Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH:21]=[O:22])[CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[O:23]>C1COCC1>[OH:22][CH:21]([C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:7](=[O:23])[N:6]([CH3:5])[C:10]=2[CH:11]=1)[CH2:1][CH3:2]
Reactant: Cn1c(=O)oc2ccc(-c3cnccc3C=O)cc21
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccncc1-c1ccc2oc(=O)n(C)c2c1
Reaction time: 3 h
Yield: 7.2 %

Procedure:
Ethylmagnesium bromide (3 M in THF, 0295 mL, 0.885 mmol) was added dropwise to a solution of 3-(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-pyridine-4-carbaldehyde (75 mg, 0.295 mmol) in THF (2 mL) at −36° C. The resulting mixture was stirred at this temperature for 3 h, and the reaction was quenched by the addition of saturated NH4Cl solution. The mixture was diluted with ethyl acetate and water. The organic layer was separated and dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by reverse phase chromatography (10%-100%, v/v, ACN-water), 6 mg of desired product was obtained. ESI-MS m/z: 285.1 [M+1]+, Retention time 1.00 min; 1HNMR (CDCl3, 400.342 MHz) δ ppm 0.74 (t, J=7.3 Hz, 3H), 1.47-1.53 (m, 2H), 3.40 (s, 3H), 4.93 (t, J=5.5 Hz, 1H), 7.03 (dd, J=8.1, 1.2 Hz, 1H), 7.16 (s, 1H), 7.25 (d, J=8.1 Hz, 1H), 8.03 (d, J=5 Hz, 1H), 8.36 (s, 1H), 8.52 (d, J=5 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:16]2[S:17][CH2:18][CH:19]([OH:28])[CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[C:10]1([C:16]2[S:17][CH2:18][CH:19]([O:28][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:21]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: OC1CSC(c2ccccc2)=NC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CSC(c2ccccc2)=NC1c1ccccc1
Yield: 60.5 %

Procedure:
Phenyl isocyanate (1.1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-thiazin-5-ol (0.86 g) in 1,2-dichloroethane (10 cc). The solution obtained is stirred under reflux for 3 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is then stirred with a mixture of ethyl acetate and cyclohexane (1:4 by volume). An insoluble precipitate is separated by filtration and the filtrate concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization in diisopropyl ether, (4RS, 5RS)-2,4-diphenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-thiazine (0.75 g), m.p. 159° C., is obtained.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:35]=[CH:34][C:15]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=[CH:21][C:20]=2[OH:33])=O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl>[CH2:1]([O:11][C:12]1[CH:35]=[CH:34][C:15]([C:16]2[O:33][C:20]3[CH:21]=[CH:22][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][C:19]=3[N:18]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Nc2cc(CCCCCCCC)ccc2O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCCCCCCCCCOc1ccc(-c2nc3cc(CCCCCCCC)ccc3o2)cc1
Reaction time: 0.62 h
Yield: 61.3 %

Procedure:
In a 30 ml-round-bottomed flask, 1.00 g (2.08 mM) of 2-(4-decyloxybenzoylamino)-4-octylphenol, 0.07 g (0.68 mM) of p-toluenesulfonic acid monohydrate and 10 ml of o-dichlorobenzene were placed, followed by stirring for 37 min. at 188°-193° C. After the reaction, o-dichlorobenzene was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 0.59 g of 2-(4-decyloxyphenyl)-5-octylbenzoxazole (yield: 61.3%). ##STR75##
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[O:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([OH:10])=[C:2]([C:13]2[CH:14]=[CH:15][O:11][CH:12]=2)[CH:7]=1
Reactant: Cc1cc(F)cc(Br)c1O
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(F)cc(-c2ccoc2)c1O
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 41.6 %

Procedure:
2-bromo-4-fluoro-6-methylphenol (337 mg, 1.20 mmol), 3-furanylboronic acid (162 mg, 1.45 mmol), Pd(dppf)Cl2 (98.3 mg, 0.12 mmol) and sodium carbonate (383 mg, 3.61 mmol) were dissolved in DME:water=20 mL:10 mL, followed by stirring in microwave at 120° C. for 20 minutes. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography (silica gel; hexane/ethyl acetate, 9/1) to obtain 4-fluoro-2-(furan-3-yl)-6-methylphenol (96 mg, 30%) as a yellow oil.
Reaction SMILES: [CH2:1]([P:3]1(=[O:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)C>O1CCCC1>[CH2:4]([P:3]1(=[O:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:1]1)[CH3:5]
Reactant: CCP1(=O)CCCc2ccccc21
Solvent: C1CCOC1
Product: CCP1(=O)C=Cc2ccccc21
Yield: 72 %

