Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (4.9 g; 21.4 mmol; 1 eq.), 2-methoxyphenylboronic acid (Aldrich 44,523-1; 3.6 g; 23.5 mmol; 1.1 eq.), potassium carbonate (14.8 g; 107 mmol; 5 eq.) and Pd(PPh3)4 (2.47 g; 2.14 mmol; 0.1 eq.) in toluene (24.5 mL) and water (24.5 mL) was refluxed for 6 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of CELITE which was further washed with toluene (500 mL). The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate (500 mL). The organic layer was washed with sat. aq. NaHCO3 (200 mL), water (200 mL) and brine (200 mL) then dried over magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography (c-hexane/ethyl acetate, 90/10) to afford the title compound (4.38 g, 80%) as a colorless oil. HPLC (Method A): Rt 4.85 min (purity 98.9%). LC/MS: 257.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([NH:13]CC2C=CC=CC=2)[C:9]2[C:21](=[O:29])[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:30]>C(O)C.C(O)(=O)C.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]2[C:21](=[O:29])[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:30]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(NCc4ccccc4)c3c1=O)CCN2C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)CCN2C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
59 mg of the compound (200) obtained in Example 71 was dissolved in 10 ml of ethanol and 10 ml of acetic acid, and 5 mg of 10% palladium on carbon was added to the solution. the solution was stirred for 24 hours under hydrogen. The catalyst was filtered, and the filtrate was evaporated. The residue was dissolved in chloroform and was washed with saturated aqueous sodium hydrogen-carbonate solution. After drying over magnesium sulfate, the solvent was removed by distillation. Solids were dispersed in ether and filtered off to obtain 27 mg of the subject compound (201) in a 59% yield.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:14][C:13]=1[F:30])=[O:11].CS(O[CH2:36][CH2:37][C:38]([F:41])([F:40])[CH3:39])(=O)=O>>[F:40][C:38]([F:41])([CH3:39])[CH2:37][CH2:36][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:10]([C:12]3[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[CH:14][C:13]=3[F:30])[O:11][C:2]=2[CH:7]=1
Reactant: C[C@@H](COc1cnc(C(=O)Nc2ccc(O)cc2O)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CC(F)(F)CCOS(C)(=O)=O
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCCC(C)(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate and 3,3-difluorobutyl methanesulfonate, and in the same manner as in Example 2, steps C-D, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=3[CH:20]=2)=[CH:24][CH:25]=1)[CH3:31]
Reactant: CN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Reactant: CCOc1ccc(OB([O-])[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To t-butyl 7-bromo-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g), 4-ethoxyphenyl borate (2.35 g), 1M potassium carbonate solution (25 ml) and ethanol (25 ml) was added toluene (100 ml), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphine palladium (0.55 g), and the mixture was refluxed under argon atmosphere overnight. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give t-butyl 7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:13]([CH3:15])=O)[C:8]([O:10]CC)=O.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[CH:25]=[C:24]([NH2:29])[N:23]=1.O>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:21][C:22]1[N:23]=[C:24]([NH2:29])[C:25]2[C:13]([CH3:15])=[C:7]([CH2:6][C:5]3[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:8](=[O:10])[NH:28][C:26]=2[N:27]=1
Reactant: Nc1cc(N)nc(N)n1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(OC)c1)C(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: COc1ccc(Cc2c(C)c3c(N)nc(N)nc3[nH]c2=O)cc1OC
Yield: 50.8 %

Procedure:
A mixture of ethyl α-(3,4-dimethoxybenzyl)acetoacetate (42 g) and 2,4,6-triaminopyrimidine (21 g) in diphenyl ether (120 ml) was heated at 190°-230° C. for 2 hours during which time the ethanol and water formed were azeotropically removed. The reaction was cooled, and methanol (250 ml) and ethanol (50 ml) were added. The resulting solid was collected by filtration and treated with boiling water (1) to give 2,4-diamino-5-methyl-6-(3,4-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine (26 g), m.p. 346°-348° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[C:22]([Br:30])[CH:23]=[C:24]3[C:28]=2[N:27]([CH3:29])[CH:26]=[CH:25]3)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[Br:30][C:22]1[CH:23]=[C:24]2[C:28](=[C:20]([CH2:19][N:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]3=[O:31])[CH:21]=1)[N:27]([CH3:29])[CH:26]=[CH:25]2
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc3ccn(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3ccn(C)c23)c2ccccc21
Reaction time: 4 h

Procedure:
To a solution of 3-[3-(5-Bromo-1-methyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (10 mg, 0.02 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (1 mg, 0.04 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that preciptate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product. LCMS (ESMS): m/z 471.17 (M+H+).
Reaction SMILES: N1(C(N)=O)CC[O:4]CC1.[Cl:10][C:11]1[C:12]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][C:14]([O:21][CH3:22])=[C:15]([CH2:17][C:18]([OH:20])=S)[CH:16]=1>C(O)(=O)C.Cl.O>[Cl:10][C:11]1[C:12]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][C:14]([O:21][CH3:22])=[C:15]([CH2:17][C:18]([OH:4])=[O:20])[CH:16]=1
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CC(O)=S
Reactant: NC(=O)N1CCOCC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCCCC2)c(Cl)cc1CC(=O)O

Procedure:
A solution of 11.07 g (30 mmole) of 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylthioacetic acid morpholinamide in 120 ml of glacial acetic acid and 30 ml of concentrated hydrochloric acid is boiled under reflux for 22 hours. The reaction mixture is cooled, diluted with water and extracted with methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulphate and concentrated by evaporation in a vacuum rotary evaporator. Chromatography over silica gel with chloroform/methanol (19:1) yields 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylacetic acid which after recrystallisation with methylene chloride/hexane melts at 120°-122°.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[C:9](C(O)=O)[S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2cc(C(=O)O)sc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: COc1ccc(F)c2ccsc12
Temperature: 200 °C
Yield: 69.5 %

Procedure:
4-Fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid (2.00 g, 8.84 mmol) was added in one portion to DBU (8 mL) and dimethyl acetamide (10 mL). This was heated in the microwave with 300 W at 200° C. for 1 h. The reaction mixture was allowed to cool and poured onto water (100 mL). Product was extracted with hexane (2×100 mL), washed with aqueous hydrochloric acid (2 N, 50 mL), aqueous sodium hydroxide (2 N, 50 mL), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [96:4] to give an oil (1.12 g, 70%): δH (300 MHz, CDCl3) 7.4 (2H, s, Ar), 6.9 (1H, t, Ar), 6.60 (1H, dd, Ar), 3.91 (3H, s, OCH3).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH:3]=[CH2:4].[Br:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=1[OH:18].N1C(C)=CC=CC=1C>CC(C)=O>[C:1]([O:13][CH2:11][C:10]1[C:9](=[C:8]([Br:7])[CH:16]=[C:15]([Br:17])[CH:14]=1)[OH:18])(=[O:5])[CH2:2][CH:3]=[CH2:4]
Reactant: O=C(O)c1cc(Br)cc(Br)c1O
Reactant: C=CCC(=O)Cl
Solvent: CC(C)=O
Solvent: Cc1cccc(C)n1
Product: C=CCC(=O)OCc1cc(Br)cc(Br)c1O

Procedure:
3,5-Dibromosalicyl 3-butenoate is prepared by reaction of an acetone solution of 3-butenoyl chloride and 3,5-dibromosalicylic acid in the presence of 2,6-lutidine. The 3-butenoate ester is isolated and purified. In a second step, the desired oxirane, 3,5-dibromosalicyl 3,4-oxabutanoate, is prepared by reaction of 3,5-dibromosalicyl 3-butenoate and 3-chloroperbenzoic acid in chloroform solution. The desired oxirane is isolated and purified.
Reaction SMILES: O[C:2]1([C:8]2[N:9]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:17][CH3:18])=[CH:12][CH:11]=3)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[O:5]1[CH2:6][CH2:7][C:2]([C:8]2[N:9]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:21])=[O:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:17][CH3:18])=[CH:12][CH:11]=3)=[CH:3][CH2:4]1
Reactant: CSc1ccc2c(c1)cc(C1(O)CCOCC1)n2S(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CSc1ccc2c(c1)cc(C1=CCOCC1)n2S(=O)(=O)c1ccccc1
Yield: 90.4 %

Procedure:
To a solution of the compound obtained in Example 14 (1) (39 mg) in benzene (10 ml), p-toluenesulfonic acid monohydrate (3.7 mg) was added and the mixture was heated under reflux for 1 hour. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 33.7 mg of the desired product as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:7]([C:12]#[N:13])=[C:8]([C:10]#[N:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].O.O.[Sn](Cl)Cl>C(O)C>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:6]2[C:7]([C:12]#[N:13])=[C:8]([C:10]#[N:11])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:20][CH:19]=1
Reactant: CCCCc1nc(C#N)c(C#N)n1Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCCCc1nc(C#N)c(C#N)n1Cc1ccc(N)cc1

Procedure:
A mixture of 2-butyl-4,5-dicyano-1-(4-nitrobenzyl)imidazole (2.00 g, 6.5 mmol, 1 eq), tin dichloride dihydrate (7.30 g, 32.3 mmol, 5 eq) and ethanol (13 mL) was stirred and heated at 70° for 50 minutes. The reaction was terminated by pouring the mixture onto ice and adjusting the pH to 8 with saturated aqueous NaHCO3. The aqueous mixture was extracted with ethyl acetate (3×100 mL) and the organic layers were dried (MgSO4) and concentrated to give a thick amber oil. This oil was flash chromatographed over silica gel in 75:25 to 70:30 hexane/ethyl acetate yielding 330 mg of yellow crystals; m.p. 99.0°-103.5°. NMR (200 MHz, CDCl3) δ6.97 (d, 2H, J=10 Hz); 6.68 (d, 2H, J=10 Hz); 5.10 (s, 2H); 2.69 (t, 2H, J=7 Hz); 1.72 (t of t, 2H, J=7,7 Hz); 1.38 (t of q, 2H, J=7,7 Hz); 0.91 (t, 3H, J=7 Hz). Mass Calcd. for C16H17N5 : 279.1483. Found: 279.1489.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[CH2:5][C:4](=O)[CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22]>CS(C)=O>[C:8]([CH:7]1[C:6](=[O:13])[C:5]2[S:22][C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:15][C:4]=2[CH2:3][CH:2]1[CH3:1])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Solvent: CS(C)=O
Product: CCOC(=O)C1C(=O)C2=C(CC1C)Nc1ccccc1S2

Procedure:
A mixture of ethyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7b (5.94 g, 30 mmole) and 2-aminothiophenol, 6 (X=H, 3.75 g, 30 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from EtOH and proves to be identical. An analytical sample of 4b, (R=H), mp 201-202° C. occurs as light orange crystals; yield: 1.80 g (30.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH:13]([CH2:29][CH2:30][CH3:31])[C:14]([NH:16][C:17]2[N:18]=[CH:19][N:20]([CH2:22][CH2:23]OS(C)(=O)=O)[CH:21]=2)=[O:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(#N)C>[N:38]1([CH2:23][CH2:22][N:20]2[CH:21]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:29][CH2:30][CH3:31])[N:18]=[CH:19]2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCOS(C)(=O)=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CCN2CCOCC2)cn1
Temperature: 65 °C

Procedure:
Methanesulfonic acid 2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-ethyl ester (1 equiv) was dissolved in acetonitrile and treated with potassium carbonate (1.5 equic) and morpholine (3 equiv). The reaction was heated to 65° C. for 18 h and quenched with water, extracted with methylene chloride, dried, and concentrated. The residue was purified by column chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 36.0, 43.1, 45.1, 53.1, 53.9, 58.9, 67.1, 102.6, 102.9, 107.9, 112.3, 112.6, 133.5, 137.6, 139.0, 161.0, 162.0, 169.3, 169.4; MS m/z 450.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:16]([CH3:41])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH2:39][CH3:40])[N:18]=3)[C:10](=[O:42])[CH:9]1[CH:43]([CH3:45])[CH3:44])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:39]([C:31]1[N:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH:9]([CH:43]([CH3:45])[CH3:44])[C:10]4=[O:42])[N:16]3[CH3:41])=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:20]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1)[CH3:40]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)OC(C)(C)C)C(C(C)C)C3=O)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNC(C(C)C)C3=O)n(C)c2n1
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2-isopropyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (104 mg, 0.17 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting mixture stirred for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 681 as an off-white solid (55 mg, 67%). LCMS (method I): RT 2.54 min, [M+H]+ 518.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-8.00 (1 H, m), 7.76-7.76 (1 H, m), 7.32-7.22 (2 H, m), 4.95-4.79 (1 H, m), 4.35 (4 H, brd s), 3.90-3.82 (7 H, m), 3.47-3.45 (3 H, m), 3.35 (2 H, q, J=7.48 Hz), 3.23-3.22 (1 H, m), 3.02 (1 H, ddd, J=12.50, 11.03, 3.93 Hz), 2.57-2.56 (1 H, m), 1.44 (3 H, t, J=7.48 Hz), 1.21 (1 H, t, J=7.02 Hz), 1.04 (3 H, d, J=7.12 Hz), 0.93 (3 H, d, J=6.80 Hz)
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18](=[O:30])[NH:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=2)[CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:10]([O:17][C:18]([NH:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](/[CH:33]=[CH:32]/[C:31]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=2)[CH2:21]1)=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CC(=O)OCC
Reactant: O=C(NC1Cc2ccc(Br)cc2C1)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc2c(c1)CC(NC(=O)OCc1ccccc1)C2
Temperature: 180 °C
Yield: 114.9 %

Procedure:
A mixture of palladium(II) acetate (3 mg, 0.01 mmol), Tri-o-tolylphosphine (7 mg, 0.02 mmol) and DIPEA (0.088 mL, 0.5 mmol) was stirred in MeCN (2 mL) at 60° C. under a nitrogen atmosphere for 20 minutes in a 5 mL microwave vial. Benzyl(5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate (174 mg, 0.5 mmol) and ethyl acrylate (28 μL, 0.25 mmol) were added and the mixture was heated in the microwave at 180° C. for 0.5 h. The mixture was adsorbed onto silica and purified by chromatography with 0-40% EtOAc/isohexane as eluent to give the title compound (105 mg, 57%) as a gum; 1H NMR (CDCl3) δ 1.32 (t, 3H), 2.62-2.88 (m, 2H), 3.12-3.36 (m, 2H), 4.18-4.29 (m, 2H), 4.46-4.62 (m, 1H), 4.76 (d, 1H), 5.09 (s, 2H), 6.32-6.41 (m, 1H), 7.10-7.44 (m, 8H), 7.57-7.68 (m, 1H); MS m/e MH+ 366.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][C:15]1[N:16]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][C:15]2[N:16]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1nc(-c2ccccc2)oc1-c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)oc1-c1ccccc1

Procedure:
A solution of potassium phthalimide (10 g, 54 mmoles) and 4-chloromethyl-2,5-diphenyloxazole (10.4 g, 40 mmoles) in 80 cc of dimethylformamide was heated at 100° C. for 2 hours. When the solution was cooled to room temperature 300 cc of water was added. The solution was extracted with chloroform several times. The combined chloroform solution was washed with 20-30 ml of 0.2N sodium hydroxide and finally with water. After drying over sodium sulfate the chloroform was concentrated. The product precipitated out.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][CH2:22][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[C:13]([C:27]([F:29])([F:30])[F:28])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNCc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 2-methoxy-benzylamine according to the procedure of Example 66. MS (ES) m/z 527.2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13]Br)[CH3:11].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde (61 g) and 2-ethylhexylbromide (106 g) were added to 150 ml of dimethylformamide containing 138 g of potassium carbonate. The mixture was refluxed overnight and then poured into a volume of cold water and extracted with ethyl acetate. The extract was dried, evaporated and distilled (0.1 millimeter vacuum) to yield 4-[(2-ethylhexyl)oxy]benzaldehyde, boiling point (b.p.) 118°-121° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:11][CH:10]=2)[C:6]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[N:7]1)(=[O:28])=[O:27]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(C(F)(F)F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)n1nc(N2C(=O)c3ccccc3C2=O)c2cc(C(F)(F)F)ccc21
Yield: 70.3 %

Procedure:
2-(5-Trifluoromethyl-1H-indazol-3-yl)-isoindole-1,3-dione (350 mg, 1.06 mmol), TEA (0.3 mL, 2.12 mmol) in DCM (5 mL) was treated with MsCl (182 mg, 1.59 mmol) at 0° C. for 2 hours. The solvent was removed and the residue was purified by silica gel column chromatography using hexanes:ethyl acetate 1:1 to give the title compound as white solid (305 mg, 69%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11](=[O:22])[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11](=[O:22])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)n(-c3ccccn3)nc2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nn(-c2ccccn2)c(=O)cc1-c1ccc(O)cc1

Procedure:
5-(4-Hydroxy-phenyl)-6-methyl-2-pyridin-2-yl-2H-pyridazin-3-one was prepared from 5-(4-Methoxy-phenyl)-6-methyl-2-pyridin-2-yl-2H-pyridazin-3-one and BBr3 in CH2Cl2 using the procedure described in Example 91 Step 3; Mp 252-4° C.; MS m/z 280 (M+H).