Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[C:13](=[O:16])([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1>CN(C=O)C.O>[Cl:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:4]3[C:5](=[O:11])[C:6]4[N:7]([CH2:24][C:26]5[CH:33]=[CH:32][C:29]([C:13](=[O:16])[C:23]6[CH:22]=[CH:21][C:20]([Cl:19])=[CH:35][CH:34]=6)=[CH:28][CH:27]=5)[CH:8]=[N:9][C:10]=4[N:2]([CH3:1])[C:3]3=[O:12])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 24.2 %

Procedure:
A solution of 3-methylxanthine (204 mg), potassium carbonate (340 mg) and 4-(4-chlorobenzoyl)benzyl bromide (754 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:1) and recrystallized from ethyl acetate-hexane to provide the title compound as colorless solid (184 mg).
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:38])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([OH:37])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45](Br)[CH:46]=[CH2:47]>CN(C=O)C.C(OCC)(=O)C.Cl>[CH2:47]([O:37][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=1)[C:24]([NH:23][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:12])=[O:38])[CH:46]=[CH2:45]
Reactant: C=CCBr
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-[(1S,2S,4R)-1-Benzyl-4-(3,3-bimethylbutylcarbamoyl)-2-hydroxypentyl]-3-hydroxy-5-(2-oxopyrrolidin-1-yl)-benzamide (E2) (0.061 g, 0.117 mmol), caesium carbonate (0.050 g, 0.152 mmol) and allyl bromide (0.016 ml, 0.176 mmol) in DMF (1 ml) was stirred vigorously at room temperature for 2 hrs. More allyl bromide (0.008 ml) was added and stirring was continued for a further 1 hr. The mixture was diluted with ethyl acetate and 2N HCl and the product was extracted into ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel (elution with 2–5% methanol in dichloromethane) gave the product, 0.047 g.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:24]=1.CC1(C)C(C)(C)OB([C:40]2[CH:48]=[CH:47][CH:46]=[C:45]3[C:41]=2[CH:42]=[N:43][NH:44]3)O1>>[NH:44]1[C:45]2[C:41](=[C:40]([C:2]3[N:3]=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:5]4[S:10][C:9]([C:21]5[CH:22]=[C:23]([CH:24]=[C:19]([NH2:18])[CH:20]=5)[C:25]([O:27][CH3:28])=[O:26])=[CH:8][C:6]=4[N:7]=3)[CH:48]=[CH:47][CH:46]=2)[CH:42]=[N:43]1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: COC(=O)c1cc(N)cc(B(O)O)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: COC(=O)c1cc(N)cc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) was coupled to 3-amino-5-methoxycarbonylphenyl boronic acid, and then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via General Procedure F. The product was purified by reverse phase HPLC to yield 5.2 mg of 300. MS. (Q1) 487.1 (M)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][Si:13](Cl)(Cl)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[C:18]([C:21]1C=CC=CC=1)(=[O:20])C.[CH2:27]([OH:29])[CH3:28]>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][Si:13]([O:20][CH2:18][CH3:21])([O:29][CH2:27][CH3:28])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccc1
Reactant: Fc1ccc(CCC2CC[Si](Cl)(Cl)CC2)cc1
Reactant: CCO
Solvent: CCN(CC)CC
Product: CCO[Si]1(OCC)CCC(CCc2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
15.1 g of acetyl chloride was added to a solution, in 200 ml of dichloromethane, of 36.0 g of 4-(2-fluorophenyl)ethyl)-1,1-diphenyl-1-silacyclohexane obtained in Preparatory Example 4 and 25.6 g of aluminium chloride at room temperature, followed by agitation for 1 hour to obtain a mixture of 4-(2-(p-fluorophenyl)ethyl)-1,1-dichloro-1-silacyclohexane and acetophenone. A mixture of 40 g of ethanol and 60 g of triethylamine was added to the solution at room temperature. The resultant reaction mixture was concentrated, after which 200 ml of hexane was added to permit secondarily produced triethylamine hydrochloride to be precipitated. This precipitate was removed by filtration and the resultant filtrate was concentrated, followed by removal of the acetophenone by distillation under reduced pressure to obtain 28.5 g of 4-(2-(p-fluorophenyl)ethyl)-1,1-diethoxy-1-silacyclohexane. This product was dissolved in 100 ml of THF and added to a solution of 10.0 g of lithium aluminium hydride in 100 ml of THF. The reaction mixture was agitated under reflux for 1 hour and then poured into 200 ml of 5% hydrochloric acid, followed by extraction with ethyl acetate. The resultant extract was washed with brine, dried and concentrated, followed by purification through silica gel chromatography