Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[F:17][C:18]1[C:23](B(O)O)=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])(=O)C.[K+].C(O)C>O>[F:17][C:18]1[C:23]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: OB(O)c1cccnc1F
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
The 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (239 mg, 1 mmol) prepared at Step 6, 2-fluoropyridin-3-yl boronic acid (189 mg, 1.3 mmol), potassium acetate (216 mg, 2.2 mmol), and bis(di-tert-butyl-(4-dimethyl amino phenyl) phosphine)dichloropalladium (14 mg, 0.02 mmol) were added into a mixed solvent of ethanol and water (5/1). The reactant was refluxed and stirred under nitrogen pressure at 80° C. for 2 hours. After the reaction, the solution was concentrated and washed with water and salt water, and then extracted with ethylacetate. After drying the organic layer with sulfuric anhydride magnesium and vacuum concentrating, the residuals were refined by means of column chromatography, so that 279 mg of the target compound, 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (percentage yield: 93%), was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:39]=[CH:38][C:13]([C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])=[CH:12][CH:11]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]3[CH:38]=[CH:39][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[CH:11][CH:12]=3)[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCBr)cc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCN2CCOCC2)cc1
Temperature: 60 °C
Yield: 30.3 %

Procedure:
A solution of 4-(8-bromooctyl)-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (36.3 mg, 0.06 mmol, e.g. which can be as prepared in Intermediate 41) in N,N-dimethylformamide (6 ml) was treated with morpholine (0.021 ml, 0.24 mmol) and N,N-diisopropylethylamine (0.042 ml, 0.24 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (11 mg). LCMS showed MH+=605; TRET=2.39 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: c1cncc(CC2CCCN2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCCC1Cc1cccnc1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 3-(pyrrolidin-2-ylmethyl)pyridine (50.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H21N3O2: 349.1426, found 349.1693.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH2:11][C:12]#[N:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>O1CCCC1>[CH3:24][C:23]1[C:18]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][C:12]#[N:13])=[N:19][CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: CCOC(=O)C(CC#N)C(=O)OCC
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)(C(=O)OCC)c1ncc([N+](=O)[O-])cc1C

Procedure:
2-(Cyanomethyl)malonic acid diethyl ester (G. Casini et al, Ann. Chim. (Rome), 51, 366-74 (1961) (81 g) was reacted with sodium hydride (8.9 g) in tetrahydrofuran at 20° C. 2-Chloro-3-methyl-5-nitropyridine (G. E. Hawkins & A. Roe, J. Org. Chem., 14, 328 (1949)) (58.5 g) was added and the internal temperature was raised to 95°-105° C. (some tetrahydrofuran was distilled off) over 11 hours. The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3), the chloroform extracts were dried and concentrated in vacuo to give an oil (132 g). The oil was distilled under vacuum, the distillate collected at 60°-98° C. (vapour temp.) 0.2 mm Hg was discarded. The residues from the distillation (65 g) were dissolved in chloroform and filtered through a silica column and then concentrated, treated with charcoal and recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (30 g) m.p. 78°-80° C.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(O)(C)(C)C>[C:17]([NH:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: c1cc(-c2csnn2)ccc1OCC1CO1
Reactant: CC(C)(C)N
Solvent: CC(C)(C)O
Product: CC(C)(C)NCC(O)COc1ccc(-c2csnn2)cc1

