Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[OH2:6]>>[CH2:1]([OH:5])[CH:2]([OH:4])[CH:1]([OH:5])[CH:2]([OH:4])[CH:3]=[O:6]
Reactant: CC(O)CO
Reactant: O
Product: O=CC(O)C(O)C(O)CO

Procedure:
Arabia gum or peach gum was dissolved into the LMP solution, or the LMP and arabia gum or peach gum was independently dissolved into a proper amount of water and then mixed to uniform, and then propylene glycol was added to obtain a glue liquid. The residual processes are identical with those disclosed in example 8.
Reaction SMILES: C(OC(=O)[CH:5]([C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]1)=[O:16])[CH2:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[OH-].[Na+]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[C:8]1([C:7](=[O:14])[CH2:6][CH2:5][C:15]([CH:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCC1CCC(C(=O)C(CC(=O)c2ccccc2)C(=O)OCC)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(C(=O)CCC(=O)c2ccccc2)CC1
Yield: 23.6 %

Procedure:
To a solution of 7.63 g (21.3 mmol) 4-oxo-4-phenyl-2-(4-propyl-cyclohexanecarbonyl)-butyric acid ethyl ester in 66 mL toluene was added 36 mL 3M aqueous sodium hydroxide and 0.32 g (0.96 mmol) tetra-n-butylammonium hydrogen sulfate. The reaction was heated to reflux over 16 hr, allowed to cool and poured into brine. The solution was extracted two times with ether and concentrated to give an oil. The crude product was chromatographed on silica to give 1.44 g 1-phenyl-4-(4-propyl-cyclohexyl)-butane-1,4-dione as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C(O)(C)(C)C.[Li].N>C1COCC1>[CH3:1][O:2][C:3]1[CH2:8][CH:7]=[C:6]([C:9]([OH:12])([CH3:10])[CH3:11])[CH2:5][CH:4]=1
Reactant: COc1ccc(C(C)(C)O)cc1
Agent: N
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC1=CCC(C(C)(C)O)=CC1
Temperature: -30 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
2-(4-methoxy-phenyl)-propan-2-ol (750 g, 4.5 mol), anhydrous THF (7.5 L) and tert-BuOH (2001.4 g, 27 mol) were added under argon to a 22 L round bottomed flask equipped with an overhead stirrer, thermometer and dropping funnel. The mixture was cooled to −30° C. Gaseous ammonia was bubbled through the reaction mixture for 30 min. Granulated lithium (125 g, 18 mol) was added portion wise to the solution during 1-1.5 hr. The stirring was continued with slow flow of ammonia for 20 rh. The reaction was quenched with a solution of 961 g NH4Cl in 2.7 L water at −20° C. The top layer was separated and evaporated on a rotary evaporator at a bath temperature of 30° C. (all these and subsequent operations are performed under inert atmosphere). The aqueous layer was extracted with MTBE (3×1 L). The concentrate and extract were combined, washed with water and brine, dried over Na2SO4 and evaporated to dryness at a bath temperature of 35° C. The crude oily product was mixed with 725 ml Hexane and filtered. The filtrate was placed in a freezer at −70° C. and left for 24 hr. The solid was decanted and rinsed with Hexane pre-cooled to −70° C. (2×100 mL) with decantation after each rinsing. After drying under vacuum at 20° C., 562 g of the target product was obtained (yield 74%), having an HPLC purity of 89%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:19])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.[C:20](#[N:24])[CH2:21][C:22]#[N:23].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1>[NH2:24][C:20]1[O:19][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:21]=1[C:22]#[N:23]
Reactant: COc1ccc(C(=O)C(O)c2ccccc2F)cc1
Reactant: N#CCC#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2c(-c3ccccc3F)oc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Put 84 g (0.32 mol) 2-(2-fluorophenyl)-2-hydroxy-1-(4-methoxyphenyl)ethanone and 32 g (0.48 mol) malononitrile in 153 ml THF. After stirring for five minutes, add 49 ml (36 g, 0.36 mol) triethylamine, with ice cooling. Stir the reaction mixture for 1 h with ice cooling. Then leave the reaction mixture to warm to room temperature and stir for 4 h at this temperature. After adding 1000 ml ethyl acetate, wash the organic phase five times with 300 ml water, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation. Take up the residue in dichloromethane and purify by flash chromatography on silica gel (solvent: dichloromethane/methanol 70:1, then cyclohexane/ethyl acetate 2:1). 37 g (0.11 mol) of 2-(2-fluorophenyl)-2-hydroxy-1-(4-methoxyphenyl)ethanone thus recovered is again reacted with 14 g (0.03 mol) malononitrile and 21 ml (15 g, 0.15 mol) triethylamine in 67 ml THF in accordance with the above procedure. A total of 70 g (52% purity, 36% of theor.) of the target compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[C:10](=O)([O-])[O-].[Cs+].[Cs+].ClCCl>CN(C)C=O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]2[O:6][CH2:10][O:9][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c(O)c1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)OCO2
Temperature: 110 °C
Yield: 303.8 %