Procedure:
This compound was prepared from 1-hydroxy-phosphindoline 1-oxide (3.0g, 17.9 mmol) by a method similar to that used for the preparation of 1-ethyl-1,2,3,4-tetrahydrophosphinoline 1-oxide described above, except that anhydrous tetrahydrofuran was used as solvent. Isolation with chloroform and bulb to bulb distillation of the residue at 160°/0,1 mm gave a colourless hygroscopic liquid (2.3 g, 72%). Preparative T.l.c. (RF 0.38, chloroform/methanol 15:1), and bulb to bulb distillation of the major component gave "pure" 1-ethylphosphindoline-1-oxide as a colourless hygroscopic liquid. This was shown to be pure by g.l.c.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1.Cl.[CH3:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:23][CH2:22][N:21]([C:2]3[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=3)[CH2:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CSc1ccc(Cl)nn1
Reactant: Cc1cccc(C2=CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CSc1ccc(N2CC=C(c3cccc(C)c3)CC2)nn1
Yield: 18 %

Procedure:
A mixture of 3.2 parts of 3-chloro-6-(methylthio)pyridazine, 3.14 parts of 1,2,3,6-tetrahydro-4-(3-methylphenyl)pyridine hydrochloride. 5.3 parts of sodium carbonate and 80 parts of 1-butanol was stirred for 48 hours at reflux temperature. The reaction mixture was evaporated. Water was added. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 0.8 parts (18%) of 3-[3.6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-6-(methylthio)pyridazine: mp. 129.8° C. (compound 214).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O.Cl[Cu]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Oc1ccccc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 36.7 %

Procedure:
Into a 100 mL 3-necked round-bottom flask, was placed a solution of 2-fluorophenol (2.6 g, 23.19 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL) and CuCl (2.2 g, 2.41 equiv). This was followed by the addition of sodium hydride (1.34 g, 55.83 mmol, 0.86 equiv) in portions and then 1-fluoro-4-nitrobenzene (2.8 g, 19.84 mmol, 0.67 equiv). The resulting solution was stirred for 5 h at 100° C. in an oil bath and the resulting solution was diluted with water/ice. The aqueous mixture was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with ethyl acetate/petroleum ether (1:100) gave 1.7 g (31%) of 1-(2-fluorophenoxy)-4-nitrobenzene as a light yellow solid.
Reaction SMILES: [OH:1]O.[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][C@H:15]5[C:16]([O:22]C)=[CH:17][CH:18]=[C:19]2[C@:7]5([C:8]=34)[CH2:6][CH2:5]1>>[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][CH:15]5[C:16]([CH:17]=[CH:18][C@:19]2([OH:1])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:22]
Reactant: OO
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 0.10 L round bottom flask (RBF) is charged with 18.9 g of formic acid, 9.9 g of water, and 7.8 g of 2-propanol. This mixture is stirred at 20–30° C. for 5 minutes. Into this solution is added 5.0 g of thebaine bitartrate monohydrate. This is stirred magnetically at room temperature for 10 minutes until dissolution is achieved. The color of the solution depends on the quality of the thebaine bitartrate. Good quality of thebaine bitartrate affords a pale yellowish solution. No exothermic effect is observed. The solution is cooled in an ice-bath for 20 minutes, and then into this solution 1.29 g of hydrogen peroxide is added. The resulting solution is stirred in the ice-bath for one hour. The ice-bath is removed, and an oil-bath with temperature controller is applied to the reaction flask. Heating is started and the temperature of the reaction mixture is kept at 45° C. for 3 h (completion of reaction tested by HPLC; residual thebaine <0.5 a/a %).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:43])[C@H:9]([CH3:42])[CH2:10][C@H:11]([OH:41])[C@@H:12]([NH:33]C(OC(C)(C)C)=O)[CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)(=[O:3])[NH2:2].[ClH:44]>O1CCOCC1>[ClH:44].[C:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:43])[C@H:9]([CH3:42])[CH2:10][C@H:11]([OH:41])[C@@H:12]([NH2:33])[CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)(=[O:3])[NH2:2]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC(N)=O)C(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C)C(=O)NCCCC(N)=O)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
84 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid [N-(3-carbamoyl-propyl)]-amide are dissolved in 3 ml of 4N hydrochloric acid in dioxane at 0° C. and the mixture is stirred for 2 hours at 0° C. The reaction mixture is lyophilised. The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.04; HPLC Rt =9.44 minutes; HR FAB-MS (M+H)+ =510.
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].O>CCCCCC>[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)=[O:21]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: OCc1ccc2c(c1)OCO2
Solvent: O
Solvent: CCCCCC
Product: CC(C)CCCCCCC(=O)OCc1ccc2c(c1)OCO2
Temperature: 50 °C
Yield: 84.4 %

