Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[OH-].[K+].[CH2:5]([O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18](C(=O)C)[N:17]=[CH:16]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.ClCCl.C(OCC)(=O)C.O>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[I:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: II
Reactant: CC(=O)n1ncc2cc(OCc3ccccc3)ccc21
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Ic1n[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
68.84 g of iodine and then 23 g of potassium hydroxide are added to a solution of 28.24 g of 1-(5-benzyloxyindazol-1-yl)ethanone in 620 ml of dimethylformamide. The reaction medium is stirred at ambient temperature for approximately 3 hours. 23 g of potassium hydroxide are added and the medium is stirred at ambient temperature for 48 hours. The medium is treated with 600 ml of a sodium thiosulfate solution (100 g of sodium thiosulfate in 250 ml of distilled water), 600 ml of distilled water and 1 liter of ethyl acetate. The medium is stirred for a few minutes and is then separated by settling out. The aqueous phase is extracted with 4×600 ml of ethyl acetate. The combined organic phases are washed with 1 liter of a saturated sodium chloride solution, and then dried over magnesium sulfate. The solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is taken up in dichloromethane, and the solid is filtered off and rinsed with dichloromethane and with ethyl ether. 20.8 g of 5-benzyloxy-3-iodo-1H-indazole are collected.
Reaction SMILES: [CH3:1][CH:2]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[O:28]1[CH2:27][CH:26]1[CH2:24][N:9]([CH:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11]
Reactant: CC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1ccccc1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Product: CC(c1ccccc1)N(CC1CO1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
2.1 g (6.6 mmol) of N-α-methylbenzyl-2-nitrobenzenesulfonamide was dissolved in 10 ml of epichlorohydrin, to which was gradually added at room temperature 0.35 g (7.3 mmol) of 50% sodium hydride, followed by agitating at room temperature for 30 minutes and reacting under reflux for 1 hour. The epichlorohydrin was distilled off under reduced pressure, water was added and extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous magnesium sulfate, concentrated, and purified by the silica gel chromatography to obtain the intended product (Compound No. 33). The yield was 97% and the nD26.5 value was 1.5572. The results of the elemental analysis are shown below.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:33](=[O:35])=[O:34]>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]3[N:7]=[C:2]([CH2:1][C:33]([OH:35])=[O:34])[CH:3]=[CH:4][CH:5]=3)(=[O:11])=[O:10])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: O=C=O
Reactant: Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: O=C(O)Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)n1

Procedure:
This material was obtained in analogy to example 71 step A] from 4′-fluoro-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide (0.5 g, product of example 17), 1.46 mL of a 2 M lithium diisopropylamide solution in THF/heptane/ethylbenzene, and dry ice to give [6-(4′-fluoro-biphenyl-4-sulfonylamino)-pyridin-2-yl]-acetic acid as a gum (0.69 g) that was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[CH2:30][CH3:31].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[C:24]3[CH2:30][CH3:31])=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CCc1n[nH]c2ccc(N)cc12
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1n[nH]c2ccc(NC(=O)C3=C(C)NC(=O)CC3c3ccc(Cl)cc3F)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
The product of Example 3, Step 2 (50 mg, 0.176 mmol, 1.00 equiv), 5-amino-3-ethylindazole (28 mg, 0.176 mmol, 1.0 equiv), and EDC (41 mg, 0.212 mmol, 1.20 equiv) were suspended in 1.5 mL DMF. Et3N (0.030 mL, 0.212 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 26 mg (35%) of the title compound as an off white solid. MS (ES+) m/e 427 [M+H]+
Reaction SMILES: C([O-])(=O)C.[Na+].S(=O)(O)[O-].[OH:10][CH2:11][C:12]([CH2:14]O)=O.Cl.N[C@H](C(O)=O)CS.Cl.Cl.[NH2:26][C:27]1[N:32]=[C:31]([NH2:33])[C:30]([NH2:34])=[C:29]([NH2:35])[N:28]=1>O>[NH2:26][C:27]1[N:32]=[C:31]([NH2:33])[C:30]2[C:29](=[N:35][CH:14]=[C:12]([CH2:11][OH:10])[N:34]=2)[N:28]=1
Reactant: O=C(CO)CO
Reactant: Nc1nc(N)c(N)c(N)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: N[C@@H](CS)C(=O)O
Solvent: O
Product: Nc1nc(N)c2nc(CO)cnc2n1

