Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
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: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ccccn2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 4-(dihydroxyboryl)benzoic acid (1.03 g, 6.21 mmol) and 2-bromopyridine (0.59 mL, 6.21 mmol) in ACN (20 mL) was added sodium carbonate (0.396 g, 3.74 mmol) in water (20 mL). The reaction mixture was degassed with argon and then tetrakis(triphenylphosphine)palladium (0.108 g, 0.09 mmol) was added. The reaction mixture was allowed to stir at 90° C. overnight and then filtered. The solution was concentrated to remove ACN and the aqueous solution was washed with DCM. The aqueous solution was acidified with 1N HCl and the resulting white precipitate was filtered and dried to give 4-pyridin-2-ylbenzoic acid (1.06 g, 85%). LCMS: (FA) ES+ 200.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([OH:20])=O)[N:4]=1.[C:21]1([S:27]([NH2:30])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH:30][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])=[O:20])[N:6]=1
Reactant: COc1cc(OC)nc(O[C@@H]2CCCC[C@H]2C(=O)O)n1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(O[C@@H]2CCCC[C@H]2C(=O)NS(=O)(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
trans-2-(4,6-Dimethoxypyrimidin-2-yl)oxycyclohexanecarboxylic acid (1.0 g), prepared as in Example 11, in dry tetrahydrofuran (10 ml) was added dropwise to a stirred solution of 1,1-carbonyldiimidazole (0.57 g) in dry tetrahydrofuran (10 ml) under nitrogen. The reaction mixture was stirred 30 minutes at ambient temperature, heated to reflux for 30 minutes and cooled to ambient temperature. Benzenesulphonamide (0.56 g) was added followed by dropwise addition of 1,8-diazabicyclo (5.4.0) undec-7-ene (0.54) in dry tetrahydrofuran (5 ml). The reaction mixture was stirred for 24 hours at ambient temperature, refluxed for 6 hours then poured into 1N hydrochloric acid (80 ml) and extracted with 3×100 ml portions of diethyl ether. The combined ether extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed on silica-gel, using a 2:1 dichloromethane/ethyl acetate eluant, to give 100 mg of the title compound, melting point 175° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@@H:19]1[CH2:23][C:22](=[O:24])[C:21]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Cl-].[NH4+]>ClCCl>[Si:11]([O:18][CH:19]1[CH2:23][C:22](=[O:24])[C:21]([S:25][CH2:26][CH2:27][CH2:28][CH:29]=[O:30])=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C(SCCCCO)C(=O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1C=C(SCCCC=O)C(=O)C1
Temperature: -30 °C
Reaction time: 0.05 h
Yield: 61 %

Procedure:
Oxalyl chloride (48 microliters; 0.55 mmole) was dissolved in 2 ml of dry dichloromethane, and the solution was cooled to -30° C. Dimethyl sulfoxide (78 microliters; 110 mmoles) was added, and the mixture was stirred for 3 minutes. A solution of 158 mg (0.5 mmole) of 4(R)-t-butyldimethylsilyloxy-2-(4-hydroxybutylthio)-2-cyclopentenone in 1 ml of dry dichloromethane was added over the course of 1 minute, and the mixture was stirred at -30° C. for 30 minutes. Then, 5 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting oily product was chromatographed on a silica gel column using hexane/ethyl acetate (5/1) to give 96 mg (yield 61%) of 4(RS)-t-butyldimethylsilyloxy-2-(4-oxobutylthio)-2-cyclopentenone.
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: CCO
Solvent: O
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) δ 6.97 (d, 2H, J=10Hz); 6.68 (d, 2H, J=10Hz); 5.10 (s, 2H); 2.69 (t, 2H, J=7Hz); 1.72 (t of t, 2H, J=7,7Hz); 1.38 (t of q, 2H, J=7,7Hz); 0.91 (t, 3H, J=7Hz). Mass Calcd. for C16H17N5 :279.1483. Found: 279.1489.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][O:22][C:21](=[O:25])[CH:20]=2)=[CH:10][CH:9]=1)(C)(C)C.[ClH:27]>O1CCOCC1.CCOCC>[ClH:27].[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][O:22][C:21](=[O:25])[CH:20]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccoc(=O)c2)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1ccc(Oc2ccoc(=O)c2)c2ccccc12
Reaction time: 8 h

Procedure:
A mixture of [4-(2-oxo-2H-pyran-4-yloxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester (0.287 g) and HCl (2 mL of a 4N solution in dioxane) in 4 mL of dioxane was stirred overnight, diluted with ether and filtered. The filtrate was dried providing 4-(4-amino-naphthalen-1-yloxy)-pyran-2-one hydrochloride salt.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN(C)C=O>[CH3:4][CH:3]([CH3:5])[CH2:2][O:21][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CC(C)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
98.66 g (0.72 mol) of 1-bromo-2-methylpropane, 74.63 g (0.54 mol) of potassium carbonate and 250 ml of dimethylformamide are added to 50 g (0.36 mol) of 4-nitrophenol. The mixture is heated to 100° C. for 4 hours and then evaporated to dryness. The residue is taken up with 500 ml of 1N sodium hydroxide solution, and 200 ml of ether are added. The organic phase is recovered and washed successively three times with 100 ml of 1N sodium hydroxide, then three times with 200 ml of water and finally with 100 ml of saturated sodium chloride solution. It is dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[CH3:25])=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]4[CH3:25])[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)C1CCCCC1C)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCCCC2C)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.58 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]-2-methylcyclohexanecarboxamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The isomers are purified by chromatography (preparative HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]([S:14](Cl)(=[O:16])=[O:15])=[C:11]([Cl:13])[Cl:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:14]([C:10]([Cl:9])=[C:11]([Cl:13])[Cl:12])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C(Cl)=C(Cl)Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1ccc(Cl)cc1)C(Cl)=C(Cl)Cl

Procedure:
A solution of 7.6 g (0.06 mol) p-chloroaniline and 7.0 g (0.03 mol) trichlorovinylsulfonyl chloride in 150 ml chloroform was heated under reflux for 3 hours. The reaction mixture was then cooled, washed with water, dried over magnesium sulfate and evaporated to give an oily residue. The residue was chromatographed on silica gel. N-(p-chlorophenyl)trichlorovinylsulfonamide, m.p. 73°-76° C., was eluted from the silica gel with 30% ether-70% hexane. Elemental analysis for C8H5Cl4NO2S showed: calculated, %S, 9.99, %Cl 44.2; found, %S, 10.1, %Cl 48.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13](=[O:17])[C:14](O)=[O:15])=[CH:5][CH:4]=1.CCCP(=O)=O.[NH4+].[Cl-].C([NH:29]C(C)C)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13](=[O:17])[C:14]([NH2:29])=[O:15])=[CH:5][CH:4]=1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc2cccc(C(=O)C(=O)O)c2c1
Agent: CCCP(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc2cccc(C(=O)C(N)=O)c2c1
Reaction time: 4 h
Yield: 80 %

Procedure:
In a reactor, 1 g of the compound obtained in Step A is introduced into 30 ml of acetonitrile, and there are then added 4.39 g of propylphosphonic anhydride and 438 mg of NH4Cl and, at the end of the addition, 3.8 ml of diisopropylamine at ambient temperature. The solution is stirred for 4 hours under nitrogen, the solvents are then evaporated off, the residue is taken up in saturated aqueous NaCl solution, and extraction with ethyl acetate is carried out. The solvents are then dried over Na2SO4 and then evaporated off to yield the title product in the form of an orange solid in a yield of 80% and with a chemical purity of 90%.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[CH:20]=[C:19]([C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:17][C:15]=3[NH2:16])=[O:13])=[CH:8][CH:7]=2)[N:5]=[N:4]1.[Cl:29][CH:30]([Cl:34])[C:31](Cl)=[O:32]>C(Cl)Cl>[Cl:29][CH:30]([Cl:34])[C:31]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([C:21]#[C:22][Si:23]([CH3:24])([CH3:26])[CH3:25])=[CH:20][C:14]=1[C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:3]2([C:2]([F:1])([F:27])[F:28])[N:5]=[N:4]2)=[CH:7][CH:8]=1)=[O:13])=[O:32]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(C(=O)c2ccc(C3(C(F)(F)F)N=N3)cc2)c1
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccc(NC(=O)C(Cl)Cl)c(C(=O)c2ccc(C3(C(F)(F)F)N=N3)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
2-({4-[3-(trifluoromethyl)diazirin-3-yl]phenyl}carbonyl)-4-[2-(trimethylsilyl)ethynyl]aniline (47 mg, 0.12 mmol, 1 eq.) was dissolved in DCM (10 mL) and cooled to 0° C. Dichloroacetyl chloride (0.013 mL, 0.14 mmol, 1.15 eq.) was then added, and the reaction was stirred at 0° C. for 10 minutes. The reaction was then warmed to room temperature and stirred for 30 minutes. The solvent was evaporated, and the residue was purified by silica column (hexanes/ethyl acetate, 3:1), resulting in 57 mg (94%) of the title compound as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 11.83 (s, 1H, CHCl2), 8.56 (d, J=8.7, 1H, Ar—H), 7.76 (d, J=9.1, 2H, Ar—H), 7.69 (dd, J=1.5, 8.8, 1H, Ar—H), 7.61 (d, J=1.8, 1H, Ar—H), 7.32 (d, J=8.2, 2H, Ar—H), 6.03 (s, 1H, NH), 0.19 (s, 9H, Si(CH3)3). 13C NMR (126 MHz, CDCl3) δ 197.81 (Ar2—CO), 163.13 (NCOC), 139.23 (C—Ar), 138.79 (C—Ar), 138.33 (C—Ar), 136.61 (C—Ar), 134.08 (C—Ar), 130.47 (C—Ar), 126.71 (q, J=1.23, C—Ar), 123.41 (C—Ar), 122.03 (q, J=274.68, CF3), 121.60 (C—Ar), 120.94 (C—Ar), 103.04 (CSi(CH3)3), 96.22 (CCSi(CH3)3), 67.16 (CCl2), 28.64 (q, J=40.83, CN2), 0.03 (Si(CH3)3). Exact Mass, 511.05. 509.4841 [M−H]−, 511.487 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]([CH3:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:15][C:16](=[N:18]O)[NH2:17].C(N(CC)CC)C>C1C=CC=CC=1.CCOCC.C(=O)(O)[O-].[Na+]>[Cl:1][CH2:2][C:3]1[O:4][N:17]=[C:16]([CH2:15][S:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:20])[CH3:6])[N:18]=1
Reactant: O=C(Cl)CCl
Reactant: CN(C)c1ccccc1SCC(N)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1SCc1noc(CCl)n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Chloroacetylchloride (2.64 ml, 3.74 g, 3.3×10-2 mol) in benzene (10 ml) was added dropwise to a stirred solution of 2-(2-dimethylaminophenylthio)acetamidoxime (6.75 g, 0.03 mol) and triethylamine (4.17 ml) in benzene (20 ml). The mixture was stirred at ambient temperature for 10 hours then refluxed for 1 hour. The cooled mixture was taken up in ether and 5% aqueous sodium bicarbonate solution. The organic layer was washed with water and saturated aqueous sodium chloride solution dried and evaporated to dryness to give a brown oil. Chromatography on silica gel (135 g), eluting with hexane:ether (3:1) gave 5-(chloromethyl)-3-(2-dimethylaminophenylthiomethyl)-1,2,4-oxadiazole as a colourless oil, nmr δ(CDCl3) 2.78(6H, CH3), 4.20(2H, ,--CH2 --), 4.65 (2H, ,--CH2 --), 6.8-7.4 (4H, m, aromatic hydrogens).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([S:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH2:18][CH2:17]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A suspension of 4-acetylaminobenzene sulfonyl chloride (4.5 mmol) in anhydrous CH2Cl2 at room temperature is treated with 1-methyl piperazine (4.5 mmol) and triethylamine (4.5 mmol). The reaction mixture was stirred at room temperature for 1 hour, water was added, and the product extracted with additional CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered, and evaporated under reduced pressure, affording the desired N-[4-(4-methylpiperazine-1-sulfonyl)phenyl]acetamide. Mp: 184° C.; Yield 41%; 1H NMR (DMSO d8): δ 2.09 (s, 3H), 2.15 (s, 3H), 2.40 (m, 4H), 2.85 (m, 4H), 7.63-7.68 (d,2H, J=10 Hz), 7.80-7.84 (d, 2H, J=8 Hz), 10.41 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18].O>CN(C=O)C>[F:12][C:2]([F:11])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:16][C:17]([OH:19])=[O:18])[CH:4]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCc1cc(C(F)(F)F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COCc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [4-(trifluoromethyl)pyridin-2-yl]methanol (340 mg, 1.9 mmol) in DMF (10 mL) was added sodium hydride (150 mg, 3.8 mmol). After being stirred at room temperature for 5 min. 1,1-dimethylethyl bromoacetate (0.28 mL, 1.9 mmol) was added. Stirring was continued at room temperature for 1 h. Water (20 mL) was added and the resulting solution was extracted with EtOAc. The water layer was neutralized to pH=5 with HCl and extracted with EtOAc twice. The combined organic layers were dried (MgSO4) and concentrated under vacuum to give the title compound which was used for the next reaction without purification. MS (M+H) 292.2.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(O[C:18]1[C@:19]2([CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH:26]=[C:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][C:29]([O:37][C:38]3[C:43]([F:44])=[C:42]([F:45])[C:41]([C:46]([F:49])([F:48])[F:47])=[C:40]([F:50])[C:39]=3[F:51])=[CH:28]4)[C@@H:21]2[CH2:22][CH:23]=1)[CH3:20])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>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.C1COCC1>[F:44][C:43]1[C:42]([F:45])=[C:41]([C:46]([F:48])([F:47])[F:49])[C:40]([F:50])=[C:39]([F:51])[C:38]=1[O:37][C:29]1[CH2:30][CH2:31][C@@:32]2([CH3:33])[C:27](=[CH:26][CH2:25][C@@H:24]3[C@@H:34]2[CH2:35][CH2:36][C@@:19]2([CH3:20])[C@H:21]3[CH2:22][CH:23]=[C:18]2[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:28]=1
Reactant: CCB(CC)c1cccnc1
Reactant: C[C@]12CCC(Oc3c(F)c(F)c(C(F)(F)F)c(F)c3F)=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@]12CCC(Oc3c(F)c(F)c(C(F)(F)F)c(F)c3F)=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Yield: 72.8 %

Procedure:
The method essentially followed that of Example 1(b) but using diethyl(3-pyridyl)borane (0.44 g, 3.0 mmol), 3-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy]androsta-3,5,16-trien-17-yl trifluoromethanesulphonate (1.27 g, 2.0 mmol), THF (10 ml), bis(triphenylphosphine)palladium(II) chloride (70 mg, 0.1 mmol), and aqueous sodium carbonate (2M, 5 ml). Chromatography, on elution with light petroleum-diethylether (3:1), afforded the title compound (0.82g, 73%) which crystallised from hexane, m.p. 166.0°-166.5° C. 1H-NMR (CDCl3) inter alia δ 1.05(3H,s,19-CH3), 1.07(3H,s,18-CH3), 5.18(1H,s,4-H), 5.32(1H,m,6-H), 6.01(1H,m, 16-H), 7.23(1H,m,Py 5-H), 7.66(1H,m,Py 4-H, 8.47(1H,m,Py 6-H), 8.63(1H,m,Py 2-H). Anal. Calcd: C, 66.07; H, 5.01; N, 2.49; F, 23.60. Found: C, 65.97; H, 5.02; N, 2.47; F, 23.41%.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([O:18]C)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][C:23](=[O:27])[CH2:22]3)=[CH:8]2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][C:23](=[O:27])[CH2:22]3)=[CH:8]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc2c(CN3CCNC(=O)C3)cn(Cc3ccc(F)cc3)c2cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CN(Cc2cn(Cc3ccc(F)cc3)c3cnc(C(=O)O)cc23)CCN1
Temperature: 10 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
To a suspension of methyl 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (18.2 g, 46.0 mmol) in methanol (450 mL) and water (200 mL) was added lithium hydroxide (1.40 g 58.3 mmol, 1.3 eq.). The suspension was heated to reflux for 10 h, and the reaction was judge to be 95% complete by HPLC-MS analysis. Methanol (200 mL) and lithium hydroxide (0.7 g, 29.2 mmol) were added and the reflux continued for 18 h total. The volatiles were removed in vacuo to a residue. Water (200 mL) was added and the mixture was cooled to 10° C. and neutrialized with aqueous concentrated hydrochloric acid to pH 7. The white solid precipitated out, and filtered followed by washing with cold water, and dried in vacuoto afford 9.10 g (52%) of 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—1.31 min, m/e=383.20 (M+H+, base). 1H NMR (400 MHz, DMSO-D6) d ppm 2.55 (t, J=5.16 Hz, 2H) 2.92 (s, 2H) 3.11 (s, 2H) 3.75 (s, 2H) 5.57 (s, 2H) 7.16 (t, J=8.81 Hz, 2H) 7.35 (dd, J=8.56, 5.54 Hz, 2H) 7.72 (s, 1H) 7.83 (s, 1H) 8.41 (s, 1H) 8.92 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[CH:4][C:3]=1[CH3:14].[I:15]Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([I:15])=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1cn(-c2ccc(N)c(C)c2)cn1
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(C)c(N)c(I)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
A mixture of 2-amino-5-(4-methylimidazol-1-yl)toluene (100 mg), iodomono-chloride (104 mg) and acetic acid (1.3 ml) was stirred at room temperature for 2 hours. Solvent was removed under reduced pressure to give a residue. The residue was made to pH 10 with saturated sodium bicarbonate solution, extracted with chloroform. The extract was dried with MgSO4, filtered and removed solvent to give 68 mg (41%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)c1cccnc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(Br)c1cccnc1
Reaction time: 7 h

Procedure:
To a stirred mixture of ethyl 2-(pyridin-3-yl)propanoate (4.2 g, 23 mmol), CCl4 (100 mL), and N-bromosuccinimide (Aldrich, 4.6 g, 26 mmol) was added 2,2′-azobisisobutyronitrile (Aldrich, 0.8 g, 5 mmol) under N2 at room temperature. The mixture was gradually heated to reflux. After 7 h, the reaction mixture was concentrated in vacuo. The crude was purified by silica gel chromatography. Mass Spec. m/z+ion 258, 260 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1(=O)CCCCC1>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=C1CCCCC1
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Yield: 38.7 %

Procedure:
In 100 ml of cyclohexanone were dissolved 4 g of the obtained methyl 4-hydroxy-4'-biphenylcarboxylate and 4 g of n-decyl bromide. To the solution were added 10 g of potassium carbonate and 10 g of potassium iodide, and reaction was carried out under reflux for 10 hours. The formed precipitate was removed from the reaction mixture by filtration, the filtrate was concentrated under a reduced pressure, and the separation of reactants was carried out by using a silica gel column and benzene as an eluant to obtain 2.5 g of methyl 4-n-decyloxybiphenyl-4'-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(N(CC)CC)C>C1COCC1>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1)(=[O:10])[CH3:9]
Reactant: Nc1ccncn1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccncn1
Temperature: 25 °C

Procedure:
The 4-aminopyrimidine (1.0 equiv.) was dissolved in THF and acetic anhydride (5 equiv.) and triethylamine (1.5 equiv.) were added and the mixture was stirred at room temperature. The volatiles were removed in vacuo and the residue purified by preparative silica gel TLC to give the 4-acetamidopyrimidine.