Procedure:
4-methylcatechol (15 g, 120.9 mmol) was added to a suspension of cesium carbonate (50 g, 154 mmol) in dimethylformamide (60 mL). The mixture was put under vacuum and purged with nitrogen three times. At ambient temperature, dichloromethane (15.4 g, 181.3 mmol) was added, and then the reaction mixture was heated at about 110° C. for about 2 hours. After cooling to ambient temperature, the reaction was quenched with water (500 mL) and extracted with ether-pentane (1:1 ratio, 3×500 mL). The combined organic layers were washed with water (3×1000 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the desired product (50 g, 30%). 1H NMR (300 MHz, CDCl3) δ 6.71-6.59 (m, 3H), 5.88 (s, 2H), 2.27 (s, 3H); GC-MS: m/z=136 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41])=O>CN(C)C=O>[F:37][C:36]1[C:31]([O:18][C:17]([C:9]2[NH:10][C:11]3[C:16]([C:8]=2[NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:19])=[C:32]([F:41])[C:33]([F:40])=[C:34]([F:39])[C:35]=1[F:38]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1[nH]c2ccccc2c1Nc1ccncc1
Yield: 39.7 %

Procedure:
Stir under N2 a suspension of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid (0.2 g, 0.78 mmol) in dimethylformamide, add pyridine (0.13 mL, 1.6 mmol) and then add dropwise pentafluorophenyl trifluoroacetate (0.31 g, 1.13 mmol). Stir the reaction overnight at ambient temperature and quench into water. Extract the aqueous mixture with ethyl acetate, wash with 5% aqueous potassium carbonate, brine and dry over MgSO4. Concentrate under vacuum to afford a crude solid, which is triturated with ether to obtain 0.13 g (41%) of the title compound: MS 420(M+H).
Reaction SMILES: O1CCCC1.C[O:7][C:8](=[O:37])[C@:9]([NH2:36])([C@@H:21]([CH2:29][C:30](=[O:35])[CH:31]=[CH:32][CH2:33][CH3:34])[O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[NH:10][C:11]([O:13][Si](C(C)(C)C)(C)C)=[O:12].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOCC.CCCCCC.O>[CH2:38]([O:13][C:11]([NH:10][C@:9]([NH2:36])([C:8]([OH:7])=[O:37])[C@@H:21]([CH2:29][C:30](=[O:35])[CH:31]=[CH:32][CH2:33][CH3:34])[O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)=[O:12])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: CCC=CC(=O)C[C@@H](OC1CCCCO1)[C@](N)(NC(=O)O[Si](C)(C)C(C)(C)C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCC=CC(=O)C[C@@H](OC1CCCCO1)[C@](N)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a tetrahydrofuran solution (1.0 ml) of the compound prepared in Example 2 (45.8 mg, 0.09 mmol), were successively added dropwise at 0° C. in a nitrogen atmosphere benzyl bromide (0.021 ml, 0.18 mmol) and a tetrahydrofuran solution of tetrabutyl ammonium fluoride (0.090 ml, 0.09 mmol). The mixture was stirred for 1 hour at 0° C., poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under vacuum. The resulting reaction mixture was subjected to column chromatography (ether/hexane=1/1) to give 31.2 mg of the titled compound (yield, 78% based on the starting materials used in Example 2).
Reaction SMILES: [OH-].[Na+].O.[CH:4](=[O:8])[CH:5]([CH3:7])[CH3:6].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][C:5]([CH3:7])([CH3:6])[CH:4]=[O:8])=[CH:12][CH:11]=1
Reactant: CC(C)C=O
Reactant: Fc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C=O)Cc1ccc(F)cc1
Reaction time: 5 h

