Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[CH:18]=[CH:17][N:16]([CH3:19])[C:8]2=[N:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)C.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].CO.C(Cl)Cl.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl.CC#N>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[CH3:19][N:16]1[C:8]2=[N:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:5]([OH:4])[C:6]([CH3:20])=[C:7]2[CH2:18][CH2:17]1
Reactant: CCCCCc1nc2c(ccn2C)c(C)c1OC(C)=O
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: CCCCCc1nc2c(c(C)c1O)CCN2C
Temperature: 78 °C
Reaction time: 1 h

Procedure:
To a solution of 20.0 mg (72.4 μmol) of 1,4-dimethyl-6-pentyl-1H-pyrrolo[2,3-b]pyridin-5-yl acetate in 1 mL of CH2Cl2 was added 217 μL (84.0 μmol, 1.0 M in hexanes) of DIBAL-H at 78° C. The reaction mixture was stirred at 78° C. for 1 h and then 2 mL of sat aq sodium potassium tartrate was added slowly. The reaction mixture was slowly warmed to room temperature over a period of 30 min. The solution was extracted with three 5-mL portions of ethyl acetate. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure to give the crude product as a yellow oil: silica gel TLC Rf 0.12 (1:9 MeOH/CH2Cl2). The residue was then dissolved in 1 mL of CH3CN and 1% aq TFA, frozen and lyophilized. The crude product was purified on a Prepex C8 reversed phase semi-preparative (250 mm×10 mm) HPLC column using a gradient of methanol and water. Linear gradients were employed using 1:4 methanol/water→4:1 methanol/water over a period of 20 min, and then 4:1 methanol/water→methanol over a period of 40 min, at a flow rate of 3.5 mL/min (monitoring at 260 nm). Fractions containing the desired product eluted at 21.6 min, and were collected, frozen, and lyophilized to give 1a as a light yellow solid: yield 13.5 mg (80%); 1H NMR (CD3CN) δ 0.88 (t, 3H, J=6.8 Hz), 1.27-1.32 (m, 4H), 1.54 (quint, 2H, J=7.6 Hz), 2.13 (s, 3H), 2.69 (t, 2H, J=8.0 Hz), 2.99 (t, 2H, J=8.4 Hz), 3.06 (s, 3H) and 3.72 (t, 2H, J=8.4 Hz); 13C NMR (CDCl3) δ 13.0, 13.3, 22.1, 24.4, 27.2, 28.3, 31.1, 32.4, 53.1, 117.3, 126.1, 132.1, 140.4, 141.6 and 152.0; mass spectrum, m/z 234.2 (M)+ (theoretical 234.2); mass spectrum (APCI), m/z 235.1806 (M+H)+ (C14H23N2O requires 235.1810).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([C:20]#[N:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:7]=1)C.N#N>CO.Cl.[Pd]>[CH3:1][O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:7]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ncccc2C#N)c1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CO
Product: COC(=O)Cc1ccc(OC)c(-c2ncccc2CN)c1
Reaction time: 8 h

Procedure:
[3-(3-Cyano-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (0.579 g, 2.0 mmol) was dissolved in MeOH (20 mL) and 12N aqueous HCl (4 mL). After the mixture was purged with N2, 10% palladium on carbon (50 wt % w/w; 0.300 g, 0.15 mmol) was added, and the reaction was stirred overnight under 55 psi of H2 using a Parr shaker. After stirring for 18 hours, the mixture was filtered and neutralized with 1N aqueous NaOH (50 mL), and then concentrated to remove MeOH. The residue was partitioned between EtOAc and H20, and the organic layer was separated and washed five times with water. The organic layer was dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.C(N(CC)CC)C.Cl.[NH2:21][OH:22]>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:21][OH:22]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ON=Cc1ccc2ccccc2c1
Temperature: 35 °C
Yield: 98.2 %

