Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1C(C(N2CCN(C)CC2)=O)=C(C)NC=1C=O.[Na].[CH3:20][C:21](=[O:26])[CH2:22][C:23](=[O:25])[CH3:24].[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=C>[Na].C(O)(=O)C.C(O)C>[C:23]([CH:22]([CH3:1])[C:21](=[O:26])[CH2:20][CH2:28][C:27]([O:31][CH2:32][CH3:33])=[O:30])(=[O:25])[CH3:24]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: C=CC(=O)OCC
Reactant: CC(=O)CC(C)=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCC(=O)C(C)C(C)=O
Temperature: 25 °C

Procedure:
Sodium metal (1 5 g) was placed in a 3 L 3 neck round bottom flask equipped with a thermometer, reflux condenser and mechanical stirring and placed in an oil bath. Absolute ethanol (1 L) was added with stirring. When the sodium had dissolved, 350 g of pentan-2,4-dione was added all at once and then 310 g of ethyl acrylate added over 30 minutes. The mixture was refluxed for 2.5 hours and then allowed to cool to room temperature overnight. Glacial acetic acid (3 mL) was added and the solvent removed by rotary evaporation. The residue was filtered through a pad of diatomaceous earth and distilled in a wiped film still at 0.1 mm. The distillate was redistilled using a 10 inch vacuum jacketed Vigreux column to give 518 g of ethyl 5-acetyl-4-oxohexanoate, BP 84-92° C. at 0.2-0.7 mm.
Reaction SMILES: Cl[C:2]([S:4][Cl:5])=[O:3].[CH3:6][CH:7]([OH:10])[CH2:8][CH3:9]>>[CH3:6][CH:7]([O:10][C:2]([S:4][Cl:5])=[O:3])[CH2:8][CH3:9]
Reactant: CCC(C)O
Reactant: O=C(Cl)SCl
Product: CCC(C)OC(=O)SCl
Yield: 39.1 %

Procedure:
Chlorocarbonylsulfenyl chloride (13.1 g, 0.1 mol) was mixed with 2-butanol (6.7 g, 0.09 mol) and warmed to about 35° to 40° C. for one hour. Distillation resulted in the title compound (5.93 g) Bp. 70° C./0.8 mm Hg. NMR spectrum was consistent with the structure.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:12]([Cl:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([OH:14])[CH:5]=1.Cl[CH2:16][CH2:17][S:18][CH3:19]>CN(C)C=O>[NH2:3][C:4]1[C:12]([Cl:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:14][CH2:16][CH2:17][S:18][CH3:19])[CH:5]=1
Reactant: CSCCCl
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCOc1cc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
A cooled (5° C.) suspension of 60% sodium hydride oil dispersion (0.52 g, 13 mmoles) in anhydrous dimethylformamide (15 mL) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid (0.94 g, 5 mmoles), stirred for 15 minutes at 25° C., treated with (2-chloroethyl)methyl sulfide (1.66 g, 15 mmoles), and heated to 100° C. for 18 hours. The solution is cooled, concentrated in vacuo, and added to water (25 mL). The aqueous solution is extracted with ether, and the extract is dried (MgSO4), concentrated in vacuo, taken up in 50% aqueous ethanol (50 mL), treated with potassium hydroxide (5.0 g), and refluxed for one hour. The mixture is concentrated, diluted with water to 75 mL total volume, extracted with ether, and acidified to pH 3 with concentrated HCl. The precipitate is filtered, washed with water, air dried, and recrystallized from ethyl acetate to afford 0.74 g (57%) of product as fine voluminous white needles, mp 137.5°-139.5° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(CCCCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>ClCCl.O1CCCC1>[C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: OCCCCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 139.9 %