Procedure:
A solution of 128 grams of sodium acetate, 136 grams of bisulphite addition product of 1,3-dihydroxyacetone (free of methyl glyoxal) and 46 grams of cysteine hydrochloride in 390 ml water was prepared at room temperature in a 2 liter three-necked flask fitted with a stirrer, an air-bubbling system and a dropping funnel. To this solution, the 400 ml of the previously prepared solution of 2,4,5,6-tetraaminopyrimidine dihydrochloride were added with energic stirring and air-bubbling. A solution of 8 g of selenium dioxide dissolved in the minimum amount of water was made. Half of this solution was added to the reaction mixture immediately after the addition of the tetraaminopyrimidine solution and the other half 4-7 hours later.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20](OS(C(F)(F)F)(=O)=O)[C:21]3[S:27][CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:15]=[CH:16][CH:17]=1.CN(C=O)C>O>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=3)[C:21]3[S:27][CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: N#CCc1ccc(N)cc1
Reactant: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A 8-mL vial was charged with 2-(4-aminophenyl)acetonitrile (40 mg, 0.3 mmol, 1.25 eq.), [2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate (100 mg, 0.24 mmol, 1. eq.) and DMF (1 ml). The resulting mixture was stirred at 70° C. overnight. After cooling to room temperature, water was added to the mixture (5 ml). The precipitate was collected by filtration and washed with water (20 ml). After drying, the crude product was purified by chromatography on silica gel using hexane/dichloromethane (1:1, 1:1.5 then 1:2) as eluent to give the title compound (35 mg, 37% yield).
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([O:11][CH:12]([F:14])[F:13])=[N:6]2.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:13][CH:12]([F:14])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:5]([N:4]=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:2]=2[C:35]2[CH:36]=[CH:37][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=2)[N:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Fc1cccc(-c2nn3nc(OC(F)F)ccc3c2Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3nc(OC(F)F)ccc23)cc1
Yield: 38.1 %

Procedure:
To a stirred solution of 3-bromo-6-difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine (286 mg) in DMF(20 ml) was added 2N aq sodium carbonate (10 ml). To this mixture was added 4-methanesulfonyl-phenylboronic acid (180 mg) and tetrakis triphenylphosphine palladium(0) (34 mg). The resulting mixture was stirred and heated to reflux for 18 hours. The cooled reaction mixture was diluted with ethyl acetate (300 ml) and the organic solution washed with water (10×30 ml) and brine (30 ml), dried (Na2SO4) and evaporated to give a gum which was purified by flash column chromatography with chloroform:ethyl acetate (50:1 to 5:1) as eluant. Combination of appropriate fractions and concentration gave the title compound as an off-white solid (132 mg, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH2:12][CH2:13][OH:14].C(=O)(O)[O-].[Na+]>CO.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[NH:11][CH2:12][CH2:13][OH:14]
Reactant: O=[N+]([O-])c1cccc(Br)c1NCCO
Agent: [Ti+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Nc1cccc(Br)c1NCCO
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of 2-[(2-bromo-6-nitrophenyl)amino]ethanol (1.95 g, 7.5 mmol) in a mixture of methanol (30 mL) and water (15 mL) sodium acetate trihydrate (56 g) was added. To this mixture titanium trichloride (65 mL, as 15% solution in 10% aqueous HCI) was added drop-wise over period of 20 min. The resulting dark solution was allowed to stir for additional 2 h, and then carefully neutralized with saturated aqueous sodium bicarbonate. The solids were filtered off, and washed with ethyl acetate. The combined organic phase was washed with water and brine, dried over Na2SO4 and concentrated yielding 2-[(2-amino-6-bromophenyl)amino]ethanol as pale-yellow oil (1.61 g, 93%) that was used in the next step without further purification. MS (ESI) m/z: 231.01[M+H].
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:31]([CH:32]=1)[CH2:30][C:8]1([CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[O:7]2)([O-:3])=[O:2].FC(F)(F)C(O)=O.BrC[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=1)=[O:43].C(N(CC)CC)C>C(Cl)Cl.O>[N+:1]([C:4]1[N:5]=[C:6]2[N:31]([CH:32]=1)[CH2:30][C:8]1([CH2:9][CH2:10][N:11]([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:42]([NH:44][C:45]4[CH:46]=[CH:47][C:48]([C:51]([F:52])([F:53])[F:54])=[CH:49][CH:50]=4)=[O:43])[CH2:18][CH2:17]3)[CH2:12][CH2:13]1)[O:7]2)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)Cn2cc([N+](=O)[O-])nc2O3)CC1
Reactant: O=C(CBr)Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCN(CC(=O)N2CCC3(CC2)Cn2cc([N+](=O)[O-])nc2O3)CC1)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.4 %