Procedure:
To a mixture of 7.8 g of 2-naphthalaldehyde and 7.1 ml of triethylamine in 100 ml of methylene chloride was added 3.54 g of hydroxylamine hydrochloride and the mixture heated at 35° C. for three hours. The organic reaction solvent was washed with water, dried and concentrated to give 8.4 g of product.
Reaction SMILES: [CH3:1][N:2](C(=O)C)[C:3]1[S:4][CH:5]=[C:6]([CH3:16])[C:7]=1[C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>C(O)C.O>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH3:16])[C:7]=1[C:8](=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)N(C)c1scc(C)c1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNc1scc(C)c1C(=O)c1ccccc1
Temperature: 95 °C

Procedure:
To a solution of 400 mg of N-methyl-2-acetylamino-3-benzoyl-4-methylthiophene in 8 ml of ethanol, is added 0.11 g of potassium hydroxide in 2.9 ml of water. The mixture is heated at 95°C for 30 minutes, evaporated under reduced pressure to a residue. Water is added to the residue and the resulting mixture is extracted with dichloromethane. The dichloromethane extracts are washed with water, dried over sodium sulfate and then evaporated under reduced pressure to give crystals, which are recrystallized from ethanol-ether to give 2-methylamino-3-benzoyl-4-methylthiophene as crystals having a melting point of 144° - 145°C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C@@H:6]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)=O)[C:7]([OH:9])=[O:8])=[O:4].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]([F:22])([F:23])[C:3]([NH:5][C@@H:6]([CH2:10][CH2:11][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: CCCc1ccc(C(=O)C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCc1ccc(CC[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reaction time: 48 h
Yield: 93.1 %

Procedure:
A solution of N-trifluoroacetyl-α-(S)-(2-(4-n-propylphenyl)-2-oxoethyl)glycine 6 (140 mg, 0.43 mmol) in ethyl acetate (10 mL) containing acetic acid (0.25 mL) and 10% palladium on carbon (10 mg) was stirred under one atmosphere of hydrogen gas. After two days, the catalyst was filtered off and fresh catalyst was added and the reaction stirred under hydrogen overnight. The mixture was filtered and the solvent evaporated in vacuo to yield the product 7 (127 mg, 93% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12].[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][Br:25])[C:5]=1[N:11]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a solution of 0.723 g (2.072 mmol) of the product of Example 187 in 70 mL of carbon tetrachloride was added 0.406 g (2.279 mmol) of N-bromosuccinimide and 0.14 g of dibenzoyl peroxide. The resulting mixture was heated to reflux for 18 h and then cooled to room temperature, washed with sodium bisulfite solution and water, dried over MgSO4, filtered and concentrated in vacuo. The residue was titurad with ether/hexanes (1:1) and then filtered to provide 0.504 g (57%) of the desired product as a white solid. Electrspray Mass Spec: 428 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([Br:18])=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:15]([Br:18])=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(Br)n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
2-(5-Bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4 g, 12.65 mmol) was dissolved in DMF and cooled to 0° C. NaH (658 mg of 60% mineral oil dispersion, 16.45 mmol) was added and the reaction mixture was aged for 13 min before addition of SEMCl (2.7 mL, 15.18 mmol) and warming to RT. After 16 h, the reaction was quenched by water, diluted with ethyl acetate (300 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (10% to 30% EtOAc/hexanes) to afford 2-[5-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (4.67 g, 83%).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17](CC1C=CC=CC=1OC)[CH2:18][C:19](=O)[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)C1C=CC=CC=1.[ClH:43]>CO.[Pd]>[ClH:43].[ClH:43].[CH:20]([CH:19]1[N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][NH:17][CH2:18]1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccccc1CN(CC(=O)C(c1ccccc1)c1ccccc1)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc(C(c2ccccc2)C2CNC[C@@H]3CCCN23)cc1