to obtain 20.1 g of 4-(2-(p-fluorophenyl)ethyl)-1-silacyclohexane. Thereafter, 20.0 g of 4-(2-(p-fluorophenyl)ethyl)-1-silacyclohexane, 24.2 g of copper (II) chloride, and 1.6 g of copper (I) iodide were added to 200 ml of diethyl ether, followed by agitation at room temperature for 8 hours to obtain 4-(2-(p-fluorophenyl)ethyl)-1-chloro-1-silacyclohexane. The copper salts were removed from the reaction mixture by filtration, after which the resultant filtrate was dropped in 100 ml of a THF solution of 1 mole/liter of 4-n-propylcyclohexylmagnesium bromide at room temperature. The reaction mixture was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The resultant extract was washed with brine, dried and concentrated by a usual manner, followed by purification through silica gel chromatography to obtain 21.2 g (68%) of the intended product. The product exhibited nematic liquid crystal properties at a temperature between 40° and 56.7° C. The results of IR analysis are shown below.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12](=N)[NH:11][C:10]2=[O:19])=[CH:4][C:3]=1[CH3:20].O.C(=O)([O-])[OH:23].[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12](=[O:23])[NH:11][C:10]2=[O:19])=[CH:4][C:3]=1[CH3:20]
Reactant: O=C([O-])O
Reactant: Cc1cc(N2C(=O)NC(=N)C23CCCC3)cc(C)c1Br
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N2C(=O)NC(=O)C23CCCC3)cc(C)c1Br
Temperature: 65 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(4-bromo-3,5-dimethylphenyl)-4-imino-1,3-diazaspiro[4.4]nonan-2-one (the crude product obtained in the previous reaction) in acetic acid (1.0 mL) and water (0.25 mL) was stirred for 1.5 hours at 65° C. under nitrogen atmosphere. After further addition of acetic acid (1.0 mL) and water (0.25 mL), the mixture was stirred for 17 hours at 65° C. under nitrogen atmosphere. The reaction mixture was cooled, followed by dilution with water and adjustment of its pH to 8 using a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 1-(4-bromo-3,5-dimethylphenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (121 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])[NH2:5].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][C:16]=2[N+:28]([O-:30])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1Nc1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A suspension of 12.7 g (60 mmols) of 3-chloro-4-trifluoromethoxyaniline and 15.15 g (60 mmols) of 1-chloro-2,4-dinitronaphthalene in 150 ml of water was heated to the boil. 5.6 g (67 mmols) of sodium bicarbonate were introduced in the course of 30 minutes and heating was continued for 2 hours under reflux. After the mixture had cooled to 20° C., the product was filtered off. 24 g of 1-(3-chloro-4-trifluoromethoxyphenylamino)-2,4-dinitronaphthalene of melting point 140° C. were obtained; after recrystallization from ethanol, 17.4 g of melting point 159° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:26])([C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:3](OC)=[O:4].[NH3:27].[NH4+]>O1CCCC1>[F:1][C:2]([F:26])([C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:3]([NH2:27])=[O:4]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 45 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A 3-1, four-necked, round-bottomed flask equipped with stirrer, thermometer, reflux condenser with bubble counter and inlet gas-tube, is charged with 745 g (1.74 mol) of methyl perfluorooctanoate and 1.5 l tetrahydrofurane. A stream of ammonia is passed from a pressure tank into the stirring solution. The ammonia feed rate is such that a negligible amount of gas is observed exiting the reactor as observed in the bubble counter. Temperature of the mixture increases to 40-50° C. Ammonium supply is continued until the temperature begins to decrease and an increasing volume of gas is observed exiting the reactor in the bubble counter . . . . After ending of ammonium supply, the mixture is left to stand for 12 hr. Solvent is removed under reduced pressure, yielding 712 g p perfluorooctanoic acid amide (99%), mp 136-137° C.
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[CH:34]1([C:37]2[NH:41][N:40]=[CH:39][CH:38]=2)[CH2:36][CH2:35]1>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:40]3[CH:39]=[CH:38][C:37]([CH:34]4[CH2:36][CH2:35]4)=[N:41]3)=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Reactant: c1cc(C2CC2)[nH]n1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2ccc(C3CC3)n2)cc1

