Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[C:9](=O)[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[C:19]([CH:20]([CH3:22])[CH3:21])[C:6]=2[O:5]1)([CH3:3])[CH3:2].C[S:24]P1(=S)SP(=S)(SC)S1>C1(C)C=CC=CC=1>[CH:1]([C@H:4]1[C:9](=[S:24])[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[C:19]([CH:20]([CH3:22])[CH3:21])[C:6]=2[O:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=O)[C@H](C(C)C)Oc2c(C(C)C)cccc21
Reactant: CSP1(=S)SP(=S)(SC)S1
Solvent: Cc1ccccc1
Product: COC(=O)CN1C(=S)[C@H](C(C)C)Oc2c(C(C)C)cccc21
Temperature: 50 °C
Reaction time: 64 h
Yield: 93.5 %

Procedure:
A mixture of (S)-methyl 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetate (3.05 g), 2,4-bis (methylthio)-1,3,2,4-dithiadiphosphetan-2,4-disulfide (Davy reagent methyl)(2.84 g) and toluene (60 ml) was stirred at 50° C. for 64 hours. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (100 g) using hexane-ethyl ether (85:15, v/v) as the eluent to yield (S)-methyl 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetate as an oil (3.00 g).
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].[ClH:6].[CH3:7][C:8]([CH2:10][C:11]([CH3:13])=O)=O>C(O)C>[ClH:6].[C:1]([N:4]1[C:11]([CH3:13])=[CH:10][C:8]([CH3:7])=[N:5]1)(=[NH:3])[NH2:2]
Reactant: CC(=O)CC(C)=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)n(C(=N)N)n1
Reaction time: 3 h

Procedure:
To 850 ml of ethanol were added 188 g of aminoguanidine hydrochloride and 170 g of 2,4-pentadione and the mixture was heated with stirring for 3 hrs. under reflux. The precipitated crystals were filtered, sufficiently washed with ethanol and dried to obtain 1-amidino-3,5-dimethylpyrazole hydrochloride of 210 g. Next, 60 g of potassium hydroxide was dissolved in water of 120 g and 1-amidino-3,5-dimethylpyrazole hydrochloride of 61.1 g was added thereto withcooling with water and stirred further for 1 hr. Chloroform of 200 ml was added to the solution for extraction. A chloroform layer was separated, washed with water and dried with anhydrous sodium sulfate, thereafter, chloroform was removed to obtain 1-amidino-3,5-dimethylpyrazole of 46.0 g.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[N:17]([CH3:25])[CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[N:17]([CH3:25])[CH:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH:10]=2)=[CH:6][CH:5]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reaction time: 8 h

Procedure:
3-[4-(4-Nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea was dissolved in tetrahydrofuran (4 ml)-methanol (4 ml), and then 10% palladium carbon (65 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under a reduced pressure to provide the titled compound (113.5 mg, quantitatively) as colorless powder.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([O:10][C:11]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:12]=1)=[O:9])([CH3:6])[CH3:5].[I-].[CH4:30].O>CN(C)C=O>[CH3:6][C:4]([O:7][C:8]([O:10][C:11]1[CH:16]=[C:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:14]=[C:13]([CH:23]([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:12]=1)=[O:9])([CH3:3])[CH3:5]
Reactant: CCOC(=O)Cc1nc(OC(=O)OC(C)(C)C)cc(N2CCOCC2)n1
Reactant: C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1nc(OC(=O)OC(C)(C)C)cc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
84 mg of sodium hydride are added to a solution of 700 mg of ethyl [4-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)-6-(morpholin-4-yl)pyrimidin-2-yl]acetate in 8 ml of N,N-dimethylformamide under argon. The reaction mixture is then stirred for 15 minutes at 0° C. 0.130 ml of methane iodide is then added and the resulting mixture is stirred at ambient temperature overnight. 0.5 ml of water is added and the reaction mixture is concentrated to dryness under reduced pressure. After purification by silica column chromatography, elution being carried out with a gradient of heptane/ethyl acetate eluent of 0% to 50% and then with ethyl acetate at 100%. 150 mg of ethyl 2-[4-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)-6-(morpholin-4-yl)pyrimidin-2-yl]propanoate are obtained in the form of a colourless oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.P(Br)(Br)([Br:21])=O.C([O-])(O)=O.[Na+]>>[Br:21][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-n2ccc(Br)cc2=O)cc1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (106.1 mg, 0.4 mmol) and phosphorous oxybromide (573.4 mg, 2.0 mmol, Alfa Aesar) was heated at 100° C. for 45 min and then cooed to room temperature. To the above residue was added saturated NaHCO3 aqueous solution at 0° C. followed by extraction with CH2Cl2 (3×). The combined extracts were washed with saturated NaHCO3 aqueous solution and brine, dried (Na2SO4) and evaporated. The residual was purified by flash chromatography (0 to 100% EtOAc/hexanes) to yield 60.7 mg (46%) of the product as a yellow solid. MS (ESI) 328 (M+H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([S:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[C:18]([CH3:27])=[CH:17]2)(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=O)C.Cl>C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([S:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[C:18]([CH3:27])=[CH:17]2)(=[O:14])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc2c(c1)c(C)cn2S(=O)(=O)c1ccc(OC)c(NC(C)=O)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)c(C)cn2S(=O)(=O)c1ccc(OC)c(N)c1
Yield: 11.2 %