Procedure:
(2S)-2-[[N-(2-Oxo-3,3-diphenylpropyl)-(2-methoxybenzyl)amino]methyl]pyrrolidine-1-carboxylic acid benzyl ester (492 mg) was dissolved in a mixture of methanol (7.4 ml) and IN hydrochloric acid (0.5 ml), and the solution was hydrogenated over 10% palladium—charcoal (50% wet) (0.15 g) at room temperature under atmospheric pressure for 15 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was partitioned between aqueous saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure and the resulting residue was treated with 4N hydrogen chloride in ethyl acetate to give (8aS)-4-benzhydryloctahydropyrrolo[1,2-a]pyrazine dihydrochloride (221.2 mg) as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH2:4]Br.[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10]>>[CH3:1][NH:2][C:3](=[O:6])[CH2:4][NH:10][C:9]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:8]=1[CH3:7]
Reactant: Cc1cccc(C)c1N
Reactant: CNC(=O)CBr
Product: CNC(=O)CNc1c(C)cccc1C
Reaction time: 8 h

Procedure:
83 g of bromoacetic acid methyl amide and 169 ml of 2,6-dimethyl aniline are stirred for 10 hours at 140° C bath temperature. The reaction mixture is left to stand overnight at room temperature. Next morning the contents of the flask are crystallised right through. The contents are filtered off and the precipitate is washed with benzene. The precipitate is subsequently dissolved in a small amount of water, the solution is brought to a pH of 10 to 11 with 30% sodium hydroxide solution and extracted with ether. The ethereal extract is dried over sodium sulphate, the ether distilled off in vacuo, and the residue is distilled in a high vacuum to yield 55 g of 2,6-dimethylanilinoacetic acid methyl amide (b.p. 152°-154° C/0.1 Torr). After recrystallisation from diisopropyl ether the product melts at 71°-73° C. 2,6-dimethylanilinoacetic acid dimethyl amide was manufactured in analogous manner: b.p. 132° C/0.3 Torr; m.p. 52°-54° C (recyrstallisation from diisopropyl ether/petroleum ether).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27]>C1COCC1.CCOC(C)=O>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:25]([C:26](=[O:27])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])([CH3:36])([CH3:34])[CH3:35]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCCBr)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCCBr)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDCI (2.10 g, 11.1 mmol) and aniline (0.68 ml, 7.5 mmol) were added to a solution of 7.4 mmol of (S)-7-bromo-2-tert-butoxycarbonylamino-heptanoic acid (Gupta P. K., et al., Bioorg. Med. Chem. Lett., 2010, 20, 23, 7067) in THF (70 ml) and the reaction mixture was stirred overnight at RT. The solvent was removed under reduced pressure and the crude reaction mixture was diluted with AcOEt, washed with water and then with 10% aqueous citric acid and finally with saturated NaHCO3. After removal of the solvent under reduced pressure and purification on silica gel (n-hexane/AcOEt: 1/9) the desired adduct was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.N>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH2:10][CH2:11][N:12]([CH2:16][C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccncc2)cc1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: N
Solvent: Cc1ccccc1
Product: C1=C(OCc2ccccc2)CCN(Cc2nc3ccccc3[nH]2)C1

Procedure:
Prepared from 4-benzyloxy pyridine and 2-(chloromethyl) benzimidazole in an analagous manner to that described previously. M.p. 170°-172° C. (PhMe); (Found: C, 75.19; H, 6.45; N, 13.02. C20H21N3O requires C, 75.21; H, 6.63; N, 13.16%). δH (CDCl3) 2.35 (2H, br s, tetrahydropyridinyl 3-CH2), 2.81 (2H, t, J 5.6 Hz, tetrahydropyridinyl 2-CH2), 3.21 (2H, br s, tetrahydropyridinyl 6-CH2), 3.98 (2H, s, NCH2Ar), 4.75 (1H, br s, tetrahydropyridinyl 5-CH), 4.81 (2H, s, PhCH2O), 7.22-7.27 (3H, m, ArH), 7.31-7.37 (6H, m, ArH), and 7.56 (1H, br s, NH); m/z (CI+, NH3), 336 (M+NH4)+.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:5].[C:13]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1)=[O:14].[Cl-].[Na+]>C(O)(=O)C>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C1OCc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCc2ccccc2C(=O)O)cc1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
In this example, 348.9 g of sodium salt of methyl p-hydroxybenzoate, 402.4 g of phthalide and 200 g of sodium chloride are mixed with one another and stirred at 150° C. for 6 hours. After completion of the reaction, the mixture is cooled until the temperature is brought back to room temperature, 4 l of aqueous 10% acetic acid solution is added thereto and the mixture is allowed to stand at room temperature overnight. After stirring the mixture at room temperature for 3 hours, deposited crystals are separated by filtration, and 6 l of water is added thereto. After stirring the mixture at room temperature for 30 minutes, the deposited crystals are separated by filtration. After the addition of 3 l of toluene to the crystals, the mixture is stirred at room temperature for one hour. The crystals are separated by filtration and dried over heating under reduced pressure to yield 393.9 g of 2-(4-methoxycarbonylphenoxy) methyl benzoic acid.
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)[CH3:2].[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([N:19]2[C@@H:23]([CH:24]([CH3:26])[CH3:25])[CH2:22][O:21][C:20]2=[O:27])=[O:18])=[C:12]([O:28][CH3:29])[CH:11]=1.BrCC#N.[NH4+].[Cl-]>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]([C:17]([N:19]2[C@@H:23]([CH:24]([CH3:26])[CH3:25])[CH2:22][O:21][C:20]2=[O:27])=[O:18])[CH2:2][C:1]#[N:4])=[C:12]([O:28][CH3:29])[CH:11]=1
Reactant: COc1cc(Br)ccc1CC(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: CC(C)[N-]C(C)C
Agent: N#CCBr
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1[C@H](CC#N)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
Lithium diisopropylamide (2.0 M in heptane/THF/ethylbenzene, 1.58 mL, 3.16 mmol) was added to a solution of (S)-3-[2-(4-bromo-2-methoxy-phenyl)-acetyl]-4-isopropyl-oxazolidin-2-one (1.126 g, 3.16 mmol) in THF (11 mL) under argon atmosphere at −78° C. The mixture was stirred for 15 minutes and bromoacetonitrile (0.23 mL, 3.32 mmol) was added at −78° C. The mixture was stirred for 3 hours at 0° C., and then a saturated solution of NH4Cl was added. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 85/15) to give 755 mg (60% yield) of (S)-3-(4-bromo-2-methoxy-phenyl)-4-((S)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4-oxo-butyronitrile as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:22][OH:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccccc2F)cc1
Yield: 83.2 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (1.634 g, 0.006001 mol) was allowed to react with hydroxylamine hydrochloride (0.500 g, 0.00720 mol) in the presence of sodium carbonate (0.763 g, 0.00720 mol) in absolute ethanol to give 1.434 g of 4-(2′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a pale yellow solid; mp 150.0-151.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[CH:12][CH:11]=1.O[N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[N:31]1([O:26][C:25](=[O:27])[C:24]2[CH:23]=[CH:22][C:21]([C:19]3[S:20][C:16]([C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][CH:14]=4)=[N:17][N:18]=3)=[CH:29][CH:28]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1
Reactant: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)O)cc3)s2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A mixture of 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazole-2-yl]benzoic acid (50 g), 1-hydroxybenzotriazole (18 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide, hydrochloride (34.86 g) in methylene chloride (1 L) was stirred for 16 hours at room temperature then evaportated under reduced pressure and dried for 1 hour under hi-vacuum. Water (1 L) was added to the residue and the resulting precipitate collected by filtration, washed with water (1 L×5), acetonitrile (1L×5), isopropyl ether (250 ml×2), then dried under hi-vacuum to give 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester (56.92 g) as a yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([CH:24]=O)[CH:22]=[CH:23][C:17]=4[N:16]4[CH:26]=[CH:27][CH:28]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2].C[CH2:34][N:35](CC)[CH2:36]C>CN(C=O)C>[CH3:34][N:35]([CH2:24][C:21]1[CH:22]=[CH:23][C:17]2[N:16]3[CH:26]=[CH:27][CH:28]=[C:15]3[C:12]3([CH2:13][CH2:14][N:9]([C:7]([C:6]4[CH:29]=[CH:30][C:3]([CH2:1][CH3:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:8])[CH2:10][CH2:11]3)[O:19][C:18]=2[CH:20]=1)[CH3:36]
Reactant: CCN(CC)CC
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C=O)ccc2-n2cccc23)cc1OC
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(CN(C)C)ccc2-n2cccc23)cc1OC

