Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.CS(C)=O.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>CO>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH:2]2[C:7]3=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]3[CH:5]([CH3:16])[CH2:4][CH2:3]2)=[CH:24][CH:23]=1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Reactant: Nc1ccc(Br)cc1
Solvent: CO
Solvent: CS(C)=O
Product: CC1CCC(Nc2ccc(Br)cc2)c2ncc(C(=O)O)c(=O)n21
Reaction time: 72 h
Yield: 45.2 %

Procedure:
2.9 g. (0.01 mole) of (-)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ([α]D20 =-105°, c=2, methanol) are dissolved in 5 ml. of dimethyl-sulfoxide and 3.8 g. (0.022 mole) of p-bromo-aniline are added. The solution is allowed to stand for 3 days at room temperature in an open vessel. 20 ml. of methanol are then added to the reaction mixture. The precipitated crystals are then filtered and washed with methanol. 1.7 g. (45.2%) of (-)-9-(4-bromo-anilino)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained. Melting point: 210°-211° C.
Reaction SMILES: C1(C)C=CC=CC=1.S(=O)(=O)(O)O.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]=1[OH:24].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[C:25]([O:24][C:15]1[C:14]([Cl:13])=[CH:22][C:21]([Cl:23])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A 1 L, round-bottom, three neck flask equipped with: a mechanical stirrer, a thermometer and a 125 mL dropping funnel with pressure equilibration was placed in a water bath maintained at 65° C. The following reagents were subsequently charged to the flask with an efficient stirring: 250 mL of dry toluene, 2.5 mL of concentrated sulfuric acid and 207 g of well ground, solid 3,5-dichlorosalicylic acid, which forms a mobile suspension. When the temperature of this constantly stirred mixture reached 60° C. (with the water bath temperature maintained at 65° C.) a drop-wise addition of 108 g (100 mL) of acetic anhydride was initiated and completed within 30 min. During the acetic anhydride addition the temperature of the reaction mixture was not allowed to exceed 75° C. After completing the addition, the mixture was stirred and heated to 70° C. for another 4 h. After this time, the agitation was stopped and the mixture cooled over night to room temperature. The white crystals that separated from the mixture were filtered off, washed with 2×10 mL of ice-cold toluene and vacuum dried at 50° C. to yield 206 g (82.7% yield) of 2-acetoxy-3,5-dichlorobenzoic acid. An additional 30.6 g (12.3%% yield) of the product was recovered by: concentrating the filtrate to ½ of the original volume, cooling the solution in an ice-water bath, filtering off the crystalline product and vacuum drying it at 50° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:35](=[O:36])[C:34]4[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:33]=4[CH3:32])=[CH:21][CH:22]=3)=[O:24])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Cc1nc2c(s1)CCN(C(=O)c1ccc(N)cc1)c1ccccc1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(s1)CCN(C(=O)c1ccc(NC(=O)c3cc(F)ccc3C)cc1)c1ccccc1-2
Reaction time: 18 h

Procedure:
To a stirred solution of 0.235 g of 5,6-dihydro-2-methyl-6-(4-aminobenzoyl)4H-thiazolo[5,4-d][1]-benzazepine in 6 ml of methylene chloride under argon is added 107 μl of triethylamine followed by the dropwise addition of 2-methyl-5-fluorobenzoyl chloride in 1 ml of methylene chloride. Stirring is continued at room temperature for 18 hours. The reaction mixture is washed with H2O, saturated NaHCO3 and brine. The organic layer is treated with activated carbon, filtered through MgSO4 and the filtrate evaporated in vacuo to a residue which is chromatographed on silica gel by elution with 15% ethyl acetate in methylene chloride to give 300 mg of the desired product as a white solid; Anal. Calc'd for C27 H22FN3O2S: C,68.8; H,4.7; N,8.9; F,4.0; S,6.8 Found: C,67.7; H,4.6; N,8.5; F,3.7; S,6.4.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[NH:24][C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[C:34](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:34])[C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a mixture of 0.10 g of methyl [3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate, 1 ml of acetonitrile, and 31 mg of potassium carbonate was added 32 mg of methyl iodide, and the mixture was stirred at room temperature for 1.5 hours. Then, 64 mg of methyl iodide was added, and the mixture was stirred at 50° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 97 mg of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[CH2:8][C:6]=2[N:7]=1.[CH3:22][NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)=[O:25].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[CH:12]1([CH2:11][N:9]2[CH2:10][C:5]3[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])=[N:3][C:2]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][C:24]([NH:23][CH3:22])=[O:25])=[CH:32][CH:31]=4)=[N:7][C:6]=3[CH2:8]2)[CH2:14][CH2:13]1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC2CC2)C3)cc1
Temperature: 130 °C
Yield: 51.5 %

