Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[I-].[K+].[C:14](=[O:17])([O-])[O-].[K+].[K+].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O>>[C:1]1([O:11][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:17][C:14]2[CH:10]=[CH:1][CH:2]=[C:22]3[C:23]=2[CH:24]=[CH:25][CH:20]=[N:21]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CCCC1=O
Reactant: Oc1cccc2ccccc12
Agent: [I-]
Agent: [K+]
Product: c1ccc2c(OCCCCCOc3cccc4ncccc34)cccc2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
The above-obtained compound (1.06 g, 3.62 mmol) was suspended together with 1-naphthol (521 mg, 3.62 mmol) and potassium iodide (60 mg, 0.36 mmol) in N-methylpyrrolidinone (10 mL). To the suspension, potassium carbonate (0.75 g, 5.42 mmol) was added. After stirred at 90° C. for 4 h, the reaction mixture was quenched with water (30 mL) followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and concentrated under vacuum. The residue was purified by silica gel chromatography to give 5-[5-(naphthalen-1-yloxy)-pentyloxy]-quinoline (1.11 g, 3.11 mmol, 86%) as a white solid.
Reaction SMILES: CN1CCCC1=O.[C:8]([OH:12])(=[O:11])[CH2:9]O.C[N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.O>[O:11]=[C:8]([OH:12])[CH2:9][N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]
Reactant: CN(CCO)CCO
Reactant: O=C(O)CO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)CN(CCO)CCO
Temperature: 70 °C

Procedure:
In a 250 ml bottle equipped with a magnetic stirrer, heating mantel, temperature controller, and dry nitrogen purge, was added DESMODUR™ N-3300 (N3300) (13.19 g, 0.020 mole, 0.068 equivalent), FBSEE (1.885 g, 0.00487 mole, 0.00974 equivalent), bicine (HOCH2CH2)2NCH2COOH) (0.815 g, 0.0050 mole, 0.010 equivalent —OH, 0.0050 equivalent —COOH), 4 drops of dibutyltin dilaurate, and 30 g N-methylpyrrolidone. The resulting mixture was stirred and heated at 70° C. for one hour, followed by addition of MeFBSE (9.996 g, 0.028 mole, 0.028 equivalent), and glycolic acid (1.368 g, 0.018 mole, 0.018 equivalent). The resulting reaction mixture was heated for another hour at 70° C., followed by addition of APTMS (0.442 g, 0.0025 mole, 0.0025 equivalent) and heated with stirring at 70° C. for an additional two hours. A 5 g portion of the resulting unneutralized chemical composition was taken for GPC analysis, and the remaining composition was cooled to 60° C. and then neutralized by adding to the composition an amount of methyldiethanolamine equivalent to the number of equivalents of carboxylic acid groups present. After 10 minutes at 60° C. the mixture was cooled and a portion of the resulting neutralized chemical composition was diluted with water to form an aqueous solution containing 3% by weight of the chemical composition. The 3% aqueous solution was evaluated for performance using Test Method I, and the results are shown in Table 3. The GPC analysis, conducted according to Test Method III, showed that the unneutralized chemical composition was comprised of components having a weight average molecular weight (Mw) of 22,183, a number average molecular weight (Mn) of 4,553, and a polydispersity (Mw/Mn) of 4.872. thus indicating the presence of both high and low molecular weight components.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:17].[Na+].C(Cl)(Cl)Cl.[OH2:23]>CC(C)=O.Cl>[CH3:4][C:5]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=2)=[O:7])=[CH:13][CH:12]=1)([C:15]([OH:23])=[O:17])[CH3:6]
Reactant: O
Reactant: [OH-]
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 4-chloro-4′-hydroxybenzophenone (116 g, 0.500 mole) and sodium hydroxide (120 g, 3.00 mole) in acetone (1 L) was heated to reflux for 2 hours. The heating was stopped and the heating source was removed. A mixture of chloroform (179 g, 1.50 mole) in acetone (300 mL) was added drop-wise. The reaction mixture was stirred overnight without heating. The mixture was heated to reflux for 8 hours and then allowed to cool to room temperature. The precipitate was removed by filtration and washed with acetone (100 mL). The filtrate was concentrated under reduced pressure to give a brown oil. Water (200 mL) was added to the brown oil and was acidified (to pH=1) with IN hydrochloric acid. The precipitate, which formed was filtered and dried under high vacuum. The remaining yellow solid (268 g) was recrystallized from toluene in 4 batches (400 mL toluene each). After filtration and drying under high vacuum, the experiment produced fenofibric acid (116 g, 73% yield) as a light yellow solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][CH:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]1)[CH2:25][OH:26].O>ClCCl.C(OCC)C>[CH3:23][CH:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]1)[CH:25]=[O:26]
Reactant: CC(CO)CC1CCCC(C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CC(C=O)CC1CCCC(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of Dess Martin periodinane (4.1 g, 9.7 mmol, 1.1 eq) in dichloromethane (43 mL) was charged into a 250 mL three-necked round-bottom flask, equipped with a mechanical stirrer and a reflux condenser. 2-methyl-3-(3-methylcyclohexyl)propan-1-ol (1.5 g, 8.8 mmol) was added dropwise, followed by a mixture of water (127 L) in dichloromethane (127 mL) at ambient temperature, over 1 h. After stirring for 1 h at ambient temperature, the mixture was diluted with diethyl ether (100 mL) and washed with a 1:1 mixture of saturated aqueous NaHCO3 and 10% aqueous Na2S2O3 (50 mL) and brine (50 mL), dried over magnesium sulphate and concentrated. The crude product was chromatographed on a silica gel column with 5% EtOAc in hexane as elution agent giving 2-methyl-3-(3-methylcyclohexyl)propanal (800 mg, gc purity>90%; yield 54%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:22]1[S:23][C:24]([CH2:27][N:28]=[N+]=[N-])=[CH:25][CH:26]=1)#[N:21]>C1COCC1.O>[C:20]([C:22]1[S:23][C:24]([CH2:27][NH2:28])=[CH:25][CH:26]=1)#[N:21]
Reactant: N#Cc1ccc(CN=[N+]=[N-])s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CN)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 166.4 %

Procedure:
Triphenylphosphine (Aldrich, 5.7 g) was added to a solution of 2-cyano-5-(azidomethyl)thiophene (compound 24, 2.5 g, 10 mmol) in THF (Aldrich, 40 mL) and water (10 mL) at 0° C. The solution was allowed to warm to room temperature and stirred at ambient temperature for 10 hours. RP-HPLC purification gave the title compound (2.3 g, 94%). MS (electrospray) 139 (M+1); 1HNMR (CDCl3) δ4.01 (s, 2H), 4.75 (br s, 2H, NH2), 6.82 (d, 1H, J=3.5 Hz), 7.08 (d, 1H, J=3.5 Hz).
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=C(NCCCO)N=1)[CH2:12][CH2:11][CH2:10]3.[OH:20]O.C(O[C:29]([C:31](F)(F)F)=[O:30])(C(F)(F)F)=O.N>C(Cl)Cl>[N+:2]([C:7]1[CH:8]=[C:9]2[C:13]([CH2:12][CH2:11][CH2:10]2)=[CH:14][C:6]=1[NH:5][C:29](=[O:30])[CH3:31])([O-:1])=[O:20]
Reactant: [O-][n+]1nc(NCCCO)nc2cc3c(cc21)CCC3
Reactant: OO
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
TFM (0.44 mL, 2.4 mmol) was added to a stirred solution of 1-oxide 50 (486 mg, 2.2 mmol) in DCM (20 mL) at 0° C. and the solution stirred at 20° C. for 16 h. H2O2 (70%, 1.1 mL, ca. 21.9 mmol) was added dropwise to a stirred solution of TFAA (3.1 mL, 21.9 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to the solution of 1-oxide 50 prepared above and the resulting solution was stirred at 20° C. for 16 h. Dilute aqueous NH3 solution (40 mL) was added and the mixture stirred vigorously for 4 h, then the mixture extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 50 (254 mg, 52%); and (ii) 1,4-dioxide 51 (166 mg, 27%) as a red solid: mp (MeOH/DCM) 182-184° C.; 1H NMR δ 8.05 (s, 1H, H-9), 8.03 (s, 1H, H-5), 7.61 (br t, J=5.7 Hz, 1H, NH), 3.82 (br t, J=5.7 Hz, 2H, CH2O), 3.78 (br s, 1H, OH), 3.71-3.77 (m, 2H, CH2N), 3.10 (br t, J=7.5 Hz, 2H, H-6), 3.04 (br t, J=7.5 Hz, 2H, H-8), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.97 (br p, J=6.0 Hz, 2H, CH2); 13C NMR δ 156.1, 149.5, 145.8, 137.8, 129.7, 115.7, 111.3, 60.2, 39.1, 33.4, 32.3, 31.5, 25.5. Anal. calcd for C13H16N4O3: C, 56.5; H, 5.8; N, 20.3. Found: C, 56.8; H, 5.9; N, 20.2%.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]3=[N:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([N:24]([CH2:29][CH2:30][CH2:31]Cl)[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[OH-].[K+]>CO>[CH2:25]([N:24]([CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]3=[N:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(CCCC)CCCCl
Reactant: Cc1cccn2c(C(=O)c3ccc(O)cc3)cnc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)c2cnc3c(C)cccn23)cc1

Procedure:
A mixture of 3-(4-hydroxybenzoyl)-8-methylimidazo[1,2-a]pyridine (2.3 g, 9.6 mmol), dibutylaminopropyl chloride (6.8 g, 33 mmol) and potassium hydroxide (1.3 g, 23 mmol) in methanol (60 ml) was stirred at reflux for 96 hours. The mixture was concentrated and the resulting oil was flash chromatographed (silica gel, 2.5% methanol in diethyl ether) to give 1.3 g (31% yield) of the free base of the title compound. The HCl salt was prepared by dropwise addition of concentrated hydrochloric acid to a solution of the free base in methanol, concentrated and recrystallized from acetone-ether to give the HCl salt of the title compound as an off-white solid, mp 105° C. to 107° C. IR(KBr): 3440, 2640, 1645, 1605 cm-1. MS: 421 (M+). 1H NMR (CD3OD): δ 9.66 (d, J=8 Hz, 1H), 8.74 (s, 1H), 8.00-7.61 (m, 4H), 7.20 (d, J=7.2 Hz, 2H), 4.29 (t, J=5 Hz, 2H), 3.41-3.15 (m, 6H), 2.75 (s, 3H), 2.31 (m, 2 H), 1.80-1.42 (m, 8H), 1.02 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[C:26]=1[Cl:27].O[CH2:29][CH:30]1[CH2:32][CH2:31]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[C:26]=1[Cl:27]
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(Cl)c1Cl
Reactant: OCC1CC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(Cl)c1Cl
Reaction time: 8 h

Procedure:
A mixture of 4.0 g (7.3 mmol) of tert.butyl (S)-7,8-dichloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 10 ml (126 mmol) of hydroxymethyl-cyclopropane and 1 g (3 mmol) of tetraethyl orthotitanate is stirred at 125° overnight, the mixture is evaporated and the residue is taken up in chloroform. The solution is stirred for 0.5 hour with 30 ml of a saturated potassium fluoride solution and the mixture is filtered through siliceous earth. The organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate there is obtained cyclopropylmethyl (S)-7,8-dichloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 185°-186°.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:26])[CH2:16][CH:17]([CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2)[OH:18])([CH3:13])([CH3:12])[CH3:11].[CH3:27][O:28][CH2:29]Cl>C(Cl)Cl>[C:10]([O:14][C:15](=[O:26])[CH2:16][CH:17]([CH:19]1[CH2:24][CH:23]2[CH2:25][CH:20]1[CH:21]=[CH:22]2)[O:18][CH2:27][O:28][CH3:29])([CH3:13])([CH3:11])[CH3:12]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)CC(O)C1CC2C=CC1C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(CC(=O)OC(C)(C)C)C1CC2C=CC1C2
Temperature: 25 °C
Yield: 81 %

Procedure:
66 g of diisopropyl ethyl amine was dropped to a solution prepared by dissolving 100 g of 3-bicyclo[2.2.1]hept-5-en-2-yl-3-hydroxy-propionic acid tert-butyl ester (BHP) i and 44 g of chloromethyl methyl ether ii in 1 L of methylene chloride while stirring at room temperature. The mixture was stirred at room temperature for 4 hours, and reaction was evaluated by thin-layer chromatography (TLC) and terminated. This was followed by workup twice with 400 ml of each of a 1 N HCl solution and a 10% Na2CO3 solution, the resultant was washed with 400 ml of distilled water, and an organic layer was collected. Methylene chloride was removed from the organic layer at reduced pressure to obtain 96 g of 3-bicyclo[2,2,1]hept-5-en-2-yl-3-methoxymethoxy-propionic acid t-butyl ester iii (Yield: 81%). The structure was identified using 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1>>[ClH:1].[ClH:1].[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][C:2]([C:25]4[CH:24]=[CH:23][C:22]5[O:17][CH2:18][CH2:19][O:20][C:21]=5[CH:26]=4)=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:16][CH2:15]1
