Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[C:4]([CH:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[C:3]=1[OH:29].[Cr](Cl)([O-])(=O)=[O:31].[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:31])=[C:4]([CH:12]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:3]=1[OH:29]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: COC(=O)CCCCCC(c1ccc(F)cc1)c1c(O)c(C)c(C)c2c1CCC2
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: Cc1c(C)c2c(c(C(CCCCCC(=O)O)c3ccc(F)cc3)c1O)CCC2=O
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of methyl 7-(6,7-dimethyl-5-hydroxyindan-4-yl)-7-(4-fluorophenyl)heptanoate (1.4 g) in benzene (40 ml) was added a mixture of pyridinium chlorochromate (3.8 g) and cerite (7 g) and the mixture was stirred for 2 hours. The reaction mixture was filtered and the filtrate was washed with water and saturated saline and dried with magnesium sulfate. Tetrahydrofuran (10 ml) and 1N sodium hydroxide (10 ml) were added to the residue and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure and the residue was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from acetonitrile to obtain 7-(6,7-dimethyl-5-hydroxy-1-oxoindan-4-yl)-7-(4-fluorophenyl)heptanoic acid (0.4 g) (Compound 37). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: CC1[O:7][CH:6]([CH3:8])OC(C)O1.[OH-].[K+].[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>CO>[CH2:14]([CH:13]1[CH2:12][CH2:17][CH2:16][CH2:8][C:6]1=[O:7])[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1=[O:18]
Reactant: O=C1CCCCC1
Reactant: CC1OC(C)OC(C)O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCCC1CC1CCCCC1=O
Reaction time: 3 h
Yield: 64 %

Procedure:
A mixture comprising 68 g of paraldehyde, 6 g of caustic potash and 188 g of methanol was added dropwise to a solution comprising 1,000 g of cyclohexanone and 188 g of methanol at 60°-70° C. over a period of 2 hours, and the resulting mixture was stirred for another 3 hours at 60°-70° C. Thereafter, the reaction mixture was decomposed with dilute hydrochloric acid, extracted with ether, washed first with 3% aqueous sodium carbonate, then with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. After recovering the solvent, the dried product was distilled under vacuum to provide 340 g (yield: 64%) of a fraction boiling at 135°-145° C./3 mm Hg.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:8]2[C@@H:12]([OH:13])[CH2:11][CH2:10][N:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([CH3:44])[CH:43]=1)[CH2:39]Br>COCCOC>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:8]2[C@@H:12]([O:13][CH2:35][C:36]3[CH:37]=[C:38]([CH3:39])[CH:41]=[C:42]([CH3:44])[CH:43]=3)[CH2:11][CH2:10][N:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)N1CC[C@H](O)[C@@H]1C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)cc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)N1CC[C@H](OCc2cc(C)cc(C)c2)[C@@H]1C(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
To a solution of cis-2-(diphenylmethyl)-3-hydroxy-1-ethoxycarbonylpyrrolidine (Example 1d, 1.00 g, 3.1 mmol) in ethylene glycol dimethyl ether (10.0 ml) was added 0.5M potassium bis(trimethylsilyl)amide (9.00 ml, 4.5 mmol) and stirred at room temperature for 1/2h before addition of 3,5dimethylbenzyl bromide (0.92 g, 4.5 mmol) in ethylene glycol dimethyl ether (2 ml). After stirring for 18 h the solvent was removed in vacuo and the residue partitioned between water/dichloromethane. The organic phase was washed with saturated brine and dried (MgSO4). The residue, after removal of solvent in vacuo, was chromatographed on silica gel using ethyl acetate/hexane (2:3) as eluant to give cis-2-(diphenylmethyl)-3-(3,5-dimethylbenzyloxy)-1-ethoxycarbonylpyrrolidine. 1H NMR (360 MHz, DMSO-d6) δ7.05-7.46 (10H, m), 6.81 (1H, s), 6.58 (2H, s), 4.86 (1H, t, J=7.0 Hz), 4.42 (1H, d, 7.5 Hz), 4.18 (1H, d, J=12.0 Hz), 4.11 (1H, m), 3.97 (1H, d, J=12.0 Hz), 3.83 (1H, m), 3.68 (1H, m), 3.31 (1H, m), 2.98 (1H, m), 2.19 (6H, s), 2.15 (1H, m), 1.95 (1H, m), 1.03 (3H, t, J=7.0 Hz). m/z (CI+) 444 (MH).