Procedure:
To a solution of (S)-4-(2-chloro-6-(cyclopropylmethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 8) (50 mg, 0.16 mmol) and 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (407 mg, 0.39 mmol) in DME/EtOH/H2O (7:3:2) (5 mL) was added Pd(PPh3)2(Cl)2 (7 mg, 0.008 mmol) and Na2CO3 (26 mg, 0.24 mmol). The reaction mixture was then heated by microwave at 130° C. for 30 minutes. The crude reaction mixture was then partitioned between water and EtOAc, the organic layer recovered, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by prep. LCMS (low pH). The solvent was removed in vacuo. The residue was then re-purified by Flash SCX2 column chromatography, affording the title compound as a white solid (34.8 mg, 51% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])=[O:6].[CH3:18][N:19](C=O)C>[Cu]>[C:18]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])=[O:6])#[N:19]
Reactant: CCCN(CCC)C(=O)c1ccc(F)c(Br)c1
Reactant: CN(C)C=O
Agent: [Cu]
Product: CCCN(CCC)C(=O)c1ccc(F)c(C#N)c1
Temperature: 25 °C

Procedure:
Combine 3-bromo-4-fluoro-N,N-dipropylbenzamide (1.0 g, 3.3 mmol) with copper cyamide (0.45 g, 5.0 mmol) in DMF (5 mL) and heat at reflux until all starting material is consumed. Cool to room temperature and partition between ethyl acetate and saturated aqueous sodium bicarbonate. Separate the organic layer and wash with saturated aqueous sodium bicarbonate, saturated sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH3:58])[C@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:4]([NH:6][C@@H:7]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:25]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[C@@H:9]([OH:36])[CH2:8][C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:2]([CH3:1])([CH3:58])[CH3:59])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccnc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccnc(-c2ccc(C[C@H](N)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 80D (0.054 g, 0.068 mmol) in a mixture of ethyl acetate (0.3 mL) and methanol (0.3 mL) was treated with Pd(OH)2 on carbon (0.014 g, 20% Pd by wt.) and HCl solution (0.068 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:6]=2[CH:17]=1.[CH3:18][S:19]([Cl:22])(=[O:21])=[O:20].N1CCCCC1>ClCCl>[ClH:22].[CH3:16][N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[C:6]3[CH:17]=[C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=2)[CH2:15][CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC(c2coc3ccc(N)cc23)CC1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CN1CCC(c2coc3ccc(NS(C)(=O)=O)cc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
A mixture of 0.018 gm (0.07 mMol) 5-amino-3-(1-methylpiperidin-4-yl)benzofuran, 16.2 μL (0.21 mMol) methanesulfonyl chloride, and 0.100 gm (4 equivalents) of polymer bound piperidine in 1.5 mL dichloromethane. The reaction mixture was agitated for 24 hours at room temperature. The reaction mixture was then loaded onto a VARIAN BOND ELUT SCX™ (Varian, Harbor City, Calif., U.S.A.) ion exchange column, eluting first with several volumes of methanol and then with 10 mL 2M ammonia in methanol. Fractions containing product were combined and concentrated under reduced pressure. The residue was dissolved in methanolic hydrogen chloride and then the solvent removed. This step was repeated three times to provide 0.0061 gm of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:11][C:12]1[N:13]([C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=2)[CH:14]=[CH:15][N:16]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(O)c1cnc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ncc(C(=O)O)cn1
Temperature: 25 °C

