Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](O)=[O:6]>O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:8]([OH:10])=[O:9]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Solvent: O
Product: O=C1CC[C@@H](C(=O)O)N1

Procedure:
The preparation process is described below by way of example. In a first stage, glutamic acid, for example, is melted at about 170-180° C., under which the cyclic amide, pyroglutamic acid (2-pyrrolidone-5-carboxylic acid) is formed by elimination of water. Instead of glutamic acid, it is also possible to use proline or a polar, high-boiling solvent such as N-methylpyrrolidone or sulfolane. Aspartic acid is then added, and the melt or the high-boiling solution is heated at 160-220° C. In this process polysuccinimide forms, which, in cases where glutamic acid is used, also contains glutamic acid units. The duration and temperature of heating is used to control the molecular mass of the growing polymer. The longer the heating time and the higher the temperature, the higher the molecular mass. In the next step, the organofunctional polysiloxane is added dropwise. The heating time after all of the polysiloxane has been added in turn influences the molecular mass of the copolymer formed. The melt is poured out and, after cooling, forms a glasslike mass, which can be readily pulverized by grinding. This is the water-insoluble form of the polypeptide-polysiloxane copolymer.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH3:22])=[N:16]2)=[CH:11][CH:10]=1.[CH3:23][O:24][CH2:25]Cl>C1COCC1.C(Cl)(Cl)Cl>[CH3:23][O:24][CH2:25][O:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH3:22])=[N:16]2)=[CH:11][CH:10]=1
Reactant: COCCl
Reactant: Cc1ccc2ccc(O)c([N+](=O)[O-])c2n1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCOc1ccc2ccc(C)nc2c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Referring to FIG. 20, triethylamine (174 μL, 1.695 mmol) was added to a solution of 5a (174 mg, 0.847 mmol) in dry THF (5 mL) under a nitrogen atmosphere. Chloromethyl methyl ether (128 μL, 1.695 mmol) was added to the mixture dropwise and the reaction was stirred for 1 h. The reaction was diluted with chloroform, washed with water followed by brine. The organic layer was dried over Na2SO4, and the solvent was evaporated to afford 8a (200 mg, 0.806 mmol, 95%) as a bright yellow solid: 1H NMR (CDCl3) δ 8.00 (1H, d, J=8.4 Hz), 7.81 (1H, d, J=9.2 Hz), 7.47 (1H, d, J=8.8 Hz), 7.26 (1H, d, J=8.4 Hz), 5.35 (2H, s), 3.52 (3H, s), 2.69 (3H, s); 13C NMR (CDCl3) δ 162.5, 148.3, 140.3, 137.7, 135.7, 130.3, 122.2, 122.2, 115.4, 95.3, 57.0, 25.9; FTIR (neat) 2955, 1626, 1525, 1508, 1377, 1247, 1226, 1193, 1153, 1065, 991, 924, 835, 806, 656 cm−1; MS (ESI) m/z calculated for (C12H12N2O4+H)+ 249, found 249; HRMS (ESI) m/z calculated for (C12H12N2O4+H)+ 249.0875, found 249.0871.
Reaction SMILES: [C:1]([C:4]1([CH2:17][CH2:18][CH2:19]N)[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[OH-].[Na+]>CO.Cl>[NH:2]1[CH2:19][CH2:18][CH2:17][C:4]2([C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:1]1=[O:3]
Reactant: NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NCCCC12c1ccccc1-c1ccccc12
Temperature: 100 °C
Yield: 72.6 %

Procedure:
A solution of 5.0 g (18.8 mM) of 9-carbamoyl-9-(3-aminopropyl)fluorene (prepared as described in U.S. Pat. No. 4,282,170) in 50 ml of methanol saturated with hydrogen chloride was heated at reflux for sixteen hours. The reaction mixture was cooled and concentrated to dryness to give a solid. The solid was dissolved in 1N hydrochloric acid and the solution was heated to 100° C. for five minutes. The acidic mixture was diluted by addition of 50% aqueous sodium hydroxide to pH 10. The aqueous alkaline solution was extracted several times with chloroform, and the extracts were combined, washed with water and with brine and dried. Removal of the solvent by evaporation under reduced pressure provided a solid that was crystallized from dichloromethane and petroleum ether to afford 3.4 g of spiro(9H-fluorene-9,3'-piperidine)-2'-one. m.p. >250° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:3]1([CH2:2][CH2:1][NH:9][C:17](=[O:19])[CH3:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
12.6 ml of phenethylamine(0.1M) and 14 ml of triethylamine(0.1M) were dissolved in 100 ml of dichloro-methane; and 6.9 ml of acetyl chloride(0.1M) was dropwise added thereto while maintaining the temperature of the reaction system below 0° C., followed by stirring at a room temperature for 10 minutes. The reaction solution was washed with water, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure to give 14.23 g Of the title compound as white solids.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([CH3:18])=[CH:17][C:10]=12.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33](O)=[O:34])[C:28]2=[O:36])=[CH:23][CH:22]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:33]([C:29]2[C:28](=[O:36])[N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH:32]=[CH:31][CH:30]=2)=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([CH3:18])=[CH:17][C:10]=12
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Cc1cc2c(Oc3ccc(N)cc3F)ccnc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2[nH]1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A mixture of 3-fluoro-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (17 mg, 0.066 mmol), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (20 mg, 0.086 mmol) in DMF (0.5 mL) was stirred with BOP reagent (50 mg, 0.11 mmol) and triethylamine (0.01 mL) at 50° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitate was collected and washed with water. The crude product was purified by preparative HPLC and the appropriate fractions were collected, neutralized and concentrated in vacuo to give the title compound (7.85 mg, 25%) as a solid. 1H NMR (DMSO-d6) δ 12.07 (s, 1H), 11.56 (s, 1H), 8.49 (d, 1H, J=6.2 Hz), 8.12 (d, 1H, J=6.2 Hz), 7.98 (dd, 1H, J=10.4, 2.6 Hz), 7.95 (d, 1H, J=5.5 Hz), 7.61 (m, 2H), 7.43 (m, 3H), 7.29 (t, 1H, J=8.40 Hz), 6.72 (t, 1H, J=6.2 Hz), 6.36 (d, 1H, J=5.5 Hz), 5.88 (s, 1H), 2.32 (s, 3H); MS(ESI+) m/z 473 (M+H)+.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][N:36](C(OC(C)(C)C)=O)[CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CO>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:22][CH2:23]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
A solution of 2.82 g (about 3.8 mmol) of crude (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-Boc-imidazole-4-propionamide and 0.35 g (2.55 mmol) of potassium carbonate in 20 ml of methanol is stirred at room temperature under argon for 1 hour. Thereafter, 0.33 g (6.1 mmol) of ammonium chloride is added and the mixture is stirred at room temperature for a further 15 minutes. The reaction mixture is subsequently evaporated under reduced pressure, the residue is taken up in 60 ml of ethyl acetate and this solution is washed in succession with 30 ml of water and 30 ml of saturated sodium chloride solution. The aqueous phases are back-extracted twice with 60 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated under reduced pressure. The residue is triturated in 15 ml of ether, then filtered off under suction and, for further purification, chromatographed on 150 g of silica gel using a 4:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There are obtained 1.13 g of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imidazole-4-propionamide as a colourless solid; MS: 631 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[OH:13][C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+].Cl>CCO.CCOC(C)=O.CCCCCC.O.CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:21]/[C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([OH:13])[CH:15]=2)=[O:22])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CC(=O)c1cccc(O)c1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(/C=C/C(=O)c2cccc(O)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3,4-dimethoxybenzaldehyde AP17380 (400 g, 2.41 moles) and 3′-hydroxyacetophenone AP17381 (328 g, 2.41 moles) in EtOH (3200 mL) was treated with a solution of aqueous KOH (536 g, 1200 mL) over a 1 hour period. The resulting solution was allowed to stir for 16 h at room temperature. The reaction mixture was then treated with EtOH (2000 mL) followed by water (1200 mL). A solution of EtOH/water (3400 mL, 1:1) was then added and the reaction mixture acidified to pH 6 using concentrated HCl (720 mL). After addition of acid, water (4000 mL) was added to induce precipitation. The resulting mixture was left stirring overnight and the solids then filtered, washed with water (2×900 mL) and then hexane (2×800 mL). The product was dried under vacuum for 3 hours and then placed in a vacuum oven at 50° C. for 6 days to provide AP14894 (609 g, 89%) as a yellow solid: mp 138-139° C.; TLC (EtOAc/hexane, 1:1) Rf=0.35; 1H NMR (DMSO-d6, 300 MHz) 9.85 (br s, 1H), 7.71 (d, J=6.6 Hz, 2H), 7.61 (d, J=7.7 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.47 (d, J=1.7 Hz, 1H), 7.39-7.34 (m, 2H), 7.07-7.00 (m, 2H), 3.87 (s, 3H), 3.82 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) 189.4, 158.2, 151.6, 149.4, 144.7, 139.7, 130.1, 127.9, 124.2, 120.4, 120.2, 119.7, 115.0, 112.0, 111.2, 56.1, 56.0; LRMS (ES+) (M+H)+285; Anal. Calcd for C17H16O4: C, 71.82; H, 5.67. Found: C, 71.55; H, 5.61.
