Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:14][CH3:15])[NH:11]2)=[C:7]([NH2:16])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C.CCOC(C)=O>[CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:14][CH3:15])[N:11]2[CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:7]([NH2:16])[N:6]=1
Reactant: CCC(C)COc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(C)COc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of 2-[(2-methylbutyl)oxy]-8-methoxy-9H-purin-6-amine (109 mg) in dry DMF (1.86 mL) was added potassium carbonate (165 mg) and the mixture was stirred at 60° C. for 90 mins. The mixture was cooled to room temperature and 4-(bromomethyl)tetrahydro-2H-pyran (59 mg) was added. The reaction was stirred at 50° C. overnight and was cooled to room temperature. The mixture was taken up in EtOAc (15 mL) and washed with water (2×10 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give a yellow viscous oil. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as a yellow oil (41 mg).
Reaction SMILES: [F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1.O.NN>CO.[Ni]>[F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)C(F)C1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN1CC=C(c2c[nH]c3ccc(N)cc23)C(F)C1
Yield: 44.9 %

Procedure:
A solution of compound 132 (0.175 g, 0.635 mmol) in dry methanol (5 mL) was treated with hydrazine hydrate (0.198 mL, 6.357 mmol) followed by Ra—Ni (˜0.05 g) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 2 min. The reaction was brought to room temperature, filtered through celite bed, washed with methanol (3×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 133 (0.07 g, 45%) as a solid. mp 176-178° C.; 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 2.40-2.56 (m, 1H), 2.73-2.83 (m, 1H), 2.99-3.08 (m, 1H), 3.30-3.42 (m, 1H), 4.51 (s, 2H), 5.37 (d, 1H, J=48.9 Hz), 6.22-6.26 (m, 1H), 6.51 (dd, 1H, J=1.8, 8.5 Hz), 6.97 (d, 1H, J=1.8 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.27 (t, 1H, J=1.8 Hz), 10.72 (s, 1H); ESI-MS m/z (%): 246 (MH+, 12), 203 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.CN1CCOCC1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([S:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 906.3 %

Procedure:
To 4.6 g (3.03 mmol) of the methyl 3-aminobenzoate prepared in Example 1 in 30 mL of methylene chloride containing 4.0 mL (36 mmol) of N-methylmorpholine was added 4.0 mL (33 mmol) of benzenesulfonyl chloride. After stirring at room temperature for 1 hr the reaction mixture was quenched with water (100 mL). The suspension was dissolved in ethyl acetate/ether combination. The organic phase was washed sequentially with 2N HCl and then sodium bicarbonate. The organic phase was dried (MgSO4), and concentrated and triturated from ethyl acetate/hexane ether to give 8.0 g (90%) of the title compound as a colorless solid: NMR (DMSO-d6 ; 300 MHz) δ 10.58 (s, 1H), 7.75-7.84 (m, 3H), 7.52-7.72 (m, 4H), 7.35-7.45 (m, 2H), and 3.82 ppm (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH3:21].[CH3:22][O:23][C:24](OC)([O:29]C)[CH2:25][CH2:26][CH2:27]Br>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][CH2:27][CH2:26][CH2:25][C:24]([O:23][CH3:22])=[O:29]
Reactant: COC(CCCBr)(OC)OC
Reactant: Cc1cc(Cl)ccc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCCc1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Diisopropylamine (841 μl, 6 mmol) was added to 20 ml of tetrahydrofuran under nitrogen atmosphere and cooled to 0° C. 5.5 ml of 2.5N n-butyllithium (13 mmol) was added and the reaction was stirred for 20 minutes. The reaction was then cooled to -78° C. 2,5-Dichlorotoluene (642 ul, 5 mmol) was added and stirring was continued for 2 hours at -78° C. Trimethyl 4-bromoorthobutyrate (1.14 g, 5 mmol) was added to the reaction mixture in 10 ml tetrahydrofuran. The reaction was stirred for 5 minutes at -78° C., allowed to come to room temperature and stirred overnight. The reaction was worked-up by adding 10 ml of saturated KH2PO4, removal of most of the tetrahydrofuran on a rotary evaporator followed by partitioning of the aqueous residue between ethyl acetate and 1N HCl. The organic phase was washed twice with 1N HCl, once with 5% sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to a residue. Flash chromatography (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.8 minutes) of a water white oil. 1H NMR (300 MHz, CDCl3) delta=7.24 (d, J=8.5 Hz, H3), 7.18 (d, J=2.5 Hz, H6), 7.09 (dd, J=2.5, 8.5 Hz, H4), 3.66 (s, --COOCH3), 2.69 (t, J=7.8 Hz, Ar--CH2 --), 2.35 (t, J=7.0 Hz, --CH2 --COO--), 1.70-1.55 (m, --CH2 --CH--CH2 --CH2 --).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[F:15].Cl[C:17](OC(Cl)(Cl)Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:5]1[C:6]2[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[O:10][C:11]=2[C:2]([N:1]=[C:17]=[O:18])=[C:3]([F:15])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)CCc2c(Cl)cc(F)c(N)c2O1
Solvent: Cc1ccccc1
Product: CC1(C)CCc2c(Cl)cc(F)c(N=C=O)c2O1
Yield: 97.8 %