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])#[N:2]>[OH-].[NH4+].CO.[Ni]>[NH2:2][CH2:1][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC#N)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCN)CC1

Procedure:
A mixture of Example 604A (500 mg) was hydrogenated in the presence of Raney® nickel (5 g) in 10 mL of 20% ammonium hydroxide in methanol at room temperature for 16 hours under 60 psi pressure. Insoluble was filtered off and the filtrate was evaporated to dryness and the residue was redissolved in ether. The ethereal solution was passed through membrane filter. The title compound was obtained after ether was removed. 330 mg. MS (ESI(+)) m/e 258 (M+H)−; 1H NMR (300 MHz, DMSO-d6) δ 4.04 (s, 2H), 3.42-3.45 (m, 4H), 3.26-3.33 (m, 42H), 1.41 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:12]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CSCCC(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In accordance with the literature (J. Peptide Sci., 2001, 7, 619-625), 10 g of DL-methionine was added to 20 ml of water and 11.5 ml of 6 N NaOH, and dissolved therein. While keeping pH at 10.5 to 11.5, 8.6 ml of benzoyl chloride was added thereto, and the mixture was stirred at room temperature for two hours. The resulting reaction mixture was filtrated and then washed with diethyl ether. Concentrated hydrochloric acid was gradually added to adjust the pH to 1 to precipitate a crystal. The crystal was filtrated, washed with water, and dried under reduced pressure to obtain 16.2 g of N-benzoylmethionine. 24 ml of acetic anhydride was added to 4.9 g of obtained N-benzoylmethionine, the solution was heated at 100° C. for 4 hours, then cooled to room temperature, and the solvent was evaporated. The steps of adding 24 ml of toluene to the residue and evaporating the solvent were repeated twice. The, the residue was dissolved in 2.5 ml of pyridine, 10 ml of 35% formaldehyde solution was added, and the solution was stirred at room temperature for 17 hours. 40 ml of water was added to the resulting reaction solution, which was then extracted with 40 ml of ethyl acetate. The extract was washed with water and saturated brine, and dried on magnesium sulfate. Magnesium sulfate was removed and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 4/1 to 1/1). After evaporating the solvent, 2.56 g of 5-benzoylamino-5-methylthioethyl-4-oxo-1,3-dioxane was obtained. 7.5 ml of 6 N hydrochloric acid was added to 1.06 g of the obtained 5-benzoylamino-5-methylthioethyl-4-oxo-1,3-dioxane, which was then heated and refluxed for 7 hours. The reaction solution was filtrated, and then the solvent was evaporated. 5 ml of water was added to the residue, which was then purified using an ion exchange resin (Amberlite 120). After evaporating the solvent, the resulting crystal was recrystallized from water/ethanol, and dried under reduced pressure to obtain 129 mg of α-methylthioethyl-serine. NMR of this compound was measured, and almost agreed with the values described in the literature.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>CS(C)=O>[Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:13])=[N:7]2
Reactant: CC(C)(C)N
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Solvent: CS(C)=O
Product: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A glass reaction vessel was charged with 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (9.705 g, 35.2 mmol) in DMSO (58.7 mL). Then tert-butylamine (Alfa Aesar; Ward Hill, Mass.) (18.51 mL, 176 mmol) was added into the mixture. The vial was sealed, then placed into a pre-heated (100° C.) oil bath and stirred 2 h. The vessel was removed from the heat source and cooled to RT. The mixture was poured into water (1100 mL) sat undisturbed 30 min, then stirred. The precipitate was collected by filtration (through a medium fritted-funnel) and the solids were washed with water. The solids were dried in a reduced-pressure oven overnight, to provide 8-bromo-N-(tert-butyl)-7-fluoro-3-methylquinoxalin-2-amine (286a) (8.27 g, 75% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (dd, J=9.00, 5.87 Hz, 1H) 7.33 (t, J=8.80 Hz, 1H) 6.30 (s, 1H) 2.54 (s, 3H) 1.59 (s, 9H). m/z (ESI, +ve) 311.9 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=C(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].Br[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:39][CH:40]=1>C1COCC1>[NH2:8][CH:7]([CH2:34][C:35]1[CH:40]=[N:39][C:38]([NH:41][C:42]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:48])=[CH:37][CH:36]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CC(N)C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
660 mg of N-(diphenylmethylene)glycine tert-butyl ester (2.23 mmol, 1.0 equiv.) were dissolved in 15 ml of dry THF and cooled to 0° C. under argon. Then 2.23 ml of 1 M lithium hexamethyldisilazane (LiHMDS) solution in THF were added dropwise, and the mixture was stirred at 0° C. for 15 min. Subsequently, 642 mg of tert-butyl (5-bromomethylpyridin-2-yl)-carbamate (2.23 mmol, 1.0 equiv.) were added, and the mixture was stirred at 0° C. for 2 h. The mixture was quenched with 18 ml of sat. citric acid and stirred at RT for 1 h. The mixture was extracted with ethyl acetate (2×30 ml), and the organic phases were washed with 50 ml of 1 M HCl. The aqueous phases were combined and adjusted to pH 10 with 2M NaOH and then extracted 3× with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel with heptane/ethyl acetate mixtures as eluent. 600 mg (80% yield) of the title compound were obtained as a colorless solid.