Reaction SMILES: O[C:2]1[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.Cl.[NH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1.C(N(CC)CC)C>C(O)C>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH:21]1[NH:20][C:2]1[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: CC(C)c1csc2ncnc(O)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC(C)c1csc2ncnc(NC3Cc4ccccc4C3)c12
Yield: 62.1 %

Procedure:
using 4-hydroxy-5-isopropylthieno[2,3-d]pyrimidine (200 mg, 1.03 mmol), phosphorus oxychloride (1.0 ml), 2-aminoindan hydrochloride (200 mg, 1.2 mmol), triethylamine (1.0 ml, 7.2 mmol) and dry ethanol (5 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (190 mg, 0.64 mmol) having the following physical properties:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)#[N:2].[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][CH2:17][NH:16][CH:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:10][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1ccccc1N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccccc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5 (200 mg, 1.00 mmol), 1 (161 mg, 1.00 mmol), and acetic acid (300 mg, 5.00 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride (66 mg, 1.05 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with three additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4 mm, 10% EtOH-90% CHCl3) afforded the title compound (12).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:11])[S:8][C:7]=2[CH:12]=1.[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[S:8][C:9]=1[CH3:11]
Reactant: COc1ccc2cc(C)sc2c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(Br)c(C)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A mixture of 20.63 g (0.13 mol) of 6-Methoxy-2-methylbenzo[b]thiophene and 250 mL of CHCl3 is cooled by using a ice-water bath. A solution consisting of 20.08 g (0.14 mol) of Br2 and 90 mL of CHCl3 is added dropwise. After the addition is completed, the mixture is stirred for 30 min at room temperature and then hydrolysed with 300 mL of saturated aqueous Na2S2O6 solution. The aqueous phase is extracted twice with 300 mL of CHCl3. The combined organic phases are washed several times with water, dried over magnesium sulfate and then are concentrated under reduced pressure. The resulting solid recrystallised from methanol gives a white solid (28.50 g, 88% yield).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]#[N:15])=[CH:11]2)=[CH:6][CH:5]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH2:16]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]#[N:15])=[CH:11]2)=[CH:6][CH:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc2ccc(O)cc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc2ccc(OCc3ccccc3)cc2c1
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Sodium hydride (151 mg, 60% in mineral oil, 3.77 mmol) is added to a stirring solution of 7-hydroxy-2-naphthonitrile (530 mg, 3.14 mmol) in DMSO (10 mL). After the bubbling subsides, benzyl bromide (448 μL, 3.77 mmol) is added and the resulting mixture is allowed to stir for 4 hours. The reaction mixture is poured into water and extracted with ether. The ether layer is dried (Na2SO4), filtered, and concentrated to dryness. The product is purified by column chromatography (step gradient, 25 to 50% CH2Cl2 in hexanes) to give 7-benzyloxy-2-naphthonitrile (735 mg, 90%) as a white solid. HRMS (EI) calculated for C18H13NO: 259.0997, found 259.0993.
Reaction SMILES: COCOC1C=CC(C(C2C=CC(OCOC)=CC=2)C2C=CC=C[C:13]=2[N:18](C)[C:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=CC=1>C(OCC)(=O)C.Cl>[CH3:13][NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2ccccc2N(C)C(=O)C2CCCCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(=O)C1CCCCC1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
In 50 ml of ethyl acetate saturated with hydrogen chloride was dissolved 2.18 g of compound 137 obtained by Example 137, and the solution was stirred for 1 hour. Thereafter, the solvent was evaporated under reduced pressure, and the residue was recrystallized from methanol to afford 0.31 g of the desired compound (Compound 138).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][CH:11]=1.[CH:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][N:26]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[C:18]([C:28]3[CH:27]=[N:26][C:25]([CH:22]4[CH2:24][CH2:23]4)=[CH:30][CH:29]=3)[CH:17]=[CH:16][N:15]=2)=[O:21])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccc(-c2nnco2)c1)c1cc(Br)ccn1
Reactant: CC1(C)OB(c2ccc(C3CC3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2nnco2)c1)c1cc(-c2ccc(C3CC3)nc2)ccn1
Temperature: 85 °C
Yield: 89.9 %

Procedure:
A suspension of N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-4-bromopicolinamide (3.0 g, 8.7 mmol), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.25 g, 9.2 mmol), dppf(Pd)Cl2 (320 mg, 5 mol %), potassium carbonate (2.4 g, 17 mmol) in degassed toluene (10 mL), degassed water (10 mL) and degassed isopropanol (10 mL) was heated at 85° C. for 4 hours. The solvent was removed under reduced pressure and the residue was suspended and sonicated in methanol (40 mL) before being filtered and washed with methanol (10 mL). The grey powder was then suspended and sonicated in water (40 mL) before being filtered and washed with water (10 mL), methanol (10 mL) and diethyl ether (10 mL) to give 6-cyclopropyl-[3,4′]bipyridinyl-2′-carboxylic acid (3-[1,3,4]oxadiazol-2-yl-phenyl)-amide (3.0 g, 90%). 384.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[N:13][N:14]=[CH:15][C:16]3[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])=[O:23])[C:17]=3[CH3:33])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:47]1[C:55]2[N:54]=N[NH:52][C:51]=2[CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[N:13][N:14]=[CH:15][C:16]3[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:52][C:51]4[CH:50]=[CH:49][CH:48]=[CH:47][C:55]=4[NH2:54])=[O:31])=[O:23])[C:17]=3[CH3:33])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2=NN=Cc1[nH]c(C)c(C(=O)NCCCCCC(=O)O)c1C
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)NC(=O)C2=NN=Cc1[nH]c(C)c(C(=O)NCCCCCC(=O)Nc2ccccc2N)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
6-(5-(((6-methoxy-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (453 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (408 mg, 75% yield) as a red solid. LC-MS (m/z) 544 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:32])[C:8]([OH:31])=[C:9]([C:13]3[CH:18]=[C:17]([O:19]C)[C:16]([O:21]CC4C=CC=CC=4)=[C:15]([O:29]C)[CH:14]=3)[O:10]2)=[CH:5][C:4]=1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:2].B(Br)(Br)Br.CO.O>ClCCl>[CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:32])[C:8]([OH:31])=[C:9]([C:13]3[CH:14]=[C:15]([OH:29])[C:16]([OH:21])=[C:17]([OH:19])[CH:18]=3)[O:10]2)=[CH:5][C:4]=1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:2]
Reactant: CCCCCCCCc1cc2c(=O)c(O)c(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)oc2cc1CC
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCc1cc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2cc1CC
Temperature: 25 °C
Reaction time: 21 h
Yield: 103.2 %

Procedure:
To a stirring solution of 7-ethyl-3-hydroxy-6-octyl-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one 59 (0.125 g, 0.2 mmol) in dichloromethane (10 ml) under Ar at 0° C. was added boron tribromide in dichloromethane (1.0M, 1.2 ml, 1.2 mmol, 5.2 equ). The mixture was warmed to room temperature and then stirred for 21 hours. Methanol (5 ml) was then added. The reaction was heated to reflux for 2 hours, then concentrated in vacuo to give a brown solid. Water (10 ml) was added then extracted into ethyl acetate (3×). The organic layer was washed with brine then dried (MgSO4) and concentrated in vacuo to give 12 (0.088 g, 100% over 2 steps) as a green solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:15]1[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]2[N:27]3[CH:28]=[C:29](F)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:16]1.O>CN(C=O)C>[CH2:16]1[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]2[N:27]3[CH:28]=[C:29]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:15]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(N3CCCCC34CC4)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCC45CC5)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To an opaque brown solution of Intermediate A (371 mg, 2.28 mmol) in dry DMF (5 mL) under N2 was added sodium hydride (60% dispersion in mineral oil, 273 mg, 6.83 mmol) and the resulting mixture stirred at RT for 30 min. (CARE: gas evolution) A solution of Intermediate 148c (448 mg, 1.82 mmol) in dry DMF (5 mL) was added and the resulting dark brown solution stirred at 60° C. for 1 h. The solution was cooled to RT, then water (0.2 mL) added (CARE: gas evolution) and the mixture concentrated in vacuo. The residue was redissolved in MeOH (10 mL), applied to an SCX-2 cartridge (25 g) and washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a dark brown gum. Flash chromatography (silica 40 g, 4-7% [2M NH3 in MeOH] in DCM) gave the title compound as a pale brown foam (446 mg, 63%). LCMS (Method 3): Rt 2.31 min, m/z 390 [MH+].
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23](OCC)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:30].Cl.[CH3:32][NH2:33]>>[CH3:32][NH:33][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][C:19]([N:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:30])[NH:4][C:5]=4[CH:11]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: CN
Reactant: CCOC(=O)c1ccc(N2CCC(Cc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1
Agent: Cl
Product: CNC(=O)c1ccc(N2CCC(Cc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Saponification of 390D was performed using the general procedure for hydrolysis of carboxylic esters. The resulting carboxylic acid and methylamine hydrochloride were used in the general procedure for coupling an amine to a carboxylic acid to give the title compound as a pinkish, tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.28 (m, 2H) 1.40 (d, J=6.57 Hz, 3H) 1.55-1.71 (m, 3H) 2.44 (d, J=6.57 Hz, 2H) 2.62-2.78 (m, 5H) 3.82 (d, J=12.63 Hz, 2H) 4.61 (q, J=6.65 Hz, 1H) 6.65-6.77 (m, 2H) 6.82-6.95 (m, 3H) 7.67 (d, J=9.09 Hz, 2H) 8.05-8.15 (m, 1H) 10.59 (s, 1H). ESI-MS: m/z 394.3 (M+H)+.