Procedure:
A mixture of sodium hydroxide (4.2 g), water (4.2 g), benzene (6 ml) and tetrabutylammonium iodide (0.45 g) was heated to 70°. A solution of isobutyraldehyde (8.65 g) and 4-fluorobenzyl chloride (13.01 g) was dripped into the mixture which was stirred at 70° for 5 hr. The product was extracted into ether, the solution was dried (MgSO4) and evaporated to give an oil b.p. 80°/1.0 mm (15.30 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][Mg]Cl.Cl[Si:13]([CH2:16][Cl:17])([CH3:15])[CH3:14]>>[Cl:17][CH2:16][Si:13]([CH2:4][C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])([CH3:15])[CH3:14]
Reactant: Fc1ccc(C[Mg]Cl)c(F)c1
Reactant: C[Si](C)(Cl)CCl
Product: C[Si](C)(CCl)Cc1ccc(F)cc1F
Yield: 95 %

Procedure:
The title compound is prepared in 95% yield from 2,4-difluorobenzylmagnesium chloride and chlorochloromethyldimethylsilane by the method described in Example 5, Step A.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(Cl)(=O)C.[CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH2:10]>>[C:1]([O:4][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:10])(=[O:3])[CH3:2]
Reactant: C=COCCCC
Reactant: CC(=O)O
Solvent: CC(=O)Cl
Product: CCCCOC(C)OC(C)=O
Reaction time: 1.5 h

Procedure:
Into a 2000 ml reaction flask, equipped with stirrer, cooling bath, thermometer, addition funnel and nitrogen blanket apparatus, is added 420 ml of acetic acid (7.0 moles) and 3.0 ml of acetyl chloride. Dropwise over a period of 1.5 hours, while maintaining the reaction mass at 50°-72° C. is added 950 ml (7.7 moles) of n-butyl vinyl ether (770 grams). At the end of the addition of said n-butyl vinyl ether, the reaction mass is stirred for a period of six hours, while maintaining the temperature thereof at 30° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: COCOc1ccccc1C=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: COCOc1ccccc1C=CC(=O)O
Yield: 87.8 %

Procedure:
To a solution of 2-methoxymethoxybenzaldehyde (15.0 g, 90.3 mmol) in pyridine (80 mL) were added malonic acid (18.8 g, 181 mmol) and piperidine (1.0 mL, 9.0 mmol) followed by heating to reflux for 6 hours. Water was added to the residue prepared by evaporation of the solvent therefrom in vacuo and the mixture was acidified with a diluted hydrochloric acid. The crystals separated out therefrom were filtered and washed with water to give the title compound (16.5 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[NH2:1][C:2]1[CH:9]=[C:8]([F:10])[C:5](/[CH:6]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([F:11])[CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1cc(F)c(C=O)c(F)c1
Solvent: CCO
Product: CCOC(=O)/C=C/c1c(F)cc(N)cc1F
Temperature: 23 °C
Reaction time: 0.42 h

Procedure:
To a solid mixture of 4-amino-2,6-difluoro-benzaldehyde (6.5 g, 41.4 mmol, 1.0 equiv.) and (carbethoxymethylene)triphenylphosphorane (18.75 g, 53.8 mmol, 1.3 equiv.) at 23° C. was added ethanol (97 mL). After stirring for 25 min at 23° C., the reaction mixture was concentrated, pre-absorbed with silica gel and purified by flash column chromatography eluting with a gradient increasing in polarity from 0 to 30% ethyl acetate in hexane. Relevant fractions were combined to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])=[C:5]([N+:19]([O-])=O)[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[C:10]4[CH2:11][CH2:12][C:13](=[O:18])[C:14]=4[CH:15]=[CH:16][C:17]=3[NH:19][C:5]=2[CH:4]=1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Product: COc1ccc2c(c1)[nH]c1ccc3c(c12)CCC3=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
A solution of 4-(4-methoxy-2-nitrophenyl)-indan-1-one (81) (42 g, 148.4 mmol, 1 eq) and triphenylphosphine (116 g, 445 mmol, 3 eq) in o-dichlorobenzene (400 mL) was refluxed with vigorous stirring for 4 h, then cooled to 0° C. Diethyl ether (4 L) was added and the precipitate filtered off, washed with diethyl ether (3×100 mL) and dried to give 17 g (46%) of (82). The filtrate was evaporated out and the residue washed with cold MeOH (5×100 ml) to give an additional 10 g (27%) of the carbazole (82). Total yield 27 g (73%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1)CCC>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:28]1([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)c2cc(C3=CCCCC3)nc(N3CCCC3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 371 mg (1 mmole) tributyl-cyclohex-1-enyl stannane, and 70 mg bis(triphenylphosphine)-palladium(II)-chloride in 20 ml dimethylformamide is stirred for 3 hours at 80° C. The solvent is removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with saturated aqueous potassium fluoride, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography of the residue (silicagel, hexane/AcOEt 3/1) yields 191 mg (50%) pure 4-(2-cyclohex-1-enyl-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine as a white solid. mp 237-238° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[CH:27]5)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:44]([NH:46][C:47](=O)[O:48]C1C=CC=CC=1)[CH3:45].O>CN(C)C=O>[CH2:44]([NH:46][C:47]([N:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][C:22]3[C:17]4[CH:16]=[C:15]([C:12]5[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)=[CH:14][CH:13]=5)[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1)=[O:48])[CH3:45]
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc4[nH]ccc4c3)ncnc21
Reactant: CCNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ncnc4c3cc(-c3ccc(OCc5ccccc5)cc3)n4COCC[Si](C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
After dissolving 6-(4-benzyloxyphenyl)-4-(1H-5-indolyloxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (81 mg) in 1 ml of dimethylformamide, 7 mg of sodium hydride (60% dispersion) was added, the mixture was stirred at room temperature for 5 minutes, and then 31 mg of phenyl ethylcarbamate was added and the mixture was stirred for another 2 hours. Water was then added, and ethyl acetate was used for liquid separation and extraction. The organic layer was concentrated and subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 62 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])/[CH:5]=[C:6]1\[N:7]=[C:8]([CH3:12])[O:9][C:10]\1=O.[CH3:17][NH2:18].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])/[CH:5]=[C:6]1\[N:7]=[C:8]([CH3:12])[N:18]([CH3:17])[C:10]\1=[O:9]
Reactant: CC1=N/C(=C\c2ccc(O)c(F)c2)C(=O)O1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1=N/C(=C\c2ccc(O)c(F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
(Z)-4-(3-fluoro-4-hydroxybenzylidene)-2-methyloxazole-5(4H)-one (13.2 g, 0.05 mol) was suspended in ethanol (100 mL), and water solution of methylamine (40%, 11.6 g, 0.15 mol) was added. The reaction mixture was stirred at r.t. for 2 hours, then potassium carbonate (13.8 g, 0.1 mol) was added, and the mixture refluxed for 4 hours. Then it was cooled down to r.t., diluted with water (400 mL) and acidified with HCl (10% in water) until the precipitate stopped to form. The precipitate was filtered, washed with cold (−20° C.) ethanol, then diethyl ether and dried under vacuum: 8.78 g. (Yield 75%)
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[C:17]([C:25]3[NH:39][C:28]4[N:29]([CH2:36][CH2:37][CH3:38])[C:30](=[O:35])[N:31]([CH3:34])[C:32](=[O:33])[C:27]=4[CH:26]=3)[CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)(C)C>[CH3:34][N:31]1[C:32](=[O:33])[C:27]2[CH:26]=[C:25]([C:17]3[CH:16]=[C:15]([S:12]([N:9]4[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]4)(=[O:14])=[O:13])[CH:20]=[CH:19][C:18]=3[O:21][CH2:22][CH2:23][CH3:24])[NH:39][C:28]=2[N:29]([CH2:36][CH2:37][CH3:38])[C:30]1=[O:35]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C(=O)OCC)CC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCOc1ccc(S(=O)(=O)N2CCNCC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Yield: 55.1 %

