Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([NH2:29])[CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].C([O-])(O)=O.[Na+].[C:35](O)(=O)[CH2:36][OH:37]>>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]3[N:28]=[C:35]([CH2:36][OH:37])[NH:29][C:24]=3[CH:23]=2)=[CH:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C(O)CO
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(N)c(N)c3)nc3ccccc3c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(C)c1ccc(-n2c(-c3ccc4nc(CO)[nH]c4c3)nc3ccccc3c2=O)cc1
Yield: 41 %

Procedure:
A solution of 3-(4-sec-butylphenyl)-2-(3,4-diaminophenyl)quinazolin-4(3H)-one (0.130 g, 0.34 mmol) was refluxed in a 70% aqueous solution of glycolic acid (10 mL) for 2 hours. The reaction was poured into a saturated solution of NaHCO3 and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 3% to 10% MeOH in CH2Cl2, afforded the title compound as a white solid (0.060 g, 41%). 1H-NMR (300 MHz, DMSO-d6): δ12.22-12.53 (m, 1H), 8.19 (d, J=7.5 Hz, 1H), 7.87-7.92 (m, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.56-7.61 (m, 2H), 7.00-7.26 (m, 6H), 5.67-5.69 (m, 1H), 4.51-4.71 (m, 2H), 1.37-1.50 (m, 2H), 1.11 (d, J=6.8 Hz, 3H), 0.58 (t, J=7.2 Hz, 3H). MS (APCI) m/z: 425 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH:13](OC(=O)C)[O:14]C(=O)C)=[C:7]([N+:22]([O-:24])=[O:23])[C:6]=1[O:25][CH3:26])(=O)C>Cl>[CH3:26][O:25][C:6]1[C:7]([N+:22]([O-:24])=[O:23])=[C:8]([CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[OH:4])[CH:13]=[O:14]
Reactant: COc1cc(C(OC(C)=O)OC(C)=O)c([N+](=O)[O-])c(OC)c1OC(C)=O
Agent: Cl
Product: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1O
Yield: 97.9 %

Procedure:
A suspension of 43 g (0.116 mole) of 4-acetoxy-1-diacetoxymethyl-3,5-dimethoxy-2-nitrobenzene in 500 cm3 of 2N hydrochloric acid is heated under reflux for 2 hours. The reaction mixture is left to return to ambient temperature, then the precipitate formed is filtered off. After washing with water and drying under vacuum, 25.8 g of the desired product is obtained in the form of a slightly yellow solid (yield=98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH2:18]([CH:22]1[CH2:23][CH:24]2[N:29]([CH2:14][C@@H:13]([CH3:16])[CH2:12][N:7]3[C:6]4[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][C:8]3=[O:11])[CH:27]([CH2:26][CH2:25]2)[CH2:28]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(F)cc21
Yield: 68.6 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.219 g, 0.6 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.6 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc (4:1-4) gave the title compound (111MF26) (0.16 g, 58%). 1H NMR (CDCl3) δ 7.16 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.90 (dd, J=5.0 Hz, J=9.0 Hz, 1H), 6.69-6.63 (m, 1H), 4.58 (q, J=14.8 Hz, J=38.0 Hz, 2H), 4.10-3.93 (m, 2H), 3.16-3.06 (m, 2H), 2.33 (dd, J=4.0 Hz, J=12.8 Hz, 1H), 2.05 (t, J=11.6 Hz, 1H), 1.94-1.82 (m, 2H), 1.58-1.43 (m, 6H), 1.39-1.32 (m, 2H), 1.31-1.15 (m, 6H), 0.90-0.87 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.7 Hz), 130.0 (d, J=10.4 Hz), 117.5 (d, J=9.3 Hz), 109.4 (d, J=23.5 Hz), 103.9 (d, J=28.9 Hz), 67.8, 61.9, 60.1, 58.2, 45.6, 38.6, 38.5, 36.9, 31.8, 29.4, 28.2, 27.4, 26.5, 23.1, 17.1, 14.3.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1>CCO.[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]([F:13])([F:12])[F:14])=[CH:4][N:3]=1
Reactant: Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ncc(C(F)(F)F)cc1N
Reaction time: 18 h
Yield: 39.1 %

Procedure:
2-Methyl-3-nitro-5-(trifluoromethyl)pyridine (51 mg, 0.247 mmol) and 10% Pd/C, (50% wet, 10 mg, 4.70 μmol) in EtOH (10 mL) were combined in a Parr hydrogenation flask. The reaction mixture was purged of air under vacuum and pressurized with hydrogen (33 psi). The flask was shaken for 18 h. An additional portion of 10% Pd/C, (50% wet, 20 mg, 9.40 μmol) was added and the mixture was hydrogenated (40 psi) overnight. The reaction mixture was filtered through Celite® and the filter cake was washed with EtOH. The combined filtrate and washings were concentrated in vacuo and purified by silica gel chromatography to provide 2-methyl-5-(trifluoromethyl)pyridin-3-amine (17 mg, 399% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.93 (s, 1 H), 7.13 (s, 1H), 5.56 (s, 2 H), 2.31 (s, 3 H); MS (ESI) m/z; 177.0 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(OC)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (200 mg, 0.58 mmol, 1.00 equiv), 1-(4-methoxyphenyl)piperazine (230.4 mg, 1.20 mmol, 2.00 equiv) and DIEA (232.3 mg, 1.80 mmol, 3.00 equiv) in DMF (6 mL) was placed in a 20-mL sealed tube and stirred overnight at 100° C. in an oil bath, then concentrated under vacuum. Purification via prep-HPLC yielded 117.1 mg (42%) of methyl 3-(4-(4-methoxyphenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])(=[O:4])=[O:3].O>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:10]=[CH:11][CH:12]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH is added to a solution of 750 mg (4.08 mmol) 3-methanesulphonyl-benzaldehyde in 20 ml ethanol (see P. L. Ornstein, T. J. Bleisch, M. B. Arnold, R. A. Wright, B. G. Johnson, J. P. Tizzano, D. R. Helton, M. J. Kallman, D. D. Schoepp, M. Herin, J. Med. Chem. 1998, 41(3), 358-378 or B. Eistert, W. Schade, H. Selzer, Ber. 1964, 97(5), 1470-81). The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is poured into water and extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried, filtered and concentrated in vacuo to afford the title compound, used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C([C:23]2[O:27]N=C(C(=O)C)C=2)C=CC=1.[BH4-].[Na+]>CO>[CH3:23][O:27][C:13]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][N:11]=1)=[O:15]
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)on1
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(Cl)c2)on1

Procedure:
A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.0 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol) in MeOH (60 ml) was heated at 80° C. for 4 h. After cooling, the mixture was filtered and washed with cold methanol to afford 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (2.0 g, 71%). 1H NMR: 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H). Step 2: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanone: In a screw cap vial equipped with stir bar was mixed methyl magnesium iodide (3M in Et2O) (0.79 ml, 2.38 mmol), toluene (1 ml), tetrahydrofuran (0.39 ml, 4.77 mmol) and TEA (1 ml, 7.15 mmol). After cooling to 0° C. a solution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (300 mg, 1.19 mmol) in toluene (5 ml) was added, followed by stirring at 0° C. for 5 h. The mixture was then quenched with aq 1N HCl (6.5 ml, 6.5 mmol), diluted with toluene (35 ml), sequentially washed with water, sat. aq. sodium bicarbonate,water and brine. The organic phase was concentrated in-vacuo. The isolated residue was dissolved in MeOH (8 ml) and 20% aq. KOH (1 ml) was added, followed by stirring at 45° C. for 30 min and then concentrated in-vacuo. The residue was dissolved in toluene (60 ml), sequentially washed with water, sat. aq. sodium bicarbonate and water. The organic phase was concentrated in-vacuo. The crude residue was purified on silica gel using 2% EA in hex. to isolate the desired compound (156 mg, 60%). 1H-NMR: 7.77 (m, 1H), 7.66 (m, 1H), 7.42 (m, 2H), 6.90 (s, 1H), 2.69 (s, 3H). Step 3: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol: In a screw cap vial equipped with stir bar was mixed 1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone (100 mg, 0.45 mmol), sodium borohydride (34 mg, 0.90 mmol) and MeOH (3 ml), followed by stirring at r.t for 3 h and the quenched with water and brine, extracted with DCM. The combined organic phase was dried (Na2SO4), filtered and concentrated in-vacuo to isolate the title compound. 1H-NMR: 7.69 (m, 1H), 7.59 (m, 1H), 7.37 (m, 2H), 6.59 (s, 1H), 5.07 (q, 1H), 3.45 (br. s, 1H), 1.58 (d, 3H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[NH2:29]>>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[NH:29][C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1Cc2ccccc2C1
Product: COCCN1C(=O)C(NC2Cc3ccccc3C2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and indan-2-amine in a similar manner as described for Example 1. 1H NMR (400 MHz, CD3CN): δ 7.65-7.60 (m, 2H), 7.55-7.50 (m, 3H), 7.13-7.11 (m, 4H), 5.90 (d, 1H), 4.06-3.98 (m, 1H), 3.83 (t, 2H), 3.67 (t, 2H), 3.38 (s, 3H), 2.84-2.81 (m, 4H); Mass Spectrum: M+H+ 399.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[OH:22][C:23]1[CH:24]=[C:25]([C:32](O)=[O:33])[C:26](=[CH:30][CH:31]=1)[C:27](O)=[O:28].O>C(O)(=O)C>[OH:22][C:23]1[CH:24]=[C:25]2[C:26](=[CH:30][CH:31]=1)[C:27](=[O:28])[N:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]1)[C:32]2=[O:33]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1C(=O)c3ccc(O)cc3C1=O)C2
Temperature: 140 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A suspension of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (1.0 g) and 4-hydroxyphthalic acid (1.0 g) in acetic acid (10 ml) was stirred for 1 hour at 140° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.5 g).
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2nc3ccc(OC)cc3n2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2nc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)n(C)c2c1
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-{[cyclohexyl(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methyl]amino}benzoate (625 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (600 mg, quantitative) as a pale-brown solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B(O)O)[CH:3]=[N:2]1.Br[C:10]1[CH:11]=[C:12]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][N:16](C3CCCCO3)[C:13]2=[CH:14][N:15]=1>>[C:19]1([C:18]2[C:12]3[C:13](=[CH:14][N:15]=[C:10]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:11]=3)[NH:16][N:17]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Reactant: OB(O)c1cn[nH]c1
Product: c1ccc(-c2n[nH]c3cnc(-c4cn[nH]c4)cc23)cc1
Yield: 23 %

Procedure:
Following the procedures as described in Example 136, 1H-pyrazol-4-ylboronic acid and 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 137 as a yellow solid (26 mg, 23%) over two steps. 1H NMR (400 MHz, DMSO) δ 12.9 (s, 1H), 9.05 (s, 1H), 8.37-8.09 (m, 5H), 7.56 (m, 1H), 7.44 (m, 1H)
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7](Cl)[N:6]=[C:5]([Cl:10])[N:4]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15].C(Cl)Cl.[K+].[Br-]>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:7]2[N:8]=[C:3]([NH:2][CH3:1])[N:4]=[C:5]([Cl:10])[N:6]=2)[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CNc1nc(Cl)nc(Cl)n1
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Cl)nc(Nc2cc(Cl)cc(Cl)c2)n1
Yield: 10 %

Procedure:
The title compound was synthesized from 2-methylamino-4,6-dichloro-1,3,5-triazine and 3,5-dichloroaniline using a similar procedure to the one used in 2, except with a longer reaction time (18 h instead of 2 h). Yield: 10%; Tm 242° C.; FTIR (CH2Cl2/KBr) 3275, 3184, 3126, 3081, 2960, 2920, 2849, 1641, 1606, 1573, 1546, 1534, 1507, 1448, 1425, 1388, 1306, 1279, 1253, 1237, 1229, 1205, 1165, 1126, 1115, 1107, 1092, 1035, 984, 954, 937, 869, 854, 837, 809, 793, 753, 725 cm−1; 1H NMR (300 MHz, DMSO-d6, 298 K) δ 10.39, 10.23 (s, s, 1H), 8.24 (s, 1H), 7.86, 7.83 (d, d, 3J=1.8 Hz, 2H), 7.23, 7.20 (t, t, 3J=1.8 Hz, 1H), 2.86, 2.82 (s, d, 3J=4.7 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 167.7, 165.7, 165.5, 163.6, 162.9, 141.5, 133.83, 133.77, 121.5, 117.8, 117.6, 27.29, 27.23 ppm; HRMS (EI) calcd. for C10H8Cl3N5 (m/e): 302.9845. found: 302.9839.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.Cl.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([CH2:48][NH2:49])=[CH:40]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:49][CH2:48][C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:39][CH:40]=1)=[O:25]
Reactant: NCc1c[nH]c2ccccc12
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2c[nH]c3ccccc23)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-(1H-indol-3-yl)-methylamine dihydrochloride.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH:6][C:7]([C:9]2[N:10]=[CH:11][O:12][C:13]=2[C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[O:8])[CH:3]=[N:2]1.Br[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[C:16]1([CH3:20])[CH:17]=[CH:18][CH:19]=[C:14]([C:13]2[O:12][CH:11]=[N:10][C:9]=2[C:7]([NH:6][C:4]2[CH:5]=[N:1][N:2]([CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH:3]=2)=[O:8])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1CBr
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cn[nH]c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC3CCCN3C(=O)OC(C)(C)C)c2)c1
Temperature: 80 °C

Procedure:
To N-(1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (150 mg, 0.56 mmol) in DMF (1.5 mL), tert-butyl 2-(bromomethyl)pyrrolidine-1-carboxylate (148 mg, 0.56 mmol) was added and K2CO3 (309 mg, 2.24 mmol) followed by tetrabutylammoniumbromide (18 mg, 0.056 mmol). The reaction mixture was heated to 80° C. for 2 h, then tert-butyl 2-(bromomethyl)pyrrolidine-1-carboxylate (1 eq.) followed by heating to 90° C. for 6 h. The reaction mixture was diluted with EtOAc, washed with sat. aq. NaHCO3-solution (1×) and brine (1×). The aq. layers were reextracted with EtOAc (1×). The combined organic layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (EtOAc/hex 9:1, Rf=0.45) yielded rac-tert-butyl 2-((4-(5-(m-tolyl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate as a yellow foam. LC-MS conditions A: tR=0.94 min, [M+H]+=452.23.
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21]>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21]
Reactant: COc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C21CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)O)C(=O)C21CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A mixture of 1,1-dimethylethyl N-((4-hydroxy-6-(methyloxy)-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (0.66 g, 1.6 mmol) in 3 mL TFA was stirred at room temperature for 30 minutes, M+1=362, M−1=360. The mixture was concentrated and triturated in DCM/heptane (5:10). The solid was filtered, washed with 10 mL DCM/heptane (5:10), and dried under high vacuum to give 0.52 g of the product as a white solid. MS (m/z)=362 (M+H)+. Calculated for C18H19NO7 361.12.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[C:7]([O:15][C:16]1[CH:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[C:7]([O:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][C:17]=1[O:24][CH3:25])[C:22]([OH:2])=[O:23])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(C=O)cc1OC(=O)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)cc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of potassium permanganate (28 g) in acetone (200 mL) is treated with 2-methoxy-5-formylphenyl benzoate (35.2 g; that is prepared as described in Reference Example 8), and the resulting vigorously reacting mixture is cooled in an ice bath. It is then stirred at room temperature for 3 hours. The mixture is then concentrated and the residue is treated with saturated aqueous sodium metabisulfite solution (300 mL). The resulting white solid is filtered off, washed well with water (200 mL), and dried, to give 3-benzoyloxy-4-methoxy-benzoic acid (29.3 g), m.p. 180°-183° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]3[C:17]([CH:18]4[CH2:28][CH:19]4[CH2:20][O:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:6]([CH2:29][C:30]([O:32]C)=[O:31])[CH:5]=1>CO>[C:30]([CH2:29][C:6]1[CH:5]=[C:4]([F:3])[CH:9]=[CH:8][C:7]=1[S:10]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([CH:18]3[CH2:28][CH:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11])([OH:32])=[O:31]
Reactant: COC(=O)Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CC(=O)O)ccc2c1OCC1CC21
Temperature: 50 °C
Yield: 99.5 %

Procedure:
1M Sodium hydroxide solution (3 mL) was added to a solution of methyl (1aRS,7bSR)-5-(4-fluoro-2-methoxycarbonylmethylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 84, 0.438 g) in methanol (6 mL) and the mixture was heated at 50° C. for 2 hours. After cooling, the mixture was evaporated to dryness and the residue was dissolved in ethyl acetate and water and acidified with concentrated hydrochloric acid. The organic layer was dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo, the residue was dissolved in toluene and re-evaporated to give methyl (1aRS,7bSR)-5-(2-carboxymethyl-4-fluorobenzene-sulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.422 g) as a white solid.
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:20][CH:19]=1
Reactant: C(=Cc1ccccc1)COc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(CC=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
Following the general procedure using cinnamyloxybenzene (53 mg, 0.25 mmol), 4-chlorophenylboronic acid (58 mg, 0.38 mmol) and PdCl2(D-t-BPF) (0.015 mmol, 9.8 mg), the reaction was stirred for 20 h at rt. Column chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a colorless liquid (43 mg, 75%).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:23])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:9]=2)=[O:4].[NH2:24][CH2:25][C:26]([O-:28])=[O:27].[Na+]>COCCO>[CH:17]1([O:16][C:10]2[CH:9]=[C:8]3[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])[C:6](=[O:23])[O:7]3)=[CH:12][CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1c(O)c2ccc(OC3CCCCC3)cc2oc1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2ccc(OC3CCCCC3)cc2oc1=O
Yield: 81 %

Procedure:
To a mixture of 7-cyclohexyloxy-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (90 mg, 0.28 mmol) and sodium glycinate (275 mg, 2.83 mmol) in 2-methoxyethanol was microwaved at 150° C. for 1 h and then concentrated. Residue was dissolved in water (60 mL) and extracted with (1/1) EtOAc/hexanes which was discarded. The aqueous layer was acidified using 1 N HCl to pH=3-4 and extracted with EtOAc (2×). Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (82 mg). MS ESI(−) m/e: 360.06 (M−1).