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carbaldehyde (88 mg, 0.20 mmol) N,N-dimethylamine hydrochloride (83 mg, 1.0 mmol), Et3N (140 μL, 1.0 mmol) and NaHB(OAc)3 (130 mg, 0.60 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O) to yield (7-((dimethylamino)methyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-ethyl-3-methoxyphenyl)methanone. ESI-MS m/z calc. 459.6. found 460.5 (M+1)+; Retention time: 1.40 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:18][C:11]3[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.[Cl:57][C:58]1[CH:73]=[CH:72][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[O:65])=[CH:60][CH:59]=1>>[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([O:62][CH2:63][C:64]([N:66]2[CH2:71][CH2:70][N:69]([C:15]3[C:10]4[CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[S:18][C:11]=4[N:12]=[C:13]([CH3:17])[N:14]=3)[CH2:68][CH2:67]2)=[O:65])=[CH:72][CH:73]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Reactant: Cc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a solution of 6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (40 mg, 0.15 mmol) and BOP (88 mg, 0.20 mmol) in CH3ON (1 ml) was added DBU (34 μl, 0.23 mmol). After stirring for 10 minutes at room temperature, 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (59 mg, 0.23 mmol) was added. The reaction was stirred at room temperature overnight and then heated at 60° C. for 4 hours. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (66 mg, 86%).
Reaction SMILES: C([O:5][P:6]([O:13][CH2:14][C:15]([NH:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:38])[O:36][CH3:37])=[CH:30][CH:29]=2)=[C:23]([NH:39][C:40]2[C:41]3[CH:49]=[CH:48][C:47]([CH:50]([CH3:52])[CH3:51])=[N:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH:22]=1)=[O:20])([CH3:17])[CH3:16])([O:8]C(C)(C)C)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+:64]>C(Cl)Cl>[P:6]([O-:7])([O-:8])([O:13][CH2:14][C:15]([NH:18][C:19](=[O:20])[C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([O:36][CH3:37])=[O:38])=[CH:30][CH:29]=2)=[C:23]([NH:39][C:40]2[C:41]3[CH:49]=[CH:48][C:47]([CH:50]([CH3:51])[CH3:52])=[N:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH:22]=1)([CH3:17])[CH3:16])=[O:5].[Na+:64].[Na+:64]
Reactant: COC(=O)Nc1ccc(Sc2ccc(C(=O)NC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1ccc(Sc2ccc(C(=O)NC(C)(C)COP(=O)([O-])[O-])cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Yield: 92.2 %

Procedure:
The product of Example 441E (240 mg., 0.32 mmol) in CH2Cl2 (1.6 ml.) was reacted with TFA (1.6 ml.) at room temperature for 30 min. The reaction was concentrated, redissolved in water (4 mL) and treated with solid NaHCO3 (270 mg., 3.2 mmol) with stirring. The solution was purified on a C-18 column eluted with a gradient of methanol in water (0-100%). to give the title compound (202 mg., 92%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.17-1.40 (m, 12 H) 2.98-3.11 (m, 1 H) 3.66 (s, 3 H) 6.65 (s, 1 H) 7.18-7.27 (m, 1 H) 7.32 (d, J=8.09 Hz, 2 H) 7.48 (d, J=8.09 Hz, 2 H) 7.51-7.62 (m, 1 H) 7.94 (s, 1 H) 8.18-8.29 (s, 1 H) 8.77 (s, 1 H) 9.84 (s, 1 H)