Procedure:
A mixture of the title compound of Example 86 (0.5 g, 0.89 mmol) and potassium hydroxide (0.58 g, 8.90 mmol, 85%) in isopropanol (20 mL) was refluxed for 18 h. The resulting mixture was evaporated under reduced pressure and the resulting residue was acidified with 6N hydrochloric acid. Then it was basified with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic extracts were dried (MgSO4) and evaporated under reduced pressure. The resulting crude residue was purified by flash column chromatography on silica-gel (dichloromethane-ethanol-ammonium hydroxide 180:8:1) to yield the title compound (0.24 g, 55%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1.CN(C(ON1N=NC2[CH:43]=[CH:44][CH:45]=[N:46]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:45]1([NH:46][C:27]([C@H:24]2[CH2:23][CH2:22][C@H:21]([C:19]3[S:20][C:16]([C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:5]5[N:4]=[C:3]([C:2]([F:1])([F:31])[F:30])[CH:8]=[CH:7][N:6]=5)[CH:11]=4)=[CH:17][N:18]=3)[CH2:26][CH2:25]2)=[O:28])[CH2:43][CH2:44]1
Reactant: O=C(O)[C@H]1CC[C@H](c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)[C@H]1CC[C@H](c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-4-[5-(3-{[4-(Trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane-carboxylic acid (27 mg, 0.060 mmol) was dissolved in DMF (0.60 mL). To this solution was added HATU (24.04 mg, 0.063 mmol), DIPEA (0.063 mL, 0.361 mmol), followed by cyclopropylamine (3.44 mg, 0.060 mmol). The reaction was complete after stirring 1 hour at room temperature. The reaction mixture was diluted with saturated NaHCO3 and 2-Me-THF. The phases were separated and aqueous was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and were concentrated in vacuo. The residue was purified by column chromatography on silica gel (Combiflash, 0-50% EtOH in DCM) to yield trans-N-cyclopropyl-4-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide (10.9 mg, 0.022 mmol, 37.1% yield) as an off-white solid. MS APCI: [M+H]+ m/z 488.1. 1H NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H); 8.85 (d, J=4.8 Hz, 1H); 8.16 (s, 1H); 7.99 (s, 1H); 7.82 (d, J=4.2 Hz, 1H); 7.65 (d, J=8.0 Hz, 1H); 7.38 (t, J=7.9 Hz, 1H); 7.34-7.28 (m, 2H); 3.04-2.92 (m, 1H); 2.64-2.59 (m, 1H); 2.21-2.06 (m, 3H); 1.87-1.77 (m, 2H); 1.61-1.40 (m, 4H); 0.63-0.57 (m, 2H); 0.42-0.34 (m, 2H), rhSYK activity=+++
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][CH:19]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Clc1cnc(Cl)cn1
Product: Clc1cnc(-c2ccc(OCc3ccccc3)cc2)cn1

Procedure:
In accordance with scheme C-I, 30 g (201 mmol) of 2,5-dichloropyrazine and 45.92 g (201 mmol) of 4-benzyloxyphenylboronic acid are coupled analogously to Example 4a to give 2-chloro-5-(4-benzyloxyphenyl)pyrazine.