Procedure:
To the phenol resin (100 mg), 4-phenylbutan-1-ol (0.42 mmol) was added at room temperature, followed by the addition of dry tetrahydrofuran (0.4 mL) and dichloromethane (0.4 mL). At room temperature, tri-n-butylphosphine (0.42 mmol) was added dropwise thereto and further 1,1′-azobis(N,N-dimethylformamide) (0.42 mmol) was added. The mixture was shaken at room temperature for 5 hours. The resin was taken up by filtration, washed with a mixed solvent (dichloromethane:tetrahydrofuran=1:1) 4 times and dichloromethane 2 times and then dried to give a phenyl ether resin (about 100 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=2)[CH:6]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@@H:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([NH:48][C@@H:49]([C:62]3[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=3)[C:50]3[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=3)=[O:16])=[CH:9][N:8]=2)[CH:6]=1
Reactant: O=C(O)c1cnc(-n2cc(F)cn2)nc1O
Reactant: CCOP(C)(=O)c1ccc([C@@H](N)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cc(F)cn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 18.7 %

Procedure:
To a stirred solution of 28-g (2.8 g, 12 mmol) and Et3N (3.5 g, 34 mmol) in MeCN (30 ml) was added HATU (4.8 g, 12 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((S)-amino(4-fluorophenyl)methyl)phenyl(methyl)phosphinate, 19-d, (3.5 g, 1 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Then it was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=l/1) to provide the product, 28-h, (1.2 g, 18.7%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7](N3CCNCC3)=[CH:8][C:9]=2[CH2:11]CC)[S:4][C:3]=1[C:20]([NH2:22])=[O:21].C([O-])([O-])=[O:24].[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].[H-].[Na+]>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][O:24][C:7]1[N:6]=[C:5]2[S:4][C:3]([C:20](=[O:21])[NH2:22])=[C:2]([NH2:1])[C:10]2=[C:9]([CH3:11])[CH:8]=1
Reactant: CCCc1cc(N2CCNCC2)nc2sc(C(N)=O)c(N)c12
Reactant: COC(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C)c2c(N)c(C(N)=O)sc2n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 8.7 %

Procedure:
To a mixture of the 4-methyl-mercaptopyridone intermediate (prepared analogous to Example 1) (62 mg) and K2CO3 (70 mg) in DMF (1 mL) was added methyl bromoacetate (50 mg). The mixture was heated under Ar at 70° C. for 2 h. After cooling to 0° C., the mixture was treated with NaH (60%, 10 mg) and stirred at room temperature for 30 min. The mixture was then poured into ice —NH4Cl mixture, extracted with EtOAc, dried with Na2SO4 and concentrated. The residue was purified by preparative TLC, providing 5 mg of the title compound (white solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([NH2:13])[NH:10][N:9]=1.[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=O)[CH2:26][C:27](OCC)=[O:28])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]2[NH:13][C:25]([C:21]3[CH:20]=[C:19]4[C:24](=[CH:23][CH:22]=3)[N:16]([CH2:14][CH3:15])[N:17]=[CH:18]4)=[CH:26][C:27](=[O:28])[N:10]2[N:9]=1
Reactant: Nc1nc(-c2ccccc2Cl)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2CC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CCn1ncc2cc(-c3cc(=O)n4nc(-c5ccccc5Cl)nc4[nH]3)ccc21
Yield: 40.4 %

Procedure:
To a solution of 3-(2-chlorophenyl)-1H-1,2,4-triazol-5-amine (50 mg, 0.25 mmol) in n-BuOH (0.2 mL) was added ethyl 3-(1-ethyl-1H-indazol-5-yl)-3-oxopropanoate (100 mg, 0.37 mmol) and p-TsOH (10 mg) at room temperature. After refluxing overnight, the solids were collected by filtration and washed with methanol (3×2 mL) to afford 2-(2-chlorophenyl)-5-(1-ethyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a yellow solid (39.5 mg, 40%).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH2:3][CH3:4])[CH3:2].CCN(CC)CC.[CH3:19][NH:20][C:21](=S)[OH:22]>C(#N)C>[CH3:19][NH:20][C:21](=[O:22])[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:1]([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccccc1O
Reactant: CNC(O)=S
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(C)c1ccccc1OC(=O)NC
Reaction time: 30 h