Procedure:
The title compound was prepared by the method of Preparation 23b using (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy)quinolin-3-yl]methyl}phenyl)boronic acid and 5-cyclopropyl-1H-pyrazole.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.Br[C:18]1[CH:23]=[CH:22][N:21]=[N:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:20]1[CH:19]=[CH:18][C:23]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:22][N:21]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Brc1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccnnc2)cn1
Temperature: 96 °C

Procedure:
To a reaction tube were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (220 mg, 1.00 mmol), 4-bromopyridazine (159 mg, 1.00 mmol), Pd(PPh3)4 (57.7 mg, 0.05 mmol) and K3PO4 (424 mg, 2.00 mmol). The tube was subjected to vacuum and back filled with argon. Dioxane (3.0 ml) and water (0.3 ml) were added and the mixture was heated at 96° C. overnight. After cooled to room temperature, the reaction mixture was filtered through celite (washed with ethyl acetate) and concentrated by evaporation. Subsequent silica gel column chromatography with 5% methanol in DCM as eluent gave 5-(pyridazin-4-yl)pyridin-2-amine 134-1 as brown solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].CC1C=C([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)C(S(C)(=O)=O)=CC=1C(OC)=O.[CH3:25][CH:26]1[C:34](=[S:35](=[O:37])=[O:36])[C:33](Cl)=[C:32]([CH3:39])[CH:31]=[C:27]1[C:28]([OH:30])=O.N1C=CN=C1.[H-].[Na+]>CN1CCCC1=O.CO.O>[NH2:3][C:2]([NH2:4])=[N:1][C:28](=[O:30])[C:27]1[CH:26]([CH3:25])[C:34](=[S:35](=[O:37])=[O:36])[C:33]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[C:32]([CH3:39])[CH:31]=1
Reactant: CC1=C(Cl)C(=S(=O)=O)C(C)C(C(=O)O)=C1
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-n2ccnc2)cc1C
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CO
Product: CC1=C(n2ccnc2)C(=S(=O)=O)C(C)C(C(=O)N=C(N)N)=C1
Reaction time: 3 h

Procedure:
A solution of 2.54 g of guanidine and 2.41 g of methyl 2-methyl-4-(1-imidazolyl)-5-methylsulfonylbenzoate [obtainable by reacting 2-methyl-4-chloro-5-methyl-sulfonylbenzoic acid with imidazole in the presence of NaH in N-methylpyrrolidone followed by esterification] in 20 ml of methanol is stirred at 500 for 3 hours. Water is then added to the reaction mixture, and the crude product which precipitates out is filtered off with suction and recrystallized from methanol. N-Diaminomethylene-2-methyl-4-(1-imidazolyl)-5-methyl-sulfonylbenzamide, m.p. 236°, is obtained.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH3:14][Mg]Br>C1COCC1>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH3:14])=[CH:12][CH:13]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(F)nc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a cold solution (−78° C.) of 6-fluoro-N-methoxy-N-methylnicotinamide (Method 38, 7.2 g, 39 mmol) in THF (130 ml), was added methyl magnesium bromide (20 ml, 59 mmol, 3M solution in ether) dropwise. The cooling bath was removed and reaction mixture was allowed to warm to room temperature and stir for 2 hours. The reaction was quenched with 3N HCl solution, layers were cut, and organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford 3.8 g (70% yield) of the title compound. 1H NMR (CDCl3) δ 8.80 (s, 1H) 8.29-8.43 (m, 1H) 6.98-7.06 (m, 1H) 2.62 (s, 3H).
Reaction SMILES: C1(C)C=CC=CC=1.[OH-].[Na+].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([CH:15]=[C:16]2[CH2:20][CH2:19][C:18]([CH:25]([CH3:27])[CH3:26])(C(OC)=O)[C:17]2=[O:28])=[CH:13][CH:12]=1.Cl>O.C(O)(C)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[C:16]2[CH2:20][CH2:19][CH:18]([CH:25]([CH3:27])[CH3:26])[C:17]2=[O:28])=[CH:29][CH:30]=1
Reactant: COC(=O)C1(C(C)C)CCC(=Cc2ccc(Cl)cc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)C1CCC(=Cc2ccc(Cl)cc2)C1=O
Reaction time: 4 h