Procedure:
Piperonyl alcohol (442 mg, 2.90 mmol), 8-methylnonanoic acid (500 mg, 2.90 mmol) and Novozyme 435 (50 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (25 ml) was added, and Novozyme 435 and the precipitated piperonyl alcohol were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (preparative thin layer chromatography, Merch Art. 13895) (n-hexane:ethyl acetate=4:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give piperonyl 8-methylnonanoate (0.75 g, yield 84.3%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[N:3]=1.[C:23]1([NH:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([NH:32][CH2:31][CH2:30][NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1C1=CCCO1
Reactant: NCCNc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccc2)nc(N)nc1C1=CCCO1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-(4,5-dihydro-furan-2-yl)-pyrimidin-4-yl ester and N-phenylethylenediamine in DME. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@@H:5]1[C@:22]2([CH3:23])[C:8]([C:9]3[CH2:10][CH2:11][CH:12]4[C@:17]([C:19]=3[CH2:20][CH2:21]2)([CH3:18])[CH2:16][CH2:15][C@H:14]([OH:24])[C:13]4([CH3:26])[CH3:25])=[CH:7][CH2:6]1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CN=C1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@@H:5]1[C@:22]2([CH3:23])[C:8]([C:9]3[CH2:10][CH2:11][CH:12]4[C@:17]([C:19]=3[CH2:20][CH2:21]2)([CH3:18])[CH2:16][CH2:15][C@H:14]([O:24][Si:28]([CH3:30])([CH3:29])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:13]4([CH3:26])[CH3:25])=[CH:7][CH2:6]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C1CC3
Temperature: 0 °C
Yield: 103.8 %

Procedure:
92 g of 4,4-dimethyl-3β-hydroxypregna-8,14-dien-21-oic acid methyl ester is stirred with 0.75 liter of N,N-dimethylformamide, 51 g of tert-butyldimethylsilyl chloride and 27.8 g of imidazole for 18 hours at 70° C. After cooling, it is poured into 10 liters of an ice-cold 0.5 molar aqueous hydrochloric acid and filtered. The filter cake is taken up in ethyl acetate, washed neutral with 1N sodium hydroxide solution, dried on sodium sulfate, filtered and concentrated by evaporation. 124.8 g of 4,4-dimethyl-3β-[[dimethyl(1,1-dimethylethyl)silyl]oxy]pregna-8,14-dien-21-oic acid methyl ester is obtained, which is further used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O:11][C:12](=O)[C:13]([C:25]#[N:26])=[CH:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)C>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5]([C:14]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[C:13]([C:25]#[N:26])[C:12](=[O:11])[O:8]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)cc(OC)c1
Reactant: Nc1cccc(O)c1
Product: COc1cc(OC)cc(-c2c(C#N)c(=O)oc3cc(N)ccc23)c1
Yield: 0.5 %

Procedure:
The title compound was prepared from 3-aminophenol and 3-(3,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 0.5% yield. 1H NMR (CDCl3): 7.42 (d, J=8.4 Hz, 1H), 6.72 (d, J=2.4 Hz, 2H), 6.61-6.60 (m, 1H), 6.20 (d, J=2.1 Hz, 1H), 6.10 (dd, J=2.1, 8.7 Hz, 1H), 4.30 (brs, 2H), 3.83 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[C:11]([CH3:27])=[CH:10][C:9]=2[C:8]([CH3:29])([CH3:28])[CH2:7][CH:6]=1)(C)(C)[CH3:2].C(=O)C>>[CH2:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[C:11]([CH3:27])=[CH:10][C:9]=2[C:8]([CH3:29])([CH3:28])[CH2:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3C(C)(C)C)cc1
Agent: CC=O
Product: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3CC)cc1
Yield: 89.2 %