Procedure:
1-(3′-Acetamido-4′-methoxybenzenesulfonyl)-5-methoxy-3-methyl-1H-indole (10 grams, 25.7 mmol) (obtained from preparation 1) was taken into a 250 mL of three necked round bottom flask containing ethanol (100 mL) and stirred the mass to obtain a clear solution. Aqueous hydrochloric acid (10 mL, 33%) was added to this clear solution and heated the mass at reflux temperature for a period of two hours. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mass was concentrated under vacuum and the residual mass was quenched into chilled water (100 mL). The pH was adjusted to 9.0 to 10.0 with dilute sodium hydroxide solution. The product was extracted with dichloro methane (2×100 mL). Organic phase was washed with brine solution, dried over anhydrous sodium sulphate and concentrated the mass under reduced pressure to obtain crude compound. The obtained technical product was purified by column chromatography using silica gel (100-200 mesh), the eluent system being ethyl acetate and n-hexane (2:8) to obtain 1.0 gram of the title product.
Reaction SMILES: [OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3]([O:5]C1C=CC=CC=1)=[CH2:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].OOS([O-])=O.[K+].[OH-:45].[K+].C[C:48]([CH3:50])=[O:49]>O.C1(C)C=CC=CC=1.C(Cl)Cl>[OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:4])[CH2:5][O:49][C:48](=[O:45])[CH3:50]
Reactant: [OH-]
Reactant: C=C(Oc1ccccc1)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reactant: CC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Temperature: 15 °C

Procedure:
17α-hydroxy-20-phenoxypregna-4,9(11),20-trien-3-one (4.05 grams, 10 mmoles) is slurried with 210 ml of an aqueous pH 8 potassium phosphate buffer (0.5M in PO4 ≡), 20 ml of acetone, 40 ml of toluene/methylene chloride (3:2) and n-tetrabutylammonium bromide is (0.645 grams, 2.0 mmole) added. The pH is adjusted to 7.0 to 8.0 and the mixture cooled to 15° C. and an OXONE® solution is (18.4 gms, 30 mmoles dissolved in 65 ml of water) added dropwise by an addition funnel while stirring and maintaining pH at 7.0 to 8.0 by addition of a 30% potassium hydroxide solution. The reaction is worked up by separating the layers and replacing the organic solvent with toluene to a volume of 100 ml so as to remove water. After cooling to 10° C., 3 ml of glacial acetic acid is added. The product is isolated by replacing the toluene with acetone and filtering to obtain 3.12 g of 17α-hydroxy-21-acetoxypregna-4,9(11)-diene-3,20-dione.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[C:5]([CH2:7]O)[N:6]=1.S(Cl)([Cl:12])=O>ClC(Cl)Cl>[ClH:12].[Cl:12][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[CH3:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(CO)c(C)o1
Solvent: ClC(Cl)Cl
Product: Cc1nc(CCl)c(C)o1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 18.5 parts of 2,5-dimethyl-4-oxazolemethanol in 200 parts of trichloromethane there were added dropwise 21.1 parts of thionyl chloride. After stirring for 2 hours at room temperature, the reaction mixture was evaporated and the residue was co-evaporated with methylbenzene, yielding 26.4 parts (100%) of 4-(chloromethyl)-2,5-dimethyloxazole hydrochloride (interm. 26).
Reaction SMILES: [CH3:1][C:2]1[N:10]2[C:5]([C:6]([CH3:11])=[CH:7][CH:8]=[CH:9]2)=[C:4]([CH2:12][OH:13])[CH:3]=1>CC(C)=O.O=[Mn]=O>[CH3:1][C:2]1[N:10]2[C:5]([C:6]([CH3:11])=[CH:7][CH:8]=[CH:9]2)=[C:4]([CH:12]=[O:13])[CH:3]=1
Reactant: Cc1cccn2c(C)cc(CO)c12
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: Cc1cccn2c(C)cc(C=O)c12
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution (3,8-Dimethyl-indolizin-1-yl)-methanol (600 mg, 3.4 mmol) in acetone (20 mL) was added MnO2 (595 mg, 6.8 mmol) at room temperature. The mixture was stirred at the same temperature for 3 hours. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 5% EtOAc in Hexane as the eluent to afford the desirable product 3,8-Dimethyl-indolizine-1-carbaldehyde (400 mg, 67%) as a grey solid.
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[CH2:2][CH2:3][C:4]([O:6]CC)=[O:5].[C:13]1([CH:23]=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[OH-].[Na+]>C(O)C>[C:13]1([CH:23]=[C:3]([CH2:2][C:1]([OH:10])=[O:9])[C:4]([OH:6])=[O:5])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(=Cc1cccc2ccccc12)C(=O)O
Yield: 55.8 %

