Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[O:14]1[CH2:19][CH2:18][CH:17]([C:20](=[S:22])[NH2:21])[CH2:16][CH2:15]1>C(O)C>[N+:11]([C:7]1[CH:6]=[C:5]([C:3]2[N:21]=[C:20]([CH:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[S:22][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: NC(=S)C1CCOCC1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2csc(C3CCOCC3)n2)c1
Yield: 98.2 %

Procedure:
A mixture of 2-bromo-1-(3-nitrophenyl)ethanone (245 mg, 1 mmol) and tetrahydro-2H-pyran-4-carbothioamide (144 mg, 1 mmol) is suspended in absolute ethanol (20 mL) and heated to reflux for 2 h. The solution is then cooled and evaporated to dryness. The crude is dissolved in DCM and washed twice with a solution of saturated sodium bicarbonate and once with water. The organic layer is dried up with sodium sulfate, filtered and evaporated to dryness to yield 285 mg of the title compound (98%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[N:19]=[CH:18]3)=[C:13]([F:31])[CH:12]=2)[CH2:6]1)=[N+]=[N-].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(OCC)(=O)C.[Pd]>[Si:24]([O:23][CH2:22][C:20]1[N:19]=[CH:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][NH:1][C:39](=[O:41])[CH3:40])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[F:31])[CH:21]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CO[Si](C)(C)C(C)(C)C)c3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To (5R)-5-azidomethyl-3-(4-(4-t-butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)oxazolidin-2-one(10.0 g) in ethyl acetate (560 ml) was added triethylamine (13.3 ml), acetic anhydride (4.5 ml), and palladium catalyst (10% on charcoal, 1.5 g), and the mixture hydrogenated at ambient temperature for 17 hours. The mixture was filtered through celite, the celite washed well with ethyl acetate, and the organic layer stirred with a saturated solution of sodium bicarbonate (100 ml) at ambient temperature for 1 hour. The organic layer was separated, dried over magnesium sulfate, and evaporated. Crude product (15 g, from two batches) was dissolved in dichloromethane and chromatographed on silica, eluting with a gradient from dichloromethane (100%) to 10% methanol in dichloromethane. Product fractions were combined to give a gum (12.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][C:6](/[CH:20]=[CH:21]/[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:7][CH:8]=2)[N:3]=1.C(Cl)(Cl)Cl>[Pd].C(O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][C:6]([CH2:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@H]1COCc2nc3c(N)nc4cc(/C=C/C(=O)N(C)C)ccc4c3n21
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C[C@H]1COCc2nc3c(N)nc4cc(CCC(=O)N(C)C)ccc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A 250-mL, glass Parr bottle was charged with palladium on carbon (10%, 0.05 g) and 2 mL of ethanol. A solution of (2E)-3-[(11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-yl]-N,N-dimethylprop-2-enamide (210 mg, 0.60 mmol) dissolved in 50 mL of ethanol was then added. The reaction mixture was placed on Parr apparatus and shaken under H2 at 50 PSI (3.4×105 Pa) overnight at ambient temperature. The reaction mixture was treated with additional palladium on carbon (10%, 0.05 g) and shaken under H2 at 50 PSI (3.4×105 Pa) for 24 hours. The reaction mixture was then filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure to give a white solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid that was crystallized from acetonitrile to give 120 mg of 3-[(11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-yl]-N,N-dimethylpropanamide as white crystals, mp 235-237° C.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Na+:5]>[Cl-].[Na+].O>[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[C:1](=[O:2])([O-:4])[O-:3].[Na+:5].[Na+:5]
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])[O-]

Procedure:
A process for forming useful sodium salts by uniquely processing dilute mine brines obtained by solution mining of a sodium bicarbonate containing ore deposit with an aqueous solvent is disclosed. The dilute mine brine is reduced in sodium bicarbonate content to prevent precipitation of the sodium bicarbonate in subsequent crystallization of sodium carbonate decahydrate. The reduced mine brine is directed to a crystallizer operated to form pure sodium carbonate decahydrate crystals and a carbonate/bicarbonate containing mother liquor in which the bicarbonate content is less than 4.5% by weight. The mother liquor is then steam stripped to convert a portion of the dissolved sodium bicarbonate in the mother liquor to sodium carbonate to form a carbonate enriched brine. The carbonate enriched brine is then recycled as a portion of said aqueous solvent to be used in the solution mining of the ore deposit.
Reaction SMILES: [OH:1][CH:2]([CH2:36][C:37]1[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40]([OH:47])=[C:39]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:38]=1)[CH2:3][N:4]1[C:11](=[O:12])[C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:8](=[O:9])[N:7]([CH2:17][CH:18]([OH:35])[CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=2)[C:5]1=[O:6].[C:52](Cl)(=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69].Cl>>[C:52]([O:35][CH:18]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:32])([CH3:33])[CH3:34])[CH:21]=1)[CH2:17][N:7]1[C:8](=[O:9])[C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:11](=[O:12])[N:4]([CH2:3][CH:2]([O:1][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:36][C:37]2[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40]([OH:47])=[C:39]([C:48]([CH3:49])([CH3:50])[CH3:51])[CH:38]=2)[C:5]1=[O:6])(=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]
Reactant: CCC1(CC)C(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CN1C(=O)N(CC(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC(=O)CCCCCCCCCCCCCCCCC)C(=O)C(CC)(CC)C1=O
Yield: 52.3 %

Procedure:
7.0 g (0.01 mol) of 1,3-bis-[2-hydroxy-3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propyl]-5,5-diethylbarbiturate and 6 g (0.02 mol) of stearic acid chloride in 50 ml of ligroin are brought to the reflux temperature and the resulting clear solution is kept at this temperature until the evolution of hydrochloric acid has ceased. After evaporating the solvent in vacuo, a syrupy residue is obtained which when chromatographed on a silica gel column gives 6.5 g (53% of theory) of 1,3-bis-[2-stearoyloxy-3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propyl]-5,5-diethylbarbiturate as an almost colourless oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([I:24])[CH:17]=1>C1COCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)=[C:18]([I:24])[CH:17]=1
Reactant: BrCc1ccc(Br)cc1I
Reactant: N#CC1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(Cc2ccc(Br)cc2I)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Lithium diisopropylamide (3.34 mL, 6.68 mmol), was added dropwise to a solution of cyclobutanecarbonitrile (0.417 g, 5.14 mmol) in THF (20 mL) at −78° C. under an argon atmosphere. The reaction mixture was stirred at −78° C. for 30 min, then was a solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239., 2.51 g, 6.68 mmol) in THF (8 mL) slowly added dropwise and the reaction was allowed to reach r.t. The mixture was stirred for another 3 h and then quenched with water. The reaction mixture was partitioned between water and EtOAc, the organic layer was dried over MgSO4 and concentrated to give a crude product which was purified by flash chromatography (eluent: heptane/ethylacetae 12:1) to afford the title compound (1.71 g, 89% yield): 1H NMR (500 MHz, CDCl3) δ ppm 2.08-2.34 (m, 4 H), 2.47-2.58 (m, 2 H), 3.18-3.23 (m, 2 H), 7.29 (s, 1 H), 7.49 (dd, 1 H), 8.03 (d, 1 H); GC MS (EI) m/z 375 M
Reaction SMILES: [C:1]([O:4][CH:5]([C:11](=O)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].C([O-])(=O)C.[NH4+:26]>C(O)(=O)C>[CH3:2][C:1]1[O:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[N:26]=1
Reactant: CCOC(=O)C(OC(C)=O)C(=O)CCc1cccc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1oc(C)nc1CCc1cccc(C)c1

Procedure:
A mixture of the product from step (ii) (19.6 g) and ammonium acetate (25.8 g) in acetic acid (150 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated to dryness and the residue partitioned between water and ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate and water, dried (MgSO4) and evaporated under reduced pressure. The product was used without purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](OCC)=[O:15])[CH3:2].O>C(O)C>[C:4]([C:5]1[O:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[C:14]=1[OH:15])([O:3][CH2:1][CH3:2])=[O:19]
Reactant: CCOC(=O)COc1ccc(Cl)cc1C(=O)OCC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1O
Temperature: 80 °C
Yield: 87.3 %