Procedure:
To a solution of 2-Sec. butylphenol (1.5 g, 0.01 mole) 0.2 ml of Et3N was added under stirring. S-methyl ester of N-methylcarbamothioic acid (1.05 g, 0.01 mole) in acetonitrile (10ml) was added dropwise over a period of 4 hrs, keeping reflux temperature. After 30 hr, acetonitrile was evaporated under vacuum. The residue was taken in dichloromethane (25 ml), washed with water and a 5% cold NaOH solution, followed by water and brine and dried over sodium sulphate. After removal of the solvent, the liquid residue obtained was further purified by distillation to give 2-Sec. butylphenyl N-methylcarbamate of the formula VI; IR: 3329 (N--H), 1730 (--COO), 1535, 1490 and 750 (aromatic); PMR (CdCl3, 90 MHz): 0.81 (3H, 1, primary methyl of side chain), 1.18 (3H, d, J=7 Hz, secondary/methyl of side chain), 1.58 (2H, m, methylene protons of side chain), 2.88 (4H, doublet overlapping a multiplet, NH--CH3 and benzylic proton), 4.97 (1H, br s, N H) and 6.95 to 7.25 (4H, m, aromatic).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:12][C:13]1[CH:18]=[C:17]([CH:16]=[CH:15][CH:14]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-hydroxybenzoate (0.400 g; 2.63 mmol), 3-fluorobenzene boronic acid (0.735 g; 5.26 mmol), copper acetate (0.955 g; 5.26 mmol) and pyridine (0.425 mL; 5.26 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH:13]([CH3:19])[CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[C:48]([O:56][CH2:57][CH3:58])(=[O:55])[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>>[CH2:57]([O:56][C:48](=[O:55])[CH:49]([C:16](=[O:17])[CH:15]=[CH:14][CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:22]=[CH:23][C:3]([C:2]([F:24])([F:25])[F:1])=[CH:4][CH:5]=2)=[CH:21][CH:20]=1)[CH3:19])[C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH3:58]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C=CC(=O)O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Product: CCOC(=O)C(C(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCC
Yield: 87 %

Procedure:
One proceeds in an analogous manner to the process disclosed in Example 4 by reacting 4-[4'-(4"-trifluoromethyl-phenoxy)-phenoxy]-2-pentenoic acid at first with 12 g of pivaloyl chloride and thereafter with diethyl-ethoxy-magnesium malonate prepared from 17.6 g of diethyl malonate. The reaction mixture is worked up. 43 g of the viscous oily desired compound are obtained which turns to a faint yellow crystalline product on standing. Mp.: 52°-55° C., yield 87%.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)N>C(O)(=O)C.C(OCC)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Solvent: CCOCC
Solvent: CC(=O)O
Product: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 150 °C
Yield: 70.1 %

Procedure:
A suspension of N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (500 mg, 2.24 mmol) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (564 mg, 2.24 mmol) in acetic acid (2.5 ml) was heated under microwave at 150° C. for 2 minutes. The crude mixture was diluted with diethyl ether and the precipitated solid was filtered, rinsed with ether and dried under vacuum to give the title compound as a white solid (675 mg, 70%); NMR spectrum: 3.79 (t, 2H), 4.31 (t, 2H), 5.26 (s, 2H), 7.18 (t, 1H), 7.25 (d, 1H), 7.29-7.33 (m, 2H), 7.44-7.49 (m, 1H), 7.57 (d, 1H), 7.87 (s, 1H), 8.27 (s, 1H), 8.47 (s, 1H); Mass Spectrum: 430 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1C=CC=CC=1>[Cl:20][CH2:21][C:22]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:2]=1[CH3:1])=[O:23]
Reactant: Cc1cccc(C)c1NCC=O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cccc(C)c1N(CC=O)C(=O)CCl
Temperature: 0 °C