Procedure:
Following General Procedure D, ethyl 4-[(8-tert-butyl-3,5,5-trimethyl-5,6-dihydronaphthalen-2yl)amino]benzoate (Compound 18, 0.14 g, 0.37 mmol) was reacted with acetaldehyde (0.40 mL, 7.4 mmol) to give 0.12 g (75%) of the title compound as a light yellow solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:21]([O:33][CH3:34])[CH:20]=3)=[CH:17][O:18][C:14]=2[CH:13]=[CH:12][N:11]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[C:21]([O:33][CH3:34])[CH:20]=3)=[CH:17][O:18][C:14]=2[C:13]([I:1])=[CH:12][N:11]=1
Reactant: COc1cc(-c2coc3ccnc(N)c23)ccc1NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
N-Iodosuccinimide (0.333 g, 1.48 mmol) was added to a solution of tert-butyl 4-(4-aminofuro[3,2-c]pyridin-3-yl)-2-methoxyphenylcarbamate (0.439 g, 1.24 mmol) in N,N-dimethylformamide (10 mL) at ambient temperature. The reaction suspension was stirred for 18 hours, at which time no starting material remained. An aqueous solution of 10% sodium thiosulfate (10 mL) was added to the suspension and stirred for 30 minutes. The precipitate was collected by vacuum filtration and washed with water. The solid was dried in vacuo to give the title compound (0.501 g, 84%) as a tan solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.08 (s, 1H), 8.07 (s, 1H), 8.06 (s, 1H), 7.85 (d, 1H), 7.13 (d, 1H), 7.04, (dd, 1H), 5.73-5.80 (bs, 2H), 3.86 (s, 3H), 1.48 (s, 9H); RP-HPLC (Conditions d) Rt 8.49 min.; MS: MH+ 482.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:51][NH:52][CH2:53][CH2:54][OH:55].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH3:51][N:52]([CH2:27][CH2:26][NH:25][C:24]([O:23][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:21][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:29])[CH2:53][CH2:54][OH:55]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCBr
Reactant: CNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCN(C)CCO
Temperature: 80 °C
Yield: 74.7 %

Procedure:
In 10 ml of chloroform was dissolved 173 mg (0.224 mmol) of 1,3-O-dioleoyl-2-O-(2-bromoethyl)carbamoylglycerol followed by addition of 543 mg (7.228 mmol) of 2-(methylamino)ethanol and 27 mg (0.209 mmol) of diisopropylethylamine and the mixture was refluxed at 80° C. overnight. The reaction mixture was then washed with 5% sodium dihydrogen phosphate-H2O, dried, and concentrated. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 128 mg (74.3%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:7](=[O:19])[C@H:6]1[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:36]C(OCC1C=CC=CC=1)=O)=[N:25]C(OCC1C=CC=CC=1)=O)=[O:4].[ClH:47].[H][H]>[Pd].C(OCC)(=O)C.CO>[ClH:47].[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:7](=[O:19])[C@H:6]1[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH2:36])=[NH:25])=[O:4]
Reactant: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Yield: 24 %

Procedure:
An ethyl acetate/methanol (2.5 mL/2.5 mL) solution of compound 8 (197 mg, 0.3 mmol) and 1N HCl (0.6 mL), containing palladium on carbon catalyst, was stirred under one atmosphere of hydrogen until TLC indicated the disappearance of the starting 8. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 30 mg (24%) of the title product as a foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:20]>ClCCl.CCOCC>[ClH:20].[N:15]1([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: c1cnn(CC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-Pyrazol-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester (215 mg) in anhydrous dichloromethane (5 ml) was added 2M hydrogen chloride in ether (4.1 ml). The reaction mixture was stirred at room temperature for 6 hours. The solvents were removed in vacuo to yield 4-Pyrazol-1-ylmethyl-piperidine hydrochloride salt.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:17])([CH3:16])[C:12]3[S:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:24]([C@:26]1([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32])#[CH:25]>>[F:23][C:3]1[C:2]([C:25]#[C:24][C@:26]2([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]2=[O:32])=[CH:7][C:6]2[C:8]3[N:9]=[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:11][C:12]=3[C:13]([OH:17])([CH3:16])[CH2:14][O:15][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CCOC(=O)c1nc2c(s1)C(C)(O)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (415 mg) was reacted with methylmagnesium bromide similarly to as described in the synthesis of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo{e}azulene-2-carboxylic amide with non-critical modifications to afford ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (272 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 23.3 mg and 27.4 mg (17.4% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined