Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18]2>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH:20]3[CH2:23][CH:17]2[CH2:22][CH2:21]3)=[CH:4][CH:3]=1
Reactant: C1CC2CC1CN2
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(CN2CC3CCC2C3)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A stirred solution of 4-bromobenzyl bromide (66 mg, 0.26 mmol), triethylamine (0.22 mL, 1.56 mmol) and 2-azabicyclo[2.2.1]heptane (71 mg, 0.52 mmol) in THF (10 mL) was heated under reflux for 5 h. The reaction mixture was cooled to ambient temperature, the solid removed by filtration and the filtrate concentrated under reduced pressure to afford the title compound (70 mg, quantitative yield) that was used in the next step without further purification. LCMS (Method B): RT=2.04 min, M+H+=266/268.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[CH3:14][C:15]1[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[CH:4][CH:3]=2)=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1noc(-c2ccc(I)cc2)n1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)cc2)n1

Procedure:
Example 25 was prepared using 5-(4-iodophenyl)-3-methyl-[1,2,4]oxadiazole (Intermediate 12) and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 25) using DMF as the solvent.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8](F)=[C:7]([F:14])[C:6]=1[F:15])[CH2:2][CH2:3][CH3:4].O.[NH2:17][NH2:18]>C(O)C>[CH2:1]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([NH:17][NH2:18])=[C:7]([F:14])[C:6]=1[F:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(F)c(F)c(F)c(F)c1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCc1c(F)c(F)c(NN)c(F)c1F

Procedure:
n-Butylpentafluorobenzene [19.0 g; described by J. M. Birchall and R. N. Haszeldine J. Chem. Soc p 3719 (1961)] was added to a solution of hydrazine hydrate (50 ml; 99-100% w/w) in ethanol (100 ml) and the mixture heated at reflux for 72 hours. The reaction mixture was cooled, evaporated to dryness to give a solid which was filtered off and washed with ethanol and hexane to give 4-n-butyl-2,3,5,6-tetrafluorophenylhydrazine (20.5 g), m.p. 80°-81° C., in the form of colourless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19].[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:26]3[CH:27]=[CH:28][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19]
Reactant: Cn1c(N2CCN(CCO)CC2)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCOc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Yield: 69.3 %

Procedure:
To 100 ml of anhydrous tetrahydrofuran were added 5.37 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione, 3.20 g of 4-nitrophenol and 6.03 g of triphenylphosphine, and the resultant mixture and 50 ml of an anhydrous tetrahydrofuran solution containing 3.9 g of diethyl azodicarboxylate were treated in the same manner as in Reference Example 4, thereby obtaining 5.40 g of crystalline 1,3-dimethyl-6-[4-(2-[4-nitrophenoxy] ethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound x).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:24])[CH:7]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[Cl:25]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6](=[O:24])[CH:7]([C:12]2[CH:13]=[C:14]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[C:15]([NH2:18])=[C:16]([Cl:25])[CH:17]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1ccc(N)c(OCC2CC2)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(N)c(OCC2CC2)c1
Yield: 34.5 %

Procedure:
2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (16.3 g, 49.1 mmol) was dissolved in chloroform (200 mL) and N-chlorosuccinimide (5.3 g, 0.75 equiv, 39.6 mmol) was added. The reaction mixture was refluxed for 1 h and after cooling treated with 10% potassium carbonate solution (100 mL). The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were dried over magnesium sulfate. Evaporation of the solvent gave the crude product as a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give 2-(4-amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (5 g, 36%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.85 (s, 1H), 6.66 (s, 1H), 3.95-3.80 (m, 4H), 3.49 (t, J=7.7 Hz, 1H), 1.94-1.82 (m, 1H), 1.63-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.66-0.58 (m, 2H), 0.53-0.47 (m, 2H), 0.37-0.32 (m, 2H), 0.25-0.20 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 174.2, 146.8, 132.6, 128.7, 120.6, 118.3, 109.4, 73.6, 69.3, 49.0, 42.6, 25.9, 22.6, 22.4, 10.4, 9.8, 3.3.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[O:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[CH3:9][C:7]1([CH3:8])[C:3]([CH3:22])([CH3:2])[O:4][B:5]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:29](=[O:31])[CH3:30])[CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[O:6]1
Reactant: CC(=O)Cl
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)cc2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) piperazine hydrochloride (419 mg, 1.29 mmol) and cesiumcarbonate (1.27 g, 3.9 mmol) in THF (30 mL) was added acetyl chloride (0.5 mL, 6.5 mmol). Then the mixture was stirred at room temperature overnight, extracted with EA, washed with NaHCO3 solution and brine. The organic solution was concentrated and purified by flash column chromatography, eluting with PE/EA, to give product as a white solid. MS (m/z): 331 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[OH-].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1>S1(CCCC1)(=O)=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([O:4][CH:1]=[CH:2][CH3:3])=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: C=CCO
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: CC=COc1ccc(C(F)(F)F)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
174 g of allyl alcohol was added to a mixture of 298 g of 85% flake potassium hydroxide and 750 ml of sulpholane under nitrogen, and the mixture was heated to 125°-135° C. 272 g of 4-chlorobenzotrifluoride was added over 20 minutes at this temperature. After 2 hours, the reaction mixture was cooled to 30° C., and distillation from the solvent gave 207 g of propenyl 4-trifluoromethylphenyl ether b.p.: 84°-88° C. at 15 Torr.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17](O)=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH2:27]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]([NH:27][CH3:26])=[O:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(=O)O
Reactant: CN
Product: CNC(=O)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 87 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazole (0.2 g) and methylamine (30% methanol solution, 0.12 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 20(a) to obtain the title compound (0.18 g, 87%) as a colorless powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([CH2:21][CH2:22][CH3:23])[C:7]([O:13]CC3C=CC=CC=3)=[CH:8][CH:9]=2)[O:4]1>CO.[Pd]>[OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([CH2:21][CH2:22][CH3:23])[C:7]([OH:13])=[CH:8][CH:9]=2)[O:4]1
Reactant: CCCc1c(OCc2ccccc2)ccc2c1OC(CO)CC2
Agent: [Pd]
Solvent: CO
Product: CCCc1c(O)ccc2c1OC(CO)CC2
Reaction time: 0.77 h
Yield: 99.2 %

Procedure:
3.97 g (12.7 mmole) of the compound from Example 33 was dissolved in 30 ml of methanol and 397 mg of 5% palladium on carbon was added. The resulting suspension was hydrogenated at 60 psi and 60° C. for 46 minutes. After cooling and removal of the catalyst by filtration, the solvent was removed by rotary evaporation to give 2.80 g (99%) of the title compound as a light yellow oil. Calc: C, 70.25; H, 8.16; Found: C, 69.54; H 8.18.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:21])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(C(=O)Cl)cc1
Temperature: 80 °C

Procedure:
To a mixture of 4-isopropylbenzoic acid (191 mg, 1.16 mmol) and pyridine (0.12 mL, 1.5 mmol) in toluene (10 mL) was added thionyl chloride (0.11 mL, 1.5 mmol). After heating at 80° C. for 3 h, the reaction mixture was cooled and concentrated in vacuo to give 4-isopropylbenzoyl chloride. A solution of this material (1.16 mmol) in methylene chloride (10 mL) was added to a mixture of 2-amino-N-(4-methoxyphenyl)benzamide (200 mg, 0.83 mmol) and pyridine (0.07 mL, 0.87 mmol) in methylene chloride (15 mL) cooled to 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was partitioned between methylene chloride (25 mL) and 1 N hydrochloric acid (10 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo to give 262 mg (81%) of the title compound as a white solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([B:15]([OH:17])[OH:16])[CH:12]=[CH:13][CH:14]=1.O>N1C=CC=CC=1>[OH:16][B:15]([OH:17])[C:11]1[CH:10]=[C:9]([NH:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cccc(B(O)O)c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CCC(=O)Nc1cccc(B(O)O)c1
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Succinic anhydride (5.00 grams, 0.05 mole) and (3-aminophenyl)boronic acid (7.75 grams, 0.05 mole) are dissolved in anhydrous pyridine (40 ml), and then allowed to stand overnight at room temperature. Water (20 ml) is added and the resulting solution allowed to stand for 1 hour. The product is then concentrated on a rotary evaporator at 85°-90° C. The resulting aqueous solution is frozen in a dry-ice-acetone-slurry and lyophilized overnight. The lyophilized product is dissolved in water (50 ml) and acidified with concentrated HCl to approximately pH 1.0. The acidified solution is cooled in an ice bath for 1 hour, and the precipitate collected by filtration. The precipitate is recrystallized from boiling water (200 ml) and dried overnight in vacuo over NaOH pellets, to afford 8.60 grams (70% yield) of N-(3-dihydroxyborylphenyl)succinamic acid. Homogeneous by TLC (CHCl3 /CH3OH/CH3COOH; 60:35:5), Rf =0.5. Melting point 186°-188° C. The structure was confirmed by 300 MHz, 1 H NMR, spectrometry in d6 -DMSO.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1.C(C1C=CC2NC(=O)CSC=2C=1)(=[O:17])C.BrBr>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1)=[O:17]
Reactant: O=C1CSc2cc(CCBr)ccc2N1
Reactant: CC(=O)c1ccc2c(c1)SCC(=O)N2
Agent: BrBr
Solvent: ClCCl
Product: O=C1CSc2cc(C(=O)CBr)ccc2N1

Procedure:
Using the procedure described in Example 5 but replacing 6-(2-bromoethyl)benzothiazolinone by 7-(2-bromoethyl) 2,3-dihydro 3-oxo 1,4-benzothiazine (obtained using 7-acetyl 2,3-dihydro 3-oxo 1,4-benzothiazine (described in Ann. Chem. Rome, 1955, 45, 172) treated with bromine in methylene chloride to give 7-bromoacetyl 2,3-dihydro 3-oxo 1,4-benzothiazine, then by triethysilane in acidic medium to give 7-(2-bromoethyl)2,3-dihydro 3-oxo 1,4-benzothiazine, the product of the title is obtained.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(N(CC)CC)C.[CH2:24]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28](Cl)=[O:29])[CH2:25][CH3:26]>C(Cl)(Cl)Cl>[CH2:24]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:29])[CH2:25][CH3:26]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCC(CCC)C(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1

Procedure:
50.3 g (230 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), are dissolved in 200 ml of chloroform and 36.3 g (359 mmol) of triethylamine at ordinary temperature. A solution of 37.4 g (230 mmol) of dipropylacetyl chloride in 50 ml of chloroform is run in and the mixture is heated under reflux for 5 hours.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH2:12]=[CH:13][CH:14]1[O:16][CH2:15]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:12]/[CH:13]=[CH:14]\[CH2:15][OH:16])=[C:4]([Cl:11])[N:3]=1
Reactant: C=CC1CO1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(C/C=C\CO)c2n1
Temperature: 60 °C

Procedure:
2-Amino-6-chloropurine (3.4 g), butadiene monoepoxide (1.65 g) and tetrakis (triphenylphosphine)palladium (0) (1.0 g) in dry dimethylformamide (75 ml) were stirred under a nitrogen atmosphere and heated at 60° C. for 45 minutes. The solvent was evaporated in vacuum (0.1 mm Mg) and the residue was triturated with hot chloroform (4×50 ml). The combined chloroform solutions were concentrated (25 ml volume) and diluted with ether (100 ml). The gummy precipitate was collected, dried and triturated with hot 1,2-dimethoxyethane (3×50 ml). The combined solutions were evaporated in vacuum (0.1 m Hg) to give a crude mixture (4 g) which was separated on a column of silica gel (500 g) eluted with chloroform+methanol 10+1 (800 ml) followed by chloroform+methanol 8+1. Fractions of about 15 ml were collected and the compound cis-4-(2-Amino-6-chloropurin-9-yl)-2-buten-1-ol was obtained as a minor product (0.2 g) in fractions 74-78. M.p. 160°-165° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:26]=[O:27])C>>[C:1]([C:5]1[N:9]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:8]([CH:26]=[O:27])=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cncn1COCC[Si](C)(C)C
Agent: [Li]CCCC
Product: CC(C)(C)c1cnc(C=O)n1COCC[Si](C)(C)C
Yield: 98.7 %

Procedure:
Reaction 5-tert-butyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (276 mg, 1.09 mmol), 2.5 M n-BuLi (567 uL, 1.42 mmol), and DMF (253 uL, 3.27 mmol) for 2 h at −40° C. gave the title compound (304 mg, 99%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.91 (t, 2H, J=9.0 Hz), 1.33 (s, 9H), 3.57 (t, 2H, J=7.5 Hz), 5.72 (s, 2H), 7.10 (s, 1H), 9.80 (s, 1H).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:11]([CH3:13])[CH:12]=1.C[O:21][B:22](OC)[O:23]C.Cl>O1CCCC1>[CH3:6][C:7]1[C:12]([B:22]([OH:23])[OH:21])=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(C)cc(-c2ccccc2)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)cc(C)c1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
t-Butyllithium (1.7 M solution in hexane, 36.2 ml, 61.6 mmol) is added dropwise to a solution of 3,5-dimethylbiphenyl (7.27 g, 28 mmol) in dry tetrahydrofuran (150 ml) at −78° C. under an atmosphere of nitrogen. The reaction mixture is stirred at −78° C. for 30 minutes, then trimethylborate (9.54 ml, 84 mmol) is added. The resulting mixture is stirred at −78° C. for 30 minutes and then allowed to warm to room temperature. The reaction mixture is acidified with 10% aqueous hydrochloric acid solution and extracted with diethyl ether. The organic layers are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness to give a yellow solid. The crude product is triturated with isohexane and filtered to give 3,5-dimethylbiphen-4-ylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[NH:5][C:6]2=O.B.C1COCC1.CO.Cl>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: O=C1NC(=O)c2c(Cl)cccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Clc1cccc2c1CNC2
Temperature: 80 °C
Yield: 53.3 %

Procedure:
To solid 4-chloro-1H-isoindole-1,3(2H)-dione (4.0 g, 22.0 mmol) was added borane-THF complex (1 M/THF, 88.1 mL, 88.1 mmol) dropwise with stirring. When the addition was complete, the reaction mixture was heated to reflux (80° C.) and stirred for 6 h. The reaction mixture was then cooled to 0° C., methanol (2.8 mL, 88.1 mmol) was carefully added dropwise and the reaction mixture was warmed to room temperature. HCl (6 N) was added until the mixture was acidic and then the mixture was concentrated. The crude product was dissolved in 1 M HCl and extracted twice with ethyl ether and twice with dichloromethane. The pH of the aqueous layer was adjusted to pH=11 with solid NaOH and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4, filtered and concentrated to give 4-chloroisoindoline (1.8 g, 53% yield). LRMS (ESI) m/z 154 [(M+H)+; calcd for C8H9ClN: 154].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3]C)=[O:2]>C(O)C.[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)O)c2)cc1
Yield: 82.8 %

Procedure:
A solution of 0.30 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 16 mL of ethanol and 8 mL of 10% aqueous sodium hydroxide was refluxed for 5 hours. After cooling, the reaction mixture was filtered, and the solvent was removed in vacuo. The residue was dissolved in water, and the solution was acidified to pH 3.5 using hydrochloric acid. The precipitated solid was recovered by filtration and recrystallized from aqueous ethanol to furnish 0.24 g of 1-[(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (m.p. 180°-181°); NMR (200 MHz, DMSO-d6): δ 8.26 (s,1H); 8.04 (d, 1H); 7.77 (d, 1H); 7.52 (t, 1H); 7.36 (A2M2, 4H); 5.30 (s, 2H); 4.48 (s, 2H); 2.57 (t, 2H); 1.64 (quint., 2 H); 1.34 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: OC(c1ccc(C2CCCCC2)cc1)c1ccccn1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(C2CCCCC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.0 g of chromium trioxide are added in portions at 5° C, whilst stirring and with exclusion of moisture, to a solution of 15.8 ml of pyridine in 200 ml of absolute methylene chloride, behind a protective shield. After the completion of the addition the mixture is stirred for a further 30 minutes at room temperature, 2.8 g of crude 2-[(p-cyclohexylphenyl)-hydroxymethyl]-pyridine, dissolved in 10 ml of methylene chloride, are then added all at once and the mixture is stirred for a further 20 minutes at room temperature. The mixture is decanted off from the brown resin which is formed and is partitioned at 0° C between 50 ml of methylene chloride and 2 lots of 50 ml of saturated sodium bicarbonate solution. The organic phase is washed successively with twice 50 ml of 0.1 N hydrochloric acid and twice 50 ml of water, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 200 g of silica gel, using chloroform as eluant, and fractional crystallisation from cold ethanol, yields 2-[(p-cyclohexylphenyl)-oxomethyl]-pyridine of the formula ##STR13## of melting point 44°-45° C (boiling point 185°-190°/0.35 mm).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:65][CH:64]=1)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:62][C:63]3[CH:64]=[CH:65][C:66]([C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)=[CH:67][CH:68]=3)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(N)nc3cc(C(=O)N[C@@H](Cc4ccc(-c5ccccc5)cc4)C(=O)N(C)C)ccc23)CC1
Reaction time: 0.17 h
Yield: 18.6 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (26 mg, 0.070 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (12 uL, 0.070 mmol). The reaction was stirred for 10 min., and the (2S)-2-amino-3-biphenyl-4-yl-N,N-dimethylpropanamide (19 mg, 0.070 mmol) was added. The reaction was stirred for 2 h. at r.t., and was purified by RP-HPLC (pH=10) to afford the desired product (3 mg, 20%) as a white solid. Analytical LCMS (M+H)+: m/z=538.0.