Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2,5-dihydroxybenzaldehyde (10 g) in dichloromethane (50 ml) at 0° C. was added triethylamine (5 ml) and pivaloyl chloride (4.4 ml). The mixture was stirred at room temperature for 18 hours, filtered and the filtrates washed with 2M HCl (100 ml), brine (100 ml) and sodium bicarbonate (100 m), dried (magnesium sulphate) filtered and evaporated. The residue was purified by chromatography on silica gel using dichloromethane:hexane (0:1 to 1:1 gradient) then ethyl acetate:hexane (1:9 to 3:7 gradient) as eluants to give 2-hydroxy-5-(t-butylcarbonyloxy)benzaldehyde (4 g) and some 2,5-dihydroxy-benzaldehyde.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[C:7]([OH:9])(=[O:8])[CH3:6].[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:16][CH2:15][CH2:14][NH2:17])=[O:9])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(CO)cc1
Reactant: NCCN
Product: CC(=O)O
Product: NCCNC(=O)c1ccc(CO)cc1
Yield: 49 %

Procedure:
Ethyl p- hydroxymethylbenzoate (0.51 g, 2.8 mmol) was dissolved in ethylene diamine and heated on a steam bath overnight. The volume was reduced under a stream of nitrogen and the residue was chromatographed by preparative thin layer chromatography (silica, CHCl3 : MeOH:HOAc, 10:10:1) to yield the product as an oil (0.35 g, 49% yield).
Reaction SMILES: O.[NH2:2][NH2:3].[IH:4].CS[C:7]1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]=1.CCOCC>CCO>[IH:4].[NH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[N:2][NH2:3]
Reactant: CSC1=NCCCCN1
Reactant: NN
Agent: I
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: NN=C1NCCCCN1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
Hydrazine hydrate (0.44 ml, 7.23 mmol) was added to a solution of 2-(methylthio)-4,5,6,7-tetrahydro-1H-1,3-diazepine hydroiodide (1.79 d, 6.58 mmol) in EtOH (12 ml). The reaction mixture was refluxed for 5 h and cooled to r.t. Et2O was added and the product was collected by filtration, washed with Et2O and dried under vacuum to give 1.46 g (100%) crude title compound which was used directly in the next step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=O)C.O>O1CCCC1>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:10][OH:9])[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCC(CO)CC1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A solution of 1.0 M lithium aluminum hydride (200 ml, 0.2 mole) in tetrahydrofuran was added dropwise to a solution of 1-methanesulfonylpiperidine-4-carboxylic acid ethyl ester (68 grams, 0.29 mole) in tetrahydrofuran (500 ml) at about +5° C. The reaction mixture was stirred at 5-10° C. for 15 minutes. Water (10 ml) was added dropwise and the mixture was filtered. The filtrate was concentrated under reduced pressure and triturated with 50% ethyl ether-hexane (100 ml). The resulting white solid was collected and dried to give 1-methanesulfonylpiperidine-4-methanol (46 grams, 82%), m.p. 96-97° C.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:3](=[O:4])[CH:2]([Cl:1])[CH3:6])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1
Product: CC(Cl)C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure of Example 1 was followed for the reaction of 63.5g (0.5 mole) of 2-chloropropionyl chloride with 67g (0.5 mole) of tert-butylbenzene. Obtained after high vacuum concentration was 100g of a clear, yellow liquid product: ir (film) 3.4 (s), 5.9 (s), 6.3 (s), 8.0 (s), 10.5 (s), 11.8 (s) microns: nmr (CDCl3) 7.67 (4H, d of d), 5.21 (1H, q), 1.67 (3H, d), 1.28 (9H, s) ppm. A VPC analysis indicated one pure product.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11](O)=[O:12].B.C1COCC1>C1COCC1.O>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][OH:12]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CO)oc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
A solution of 3-methyl-benzofuran-2-carboxylic acid (2.0 g, 11.4 mmol, 1 eq) in 60 mL of THF under nitrogen was placed in water bath. Then 30 mL of BH3.THF (1.0 M in THF, 30 mmol, 2.6 eq) was added dropwise. The reaction mixture was allowed to stir at room temperature for 12 h. Then the reaction was quenched with methanol (10 mL). Solvent was removed in vacuo and the residue was subjected to column chromatography eluting with 20% ethyl acetate/hexane to give (3-methyl-benzofuran-2-yl)-methanol (1.6 g) in 87% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.2 (s, 3 H) 4.5 (d, J=5.8 Hz, 2 H) 5.3 (t, J=5.8 Hz, 1 H) 7.3 (m, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H).