Reactant: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Product: Cl
Product: c1cc2c(cc1-c1ccc(N3CCN(C4CC4)CC3)nn1)OCCO2

Procedure:
The title compound was prepared by a similar procedure to that described in Example 68, starting from 3-chloro-6-(4-cyclopropyl-piperazin-1-yl)-pyridazine and 1,4-benzodioxane-6-boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, 1H), 7.95 (d, 1H), 7.63 (m, 1H), 7.58 (m, 1H), 7.05 (d, 1H), 4.57 (broad m, 2H), 4.32 (m, 4H), 3.63 (broad m, 4H), 3.39 (broad m, 2H), 2.88 (broad m, 1H), 1.23 (m, 2H), 0.82 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH2:26])=[C:24]([O:30][CH3:31])[CH:23]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH:26][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:10]=[C:11]([C:12]([F:13])([F:14])[F:15])[C:4]=3[N:3]=2)=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: CCC(CC)c1ccc(C(F)(F)F)c2nc(Cl)n(C)c12
Reactant: COc1cc(Cl)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(C(F)(F)F)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 110 °C
Yield: 33.7 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole (290 mg, 0.95 mmol), 4-chloro-2-methoxy-6-methylaniline (491 mg, 2.86 mmol) and N-methyl-2-pyrrolidinone (3 drops) was heated at 110° C. for 72 h. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 10% ethyl acetate/n-hexane and recrystallized from diisopropylether/n-hexane to give 140 mg (0.32 mmol, 34%) of the title compound as a white powder.
Reaction SMILES: [N:1]([CH:4]1[CH2:24][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][C:10]=3[F:23])=[N+:2]=[N-:3].[CH3:25][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:27]#[CH:28].BrC(C1C=CC=CC=1)C.C([Si](C)(C)C)#C>>[F:23][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]1[CH2:24][CH:4]([N:1]3[C:27]([CH:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH3:25])=[CH:28][N:3]=[N:2]3)[CH2:5][CH2:6][C:7]1=[C:15]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: C#CC(C)c1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Agent: C#C[Si](C)(C)C
Agent: CC(Br)c1ccccc1
Product: CC(c1ccccc1)c1cnnn1C1CCc2c(CC(=O)O)c3cccc(F)c3n2C1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and (1-methylprop-2-yn-1-yl)benzene prepared from (1-bromoethyl)benzene and ethynyltrimethylsilane. Separation of the resulting diastereoisomeric esters by flash chromatography using a gradient of 10-70% EA/Hex afforded 2 enantiomeric mixtures. The less polar enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralpak AD column eluting with 20% iPrOH, 20% EtOH, 59.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm. The resulting chiral esters (retention times=7.8 and 11.9 min) were hydrolyzed separately to afford EXAMPLE 32.1 and 32.2 respectively. The more polar enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD column eluting with 20% MeOH, 20% EtOH, 60% Hexanes at 1 mL/min and 254 nm. The resulting chiral esters (retention times=9.6 and 10.5 min) were hydrolyzed separately to afford EXAMPLE 32.3 and 32.4 respectively. MS (+ESI) m/z: 419.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:22]=[C:21]([OH:23])[C:20]([CH3:24])=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[OH:23][C:21]1[CH:22]=[C:17]([NH:16][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:18]=[CH:19][C:20]=1[CH3:24]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: O
Product: COc1ccc2ncc(C#N)c(Nc3ccc(C)c(O)c3)c2c1

Procedure:
To a suspension of 218.6 mg (1.0 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile and 147.8 mg (1.20 mmol) of 5-amino-o-cresol in 10 mL of 2-ethoxyethanol was added 115.6 mg (1.0 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hr, and then the solvent was removed to give a residue. To the residue was added about 30 mL of water and neutralized to pH 7-8 by addition of diluted sodium carbonate solution. The precipitate was collected by filtration and washed with water and ether. After drying in vacuo, this afforded 278.3 mg (91%) of the product as a yellow solid, m.p.>250° C. (dec.), mass (electrospray, m/e): M+H 305.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:20]([O:19][C:17]([NH:16][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate, (3.12 g, 8.08 mmol), and 5-fluoro-2-methoxyphenylboronic acid (2.2 g, 12.93 mmol) in toluene (52 mL) and is added PdCl2(dppf)CH2Cl2 adduct (0.66 g, 0.81 mmol) and 2M aq. Na2CO3 (8.1 mL, 16.16 mmol). After stirring at 95° C. under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with ice water. The crude is diluted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 50:50) to give (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate (2.86 g). HPLC retention time=1.80 minutes (condition A); MS (m+1)=432.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.1 Hz, 3H) 1.45 (s, 9H) 2.45-2.65 (m, 2H) 2.83-2.94 (m, 1H) 2.94-3.09 (m, 1H) 3.80 (s, 3H) 4.20 (q, J=7.2 Hz, 2H) 4.24-4.33 (m, 1H) 5.11 (br. s., 1H) 6.90-6.96 (m, 1H) 7.00 (dd, J=7.8, 3.3 Hz, 1H) 7.06 (dd, J=9.2, 3.2 Hz, 1H) 7.27 (d, J=7.8 Hz, 2H) 7.49 (d, J=7.8 Hz, 2H)
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C@H:3]2[NH:14][C:15]([NH:17][C@@H:2]12)=[O:16].O[N:19]=[C:20]([NH2:36])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=2[O:27][C:26]1=[O:35].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.ClCCl>[O:16]=[C:15]1[NH:17][C@H:2]2[CH2:1][S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]/[N:19]=[C:20](\[NH2:36])/[CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:29]4[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=4[O:27][C:26]3=[O:35])=[O:12])[C@H:3]2[NH:14]1
Reactant: Cc1ccc2oc(=O)n(CCCCC(N)=NO)c2c1
Reactant: O=C(O)CCCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc2oc(=O)n(CCCC/C(N)=N/OC(=O)CCCCC[C@@H]3SC[C@@H]4NC(=O)N[C@@H]43)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
To a suspension of homobiotin 83 (10 mg, 0.039 mmol) and compound 13 (11 mg, 0.043 mmol) in anhydrous DMF (0.5 ml) was added EDCl (7 mg, 0.047 mmol) and DIPEA (6 mg, 0.045 mmol) and stirred under a nitrogen atmosphere at ambient temperature for 12 h. The reaction mixture was diluted with dichloromethane (25 ml) and washed with water (25 ml) and brine (25 ml). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 19:1 dichloromethane/methanol to give a yellow oil (18 mg, 46%).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:21].[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:22]2[CH:23]=[C:24]([CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[N:25]=[N:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(F)c3ccccc23)OC1(C)C
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc(F)c3ccccc23)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=319.3 (M+H+), was prepared from 2-(4-fluoro-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][N:40]([C@@H:45]4[CH2:49][CH2:48][CH2:47][C@@H:46]4[C:50]([O:52][CH3:53])=[O:51])[C:41]3=[O:44])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)([O-])=O>>[NH2:26][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][N:40]([C@@H:45]4[CH2:49][CH2:48][CH2:47][C@@H:46]4[C:50]([O:52][CH3:53])=[O:51])[C:41]3=[O:44])=[CH:37][CH:36]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Yield: 90 %

Procedure:
The compound of example 592 was prepared analogous to the compound of example 6 by reduction of the compound of example 591.