Procedure:
12.3 g (0.11 mol) of potassium tert.-butylate were added in portions to a solution of 28.6 g (0.1 mol) of (2-carbethoxy-4-chlorophenoxy)-acetic acid ethyl ester in 50 ml of ethanol. The batch was warmed to 80° C. for 2 hours and was then cooled, and the reaction mixture was poured into 200 ml of water. The aqueous solution was first extracted with methylene chloride (to remove neutral impurities) and was then acidified with hydrochloric acid while cooling with ice. The acid solution was repeatedly extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and then concentrated. 21 g (87.5% of theory) of 2-carbethoxy-5-chloro-3-hydroxy-benzofuran were obtained in the form of colorless crystals of melting point 100°-102° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:1]([O:9][CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C=O)c1cc(F)ccc1C(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoic acid (42.7 g) and triethylamine (64.8 ml) were dissolved in dichloromethane (250 ml) at 0° and this solution was added to the dichloromethane solution of 2'-(2-chloroacetyl)-5'-fluoro-N-methylformanilide over a period of hour whilst maintaining the temperature below 5° with ice/water bath cooling. After stirring for 1 hour at 5°, the mixture was heated under reflux under nitrogen for 16 hours. Further triethylamine (16 ml) was added and the mixture heated under reflux for a further 16 hours. The mixture was allowed to cool to ambient temperature, washed with water (2×250 ml) and dried over magnesium sulphate. Evaporation of the solvent gave the novel compound 2-[4-fluoro-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate, m.p. 93°-95°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[N:34]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:41][CH2:40][CH2:39][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:14])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 79.7 %

Procedure:
Following General Procedure R, the title compound (388 mg, 80%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (411 mg, 0.77 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.15 ml, 1.15 mmol), EDC (294 mg, 1.53 mmol) and DMAP (cat.) in DMF (10 ml).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2CCC#N)=[CH:4][C:3]=1[F:22].C(OC([NH:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=O)(C)(C)C>C(#N)C>[NH2:30][C@H:31]1[CH2:35][CH2:34][N:33]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][NH:9]3)=[CH:4][C:3]=2[F:22])[CH2:32]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Product: N[C@H]1CCN(c2nc3[nH]cc(C(=O)O)c(=O)c3cc2F)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of Example 7C (32.4 mg) and (3S)-3-(tert-butoxycarbonylamino)pyrrolidine (55.8 mg) in acetonitrile (1 mL) in a sealed vial was heated for 24 hours then cooled and concentrated. The concentrate was dissolved in 1:1 DMSO/methanol (1 mL) and chromatographed by reverse phase HPLC. The product was suspended in 2-propanol (1 mL), treated with 1M LiOH (1.2 mL), heated at 80° C. for 18 hours in a sealed vial for 24 hours, and concentrated. The concentrate was treated with 10% citric acid to pH 4-6 and filtered. The filtrant was dissolved in 4M HCl/dioxane (1.5 mL), and this solution was stirred for 2 hours and concentrated. NMR (500 MHz DMSO-d6) δ 13.4 (m, 1H), 8.50 (m, 1H), 8.45 (s, 2H), 8.00 (m, 1H), 4.00-3.40 (m, 5H), 2.38 (m, 1H), 2.18 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22](=O)[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([O:37][CH2:38][CH2:39][OH:40])=[C:25]([Br:41])[CH:24]=1)C>C1COCC1.O.Cl>[CH2:1]([NH:13][C:22](=[O:21])[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([O:37][CH2:38][CH2:39][OH:40])=[C:25]([Br:41])[CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Reactant: CCCCCCCCCCCCN
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
Into a flamed dried round bottom flask charged with n-dodecylamine (586 mg, 3.16 mmol) in 7 mL THF at −20° C. was added n-BuLi (1.8 mL, 3.6 mmol) as a solution in hexanes. After the addition, the reaction was warmed up to room temperature and stirred for one-half hour. Then the solution was cooled to −20° C. and was added to a solution of 3-bromo-4-(2-hydroxyethoxy)-5-(3-chloro-4-fluorophenyl)benzoic acid ethyl ester (400 mg, 0.957 mmol) in 8 mL THF that had been previously cooled to −40° C. The resulting mixture was stirred at −40° C. for 5 min after which point the reaction mixture was allowed to warm up to room temperature. The reaction was diluted with water and 2N HCl then extracted with EtOAc three times. The combined organic extracts were washed with sat NaHCO3 then dried over Na2SO4. After filtering and removal of solvent in vacuo, there yielded a yellow oil that was subjected to column chromatography on silica gel (10% EtOAc: 90% Hexanes followed by 25% EtOAc: 75% Hexanes). There resulted 300 mg, 58% of the amide as a yellow oil. 1H NMR (CDCl3) 0.868 (t, J=8.13 Hz, t); 1.20–1.40 (m, 18H); 1.48–1.67 (m, 2H); 1.895–2.00 (bs, 1H); 3.427 (q, J=8.13 Hz, 2H); 3.636–7.71 (m, 4H); 6.014 (m, 1H); 7.20–7.24 (m, 1H); 7.40–7.454 (m, 1H); 7.586–7.668 (m, 2H); 7.868 (d, J=2.04 Hz, 1H).
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[O:15])[CH:9]=[CH:10]2)=[N:5]1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.C([BH3-])#N.[Na+]>C1COCC1.C(OCC)(=O)C>[CH:30]1([NH:35][CH2:2][CH2:3][N:4]2[CH:12]=[C:11]3[C:6]([CH:7]=[C:8]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:19][CH:18]=4)=[O:15])[CH:9]=[CH:10]3)=[N:5]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCC1
Reactant: O=CCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2cn(CCNC3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-[2-(2-oxo-ethyl)-2H-indazol-6-yl]-3-(4-phenoxy-phenyl)urea (20 mg, 0.05 mmol) and cyclopentylamine (10 mL, 0.10 mmol) in THF (0.5 mL) was shaken at room temperature for 30 minutes. 1M Sodium cyanoborohydride in THF (104 μL, 0.10 mmol) was added and the solution was shaken at room temperature for 16 hours. The sample was diluted with ethyl acetate, washed with water, concentrated under reduced pressure and purified by RP-HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.6 (m, 6 H), 2.0 (m, 2 H), 3.55 (m, 2 H), 4.35 (m, 2 H), 4.70 (t, 2 H), 6.97 (m, 5 H), 7.12 (m, 1 H), 7.35 (m, 2 H), 7.52 (m, 2 H), 7.65 (d, 1 H), 7.95 (s, 1 H), 8.35 (s, 1 H) and 8.70 (m, 2 H.); MS (ESI) 456 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:2]2[N:27]=[CH:26][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: OCc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Reactant: C1CCNC1
Product: OCc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4)cc2OCC3)n(CC(F)(F)F)n1

