Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.O>C(O)=O.C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Agent: C=O
Solvent: O=CO
Solvent: O
Product: CN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
Tert-butyl 3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate (160 mg, 394 μmol, Eq: 1.00) was dissolved in a solvent mixture of formic acid (6.0 ml) and formaldehyde, 37% (12.0 ml). The solution stirred at 70° C. for 18 h. The solution was cooled to room temperature. Water was added. The reaction mixture was extracted once with DCM. Solid K2CO3 was slowly added to the aqueous layer until the pH=14. A solid formed that was subsequently filtered. The solid was dried to give 6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (70 mg, 55%). LC/MS-ESI observed [M+H]+ 320.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3]/[CH:4]=[C:5](\[CH3:10])/[C:6]([O:8]C)=[O:7].[Li+:12].[OH-]>O1CCCC1.O>[CH3:1][N:2]([CH3:11])[CH2:3]/[CH:4]=[C:5](\[CH3:10])/[C:6]([O-:8])=[O:7].[Li+:12]
Reactant: COC(=O)/C(C)=C/CN(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C/C(=C\CN(C)C)C(=O)[O-]
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To methyl(2E)-4-(dimethylamino)-2-methylbut-2-enoate (238 mg, 1.51 mmol) in tetrahydrofuran (0.95 mL) and water (0.95 mL) was added LiOH (36 mg, 1.5 mmol). The solution was stirred at 40° C. for 4 hours before being frozen and lyophilized to afford a white semi-solid that was taken on to the next step as is. LRMS (ESI) calc'd for C7H13NO2 [M+]+: 144, found 144.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:19]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCCOc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCCOc1ccncc1
Yield: 77.3 %

Procedure:
To a solution of 700 mg (4.60 mmol) of 4-(3-aminopropyloxy)pyridine and 0.77 ml (5.52 mmol) of triethylamine in 30 ml of methylene chloride, 0.57 ml (4.63 mmol) of pivaloyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 840 mg of the desired compound (yield: 77.3%, colorless crystals).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.Cl.[O:18]([NH2:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][O:18][N:20]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CON
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(4-fluorophenyl)-1-phenyl-1-ethanone (5 g, 30 mmol) in 30 ml pyridine under nitrogen was added methoxylamine hydrochloride (3.8 g, 45 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 17 hours. The pyridine was removed in vacuo with heating. The residual solids were a mixture of the oxime geometrical isomers as a white syrup and it was used for the next step without further purification. Rf : 0.48, 0.70 (CH2C12).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.C([NH:15][C:16]1[C:21]([C:22](OCC)=[O:23])=[CH:20][N:19]=[CH:18][N:17]=1)(=O)C>C(Cl)Cl>[NH2:15][C:16]1[C:21]([C:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])=[CH:20][N:19]=[CH:18][N:17]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cncnc1NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Nc1ncncc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
To a solution of aniline (336.0 mg, 3.6 mmol) in 7.5 mL of dry CH2Cl2 was slowly added 2.17 mL of Me3Al (2M solution in hexanes) at RT under N2. After 20 min of stirring compound 22 (301 mg, 1.44 mmol) was added to the reaction mixture as a solution in 2 mL of dry CH2Cl2. The reaction mixture was stirred at RT for 16 h and then quenched with NH4Cl (sat.) followed by extraction into CH2Cl2. The combined organic layers were washed with NaHCO3 (sat.), brine and dried over Na2SO4. The crude material was purified by flash chromatography (CH2Cl2/EtOAc) to yield 75.0 mg of the target compound 23 in 24% yield.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
7 g (30.56 mmol) of ethyl 4-bromobenzoate are dissolved in 60 ml of 1,2-dimethoxyethane and, under argon, 6.96 g (36.67 mmol) of 4-trifluoromethylphenylboronic acid, 271 mg of bis(triphenylphosphine)palladium(II) chloride and 40.7 ml of a 2 M sodium carbonate solution in water are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelute, washed with dichloromethane and concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/dichloromethane 2:1). 6.31 g (21.4 mmol, 70% of theory) of a colorless solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.N[C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1N.IC1C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccccc3)c3cc(Cl)ccc23)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.252 g, 0.759 mmol), (±)-trans-1,2-diaminocyclohexane (18 μL, 0.15 mmol), iodobenzene (103 μL, 0.911 mmol), K3PO4 (0.402 g, 1.89 mmol) and copper(I) iodide (0.0072 g, 0.04 mmol) were dissolved in toluene (0.750 mL) and the reaction vessel was purged with N2 (g) for 1 minute. The reaction was heated to 120° C. and stirred overnight. Standard workup procedure followed by silica gel chromatography (0-20% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: [N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:38])[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[CH:25][CH:24]=3)=[O:21])=[CH:15][C:14]=2[O:39][CH3:40])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([CH:29]([CH3:38])[CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=3)=[O:21])=[CH:15][C:14]=2[O:39][CH3:40])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(CC(=O)Nc2ccc(C(C)CC(=O)OC(C)(C)C)cc2)ccc1NC(=O)N1CCc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)Nc2ccc(C(C)CC(=O)O)cc2)ccc1NC(=O)N1CCc2ccccc21
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A solution of tert-butyl 3-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-butyrate [580 mg, Reference Example 1(a)] in dichloromethane (20 ml) was treated with treated with trifluoroacetic acid (1 ml). After 2 hours at room temperature further (1 ml) trifluoroacetic acid was added and the solution was then kept at room temperature overnight. The reaction mixture was evaporated and the residue was suspended in water. This suspension was treated with 1.0 M sodium hydroxide solution (5 ml) and then washed twice with ethyl acetate, then acidified to pH 1 with hydrochloric acid and then filtered. The resultant white solid was washed with water then dried to give the title compound (450 mg) as a white powder, m.p. 152-154° C. [Elemental analysis: C, 67.35; H, 6.02; N, 8.46%. Calculated for C28H29N3O5.0.63H2O: C, 67.41; H, 6.11; N, 8.42%].
Reaction SMILES: CN(C)[N:3]=[CH:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1.Cl[C:13](=[CH2:16])[C:14]#[N:15].C(N(CC)CC)C>O1CCOCC1>[C:14]([C:13]1[N:3]=[CH:4][C:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:16]=1)#[N:15]
Reactant: C=C(Cl)C#N
Reactant: CN(C)N=CC1=CCCCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1cc2c(cn1)CCCC2

Procedure:
7.6 g cyclohex-1-ene-carboxaldehyde-N,N-dimethylhydrazone, 4.4 g of 2-chloroacrylonitrile and 10.1 g of triethylamine are heated in 75 ml of dioxane for 18 hours to 90° C. The reaction mixture is concentrated by evaporation and the residue is acidified with 1N HCl and extracted three times with chloroform. The combined extracts are dried and concentrated by evaporation and the residue is chromatographed over silica gel. Pale yellow crystals of the title compound are isolated. Melting point: 56°-59° C.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[NH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:10])[CH3:9].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1.O>CN(C)C(=O)C>[C:41]([O:40][C:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:14]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]([C:8]([OH:7])([CH3:10])[CH3:9])[N:12]=[C:13]2[CH2:21][CH2:22][CH3:23])=[CH:27][CH:28]=1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
3.00 g of potassium t-butoxide were added, whilst ice-cooling, to a solution of 6 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 40 ml of N,N-dimethylacetamide, and the resulting mixture was stirred for 10 minutes, after which a solution of 9.00 g of t-butyl 4'-bromomethylbiphenyl -2-carboxylate in 40 ml of N,N-dimethylacetamide was added. After the reaction mixture had been stirred at room temperature for 1 hour and then at 50° C. for 2 hours, it was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 11.6 g of the title compound as a solid, softening at above 85° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[C:7]([O:18][CH3:19])[CH:6]=1)=[O:4].CO.[OH-].[Na+]>O1CCCC1>[CH3:19][O:18][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: 105 °C
Yield: 87.3 %

Procedure:
To the ester of Step C (26 mmol) was added methanol (10 mL), tetrahydrofuran (45 mL), and 1 N sodium hydroxide (33 mL). The solution was refluxed vigorously in an oil bath at 105° C. for one hour. The volatile solvents were evaporated and the solution was chilled in ice. Hydrochloric acid (2.0 N) was added until the pH was −1. The product was extracted into ethyl acetate, dried with anhydrous magnesium sulfate, filtered and evaporated to a white solid. This was recrystallized in ethyl acetate and hexane to afford 5.5 g of the title compound (86%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4](C(OCC)=O)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37].CO>CN(C=O)C>[CH3:39][N:38]([CH3:40])[C:36](=[O:37])[CH2:35][O:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: CCOC(=O)n1[nH]c(=O)c2cnc(NC(=O)N[C@H](C)c3ccccc3)cc21
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(OCC(=O)N(C)C)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-Ethyl 3-oxo-6-(3-(1-phenylethyl)ureido)-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (29 mg, 0.079 mmol), potassium carbonate (32.6 mg, 0.236 mmol), and 2-chloro-N,N-dimethylacetamide (8.8 μL, 0.087 mmol) were stirred in DMF (1 mL) at room temperature for 24 h. MeOH (0.5 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The insoluble inorganics were removed by filtration and the reaction mixture was purified via mass triggered, reverse phase prep-HPLC. Fractions containing pure product were concentrated in vacuo and the residue dissolved in MeOH. The MeOH solution was passed through a PS—HCO3 cartridge and the filtrate concentrated in vacuo to give (R)—N,N-dimethyl-2-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yloxy)acetamide. MS ESI calc'd. For C19H22N6O3 [M+1]+ 383. found 383. 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.94 (s, 1H), 8.58 (s, 1H), 7.77 (br s, 1H), 7.49 (s, 1H), 7.34-7.31 (m, 4H), 7.25-7.20 (m, 1H), 5.04 (s, 2H), 4.89-4.83 (m, 1H), 2.98 (s, 3H), 2.82 (s, 3H), 1.39 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (31.2 g, 200 mmole) in dry THF (250 ml) was added to a solution of 4-fluorophenylmagnesium bromide in dry THF at 60° C. The mixture was allowed to warm to 25° C. and quenched with saturated NH4Cl solution and extracted with ether. The extracts were dried with Na2SO4 and the solvent removed in vacuo. The residue was crystallized from hexane to give the product (89%, mp: 133°-135° C). Calc'd for C14H17FO3 : C, 66.66%; H, 6.80%. Found: C, 66.54%; H, 7.12%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CC(C)=O>[OH:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[C:4]([O:8][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)COc1cccc(O)c1C(C)=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a mixture of 2′,6′-dihydroxyacetophenone (6 g) and potassium carbonate (5.72 g) in acetone (20 mL) was added methyl bromoacetate (3.73 mL), and the mixture was stirred at room temperature for 5 days. To the reaction mixture was added water, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (7.89 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31])=[CH:24][CH:23]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH:10]([NH:12][C:30](=[O:31])[C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)([CH3:34])[CH3:33])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(C)(Nc1ccc(Cl)cc1)C(=O)O
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(NC(=O)C(C)(C)Nc1ccc(Cl)cc1)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Diastereomer α, Section I, Reference Example 1, 0.31 g, 0.94 mmol) and 2-(4-chlorophenylamino)-2-methylpropionic acid (0.20 g, 0.94 mmol) in 5 mL CH2Cl2 was added N-methylmorpholine (0.41 mL, 3.5 mmol) and tris(pyrrolindinyl) phosphonium hexafluorophosphate (0.73 g, 1.4 mmol). After stirring at RT overnight, the reaction mixture was loaded onto a silica gel column eluted with 30% EtOAc in hexane to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.18 (d, 2H), 7.04 (d, 2H), 7.02 (d, 2H), 6.97 (d, 2H), 6.70 (d, 2H), 6.56 (d, 2H), 4.20 (m, 1H), 3.02 (dd, 1H), 2.78 (ddd, 1H), 2.64 (dd, 1H), 1.52 (s, 3H), 1.45 (s, 3H), 0.82 (d, 3H). LC-MS: m/e 489 (M+H)+ (4.3 min).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.ClCCl>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Clc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Nc1ncc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)cn1
Temperature: 140 °C
Yield: 14 %

Procedure:
A degassed mixture of 6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (74.4 mg, 0.197 mmol), 2-aminopyrimidine-5-boronic acid, pinacol ester (45.8 mg, 0.207 mmol), and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (1:1) (8.1 mg, 9.87 umol, 5.0 mol %) in acetonitrile (0.74 mL) and 1M aqueous potassium carbonate solution (0.74 mL) was heated under microwave irradiation (140° C.) for 30 minutes. Further portions of the boronate ester (1.0 eq) and catalyst (5 mol %), acetonitrile (0.74 mL), and 1M aqueous potassium carbonate solution (0.74 mL) were added and the mixture heated under microwave irradiation (140° C.) for an additional 30 minutes. The mixture was concentrated in vacuo and the residue dissolved in water and DMF, and acidified with 10% (v/v) sulfuric acid. The resultant solid was removed by filtration and the filtrate concentrated in vacuo. The resultant residue was dissolved in DMSO and purified by preparative HPLC [0-30% MeCN/water modified with 0.1% formic acid] to afford an orange fluffy solid (5.1 mg, 14%). LCMS (Method E): RT=5.45 min, M+H+=436.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxybenzaldehyde (10.0 g, 81.8 mmol), 1-bromooctane (15.8 g, 81.8 mmol), and K2CO3 (34.0 g, 0.25 mol) in DMF (150 mL) was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was subsequently diluted in toluene. The organic layer was washed with HCl (10%), brine, and water. The solvent was concentrated in vacuo and the oil was purified by short silica gel plug (dichloromethane (DCM) in n-hexanes, 10%). Solvent was dried in vacuo to afford the product 4-octyloxy benzaldehyde as a slightly colored oil.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[NH2:20])=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:20][CH2:9][CH:7]([OH:8])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([CH3:21])[CH3:22])=[CH:14][CH:13]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: Cc1ccc(CC(C)(C)N)cc1
Product: Cc1ccc(CC(C)(C)NCC(O)c2ccccc2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using phenylglyoxal and 2-(4-methylphenyl)-1,1-dimethylethanamine. The chromatographed material was recrystallized from cyclohexane to give the title compound m.p. 137. τ(CDCl3 +d6DMSO) 8.95 (6H, s), 7.7 (3H, s), 7.35 (2H, s), 7.0-7.3 (2H, dd), 5.3 (1H, dd), 2.9 (4H, s), 2.5-2.7 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][C:28]([CH3:40])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH3:29])=[O:26])[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C[CH2:52][N:53]=[C:54]=NCCCN(C)C.Cl.Cl.CNC.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([N:53]([CH3:54])[CH3:52])=[O:19])[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][C:28]([CH3:40])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=3)[CH3:29])=[O:26])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)O)c2)c1=O)c1cccc(C(F)(F)F)c1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NC(C)(C)c3cccc(C(F)(F)F)c3)c2=O)c1
Reaction time: 0.17 h

Procedure:
30 mg (0.052 mmol) of 3-(3-(4-chlorophenyl)-1-[2-(1-methyl-1-[3-(trifluoromethyl)phenyl]ethylamino)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-ylmethyl)-benzoic acid (Example 471) are placed in 0.5 ml of DMF and treated with 9.2 mg (0.068 mmol) of HOBt and 13.0 mg (0.068 mmol) of EDC hydrochloride. After 10 mins' stirring, 6.0 mg (0.073 mmol) of dimethylamine hydrochloride and 10.2 mg (0.079 mmol) of N,N-diisopropylethylamine are added and the mixture is stirred overnight at RT. Without further workup, the crude product is purified directly by preparative HPLC [Method 10]. 29.8 mg (95% of theory) of the target compound are thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13]
Reactant: O=C(O)CCCc1ccccc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCc1ccccc1F
Yield: 99.8 %

Procedure:
A mixture of 4-(2-fluorophenyl)butyric acid (100 g, 0.55 mol) and thionyl chloride (418.8 g, 3.51 mol) was refluxed for 3 h. The excess thionyl chloride was removed in vacuo to give 110.1 g (100%) of 4-(2-fluorophenyl)butyryl chloride.