Procedure:
To a solution of 32.3 g of diethyl succinate and 29.0 g of 1-naphthaldehyde in 100 ml of absolute ethanol was added 10.7 g of sodium hydride (50% dispersion in mineral oil) under ice-cooling, and then the mixture was heated under reflux for 0.5 hours. To the reaction was added 230 ml of 1N-aqueous sodium hydroxide solution, and the mixture was heated under reflux for 1 hour. The reaction mixture was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether to remove neutral substances. The aqueous layer was acidified by adding concentrated hydrochloric acid, and extracted with diethyl ether. The ethereal layer was washed a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Benzene was added to the residue, and the precipitated crystals were collected by flitration to obtain 26.5 g of 2-(1-naphthylmethylene)succinic acid as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.Cl[CH2:21][C:22](Cl)=[O:23].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][CH2:21][C:22](=[O:23])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1
Yield: 52.5 %

Procedure:
Using 2-amino-4-chloro-5-nitrophenol (3.0 g, 15 mmol), triethylamine (2.7 mL, mmol) and chloroacetyl chloride (2.0 g, 17 mmol) in THF (100 mL) followed by sodium hydride (1.3 g of a 60% suspension in oil, 30 mmol) to yield the title compound as an orange solid (1.8 g, 54%). δH (DMSO-d6) 4.74 (2H, s), 7.07 (1H, s), 7.77 (1H, s), 11.29 (1H, br s).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=4)[CH2:11]3)[C:9](=[O:22])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>CCOC(C)=O.CO.[Pd]>[NH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:3]3[CH:2]=[N:7][CH:6]=[N:5][C:4]=3[NH:8][C:9]1=[O:22])[CH2:18]2
Reactant: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncncc21
Reaction time: 24 h