Procedure:
To a solution of 660 mg. of 4-[4(2,3-epoxypropoxy)phenyl]-1,2,3-thiadiazole in 29.7 ml. of t-butylamine is added 3.3 ml. of t-butanol and the reaction mixture is stirred at room temperature for 24 hours. It is then evaporated to dryness under vacuo and the residue taken up in methylene chloride. The resulting solution is extracted with dilute hydrochloric acid and the aqueous phase made alkaline with sodium carbonate. It is then extracted with ethyl acetate and the organic extracts washed to neutrality, dried over sodium sulfate and evaporated to dryness. The solid residue is purified by two recrystallizations from methylene chloridehexane (after decolorization with charcoal) and then by three crystallizations from benzene, thus obtaining the pure 4-[4(3-t-butylamino-2-hydroxypropoxy)phenyl]-1,2,3-thiadiazole, m.p. 124°-125° C; λmax 256, 304 nm, (ε 20,000;2,000) ir 3340, 1615, 1580, 1535, 835 cm-1.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[NH:16][C:15]2=[O:22])=[CH:5][CH:4]=1.Cl[CH2:24][CH2:25][CH2:26][CH2:27][S:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:27][CH2:26][CH2:25][CH2:24][N:16]2[C:17]([CH3:20])([CH3:21])[C:18](=[O:19])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][S:9][C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[C:15]2=[O:22])=[CH:30][CH:31]=1
Reactant: CC1(C)NC(=O)N(CCCCSc2ccncc2)C1=O
Reactant: ClCCCCSc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(CCCCSc2ccncc2)C(=O)N1CCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To a suspension of 96 mg (2.4 mmol) of 60% sodium hydride (oily) in 15 ml of dimethylformamide, 587 mg (2.0 mmol) of 3-[4-(4-pyridylthio)butyl]-5,5-dimethylhydantoin was added, and the mixture was stirred at room temperature for 10 minutes. To this reaction mixture, 807 mg (4.0 mmol) of 4-(4-chlorobutylthio)pyridine was added with stirring under ice-cooling, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/ethanol =10:1) to give 0.74 g of the desired product (80.7% yield, yellow oil).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].CO[C:12](=[O:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=1.Cl>O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:17]([C:16]1[CH:15]=[CH:14][C:13]([C:12](=[O:23])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:22][CH:21]=1)=[O:19]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1ccc(C(=O)CC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
In a 2 1 four-necked flask equipped with a mechanical stirrer, dropping funnel, thermometer, reflux condenser, and a nitrogen-inlet tube, 32 gm (0.8 mol) of 60% sodium hydride, 79 gm (0.79 mol) of pinacolone, and 700 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream. To this solution, 70 gm (0.36 mol) of dimethylterephthalate in 300 ml of tetrahydrofuran was added dropwise over one hour. After the addition, the reaction mixture was refluxed with heating for 6 hours, and was cooled to room temperature. After addition of 180 ml of 2N aqueous hydrochloric acid, the reaction mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give a crude product. The crude product was recrystallized using hexane to obtain 78 gm of the target compound as colorless scales (yield: 66%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:28])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][Si](C(C)(C)C)(C)C)[CH:15]=2)=[N:8][C:7]=1[CH3:29])=[O:5])C.O.[OH-].[Li+]>C1COCC1.O>[OH:20][C:16]1[CH:15]=[C:14]([CH2:13][C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:29])[N:8]=2)=[O:28])[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1sc(NC(=O)Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(NC(=O)Cc2cccc(O)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A mixture of 2-{2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-acetylamino}-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.02 g, 2.347 mmol) and lithium hydroxide monohydrate (1 g, 23.83 mmol) in THF (21 mL) and water (7 mL)) was stirred at 25° C. for 16 h. The reaction was quenched by addition of aqueous 2N HCl (25 mL) followed by addition of sodium chloride. The resultant biphasic solution was extracted with 7:3 ethyl acetate/THF (3×125 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 2-[2-(3-Hydroxy-phenyl)-acetylamino]-4-methyl-thiazole-5-carboxylic acid (0.62 g, 90.4%) as a white solid. MS m/e 293.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]CC3C=CC=CC=3)[CH:14]=2)=[CH:8][C:7]=1[CH3:27]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[CH:8][C:7]=1[CH3:27]
Reactant: COC(=O)CCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Oc2cccc(O)c2)cc1C
Yield: 102 %

Procedure:
A mixture of 3-[4-(3-benzyloxy-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (10.54 g, 28.0 mmol) and 10% Pd/C (5 g) in ethyl acetate (150 mL) is purged with N2 and then H2. The mixture is stirred under a hydrogen balloon. Upon completion, the mixture is filtered through hyflo, and the solvent is removed in vacuo to afford 8.18 g (100%) of the titled compound. Rf=0.59 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C17H18O4 286, found 287 (M+1, 100%).
Reaction SMILES: [CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](Cl)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1>N1C=CC=CC=1>[CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](=[O:8])[NH:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: c1ccncc1
Product: CCCCCN(C(=O)Nc1ccc(C(=O)OC)cn1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 72 h
Yield: 11.2 %