Procedure:
The dimethyl acetal of 2-(2,6-dimethylanilino)-acetaldehyde (12.2 grams), triethylamine (8.1 ml) and benzene (50 ml) were charged into a reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture was cooled to about 0° C. and chloroacetyl chloride (4.4 ml) was incrementally added with stirring. After the addition was complete stirring was continued and the reaction mixture was permitted to warm to room temperature. After this time the mixture was filtered, washed with dilute hydrochloric acid and stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2,6-dimethylanilino)acetaldehyde.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:23])[CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].N1C=CC=CC=1.[C:30](Cl)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][CH2:2][CH:3]([O:23][C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:20])[CH3:21])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(O)CBr
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(CBr)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-bromo-2-hydroxy-1-(N-CBZ-L-valyloxy)-propane (7.9 g, 20 mmol) and pyridin (3.2 g, 40 mmol) in 250 ml dichloromethane was added dropwise a solution of stearoyl chloride (9.1 g, 30 mmol) in 50 ml dichloromethane between 10° C. and 15° C. The solution was stirred overnight at room temperature. 150 ml of 5% sodium hydrogen carbonate solution was added and the mixture stirred for 30 minutes. The organic phase was separated and the water phase was extracted two times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo . The product was isolated by silica gel column chromtography. Yield: 10.5 g
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)=[O:6].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([Sn](CCCC)(CCCC)CCCC)=[N:31][CH:32]=1.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>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([C:2]2[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:18]=2)[C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=2)=[O:6])=[N:31][CH:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: Cc1ncc(CNC(=O)c2cc(Br)cc(C(=O)N3CCCC3)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCCC3)c2)nc1

Procedure:
A mixture of 3-bromo-N-((2-methylpyrimidin-5-yl)methyl)-5-(pyrrolidine-1-carbonyl)benzamide (25 mg, 0.059 mmol), 5-methyl-2-(tributylstannyl)pyridine (40 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.0043 mmol), and toluene (1 mL) under nitrogen was subjected to microwave irradiation at 120° C. for 1 hour. After cooling, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated. The residue was purified by flash chromatography to afford the title compound as a white solid.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][CH:3]=[C:2]1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1.C([Li])CCC.[BH:30]([OH:32])[OH:31].O[C:34]([C:37](O)([CH3:39])[CH3:38])([CH3:36])[CH3:35]>C1COCC1>[C:16]([Si:13]([CH3:14])([CH3:15])[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1[S:1][C:2]([C:20]2[S:21][C:22]([B:30]3[O:32][C:37]([CH3:39])([CH3:38])[C:34]([CH3:36])([CH3:35])[O:31]3)=[CH:23][CH:24]=2)=[CH:3][CH:4]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCc1ccc(-c2cccs2)s1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OBO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-c3ccc(CCCCCCO[Si](C)(C)C(C)(C)C)s3)s2)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To an ice-cooled solution of (6-[2,2′]bithiophenyl-5-yl-hexyloxy)-tert-butyl-dimethylsilane (10 g, 19.76 mmol) in anhydrous THF (150 ml) was added dropwise a solution of n-butyllithium (2.5 M in hexanes, 7.91 ml, 19.76 mmol) under nitrogen, with stirring. After 2 h, pinacol boronate (4.04 g, 21.72 mmol) was added. The ice bath was removed, and the resultant mixture was stirred overnight at room temperature. The reaction was quenched with the addition of saturated aqueous NH4Cl and the mixture extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica, eluting with petroleum ether/ethyl (9:1), to give the product as a blue oil (9.52 g, 72%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.46 (d, J=3.6 Hz, 1H, Ar—H), 7.10 (d, J=3.6 Hz, 1H, Ar—H), 6.99 (d, J=3.4 Hz, 1H, Ar—H), 6.62 (d, J=3.4 Hz, 1H, Ar—H), 3.56 (t, J=6.4 Hz, 2H, OCH2), 2.73 (t, J=7.4 Hz, 2H, ArCH2), 1.21-1.70 (m, 20H, CH2 and CH3), 0.86 (s, 9H, CH3), 0.01 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 145.9 (2×quat.), 144.8 (quat.), 138.0 (CH.), 134.7 (quat.), 125.0 (CH), 124.2 (CH), 124.1 (CH), 84.1 (quat.), 63.2 (OCH2), 32.8 (CH2), 31.6 (CH2), 30.2 (CH2), 28.9 (CH2), 26.0 (CH3) 25.6 (CH2), 24.8 (CH3), 18.4 (quat.), −5.2 (CH3); MS (m/e): 506 (M+, 32%), 331 (31), 305 (31), 279 (100), 261 (32), 205 (51), 83 (71).
Reaction SMILES: [C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[NH:16][CH2:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>CN(C)C=O>[C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[N:16]([CH2:34][CH2:33][CH2:32][CH2:31][Br:30])[CH2:15]3)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCCCBr
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CNC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CN(CCCCBr)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
A solution of 17β-N-t-butylcarbamoyl-6-azaandrost-4-en-3-one (373 mg. 1.00 mmol), in dimethylformamide is treated with sodium hydride (50 mg, 60%, 1.25 mmol) at 0° C. for 30 minutes before the addition of 1,4-dibromobutane (0.179 mL, 1.5 mmol). After 30 minutes further the reaction is poured into ice water and extracted with methylene chloride (3×10 mL), dried over Na2SO4, concentrated and filtered through a plug of silica with 1:1 methylene chloride/acetonitrile followed by 10% methanol/methylene chloride. The methanolic fractions are concentrated to give crude 17β-N-t-butylcarbamoyl-6-(4-bromobutyl)-6-azaandrost-4-en-3-one. This material is dissolved in toluene (5 mL) and dimethylformamide (1.5 mL), sodium iodide added and the mixture heated at reflux for 7 hrs. The reaction is cooled, water added, extracted with methylene chloride (3×20 mL), dried over Na2SO4, concentrated and chromatographed (50% ethyl acetate/hexane) to give 17β-N-t-butylcarbamoyl-6-azaandrost-4,6-butano-4-en-3-one as a white solid; yield: 150 mg (35%). Recrystallization from ethyl acetate/hexanes gives an analytical sample as white crystals; m.p. 173°-174° C. Anal. Calcd. for C27H42N2O2.1/4H2O; C, 75.29; H, 9.94; N, 6.50. Found: C, 75.21; H, 10.04; N, 6.20.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](O)(=O)[CH2:11]O.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[ClH:17].[Cl:17][CH2:11][C:10]1[NH:1][C:2]2=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CO
Reactant: Cc1ccc(N)c(N)n1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2nc(CCl)[nH]c2n1
Product: Cl