Procedure:
Tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazol-2,4′-piperidin]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (10 ml) was added followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. To the residue, methylene chloride (1 ml) and triethylamine (1 ml) were added followed by stirring at room temperature for 5 minutes, and then the solution was concentrated under reduced pressure. The residue was dissolved in DMF (10 ml). To the solution, 2-bromo-N-(4-trifluoromethylphenyl)acetamide (207 mg, 0.73 mmol) and triethylamine (0.28 ml, 2.0 mmol) were added followed by stirring at 100° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-diisopropyl ether to afford 2-{4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidin]-1′-yl)-2-oxoethyl]piperazin-1-yl}-N-[4-trifluoromethylphenyl]acetamide (275 mg, yield 75%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3=[CH:24][CH:25]=[C:21]4[N:22]3[C:17](=[C:18]([CH2:26][OH:27])[CH:19]=[CH:20]4)[C:16]=2[CH2:28][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(O)C>CS(C)=O.O.C(OCC)C.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3=[CH:24][CH:25]=[C:21]4[N:22]3[C:17](=[C:18]([CH2:26][O:27][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:19]=[CH:20]4)[C:16]=2[CH2:28][CH3:29])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCCC1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2ccc3ccc(CO)c1n32
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2ccc3ccc(COCCN4CCCC4)c1n32
Yield: 101.3 %

Procedure:
2-(4-Benzyloxyphenyl)-1-ethyl-7-hydroxymethylpyrrolo[2,1,5-cd]indolizine (0.5 g, 1.3 mmol) was dissolved in 20 ml of dry dimethylsulfoxide under a nitrogen atmosphere. Sodium hydride (100%) (136 mg, 5.7 mmol) was added in portions and stirring was continued for ten minutes. 1-(2-Chloroethyl)pyrrolidine hydrochloride (0.33 g, 1.94 mmol) was added, and the solution was stirred for 4 hours. Ethanol (2 ml) was added dropwise, and the reaction mixture was diluted with 50 ml of water, 50 ml of diethyl ether and 50 ml of brine. The organic material was extracted into diethyl ether (2×50 ml), and the combined organic layers were washed with 3×50 ml of water, 25 ML of brine, dried overmagnesium sulfate, treated with decolourising charcoal and filtered through celite. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using 10% of methanol in dichloromethane as the eluent to afford 0.63 g (100%) of 2-(4-benzyloxyphenyl)-1-ethyl-7-((2-pyrrolidinoethoxy)methyl)pyrrolo[2,1,5-cd]indolizine as a yellow oil. 1H--NMR (CDCl3, 200 MHz) δ: 1.44 (t, 3 H); 1.82 (m, 4 H); 2.70 (m, 4 H); 2.85 (t, 2 H); 3.29 (q, 2 H); 3.82 (t, 2 H); 5.19 (s, 2 H); 5.24 (s, 2 H); 7.11-7.24 (m, 3 H); 7.31-7.60 (m, 6 H); 7.65-7.79 (m, 3 H); 7.89 (d, 1 H).
Reaction SMILES: [CH2:1]=[C:2]1[C:15](=[CH2:16])[CH:14]2[O:17][CH:3]1[C:4]1[CH2:5][CH:6]3[CH:11]([CH2:12][C:13]=12)[C:10](=[O:18])[CH:9]=[CH:8][C:7]3=[O:19].[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C(Cl)Cl.CO>[CH2:16]=[C:15]1[C:2](=[CH2:1])[CH:3]2[O:17][CH:14]1[C:13]1[CH2:12][CH:11]3[CH:6]([CH2:5][C:4]=12)[C:7](=[O:19])[CH:8]=[CH:9][CH:10]3[OH:18]
Reactant: C=C1C(=C)C2OC1C1=C2CC2C(=O)C=CC(=O)C2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: C=C1C(=C)C2OC1C1=C2CC2C(O)C=CC(=O)C2C1
Temperature: -70 °C
Reaction time: 1.75 h
Yield: 74 %

Procedure:
A solution of 3.38 g of 1,2,3,4,8a,9,10,10a-octahydro-2,3-dimethylene-1,4-epoxyanthracene-5,8-dione in 50 ml of methylene chloride and 50 ml of methanol was cooled to -70° C. and treated under nitrogen with 2.04 g of tetra-n-butylammonium borohydride in 10 ml of methylene chloride. The mixture was then stirred at -70° C. for 1.75 hours. After the addition of 100 ml of aqueous ammonium chloride solution, the solution was stirred for a further 1 hour. The phases were separated, the aqueous phase was extracted twice with 50 ml of methylene chloride each time and the combined organic phases were washed with two 100 ml portions of water and subsequently dried over magnesium sulphate. After concentration and recrystallisation, there were obtained 2.52 g (74%) of 1,2,3,4,5,8,8a,9,10,10a-decahydro-2,3-dimethylene-1,4-epoxy-8-hydroxy-anthracen-5-one of melting point 206°-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:11][CH2:12][C:13]([F:14])([F:16])[F:15])[N:3]=1
Reactant: NC(=O)c1ccc(Cl)nc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(Cl)nc1OCC(F)(F)F
Temperature: 55 °C
Yield: 92.4 %