Procedure:
By the method of Example 1, Step F, 3.6 grams (0.016 mole) of 8-amino-5-chloro-3,4-dihydro-2,2-dimethyl-7-fluoro-2H-1-benzopyran and 3.1 grams (0.016 mole) of trichloromethyl chloroformate were reacted in 100 mL of toluene, yielding about 4.0 grams of 5-chloro-3,4-dihydro-2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-yl isocyanate. The product was taken to the next step without further characterization.
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH2:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C(O)C.CCOCC>[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:2]3[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=3[N+:8]([O-:10])=[O:9])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Solvent: CCO
Solvent: CCOCC
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Nc1ccc2c(c1)CCC2
Yield: 93.3 %

Procedure:
A solution of 3-fluoro-4-nitropyridine-1-oxide (12 g) and indan-5-amine (10 g) in 200 ml ethanol was stirred at reflux for two hours, and thereafter cooled, diluted with ether and filtered to give 19 g solid, m.p. 195°. Four grams were recrystallized from ethanol to give 2.6 g crystals, m.p. 194°-195°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:14]1([N:13]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=2)[CH3:11])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2ccccc12
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C(C)=Nc2cccc3ccccc23)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.6 %

Procedure:
2,6-Diacetylpyridine (5.49 g, 33.6 mmol) and 1-aminonaphthalene (4.8 g, 33.5 mmol) were dissolved in 100 ml of toluene. To this solution molecular sieves (4 Å) were added. After standing for 20 hours at room temperature, the mixture was filtered. The solvent was removed in vacuo. The resulting mixture of 2,6-diacetylpyridine, 2,6-bis-[1-(1-naphthylimino)ethyl] pyridine and 2-[1-(1-naphthylimino)ethyl]-6-acetylpyridine was dissolved in 50 ml THF. The diiminepyridine by-product 2,6-bis-[1-(1-naphthylimino)ethyl]pyridine was removed by selective complexation to a metal halide. FeCl2 (0.79 g , 6.23 mmol) was added in an inert atmosphere. After stirring for 16 hours at room temperature, the solvent was removed in vacuo. Toluene (100 ml) was added to the resulting mixture. The precipitated complex was filtered off over a small layer of silica, yielding a yellow solution. The solvent was removed vacuo. Crystallisation from ethanol yielded 3.25 g of 2-[1-(1-naphthylimino)ethyl]-6-acetylpyridine (6) (33.6%). 1H-NMR (CDCl3) δ 8.65 (d, 1H, Py-Hm), 8.15 (d, 1H, Py-Hm), 7.95 (t, 1H, Py-Hp), 7.87 (d, 1H, ArH), 7.76 (d, 1H, ArH), 7.64 (d, 1H, ArH), 7.4-7.6 (m, 3H, ArH), 6.82 (d, 1H, ArH), 2.79 (s, 3H, Me), 2.38 (s, 3H, Me).
Reaction SMILES: [NH4+:1].[NH:2]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:16][CH:15]=[CH:14]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl([O-])(=O)(=O)=O.[Na+]>[CH:8]1[CH:3]=[CH:4][C:5]([NH:1][C:9]2[CH:10]=[CH:11][C:12]([C:12]3[CH:11]=[CH:10][C:9]([NH:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[C:17]4[S:19]([OH:22])(=[O:20])=[O:21])=[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([S:19]([OH:22])(=[O:20])=[O:21])[C:18]=23)=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])c1cccc2cccc(Nc3ccccc3)c12
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O=S(=O)(O)c1cccc2c(-c3ccc(Nc4ccccc4)c4c(S(=O)(=O)O)cccc34)ccc(Nc3ccccc3)c12
Reaction time: 2 h
Yield: 30.1 %