Procedure:
A solution of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (53) (0.24 g, 0.73 mmole) in 3 mL pyridine was treated with 0.22 g of methyl 6-aminonicotinate (Bionet) and stirred at 40° C. for three days. Volatile materials were removed in vacuo and the residue was subjected to flash chromatography (SiO2, 10%-50% ethyl acetate/hexanes) to yield 37 mg of methyl 6-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-nicotinate (55).
Reaction SMILES: [CH2:1]([C:5]1([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[O:10][C:9](=[O:11])[CH:8]([Cl:12])[C:7](=[O:13])[CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.Cl>CN(C=O)C.C(NC(C)C)(C)C.C(Cl)Cl.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.[Cu]I>[Cl:12][CH:8]1[C:7](=[O:13])[CH2:6][C:5]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)([CH2:1][CH2:2][C:3]#[C:4][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[O:10][C:9]1=[O:11]
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Reactant: Oc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Cl
Temperature: 90 °C

Procedure:
A solution of 6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione (200 mg, 0.66 mmol) from Step 4 above, 3-iodophenol (145 mg, 0.66 mmol), bis(triphenylphosphine)palladium (II) dichloride (18 mg, 0.026 mmol), and copper (I) iodide (10 mg, 0.052 mmol) in DMF (0.66 mL) and diisopropylamine (0.66 mL) was sonicated for 1 minute and then heated to 90° C. for 20 minutes. The reaction was cooled to room temperature, and then diluted with 10 mL CH2Cl2 The reaction was then neutralized to a pH of 4 with 6 N HCl and the layers were separated. The aqueous layer was extracted with 3×10 mL CH2Cl2 and the organic layers were combined, and then dried over sodium sulfate. After filtering the solids, the organic layer was concentrated to a dark oil, which was used without further purification. MS (ESI): 359 (M−H), 361 (M+2−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:20]C)[C:10](=[O:19])[N:11]([CH3:18])[C:12]=2[CH2:16][CH3:17])[C:7]1=[O:22].[N+](=[CH2:29])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:20])[C:10](=[O:19])[N:11]([CH3:18])[C:12]=2[CH:16]2[CH2:29][CH2:17]2)[C:7]1=[O:22]
Reactant: CCc1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: Cn1c(C2CC2)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-5-vinyl-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (0.12 g, 0.32 mmol; Example 83, step 2) in diethyl ether (5 mL), a solution of diazomethane (˜3 mmol) in diethyl ether was added. Catalytic amount of palladium (II) acetate was added and the mixture was stirred at the same temperature for 30 minutes. The product mixture was filtered and concentrated under vacuum. The residue was subjected to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provide the cyclopropanation intermediate. Following the demethylation procedure described in Example 83, step 3, the above intermediate was converted to the titled compound.
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])C.Cl>C(O)C>[Cl:29][C:25]1[N:24]=[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:10]3[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:19]=2)[C:26]=1[CH:27]=[O:28]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
1.9 g of 4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acid dimethylaminomethylenamide were dissolved in 20 ml of ethanol and 20 ml of a saturated aqueous HCl solution were added. The mixture was heated under reflux for 2 hours, then the volatile constituents were removed in vacuo, the residue was taken up using 200 ml of water, the solution was adjusted to pH-7 using aqueous NaOH solution and stirred for 1 hour, and the precipitate was filtered off with suction. The product was dried in vacuo, and 1.7 g of a colorless solid were obtained,
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+:15]>CO>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1.[Na+:15]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-trifluoromethyl benzoic acid (0.100 g, 0.239 mmole) in methanol (2.0 mL), is added sodium hydroxide (0.093 g, 0.287 mmole) and stirred at room temperature for 2 hours. The mixture is concentrated to dryness in vacuo to give sodium 4-trifluoromethyl-benzoate as a white solid. It is then mixed with NH4OAc (8.32 g, 107.9 mmole) in glacial acetic acid (500 mL) and heated at 100° C. for 16 hours. After removed the solvents on rota-vapor, the residue is partitioned between ethyl acetate (300 mL) and saturated sodium bicarbonate (300 mL). Extracted the aqueous layer with ethyl acetate (300 mL) one more time. The combined organic is ish with brine (3×500 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography on silica gel column, gradient elute with 0 to 10% ethyl acetate in hexane and concentrated to provide the titled compound as a white solid. Mass [EI+] 300 (M++H).
Reaction SMILES: C(O[CH2:5][CH:6]=[CH2:7])(=O)C.C(N(CC)CC)C.CN(C)C(=NC)N(C)C.[CH2:24]([CH:31]1[C:35](=[O:36])[O:34][C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:7]([C:31]1([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:35](=[O:36])[O:34][C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:32]1)[CH:6]=[CH2:5]
Reactant: O=C1OC(c2ccccc2)=NC1Cc1ccccc1
Reactant: C=CCOC(C)=O
Agent: CN=C(N(C)C)N(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCC1(Cc2ccccc2)N=C(c2ccccc2)OC1=O