Procedure:
To a mixed solution of 150 ml of toluene, 50 ml of isopropanol, and 100 ml of water were added 58.6 g of sodium hydroxide and 50 g of methyl 3-(4-chlorobenzylidene)-1-isopropyl-2-oxocylopentanecarboxylate (prepared in Example 2). The mixture was stirred for 4 hours at 70°-80° C. The reaction mixture was poured into 2000 ml of 10% aqueous solution of hydrochloric acid and extracted with 300 ml of ethyl acetate. The organic layer was washed with water and dried, followed by evaporation of the solvent to obtain the target compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:21])[C:17]([OH:20])=[CH:18][CH:19]=3)[S:13][C:6]=12.Br[CH2:30][CH2:31][CH2:32][Cl:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:33][CH2:32][CH2:31][CH2:30][O:21][C:16]1[CH:15]=[C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=3[F:1])[CH:11]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:30][CH2:31][CH2:32][Cl:33]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)c(O)c4)sc23)c(F)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(OCCCCl)c(OCCCCl)c4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a stirred solution of 332 (140 mg, 0.35 mmol) in anhydrous DMF (5 ml) were added 1-bromo-3-chloropropane (553 mg, 3.51 mmol) and cesium carbonate (573 mg, 1.76 mmol), respectively. The reaction mixture was stirred for 2 hrs at room temperature, diluted with AcOEt, and successively washed with water, sat. ammonium chloride, water, and concentrated. The crude material was adsorbed on silica gel and purified by flash column chromatography (eluents AcOEt/CH2Cl2: 10/90 to 20/80) to afford title compound 333 (120 mg, 62% yield) as a yellow solid. MS (m/z): 551.0 and 553.0 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([O-:27])(=O)=[O:25])[CH:18]=[CH:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na+]>CN(C)C=O>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([Cl:3])(=[O:27])=[O:25])[CH:18]=[CH:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCOc1ccc2cc(S(=O)(=O)[O-])ccc2c1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To a solution of thionyl chloride (0.692 ml) and N,N-dimethylformamide (0.022 ml) was added sodium 6-octyloxy-2-naphthalenesulfonate (1 g) under ice-cooling and stirred for 1.5 hours at 95° C. The reaction mixture was evaporated under reduced pressure to give 6-octyloxy-2-naphthylsulfonyl chloride (1 g).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH3:11].C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1>[CH3:10][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:17]([OH:22])[OH:18])=[C:3]([CH3:11])[CH:4]=1
Reactant: COc1cc(C)c(Br)c(C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)c(B(O)O)c(C)c1
Temperature: -78 °C
Yield: 82.8 %

Procedure:
An oven-dried three-neck round-bottom flask equipped with two rubber septum-sealed addition funnels and a sidearm stopcock was evacuated and backfilled with N2. Dry THF (100 mL) and 2-bromo-5-methoxy-1,3-dimethyl-benzene (21.5 g, 0.100 mol) were then added via syringe. The mixture was then cooled to −78° C. with stirring in a dry ice-acetone bath. Next, n-butyl lithium (2.5 M solution in hexane, 44 mL, 0.11 mol) was added dropwise via syringe with stirring over the course of 45 min at −78° C., and the mixture was allowed to stir at −78° C. for an additional 30 min. Triisopropyl borate (28.2 g, 0.150 mol) was then added dropwise via syringe over the course of 30 min at −78° C. After stirring at −78° C. for an additional 1 h, the mixture was quenched with saturated aqueous NH4Cl solution (100 mL), and the resulting mixture allowed to gradually warm to room temperature. The organic layer was next separated, and the aqueous layer was extracted with a mixture of ethyl acetate and THF (1:1, 50 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting sticky oil was suspended in hexane (100 mL) and stirred at room temperature for 30 min. The resulting solid was collected by filtration and washed with hexane to yield 14.9 g of the title compound as a colorless solid (83%). 1H NMR (400 MHz, CDCl3): δ 6.552 (s, 2H), 4.684 (s, 2H), 3.780 (s, 3H), 2.370 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 141.714, 122.607, 112.325, 111.815, 55.238, 22.663. MS (EI): m/z 180.1 [M+, 100]. Anal. Calcd. For C9H13BO3: C, 60.05; H, 7.28. Found: C, 60.27; H, 7.42.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:13]=[CH:14][CH:15]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.C1C(=O)N([I:31])C(=O)C1>CC(C)=O>[I:31][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:13]=[CH:14][CH:15]=3)[CH:9]=2)[NH:1][CH:2]=1
Reactant: O=C(c1cccc(-c2cnc3[nH]ccc3c2)c1)N1CCOCC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: O=C(c1cccc(-c2cnc3[nH]cc(I)c3c2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
To a solution of (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (550 mg, 1.79 mmol) in acetone (10 mL) was added NIS (604 mg, 2.68 mmol) and the mixture was stirred at room temperature for 20 minutes. Acetone was removed by reduced pressure and the crude product was purified by silica gel chromatography to afforded (3-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (600 mg, 77% yield). MS: m/z 434.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([O:32]C)=[O:31])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:34].[Li+].[OH-]>CO.O>[CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[CH2:6][CH2:5]2)[C:3]1=[O:34]
Reactant: COC(=O)c1ccc2c(c1)C1(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC1)C(=O)N2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 144.5 %

Procedure:
To a solution of (E)-methyl 1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate (75 mg, 0.16 mmol) in methanol (4 mL) was added a solution of LiOH in H2O (2 M, 4 mL) at rt and the mixture was stirred for 8 h at rt. The reaction mixture was concentrated to remove methanol and extracted with CH2Cl2 twice. The combined organic phases were dried, filtered and concentrated to give (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (106 mg, 65%). 1H NMR (CD3OD): 1.94 (m, 4H), 3.26 (s, 3H), 4.15 (m, 3H), 4.22 (m, 1H), 7.01 (d, 1H), 7.28 (d, 1H), 7.53 (m, 1H), 7.66 (m, 1H), 7.76 (m, 1H), 8.01 (m, 3H), 8.08 (m, 1H).