Procedure:
To a solution of 6-chloro-2-(2,2,2-trifluoro-ethoxy)-nicotinamide (3, 4.68 g, 18.3 mmol) in acetonitrile (anhydrous, 100 mL) were added pyridine (11.86 mL, 146.8 mmol) and POCl3 (6.72 mL, 73.4 mmol). The reaction was heated at 55° C. for 3 hours. After cooling to room temperature, NaOH solution (10% aq.) was slowly added till pH 9. EtOAc (200 mL) was added and layers separated. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The purification was accomplished by silica gel chromatography, eluting with 2%-20% EtOAc/hexanes gradient, to afford 4 g (92% yield) of the titled product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[K+].[CH3:25][CH:26](C([O-])=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].[Cl-].[Mg+2].[Cl-]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH:26]([CH3:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(C)C(=O)[O-]
Reactant: O=C(O)Cc1ccccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Product: CCOC(=O)C(C)C(=O)Cc1ccccc1F

Procedure:
That is, 2-fluorophenylacetic acid (4) and 1,1′-carbonyldiimidazole (CDI) are reacted, followed by treatment with ethyl methylmalonate mono potassium salt in the presence of magnesium chloride to obtain ethyl 4-(2-fluorophenyl)-2-methyl-3-oxobutyrate (5).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1COCC1.F[C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1>CN(C=O)C>[C:43]([C:42]1[CH:45]=[CH:46][C:39]([O:1][C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=2)[C:5]([NH:7][C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)=[O:6])=[CH:40][CH:41]=1)#[N:44]
Reactant: N#Cc1ccc(F)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(C#N)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred solution of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.164 mmol) in DMF (1 mL) was added a 1M solution of sodium hexamethyldisilazide in THF (0.164 mmol). The reaction was stirred at RT for 10 minutes before adding 4-fluorobenzonitrile (0.164 mmol) The reaction was stirred overnight at RT, then heated to 60° C. and stirred for a further 4 hours. The reaction was allowed to cool to RT, and treated with a further 0.2 equivalents of 4-fluorobenzonitrile and sodium hexamethyldisilazide, heated to 70° C. and stirred at this temperature for 3 hours. The reaction was cooled to RT, and treated with a further 0.2 equivalents of sodium hexamethyldisilazide, warmed to 70° C., and stirred at this temperature overnight. The solvent was removed in vacuo and the residual oil partitioned between ethyl acetate and water. The water layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to a residue which was chromatographed on silica, using 0-1% methanol in DCM as the eluent, to give the desired product (60% yield).
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1>>[CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1ccccc1)CO2
Reactant: Cc1cccc(CBr)n1
Product: Cc1cccc(COc2ccc3c(c2)[C@@H](O)[C@H](Cc2ccccc2)CO3)n1

Procedure:
By the method of Example 5, 500 mg (1.96 mmol) of trans-3-benzyl-4,6-chromandiol and 401 mg of 2-(bromomethyl)-6-methyl pyridine were converted to present title product, purified by flash chromatography on silica gel using 1:1 ethyl acetate:hexane as eluant to yield 0.38 g (53%) of present title product as white crystals, m.p. 87°-90° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.ClC(OCC)=O.[BH4-].[Na+].Cl>O1CCCC1.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[CH2:8][OH:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OC/C=C/c1ccc(F)cc1
Reaction time: 1 h
Yield: 102.2 %

Procedure:
4-Fluorocinnamic acid (10 g) was dissolved in tetrahydrofuran (120 mL), triethylamine (10.12 mL) and ethyl chloroformate (6.92 mL) were added dropwise under ice-cooling, and the mixture was stirred for 1 hr. An aqueous solution (60 mL) of sodium tetrahydroborate (6.87 g) was added dropwise to the reaction solution, and the mixture was stirred at room temperature overnight. Aqueous hydrochloric acid solution (1 mol/L, 200 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1 to 1:1) to give the title compound (9.36 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Br:20])=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1cc(CCBr)ccc1OCc1ccccc1
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol (1.0 g, 4.0 mmol) and CBr4 (1.5 g, 4.5 mmol) in CH2Cl2 (10 mL), was PPh3 (1.2 g, 4.5 mmol) added portionwise at 0° C. The reaction mixture stirred for 2 hours at the same temperature. The reaction was concentrated under vacuum and the residue was stirred in ether (10 mmol). The solid, mainly triphenylphosphine oxide, was filtrated off and the filtrate was concentrated under vacuum. The residue was purified over SiO2 to afford the desired compound (1.15 g, 93.5%) as a white crystal. 1H NMR (400 Mz, DMSO-d6) δ 7.36-7.49 (m, 5H), 7.17-7.23 (m, 2H), 7.03-7.05 (m, 1H), 5.18 (s, 2H), 3.72 (t, 2H), 3.08 (t, 2H). LCMS 273.4 [MH+].