Procedure:
Allyl acetate (21.6 μL, 200 μmol) was added to a solution of triethylamine (56 μL, 400 μmol) or pentamethylguanidine (51.7 mg, 400 μmol) and 4-benzyl-2-phenyl-2-oxazolin-5-one (450 μmol) in acetonitrile (1 mL). Then a preformed solution of bis(η3 -allyl)di-,μ-chlorodipalladium (II) (1.8 mg, 4.9 μmol) and ligand 1 (10.4 mg, 15.1 μmol) in acetonitrile (1 mL) was added via cannula. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt (95:5) to give 4-allyl-4-benzyl-2-phenyl-2-oxazolin-5-one. ##STR15##
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[NH:6]2.[CH3:29][CH2:30]N(P1(N(C)CCCN1C)=NC(C)(C)C)CC.C(I)C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:29][CH3:30]
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCI
Product: CCn1c(=O)[nH]c2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31.2 %

Procedure:
200 mg (0.531 mmol) of the compound from example 33 and 146 mg (0.531 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 82 mg (0.531 mmol) of ethyl iodide in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 10:90→90:10). 67 mg of the title compound were obtained (31% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(N(CC)CC)C.[S:18]1[C:22]2[C:23]([C:27](Cl)=[O:28])=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1>C(OCC)(=O)C>[S:18]1[C:22]2[C:23]([C:27]([O:8][C:6]3[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=3)=[O:28])=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C(Cl)c1cccc2nnsc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)C=C(OC(=O)c2cccc3nnsc23)C1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
5.6 g (0.04 mol) of 5,5-dimethyl-1,3-cyclohexanedione are dissolved in a mixture of 4.4 g (0.044 mol) of triethylamine and 120 ml of ethyl acetate. 8.7 g (0.044 mol) of benzothiadiazole-7-carboxylic acid chloride are added dropwise at 15° to 20° C., and the mixture is subsequently stirred overnight at room temperature. The ethyl acetate solution is washed with H2O, dried and concentrated. Purification by column chromatography using ethyl acetate/hexane gives 10.5 g (87.5%) of the title compound, melting point 131°-133° C.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[C:3](=O)[CH3:4].[C:14]([C:16]1[CH:17]=[C:18]([NH:28][C:29]([NH2:31])=[S:30])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1)#[N:15]>>[Cl:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][C:2]1[S:30][C:29]([NH:28][C:18]2[CH:19]=[CH:20][C:21]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:16]([CH:17]=2)[C:14]#[N:15])=[N:31][C:3]=1[CH3:4]
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2C#N)cn1
Reactant: CC(=O)C(Cl)Cc1cccc(Cl)c1
Product: Cc1cn(-c2ccc(Nc3nc(C)c(Cc4cccc(Cl)c4)s3)cc2C#N)cn1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 54 mg (0.25 mmol) 3-chloro-4-(3-chlorophenyl)-2-butanone and 64 mg (0.25 mmol) [3-cyano-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 50 mg (48%) 5-[5-(3-chloro-benzyl)-4-methyl-thiazol-2-ylamino]-2-(4-methyl-imidazol-1-yl)-benzonitrile as a light yellow solid. MS ISP (m/e): 420.1/422.2 (100/38) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.55 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.88 (d, 1H), 7.55 (d, 1H), 7.36-7.20 (m, 5H), 4.03 (s, 2H), 2.27 (s, 3H), 2.18 (s, 3H).