Procedure:
2-Chloropyrimidine-5-carboxylic acid (0.75 g), 2-methylimidazole (0.117 g) and potassium carbonate (1.96 g) in 3.75 mL of N,N-dimethylformamide are heated in microwave at 50° C. for 30 min, then cooled to room temperature and acidified with 3 mL of 1 N HCl, followed by addition of conc. HCl to pH 2. The precipitate is filtered, washed with minimum amount of water, diethyl ether and dried in vacuo to afford the title compound. LC (method 20): tR=0.48 min; Mass spectrum (APCI): m/z=205 [M+H]+.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:18][CH:15]1[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: NC1CC1
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
In an argon atmosphere, 6.22 g (26.7 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 30 mL of hexane and after adding 3.14 g (56.0 mmol) of cyclopropylamine, the mixture was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 100° C./3.7×102 Pa) to obtain 1,3-di-tert-butyl-2-cyclopropylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHcPr) as a colorless liquid (yielded amount: 6.07 g, yield: 90%).
Reaction SMILES: [I:1]I.N[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8].[O-]S([O-])=O.[Na+].[Na+]>CC#N.O>[I:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(C)c(I)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.1 %

Procedure:
To a stirring mixture of 23.0 g (90.6 mmol) of I2 and 5.4 mL (45.5 mmol) of tert-butylnitrile in 40 mL of CH3CN at 35° C. was added 5.0 g (30.3 mmol) of methyl 3-amino-4-methylbenzoate in 4 portions. Stirring was continued with cooling to r.t. in the dark (light off only). After 2.5 h, 400 mL of Na2SO3 in H2O was added gradually. The layers were separated, and the organic layer was washed with 80 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 5.7 g of methyl 3-iodo-4-methylbenzoate as a red liquid with some impurity in approximately 68% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][O:10]C2=O)[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH:3]=1.[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]([NH:8][C:6]2[CH:5]=[C:4]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:3]=[C:2]([NH:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:7]=2)[CH2:11][OH:10])=[CH:18][CH:17]=1
Reactant: Cn1cc(-c2cc(Cl)nc(N3C(=O)OCC3c3ccc(F)cc3)c2)cn1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Nc3cnccn3)nc(NC(CO)c3ccc(F)cc3)c2)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
80 mg of 3-[6-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-4-(4-fluorophenyl)oxazolidin-2-one, 20 mg of 2-aminopyrazine, 20 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 41 mg of sodium t-butoxide and 22 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2.5 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 34 mg of the objective compound as white powder.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=O)[CH2:16][OH:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:15]([CH2:16][OH:17])=[N:14][N:13]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CO
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 1-(6-phenylpyridazin-3-yl)hydrazine (2.00 g, 10.7 mmol), glycolic acid (0.825 g, 10.8 mmol), p-TsOH.H2O (2.55 g, 13.4 mmol) in PhMe (50 mL) was refluxed for 14 h. PhMe was removed in vacuo. The resulting solids were diluted with water (30 mL). The mixture was brought to pH˜10 with 2N NaOH. The solids were isolated solid by filtration, washed with water and dried under vacuum to give an off white solid which was used without further purification. (ESI, pos. ion) m/z: 227.0 (M+H). Step 2.
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH2:4].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.C(OCC)(=O)C>CN(C=O)C>[Si:21]([O:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH:3]=[CH2:4])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To the resultant compound from Example 4 (0.264 g, 0.932 mmol) in DMF (4 mL) was added tert-butyldimethylsilyl chloride (0.300 g, 1.99 mmol) and imidazole (0.269 g, 3.95 mmol). The mixture was stirred at room temperature for 12 hours, poured into ethyl acetate and washed sequentially with 0.5M H3PO4, saturated NaHCO3 solution and brine, then dried over Na2SO4 and evaporated to afford 0.355 g (96%) of the desired compound. Mass spectrum: (M+H)+ =398.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17](=[O:26])[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:13]N(C)C)=[CH:8][CH:7]=1)([OH:3])=[O:2].Cl.[OH-:28].[K+]>>[OH:19][C:18]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][CH:8]=2)=[CH:13][O:28]1
Reactant: [OH-]
Reactant: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(CCC(=O)O)cc1
Agent: Cl
Agent: [K+]
Product: O=C(O)CCc1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Yield: 93 %

Procedure:
A solution of 3.95 g of 2-[4-(2-carboxyethyl)phenyl]-1-dimethylamino-4-phenyl-1-butene-3,4-dione in 100 ml of 2% potassium hydroxide solution was stirred at room temperature for 31/2 hrs. The reaction mixture was poured onto 300 ml of icewater, acidified with 100 ml of 1N hydrochloric acid and extracted with methylene chloride. The organic extract was washed with water, dried, filtered and evaporated. Recrystallization of a sample of the residue from methylene chloride-petroleum ether gave 2-hydroxy-2-phenyl-4-[4-(2-carboxyethyl)phenyl]-3(2H)-furanone as colorless crystals, m.p. 89°-95° dec., after drying at 50° C.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])=[CH:15][CH:14]=1.[Li]CCCC.CN(C=O)C>>[CH3:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:8]=[O:9])=[CH:14][CH:15]=1)([CH3:23])[CH2:20][CH3:21]
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: CCC(C)(C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(C=O)cc1
Yield: 90 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 1-bromo-4-(1,1-dimethylpropyl)-benzene [synthesized in analogy to a procedure described in J. Chem. Res. Miniprint. 12:2701-2733 (1997)] (250 mg, 1.10 mmol), n-BuLi (825 μl, 1.6M solution in hexane, 1.32 mmol) and DMF (427 μl, 5.50 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-(1,1-dimethylpropyl)-benzaldehyde (175 mg, 90%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 9.99 (s, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H), 1.69 (q, J=7.5 Hz, 2H), 1.32 (s, 6H), 0.68 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]5[CH2:29][O:28]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]([OH:28])[CH2:29][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCC4CO4)cc32)nc1-c1cccc(Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CC(O)COc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Yield: 56.9 %

Procedure:
A mixture of 0.021 g (0.05 mmole) of 4-(3-chloro-phenyl)-2-(6-oxiranylmethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.39a), 0.5 mL of dimethylformamide, 0.035 g (0.25 mmole) of potassium carbonate and 0.017 mL (0.15 mmole) of 1-methyl-piperazine was heated at 100 degrees for 5 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 20:80-100:0) to give 0.015 g of 4-(3-chloro-phenyl)-2-{6-[2-hydroxy-3-(4-methyl-piperazin-1-yl)-propoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.39) as a white powder. MH+/Z=527
Reaction SMILES: [N:1]#[C:2][NH2:3].CC(C)([O-])C.[K+].[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([CH:25]=[C:26]2[O:30][C:29](SC)=[N:28][C:27]2=[O:33])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])([CH3:13])[CH3:12]>C(O)C>[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([CH:25]=[C:26]2[O:30][C:29]([NH:3][C:2]#[N:1])=[N:28][C:27]2=[O:33])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])([CH3:13])[CH3:12]
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)O1
Reactant: N#CN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2OC(NC#N)=NC2=O)cc(C(C)(C)C)c1O
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A suspension of 0.38 g (0.0090 mole) of cyanamide in 50 mL of ethanol is cooled in ice and treated in small portions with 0.93 g (0.0083 mole) of potassium tert-butoxide. After stirring for 15 minutes, 2.6 g (0.0075 mole) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-(methylthio)-4(5H)-oxazolone is added, followed by an additional 25 mL of ethanol. The mixture is stirred at reflux for 3 hours, then cooled to allow precipitation of the potassium salt of the product. The salt is filtered, washed several times with ether, suspended in 100 mL of cold water, and acidified with 1.0 mL of acetic acid. The mixture is stirred for 30 minutes and extracted with ethyl acetate (4×75 mL). The combined organic layers are washed with brine (2×150 mL), dried (anhydrous sodium sulfate), and evaporated to yield 1.0 g (38%) of the nitrile product, [5-[[3,5-bis(1,1 -dimethylethyl)-4-hydroxyphenyl]methylene]-4,5-dihydro-4-oxo-2-oxazolyl]cyanamide. A sample recrystallized from hexane:ethyl acetate had mp 220° C. dec.