Procedure:
In accordance with scheme 4, a corresponding 2,3-diamino-6-methyl pyridine (R5=methyl, XV) and glycolic acid were heated at 150° C. for about 1 h. The residue was suspended in chloroform and treated with thionyl chloride for about 4 h. After workup 2-chloromethyl-5-methyl-3H-imidazo[4,5-b]pyridine hydrochloride (XVII) was obtained.
Reaction SMILES: NCOC(=O)CCC1C=CC=CC=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[Br:23]Br>>[Br:23][C:20]1[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][C:17]=1[CH:18]=[O:19]
Reactant: BrBr
Reactant: O=Cc1cccc(O)c1
Agent: NCOC(=O)CCc1ccccc1
Product: O=Cc1cc(O)ccc1Br

Procedure:
Reaction Scheme 9 shows the synthetic route to prepare aminomethyldihydrocinnamate headpiece. 3-Hydroxybenzaldehyde (29) is reacted with bromine to give 2-bromo-5-hydroxybenzaldehyde (30), which is then coupled to t-butylacrylate to give the compound (31). Compound (31) is treated with NH2OH to give oxime (32), which undergoes hydrogenation to give aminomethyldihydrocinnamate (33). Various functional groups (Z2) can be introduced at the aminomethyl portion of compound (33) to afford compound (34).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:26])[CH:3]=1.[O:27]1[CH2:31][CH:30]=[N:29][C:28]1=[O:32]>>[CH:23]1([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:5]4[C:6]([F:8])=[CH:7][C:2]([N:29]5[CH2:30][CH2:31][O:27][C:28]5=[O:32])=[CH:3][C:4]=4[F:26])=[O:10])[CH2:12][CH2:13]3)=[N:18][CH:19]=2)[CH2:25][CH2:24]1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Reactant: O=C1N=CCO1
Product: O=C(c1c(F)cc(N2CCOC2=O)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Yield: 68.2 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2,6-difluorophenyl)[4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl]methanone (422 mg) described in Preparation Example 189 and oxazolin-2-one (104 mg), the title compound (292 mg) was obtained.