Procedure:
(5-(9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol 387 was reacted with pyrrolidine to give 390 (13 mg) as a colorless solid. LCMS: 436.1. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 7.93 (s, 1H), 5.95 (s, 1H), 5.84 (q, J=8.9 Hz, 2H), 5.32 (t, J=6.1 Hz, 1H), 4.50 (m, 4H), 4.45 (d, J=6.0 Hz, 2H), 3.41 (m, 4H), 1.95 (m, 4H)
Reaction SMILES: O.CC#[N:4].N[C@H:6]([CH2:13][C:14]([OH:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C(N)(CO)CO.Cl>[NH2:4][C@H:13]([C:14]([OH:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC#N
Reactant: N[C@H](CC(=O)O)c1ccccc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 18 h

Procedure:
The standard PAM activity assay mixture contains 5 mM L-α-phenylalanine, 1 to 10 μg enzyme in 50 mM Tris-HCl buffer (pH 7.5) in a final volume of 0.5 ml. Enzyme reactions were carried out at 28° C., 150 rpm for 18 hours and terminated by addition of 50 μl ethanol to precipitate proteins. After centrifugation for 5 minutes, the supernatants were analyzed by a reverse phase HPLC method. The formation of β-phenylalanine was quantified based on peak area compared to the β-phenylalanine standard curve. Enzyme activity is expressed as μg β-phenylalanine formed per hour per mg protein. HPLC analysis used a YMC Ph column (4.6×150 mm; Waters, Milford, Mass.), and a flow rate of 1.2 ml/minutes. Absorbance was monitored at 210 nm. The method employed two solvents A, water; and B, CH3CN and a gradient consisting 0% to 12% B for 6 minutes, 12% to 90% in 1 minute and returning to 0% in 1 minute. Retention times of L-α-phenylalanine and β-phenylalanine are 4.3 minutes and 3.5 minutes, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cc1
Yield: 73.7 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluoro-benzaldehyde (1.71 g, 10.9 mmol) (Beta Pharma) was reacted with 4-nitrophenol (1.67 g, 12 mmol) (Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-chloro-2-(4-nitro-phenoxy)-benzaldehyde as a brown oil (Yield 2.23 g, 73%).