Procedure:
To a solution of (±)-4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7H)-one from Step C (400 mg, 1.26 mmol) in EtOAc (40 mL) and MeOH (10 mL) was added triethylamine (0.88 mL, 6.315 mmol). The mixture was hydrogenated at 50 psi hydrogen over 10% Pd/C (100 mg). After 24 h and 90 h, an additional amount of palladium on carbon (100 mg) was added to the reaction mixture and hydrogenation was continued for a total of 180 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=253 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1([O:23][C:24](=[O:34])[C@H:25]([CH3:33])[NH:26]C2C=CC=CC=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](O[C:45](=O)[CH3:46])OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl.C(O)(=O)C>[CH:18]1([O:23][C:24](=[O:34])[C@@H:25]([NH:26][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[CH:10][CH:11]=2)[CH2:33][C:46]2[CH:45]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C[C@H](Nc1ccccc1)C(=O)OC1CCCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(4-Formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.85 mmol) was dissolved in DCE (10 mL) and to this was added phenyl alanine cyclopentyl ester (214 mg, 0.94 mmol). The reaction was stirred at r.t. for 15 min. Sodium triacetoxyborohydride (538 mg, 2.55 mmol) and acetic acid (60 uL) were added and the reaction stirred for a further 1 h. Saturated sodium bicarbonate (10 ml) was added and the solution diluted with DCM (20 mL). The organic layer was isolated and concentrated to afford the desired product which was taken onto the next step without further purification. m/z 453 [M++H+
Reaction SMILES: [O:1]1[C:5]2[C:6]3[C:7](=[CH:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1>CO.[C].[Pd]>[O:1]1[C:5]2[C:6]3[CH:7]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1
Reactant: CCC(=O)NCC=C1CCc2ccc3ncoc3c21
Agent: [Pd]
Solvent: CO
Product: CCC(=O)NCCC1CCc2ccc3ncoc3c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
N-[2-(6,7-Dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]propionamide (28.7 mg, 0.112 mmol) was dissolved in methanol (1.1 mL), a 10% palladium-carbon powder (14 mg) was added, and the mixture was stirred at room temperature for 1.5 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (25.6 mg, yield 88%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([C:21]([C:20]2[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:22])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
Aluminum chloride (2.15 g, 16.12 mmol) was added to a stirred mixture of 1,2-dimethoxybenzene (2.03 g, 14.65 mmol) in anhydrous methylene chloride (20 ml) in an ice bath. Then a solution of 4-methoxybenzoyl chloride (2.50 g, 14.65 mmol) in anhydrous methylene chloride (50 ml) was added. The mixture was allowed to warm up to rt, then refluxed overnight. After cooling down to rt, the mixture was poured to ice water (50 ml), stirred for 20 min., and extracted with methylene chloride (3×50 ml). The combined organic extracts were washed with sat. NaHCO3 (3×50 ml), H2O (2×50 ml), brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (10% EtOAc in hexane) to give (3,4-dimethoxy-phenyl)-(4-methoxy-phenyl)methanone as an off-white solid (3.66 g, 92%); 1HNMR (CDCl3) δ 7.80 (d, J=8 Hz, 2H, Ar), 7.44 (d, J=1 Hz, 12H, Ar), 7.37 (dd, J=1 Hz and 8 Hz, 1H, Ar), 6.97 (d, J=8 Hz, 2H, Ar), 6.90 (d, J=8 Hz, 1H), 3.96 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.89 (s, 3H, OCH3). The product was carried over to the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=1[F:20].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.O>[Si:31]([O:30][CH2:29][CH2:28][O:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]([C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[F:20])=[C:2]([F:1])[CH:7]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(O)cc2F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(OCCO[Si](C)(C)C(C)(C)C)cc2F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
To a solution of methyl 6-(2,6-difluoro-4-hydroxyphenyl)-5-fluoropicolinate (1.0 equiv.) and potassium carbonate (4.0 equiv.) in DMF (0.4 M) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (2 equiv.). After stirring for 72 hours at rt the heterogeneous solution was diluted with water, extracted with EtOAc, dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield methyl 6-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2,6-difluorophenyl)-5-fluoropicolinate in 74% yield. LC/MS=442.1 (M+H), Rt=1.22 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1.[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1.C(O)C>C(N(CC)CC)C>[NH2:9][C:10]1[N:15]=[C:14]([NH:1][CH2:2][C:3]2([CH2:7][OH:8])[CH2:6][O:5][CH2:4]2)[CH:13]=[C:12]([Cl:17])[N:11]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCC1(CO)COC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCC2(CO)COC2)n1
Yield: 32.7 %

Procedure:
A mixture of 3-aminomethyl-3-hydroxymethyloxetane (1.17 g, 0.01 mol), 2-amino-4,6-dichloropyrimidine (1.64 g, 0.01 mol), ethanol (40 ml) and triethylamine (4 ml) was refluxed for one day. The solvent was distilled away under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1, later 10:1) to give colorless prism crystals (0.8 g, 32.8%), m.p. 185-186° C. (acetone).
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:9][C:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][C:12](=[O:17])[CH:11]=1>Cl>[CH3:16][C:14]1([P:4]([O:5][CH2:6][CH3:7])(=[O:8])[O:3][CH2:1][CH3:2])[CH2:13][C:12](=[O:17])[CH2:11][CH:10]([CH3:9])[CH2:15]1.[CH3:16][C:14]1([P:4]([OH:3])(=[O:5])[OH:8])[CH2:13][C:12](=[O:17])[CH2:11][CH:10]([CH3:9])[CH2:15]1
Reactant: CCOP([O-])OCC
Reactant: CC1=CC(=O)CC(C)C1
Agent: Cl
Product: CC1CC(=O)CC(C)(P(=O)(O)O)C1
Product: CCOP(=O)(OCC)C1(C)CC(=O)CC(C)C1

Procedure:
Diethyl 1,3-dimethyl-5-oxocyclohexanephosphonate (B.pt. 120°/0.1 mm) was prepared by the base catalysed addition of diethylphosphite to 3,5-dimethyl-2-cyclohexen-1-one. Hydrolysis of the ester in concentrated HCl gave 1,3-dimethyl-5-oxocyclohexanephosphonic acid as a viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][S-:14].[Na+]>O1CCCC1>[F:9][C:7]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([CH2:2][S:14][CH3:13])[CH:8]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(F)cc1CBr
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10.0 g (42.7 mmol) of the compound from Example 1A were introduced into 100 ml of tetrahydrofuran at RT, 3.29 g (47.0 mmol) of sodium methanethiolate were added, and the mixture was stirred at RT for 4 h. It was filtered with suction through kieselguhr and washed with tetrahydrofuran, and the filtrate was concentrated to result in 9.00 g (100% of theory) of the title compound which were reacted without further purification.