Procedure:
A process for the production of bis-(5,5')-8- Anilino -1-naphthalene Sulfonate using an electrochemical cell, consisting of a container (a beaker), a carbon cloth anode, and a metal cathode. The electrochemical cell is charged with ingredients in accord with the following proportions--2.136 g (6.71 mmol) of 8- anilino - 1- naphthalene sulfonic acid ammonium salt dissolved in 100 mL of 0.1 M aqueous sodium perchlorate. As the solution is stirred (A stirring mechanism is used such as a magnetic stirring bar with the container (beaker) supported on a combination heat plate and magnetic drive stirrer), the D.C. power supply voltage is increased until current begins to flow between the electrodes. This solution is electrolyzed for approximately two hours through which time periodic samples are removed and monitored by Hplc (high performance liquid chromatography) until the amount of product reaches a maximum. Thereafter, the solvent is removed and the residue dissolved in a minimal amount of methanol and chromatographed on a short column of neutral alumina using methanol as the eluent. The solvent is removed and the residue dissolved in a minimum amount of water. Excess barium acetate is added to precipitate bis-Ans as barium salt that is collected and dissolved in water. An excess of potassium sulfate is added to convert the barium salt to dipotassium salt. This salt is recrystallized to give 0.686 g (1.01 mmol) of bis - (5,5') - 8 - anilino - 1 - naphthalene sulfonic acid dipotassium salt corresponding to substantially a thirty percent product yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:17])[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][CH3:26])[C:22]([C:27]([F:30])([F:29])[F:28])=[CH:21][N:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:8][C:7]1[C:2]([NH:1][C:19]2[N:24]=[C:23]([NH:25][CH3:26])[C:22]([C:27]([F:30])([F:28])[F:29])=[CH:21][N:20]=2)=[CH:3][C:4]([CH3:17])=[C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=1
Reactant: Cc1cc(N)c(Cl)cc1C(=O)N1CCOCC1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc(C)c(C(=O)N3CCOCC3)cc2Cl)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 53.3 %

Procedure:
A mixture of (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (79 mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 4 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC to give (5-chloro-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone (71 mg, 53%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=430 at 3.47 min. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.21 (d, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 5.30 (br s, 1H), 3.79 (br d, 4H), 3.60 (br s, 2H), 3.32 (br s, 2H), 3.11 (d, 3H), 2.32 (s, 3H).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:22]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])=[O:24]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH2:12][C:13](=[O:15])[NH:20][C:21]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:22]=1[C:23](=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
45 g of carbobenzoxy-glycine dissolved in 1 liter of absolute tetrahydrofuran are treated dropwise while cooling with ice with 20 ml of thionyl chloride and stirred for 1 hour while cooling with ice. There is then rapidly added dropwise thereto a suspension of 50 g of 2-amino-5-nitro-2'-fluorobenzophenone in 200 ml of absolute tetrahydrofuran and the mixture is stirred at room temperature for 18 hours. The solution obtained is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is dissolved in a small amount of hot ethyl acetate, concentrated partially and treated with ether. Benzyl{[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]methyl}-carbamate is obtained. The mother liquors are purified on a 100 g silica gel column using methylene chloride as the eluting agent, an additional amount of the aforementioned product being obtained.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[N+]=[N-])=[CH2:3].[F:7][C@:8]12[C@@H:28]([OH:29])[CH2:27][C@@:26]3([CH3:30])[C@@H:18]([CH2:19][C@@H:20]([OH:32])[C@:21]3([OH:31])[C:22](=[O:25])[CH2:23][OH:24])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:34])[CH2:10][CH2:11][C:12](=[O:33])[CH:13]=1>CCOCC.CO>[F:7][C@:8]12[C@@H:28]([OH:29])[CH2:27][C@@:26]3([CH3:30])[C@@H:18]([CH2:19][C@@H:20]([O:32][CH2:3][C:2]([CH3:4])=[CH2:1])[C@:21]3([OH:31])[C:22](=[O:25])[CH2:23][OH:24])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:34])[CH2:10][CH2:11][C:12](=[O:33])[CH:13]=1
Reactant: C=C(C)C=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Solvent: CO
Solvent: CCOCC
Product: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Temperature: 0 °C

Procedure:
A solution of 2-methyl-3-diazo-1-propene in 250 ml of ether (prepared from 0.2 mole of N-(2-methyl-2-propenyl)ethyl carbamate by the method of J. L. Brewbaker and H. Hart, J. Am. Chem. Soc., 91, 711 (1969) is diluted with 300 ml of methanol and cooled to 0°C. A total of 6.5 g of 9-fluoro-11β ,16α ,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions until the initial red color fades and nitrogen evolution ceases. The solvent is evaporated in vacuo and the residue dissolved in chloroform and chromatographed on a 100 g - silica gel column. Elution with chloroform and chloroform-ethyl acetate gives TLC homogeneous material which crystallizes from acetone-hexane to give 3.73 g of 9-fluoro-11β ,17,21-trihydroxy-16α-[(2-methyl-2-propenyl)oxy]pregn-4-ene-3,20-dione, melting point 213°-215°C, softening at 198°-200°C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@@H:39]([CH3:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[C@@H:28]([CH3:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:25])[CH2:15][CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])=[O:8])=[O:4]>CO.[H][H].[C].[Pd]>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[C@@H:39]([CH3:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[C@@H:28]([CH3:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:25])[CH2:15][CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:12])=[O:8])=[O:4]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)CNC(=O)CNC(=O)CN)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C

Procedure:
Z-Gly-Gly-Gly-Glu(OtBu)-Thr(tBu)-Thr(tBu)-OtBu (SEQ ID No. 12) (1.97 g, 2.24 mmol) obtained in Example 4-IV) was dissolved in methanol (60 ml). To the solution was added 10% palladium-carbon (120 mg), and the mixture was stirred for 2 hours in hydrogen streams at 20° C. under 1 atom. The catalyst was removed, then the solvent was distilled off to leave H-Gly-Gly-Gly-Glu(OtBu)-Thr(tBu)-Thr(tBu)-OtBu (SEQ ID No. 81) as a solid product.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=2)=[N:7][CH:6]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Reactant: Brc1cnc(Br)nc1
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)cc1

Procedure:
2,5-Dibromopyrimidine and 4-octyloxybenzeneboronic acid are reacted analogously to Example 1 to give 5-bromo-2-(4-octyloxyphenyl) pyrimidine. ##STR34##
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[Cl:6][C:7]1[CH:16]=[C:15]([SH:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>>[Cl:6][C:7]1[CH:16]=[C:15]([S:17][CH2:4][C:2]([OH:5])([CH3:3])[CH3:1])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(S)cc1Cl
Reactant: CC1(C)CO1
Product: COC(=O)c1ccc(SCC(C)(C)O)cc1Cl

Procedure:
8 g of methyl 4-amino-2-chlorobenzoate was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 mL of concentrated hydrochloric acid and was then cooled to 0° C. A solution of 3.9 g of sodium nitrite in 15 mL of H2O was added dropwise over 30 min. The reaction was stirred at 0° C. for an additional 1 h. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL of H2O at 50˜60° C. The reaction was heated to 65° C. for 2 h and monitored by TLC until complete. The mixture was cooled to 25° C. and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetate/hexane) to afford methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate. A solution of 2.6 g of sodium hydroxide in 20 mL of H2O was added to 5.9 g of methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH The reaction mixture was heated to 70° C. for 1 h. Upon completion, the mixture was cooled to 25° C., and then acidified to pH 3 by the addition of 10 N HCl. The solid was filtered and washed with H2O to give 2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonic acid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogen atmosphere for 3 h. After concentration of the reaction mixture, 10 mL of H2O was added and the resulting mixture was made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield methyl 2-chloro-4-mercaptobenzoate. 80 mg of isobutylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate. 190 mg of methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate was hydrolyzed via Procedure M to give 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid. 160 mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid was reacted via procedure R to give 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-methylpropylsulfonyl)benzamide. MS (Q1) 479.1 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=2)=[CH:6][N:7]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Br:22])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CCNC(=O)c1nc(-c2cccc(CO)c2)cnc1N
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCNC(=O)c1nc(-c2cccc(CBr)c2)cnc1N
Reaction time: 7 h
Yield: 76.6 %

Procedure:
To a solution of 3-amino-N-ethyl-6-[3-(hydroxymethyl)phenyl]pyrazine-2-carboxamide (566.1 mg, 1.0 eq) in dichloromethane (20 mL) were added carbon tetrabromide (749.8 mg, 1.1 eq), triphenylphosphine (600 mg, 1.1 eq) at ambient temperature. After being stirred for 7 h, the reaction mixture was partitioned with dichloromethane (10 mL×3), washed with brine. The organic layer was combined and dried over anhydrous magnesium sulfate. Filteration and concentration in vacuo gave a crude product. Purification by column chromatography afforded the 3-amino-6-[3-(bromomethyl)phenyl]-N-ethylpyrazine-2-carboxamide (534 mg, 77% yield): 1H NMR (400 MHz, DMSO-d6): δ 8.87 (m, 2H), 8.84 (s, 2H), 8.23 (m, 1H), 7.61 (bs, 1H), 7.45 (m, 1H), 4.77 (s, 2H), 3.38 (m, 2H), 1.16 (m, 3H).