Reaction SMILES: C([N:4]1[CH2:27][CH2:26][C:7]2[N:8]([CH2:16][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)([OH:19])[CH3:18])[C:9]3[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:16][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)([OH:19])[CH3:18])[C:7]3[CH2:26][CH2:27][NH:4][CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: C=CCN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: CC(O)(Cn1c2c(c3cc(Cl)ccc31)CNCC2)c1ccncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1-(2-Allyl-8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyrimidin-4-yl-propan-2-ol (300 mg, 0.785 mmol) was dissolved in DCM (6 mL) and N2 was purged for 5 min into the reaction mixture. 1,3-Dimethylbarbituricacid (367 mg, 2.356 mmol) and Pd(PPh3)4 (18 mg, 0.0157 mmol) was added and the mixture stirred for 1 h at RT. After consumption of starting material, the reaction mixture was diluted with saturated potassium carbonate (50 mL) and extracted with DCM (2×40 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated, crude was purified by reverse phase chromatography to obtain 97 mg of 1-(8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyrimidin-4-yl-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 9.13 (s, 1H), 8.45 (d, 1H), 7.31 (d, 1H), 7.25 (s, 1H), 6.94 (s, 2H), 4.3 (q, 2H), 3.93 (q, 2H), 3.13 (m, 2H), 2.78 (d, 1H), 2.57 (d, 1H), 1.6 (s, 3H). Separation by chiral HPLC provided enantiomers 42a and 42b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.[Cl-].[NH4+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[CH:19]=2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(Cl)ccc3O)ccn2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 4-chloro-2-iodophenol (367 mg, 1.44 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (707.5 mg, 1.817 mmol), and sodium carbonate (615.0 mg, 5.802 mmol) in 1,4-dioxane (6.0 mL, 77 mmol) and water (2.0 mL, 110 mmol) was sparged 5 minutes with argon. Tetrakis(triphenylphosphine)palladium(0) (100.0 mg, 0.08654 mmol) was added, the vial was capped, and the reaction mixture was heated at 90° C. After 4 hours, the reaction mixture was cooled to ambient temperature and poured into water. Saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated onto diatomaceous earth. The residue was purified by automated flash chromatography (24 g SiO2, hexanes to ethyl acetate) to afford the product as an amber oil that solidified on standing (491 mg, 74%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1>CC1C=CC=CC=1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCN(C(C)=O)CC1
Yield: 82 %

Procedure:
A mixture of 200 parts of acetic acid anhydride, 90 parts of ethyl 4-piperidineacetate and 225 parts of methylbenzene is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is diluted with water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 92 parts (82%) of ethyl 1-acetyl-4-piperidineacetate as a residue.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)c(F)ccc12
Reactant: COc1ccc(C)cc1B(O)O
Product: COc1ccc(C)cc1-c1c(F)ccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 65.2 %

Procedure:
Using Method A, 4-amino-8-bromo-7-fluoro-N-cyclobutyl-cinnoline-3-carboxamide (175 mg) and 2-methoxy-5-methyl-phenyl boronic acid (187 mg) were reacted to afford the title compound (128 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.18 (d, 1H), 8.50 (m, 1H), 7.71 (m, 1H), 7.24 (m, 1H), 7.07 (m, 1H), 7.03 (m, 1H), 4.49 (m, 1H), 3.61 (s, 3H), 2.29 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=381 (M+H).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[CH:7]1[N:8]=[C:9]([NH2:50])[C:10]2[N:15]=[CH:14][N:13]([C@@H:16]3[O:20][C@H:19]([CH2:21][O:22][P:23]([O:26][P:27]([O:30][CH2:31][C@H:32]4[O:36][C@@H:35]([N:37]5[CH:42]=[C:41]([C:43]([NH2:45])=[O:44])[CH2:40][CH:39]=[CH:38]5)[C@H:34]([OH:46])[C@@H:33]4[OH:47])([OH:29])=[O:28])([OH:25])=[O:24])[C@@H:18]([OH:48])[C@H:17]3[OH:49])[C:11]=2[N:12]=1>>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH:7]1[N:8]=[C:9]([NH2:50])[C:10]2[N:15]=[CH:14][N:13]([C@@H:16]3[O:20][C@H:19]([CH2:21][O:22][P:23]([O:26][P:27]([O:30][CH2:31][C@H:32]4[O:36][C@@H:35]([N:37]5[CH:42]=[C:41]([C:43]([NH2:45])=[O:44])[CH2:40][CH:39]=[CH:38]5)[C@H:34]([OH:46])[C@@H:33]4[OH:47])([OH:29])=[O:28])([OH:25])=[O:24])[C@@H:18]([OH:48])[C@H:17]3[OH:49])[C:11]=2[N:12]=1
Reactant: CC(=O)C(=O)[O-]
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: CC(O)C(=O)[O-]

Procedure:
the pyruvate is reacted with NADH in the presence of the LDH to give lactate and NAD; and
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([C@H:27](OS(C)(=O)=O)[CH3:28])(=[O:26])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C@@H:27]([CH3:28])[C:24]([NH2:25])=[O:26])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C[C@@H](OS(C)(=O)=O)C(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 (100 mg, 0.32 mmol), methanesulfonic acid (R)-1-carbamoyl-ethyl ester (64 mg, 0.38 mmol) and potassium carbonate (67 mg, 0.48 mmol) were suspended in DMF (3 mL) and the reaction mixture stirred at RT for 24 h then at 50° C. for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected flash chromatography (SiO2 gradient 0-10% methanol in ethyl acetate) to yield 436 as a white solid (59 mg, 48%). LCMS: RT=3.07 min; [M+H]+=383; 1H NMR (400 MHz, d6-DMSO) 8.26 (1H, d, J=8.6 Hz), 7.81 (1H, s), 7.85 (1H, s), 7.51 (1H, s), 7.21 (1H, s), 6.72 (1H, dd, J=8.6, 2.6 Hz), 6.49 (1H, d, J=2.6 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.62 (1H, q, J=6.6 Hz), 4.55-4.36 (4H, m), 1.47-1.36 (9H, m). ee>99% (chiralpak IC, 1 mL/min, 20% ethanol in heptane, 50 min run)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCO>O.C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Brc1cccnc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCCO
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A mixture of 3-nitrophenylboronic acid (50 g, 0.3 mol), 3-bromopyridine (48 ml, 0.5 mol), potassium carbonate (207 g, 1.5 mol), 1,3-propanediol (107 ml, 1.5 mol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g) in a mixture of water (200 ml) and dimethoxyethane (400 ml) was stirred in a nitrogen atmosphere at 80° C. for 3 hours. After cooling the dimethoxyethane was removed under reduced pressure and the residue was stirred with additionally 200 ml water overnight. The precipitate was filtered off and extracted with aqueous hydrochloric acid (4M, 300 ml). The extract was rendered alkaline by addition of aqueous sodium hydroxide (12M). The product was filtered off, washed with water and dried with suction to yield 3-(3-nitrophenyl)pyridine (50.6 g, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][CH2:10][CH2:11][N:12]([CH3:29])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][CH2:10][CH2:11][N:12]([CH3:29])[C:13]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=1)=[O:14])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CCNc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(CCCN(C)C(=O)c1ccc(NCCC(=O)O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound (355 mg, 0.84 mmol) obtained in Example 94a was dissolved in ethanol (4 mL), a 1 N aqueous sodium hydroxide solution (1.26 mL, 1.26 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, a 1 N aqueous hydrochloric acid solution (1.26 mL, 1.26 mmol) was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude N-{4-[{3-([tert-butoxycarbonyl)(methyl)amino]propyl}(methyl)carbamoyl]phenyl}-β-alanine.