S:48]([O-:51])(=[O:50])=[O:49])[C:20]=3[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.[Na+:52]
Reactant: COc1ccc(C2(OCCCBr)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C2(OCCCS(=O)(=O)[O-])OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
To 50 mL 1,4-dioxane was added 3-Benzo[1,3]dioxol-5-yl-5-(3-bromo-propoxy)-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)5H-furan-2-one 2.0 g (3.19 mmol). A solution of sodium sulfite, 0.88 g (7.0 mmol) in 50 mL water was added, and the mixture was refluxed for 18 hours. The mixture was evaporated in vacuo and the residue was suspended in ethyl ether and water. The suspension was acidified to pH 1 with 2 N HCl, giving an oily precipitate in the aqueous phase. The ether was decanted, and the oil was extracted into ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and diluted with ethyl ether, giving a solid. The solid was filtered and dried in vacuo, giving a white solid, 1.07 g. The product was identified by 1H NMR, MS [M--H]+ =627.3 Da. Elemental analysis indicated the material to contain 1/2 sodium salt per molecule.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccncc2)cc1
Yield: 80.1 %

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide (Method 14; 136 mg, 0.33 mmol), pyridine-4-boronic acid (48 mg, 0.39 mmol), tetrakis(triphenylphosphine) palladium (5 mg, 0.005 mmol), THF (2 ml) and a saturated aqueous solution of sodium hydrogen carbonate (2 ml) were stirred at 55° C. under an atmosphere of argon for 96 hours. The cooled mixture was partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate, filtered and evaporated, to give the title compound (103 mg, 80%), which was used without further purification; Mass Spectrum: M+H+ 390.
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O>>[CH3:1][C@@H:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c1C[C@H](C(=O)O)[C@@H]2C
Product: Cc1cccc2c1C[C@H](C(=O)Cl)[C@@H]2C
Yield: 92 %

Procedure:
cis-2,3-Dihydro-1,4-dimethyl-1H-indene-2-carboxylic acid is converted to its acid chloride by treatment with thionyl chloride. Yield 92%.
Reaction SMILES: CS(C)=O.[I-].[CH3:6][S+](C)(C)=O.[H-].[Na+].[CH3:13][C:14]([CH3:24])([CH3:23])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16]>O1CCCC1>[C:14]([C:15]1([C:17]2[CH:22]=[N:21][CH:20]=[N:19][CH:18]=2)[CH2:6][O:16]1)([CH3:24])([CH3:23])[CH3:13]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)C(=O)c1cncnc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)C1(c2cncnc2)CO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 10 ml of dimethyl sulphoxide are slowly added dropwise to 0.96 g (4.3 mmol) of trimethylsulphoxonium iodide and 0.17 g of sodium hydride (60%, 4.3 mmol). The reaction mixture is then stirred at room temperature for 15 min, and 0.65 g (3.9 mmol) of 2,2-dimethyl-1-(5-pyrimidinyl)-1-propanone, dissolved in 2 ml of tetrahydrofuran, is added. The reaction mixture is stirred at 50° C. for 90 min. The reaction mixture is then concentrated under reduced pressure, and saturated aqueous sodium chloride solution and ethyl acetate are added to the residue. The organic phase is separated off, dried with sodium sulphate, filtered and concentrated. This gives 0.70 g (99%) of the desired product, which is reacted without further purification.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][N:9]([C:16]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[C:10](=[O:15])C(Cl)(Cl)Cl.C([O-])(=O)C.[NH4+:37]>C(O)(C)(C)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][N:9]1[C:16]2[C:17](=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:37][C:10]1=[O:15]
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1N(CC1CC2CCC1C2)C(=O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Solvent: CC(C)(C)O
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC1CC2CCC1C2
Reaction time: 8 h

Procedure:
To a solution of 2.5 g of 2-[ N-(2-norbornylmethyl)trichloroacetamido]-5-nitrobenzophenone in 50 ml of tert-butyl alcohol was added 2 g of ammonium acetate and the resulting mixture was heated under reflux for 7 hours. Then 2 g of ammonium acetate was added thereto and the reaction was continued for additional 8 hours. The solvent was removed under reduced pressure, and the residue was extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residual oil was crystallized from a mixture of carbon tetrachloride and diethyl ether to give 1-(2-norbornylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 160°C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[C:9]([F:12])[C:8]([O:13][CH2:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].COC(C1C2N=C(N)[NH:25][C:24]=2C=CC=1)=O.BrC#N>CO>[NH2:25][C:24]1[NH:11][C:10]2[C:9]([F:12])=[C:8]([O:13][CH2:14][CH3:15])[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: CCOc1cc(C(=O)O)c(N)c(N)c1F
Agent: N#CBr
Solvent: CO
Product: CCOc1cc(C(=O)O)c2nc(N)[nH]c2c1F

Procedure:
0.8 g (3.7 mmol) of 2,3-diamino-5-ethoxy-4-fluoro-benzoic acid was subjected to a similar cyclization condition as illustrated in intermediate A by using 1.2 g (11.2 mmol) of BrCN in methanol to produce 2-amino-6-ethoxy-7-fluoro-1H-benzoimidazole-4-carboxylic acid. LCMS: 240 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH2:17]([N:24]([CH2:28][Si](C)(C)C)[CH2:25]OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([CH:4]1[CH:5]([CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[CH2:28][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25]1)=[O:16]
Reactant: COC(=O)/C=C/CCO[Si](C)(C)C(C)(C)C
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: COC(=O)C1CN(Cc2ccccc2)CC1CCO[Si](C)(C)C(C)(C)C

Procedure:
105.1 In analogy to example 101.1 ((E)-5-(tert-butyl-dimethyl-silanyloxy)-pent-2-enoic acid methyl ester (CAS 688801-64-1) and N-benzyl-N-(methoxymethyl)tri-methylsilylmethylamine (CAS 93102-05-7) were reacted to give (3RS,4RS)-1-benzyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-pyrrolidine-3-carboxylic acid methyl ester. Light yellow oil. MS 378.3 ([M+H]+)
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:33])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]=[O:32])=[CH:21][CH:20]=1)[NH:7][C:8](=[O:17])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16]>CO>[CH3:3][O:4][C:5](=[O:33])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][OH:32])=[CH:21][CH:20]=1)[NH:7][C:8](=[O:17])[C:9]1[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2CO)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
NaBH4 (21 mg) was added to a solution of N-(2,6-dichlorobenzoyl)-4-(2-formylphenyl)-L-phenylalanine methyl ester (0.23 g) in MeOH (5 mL) and the mixture was stirred at room temperature for 3 h. The reaction was quenched with acetone and the mixture was evaporated. The residue was partitioned between EtOAc and water. The EtOAc layer was dried (MgSO4) and evaporated to yield N-(2,6-dichlorobenzoyl)-4-[2-(hydroxymethyl)phenyl]-L-phenylalanine methyl ester (0.24 g). ESMS: m/z 480 ([M+Na]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)/[CH:22]=[CH:23]\[O:24][CH2:25][CH3:26])CCC.[F-].[K+]>[Cl-].C([N+](CC)(CC)CC)C.CN(C=O)C.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([O:24]/[CH:23]=[CH:22]\[C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1)[CH3:26]
Reactant: Brc1cc(-c2ccccc2)c2nncn2c1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCO/C=C\c1cc(-c2ccccc2)c2nncn2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
A mixture of 6-bromo-8-phenyl-[1,2,4]triazolo[4,3-a]pyridine (26.1 mg, 0.095 mmol), (Z)-tributyl(2-ethoxyvinyl)stannane (34.6 mg, 0.095 mmol) and tetraethylammonium chloride (16 mg, 0.095 mmol) in DMF (0.5 mL) was added PdCl2(PPh3)2 (2 mg, 0.005 mmol). The reaction was heated at 80° C. overnight, cooled to rt, added an aqueous of KF (1.1 eq) in water (95 μL) and further stirred for 30 mins, then diluted with ethyl acetate (2 mL), filtered and rinsed with ethyl acetate (8 mL). The mixture was then washed with water (2×2 mL), separated, dried and concentrated. The residue was purified by a flash column using a gradient of ethyl acetate in hexane (50-75%) as an eluent to give compound (13 mg, 52% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11](/[C:13](=[N:17]/[O:18][CH3:19])/[C:14]([OH:16])=O)[N:12]=1)=[O:6])[CH:2]=[CH2:3].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[C:39]([C:43]1[CH2:50][N:49]2[N:45]([C:46](=[O:52])[CH:47]([NH2:51])[CH2:48]2)[C:44]=1[C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])(=[O:42])[CH2:40][CH3:41]>C(Cl)Cl.C(OCC)(=O)C>[C:39]([C:43]1[CH2:50][N:49]2[N:45]([C:46](=[O:52])[CH:47]([NH:51][C:14](=[O:16])/[C:13](/[C:11]3[N:12]=[C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[S:9][CH:10]=3)=[N:17]\[O:18][CH3:19])[CH2:48]2)[C:44]=1[C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])(=[O:42])[CH2:40][CH3:41]
Reactant: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)O)cs1
Reactant: C=CCOC(=O)C1=C(C(=O)CC)CN2CC(N)C(=O)N12
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)NC2CN3CC(C(=O)CC)=C(C(=O)OCC=C)N3C2=O)cs1
Temperature: 0 °C
Yield: 56.8 %

Procedure:
Under a nitrogen atmosphere, 2-[2-(allyloxycarbonylamino)thiazol-4-yl]-2-(Z)-methoxyiminoacetic acid (248 mg, 0.87 mmol) was suspended in methylene chloride (5 ml) and the suspension was cooled to 0° C. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (153 mg, 0.87 mmol) then N-methylmorpholine (0.095 ml, 0.87 mmol) were added and the resultant solution was stirred at 0° C. for 30 minutes. A methylene chloride solution (10 ml) of allyl 3-(propionyl)-7-(R,S)-amino-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate hydrochloride (0.87 mmol) was added followed by the addition of N-methylmorpholine (0.095 ml, 0.87 mmol). The solution was allowed to warm gradually to room temperature over 1.5 hours and then the methylene chloride was removed in vacuo. The resultant residue was flash chromatographed on silica gel eluted with 10% hexane:ethyl acetate to give 270 mg, 57% yield of allyl 3-(propionyl)-7-(R,S)-[2-(2-(allyloxycarbonylamino)thiazol-4 -yl)-2-(Z)-methoxyiminoacetamido]-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate: n.m.r. (90 MHz, CDCl3): δ 1.11 (t, 3, J=7.2), 2.39-2.79 (m, 2), 3.09 (dd, 1, J=9 and 11.7), 3.95 (s, 3), 3.80-4.24 (m, 3), 4.42 (1/2ABq, 1, J=12.5), 4.60-4.96 (m, 4), 5.16-5.68 (m, 4), 5.72-6.22 (m, 2), 7.09 (s, 1), 8.28 (br.d, 1, J=7.2), 9.55 (br.s, 1); i.r. (CHCl3): 3230, 1733, 1679, 1554, 1423, 1377, 1353, 1044 cm-1 ; u.v. (EtOH): λhd max=208 (ε=21522), 228 (ε=22084), 261 (ε=13612), 365 (ε=8122); f.d.m.s. (m/e): M+ +1=547; m.p. 183°-186° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15](=[O:21])[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.[CH2:29]([CH:31]([CH2:35][CH3:36])[C:32](Cl)=[O:33])[CH3:30]>C(Cl)Cl>[CH2:17]([CH:16]([CH2:19][CH3:20])[C:15]([N:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[CH:3][C:4]=2[F:28])[CH2:9][CH2:10]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])[CH3:18]
Reactant: CCC(CC)C(=O)N(c1ccccc1)C1CCN(c2ccc(N)cc2F)CC1
Reactant: CCC(CC)C(=O)Cl
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1ccc(N2CCC(N(C(=O)C(CC)CC)c3ccccc3)CC2)c(F)c1
Reaction time: 16 h
Yield: 31.1 %

Procedure:
To a mixture of N-[1-(4-amino-2-fluoro-phenyl)-piperidin-4-yl]-2-ethyl-N-phenyl-butyramide (0.30 mmol) and TEA (2.0 mmol) in DCM (10 mL) was added 2-ethyl-butyryl chloride (1.0 mmol). After 16 h, the mixture was washed with H2O (10 mL). The organic layer was concentrated and the residue was purified by PTLC to provide the title compound (45 mg, 31%). MS (ESI): mass calcd. for C29H40FN3O2, 481.31. m/z found, 482.4 [M+H]+. 1H NMR (CDCl3): 7.50-7.35 (m, 5H), 7.15-7.03 (m, 2H), 6.86 (t, J=8.8, 1H), 4.90-4.72 (m, 1H), 3.44-3.30 (m, 2H), 2.80-2.67 (m, 2H), 2.30-1.30 (m, 14H), 0.95 (t, J=7.3, 6H), 0.80 (t, J=7.2, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][C:4]2[S:14][CH:15]=[CH:16][C:3]1=2.C1(C)C=CC=CC=1>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][C:4]2[S:14][CH:15]=[CH:16][C:3]1=2
Reactant: CCOC(=O)N1CCc2sccc2C(=O)C1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCc2sccc2[C@H](O)C1

Procedure:
3.86 g (16.1 mmol) ethyl 4-oxo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylate (prepared analogously to WO2007/84622) in 50 ml methylene chloride are combined, under argon, at −25° C., first with 1.92 ml of a 1.0 M toluene solution of (S)-3,3-diphenyl-1-methyl-tetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolidine and then with 20.2 ml of a 2 M borane-dimethylsulphide complex-toluene solution in 70 ml methylene chloride, and chilled to −18° C. for 3 days. Then sat. NH3Cl solution is added and the mixture is extracted 3× with methylene chloride. The combined organic phases are dried with NaSO4, concentrated and the crude product is purified by flash chromatography on silica gel (eluant DCM/methanol 95:5).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]2[CH2:19][C:18](=[O:20])[O:17][C:16](=[O:21])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:18](=[O:20])[CH2:19][N:14]([CH2:15][C:16]([OH:17])=[O:21])[C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C1CN(c2cccc(Oc3ccccc3)c2)CC(=O)O1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2cccc(Oc3ccccc3)c2)C1
Reaction time: 72 h

Procedure:
To a solution of 4-(3-phenoxyphenyl)morpholine-2,6-dione 26 (4.7 g, 0.0166 mol) in THF (50 mL) was added (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (4.11 g, 0.0221 mol). The reaction mixture was stirred for 3 days after which time a precipitate had formed. This material was collected by filtration, then washed with ethyl acetate to give the first crop of the title compound. A further crop was obtained by evaporating the filtrate in vacuo. The resultant residue was dissolved in ethyl acetate, washed with 10% hydrochloric acid and brine, dried (Na2SO4) and concentrated in vacuo. The second crop of title compound which precipitated was collected by filtration to give a total yield of 4.36 g (50%), as a cream solid. 1HNMR (300 MHz) (d6-DMSO, 100° C.)) δ 1.43 (9H, s), 1.75-2.20 (2H, 2×m), 2.75-3.1 (1H, br), (1H, br), 3.20-3.75 (4H, m), 4.09 (2H, s), 4.21 (2H, s), 6.22 (1H, br s), 6.37 2H, br t), 6.70 (1H, br), 6.99 (2H, d), 7.14 (2H, m) and 7.37 (2H, br t).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: O=C(O)c1oc(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c1OCc1ccccc1
Product: Cn1c(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Yield: 74.36 %

Procedure:
3-Benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-07) (2.3 g, 74.36%) was synthesized as a yellow solid from 3-benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-07) (3.0 g, 6.68 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: [CH2:1]1[O:6]C(C2C=CC=CC=2)[O:4][CH2:3][CH:2]1[OH:13].[H-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[N:24]1[C:29]2[N:30]=[C:31](S(C)(=O)=O)[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[C:28]=2[CH:27]=[CH:26][C:25]1=[O:46]>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[N:24]1[C:29]2[N:30]=[C:31]([O:13][CH:2]([CH2:3][OH:4])[CH2:1][OH:6])[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[C:28]=2[CH:27]=[CH:26][C:25]1=[O:46]
Reactant: OC1COC(c2ccccc2)OC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(OC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 23 °C

Procedure:
1,3-O-Benzylideneglycerol (100 mg, 0.55 mmol) was dissolved in dry THF (5 mL) and stirred under Ar at 23° C. NaH (14 mg, 0.55 mmol) was added and the mixture stirred for 15 minutes at 23° C., and then cooled to −78°. The product of Example 48 (222 mg, 0.5 mmol) was added, and the mixture was allowed to slowly warm to 23°. The solvent was removed in vacuo, and the residue was dissolved in acetic acid (2 mL), and H2O (0.5 mL) was added. The mixture was heated in an oil bath to 60° C. for three h, and then the solvents were removed in vacua to give the crude product. The crude product was flash chromatographed twice on silica gel eluted with 20-50% EtOAc/CH2Cl2 to give the product as a white-amorphous solid. 104-107° C., LC MS m/z=458 (MH+) Retention time=1.88 min.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:18])[NH:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:24][CH2:25]Br>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:10][N:9]1[CH2:25][CH2:24][N:7]([CH2:6][CH2:5][CH2:4][CH:3]([O:19][CH3:20])[O:2][CH3:1])[C:8]1=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCCBr
Reactant: COC(CCCNC(=O)NOCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(CCCN1CCN(OCc2ccccc2)C1=O)OC
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of 3-(4,4-dimethoxy-butyl)-1-(benzyloxy)-urea (4.14 g, 14.7 mmol) in DMF (40 mL) was added NaH (60 wt % in mineral oil, 0.659 g, 16.5 mmol). After 30 minutes, 1,2-dibromoethane (1.30 mL, 15.1 mmol) was added and the mixture was stirred for an additional 40 minutes. An additional amount of NaH (60 wt % in mineral oil, 0.636 g, 15.9 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (150 mL), washed with brine (5×25 mL), dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (1:1 hexanes-EtOAc) provided 1.61 g (36%) of 1-Benzyloxy-3-(4,4-dimethoxy-butyl)-imidazolidin-2-one as a colorless oil.