Reaction SMILES: [H-].[K+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.CI.[C:20](O)(=O)C>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH3:20])[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 35% potassium hydride in oil (6.04 g, equivalent to 2.11 g, 53 mmol of potassium hydride) in 240 ml of sieve dried tetrahydrofuran was cooled to 0° C. The cold mixture was treated with homoterephthalic acid dimethyl ester (10.0 g, 48 mmol). The mixture was stirred at 0° C. for 1 hour. Methyl iodide (7.51 g, 53 mmol) was added and the mixture stirred at 0° C. for 30 min, then at room temperature for 16 hours. The resulting mixture was treated with 4.8 ml of 50% acetic acid, then poured into 480 ml of water. The mixture was extracted with ether (2×250 ml). The ether extracts were combined, dried on magnesium sulfate, and concentrated to a brown oil, 15.67 g. Chromatography on 250 g of flash silica gel (10% ether in hexanes eluent) gave the product VII-2 as a pale yellow oil, 7.24 g (67.9% theory).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:11][C:12]1[CH:13]=[N:14][N:15]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=2)[CH:16]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCc1ccc(Cn2cc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A mixture of 4-(chloromethyl)benzyl alcohol (0.500 g, 3.19 mmol), 4-chloro-1H-pyrazole (0.753 g, 7.34 mmol), and potassium carbonate (0.908 g, 7.02 mmol) in acetonitrile (40 mL) was stirred at rt overnight. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.375 g, 75%) as a white solid. MW=222.67. 1H NMR (CDCl3, 500 MHz) δ 7.45 (s, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 7.22 (s, 1H), 5.24 (s, 2H), 4.70 (d, J=5.9 Hz, 2H), 1.68 (t, J=5.9 Hz, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:9]1[CH:14]=[C:13]([CH:23]=[CH2:24])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1NC(=O)C(F)(F)F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(NC(=O)C(F)(F)F)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of N-(2-benzoyl-4-bromophenyl)-2,2,2-trifluoroacetamide (a) (0.37 g, 1.0 mmol) in degassed dry toluene (10 mL) was added a solution of tetrakis(triphenyl-phosphine) palladium [Pd(PPh3)4] in toluene (5 mL) under argon. The mixture was heated to reflux and tributyl(vinyl)tin (0.29 mL, Immol) was added in a dropwise fashion. After refluxing overnight, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel [hexanes: ethyl acetate (9:1)] to give N-(2-benzoyl-4-vinylphenyl)-2,2,2-trifluoro-acetamide (b) (0.22 g, 70%). 1H NMR (300 MHz, CDCl3) δ 12.0 (s, 1H), 8.62 (d, J=10.9 Hz, 1H), 7.80-7.60 (m, 5H), 7.60-7.43 (m, 2H), 6.65 (dd, J=11, 19.6 Hz, 1H), 5.69 (d, J=19.6 Hz, 1H), 5.29 (d, J=11 Hz,1H). MS: 320.2 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH2:14][CH:15]1[C:19]2([CH2:21][CH2:20]2)[NH:18][C:17](=[O:22])[O:16]1.O>C(Cl)Cl>[CH3:1][S:2]([O:13][CH2:14][CH:15]1[C:19]2([CH2:21][CH2:20]2)[NH:18][C:17](=[O:22])[O:16]1)(=[O:4])=[O:3]
Reactant: O=C1NC2(CC2)C(CO)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1OC(=O)NC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (1.36 g, 11.1 mmol) and triethylamine (2.51 mL, 18.4 mmol) were added to a solution of 7-(hydroxymethyl)-6-oxa-4-azaspiro[2.4]heptan-5-one (1.32 g, 9.2 mmol) in DCM (47 mL) at 0° C. and this mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (10 mL×3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate) to afford (5-oxo-6-oxa-4-azaspiro[2.4]hept-7-yl)methyl methanesulfonate. MS ESI calc'd. for C7H12NO5S [M+H]+ 222. found 222.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.O=P(Cl)(Cl)Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19]=1[O:28][CH3:29]>C(Cl)Cl.CCOC(C)=O>[CH3:16][O:17][C:18]1[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]([O:24][CH3:25])=[CH:22][C:23]=1[CH:9]=[O:10]
Reactant: CN(C=O)c1ccccc1
Reactant: COc1ccc(OC)c(OC)c1OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.7 %

Procedure:
Following the procedure by Syper et al.,19 N-methylformanilide (1.0 mL, 8.1 mmol) was added to a flame dried 10 mL round bottom flask under argon and a drying tube. POCl3 (1.0 mL, 11 mmol) was added at room temperature and the Argon line was removed. After 5 minutes 18 (1.067 g, 5.38 mmol) was dissolved in CH2Cl2 (2.0 mL) and added at room temperature. The reaction was stirred at room temperature under a drying tube for 48 hrs and monitored by 1H NMR. When complete the reaction was diluted with EtOAc, washed with saturated brine, dried over MgSO4, filtered, and condensed. The resulting product was separated from remaining N-methylformanilide using flash chromatography (1:4 Et2O:hexanes) to provide 19 (1.141 g, 5.04 mmol, 94%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH:9]=C)[CH3:2].I([O-])(=O)(=O)=[O:31].[Na+].C(#N)C.O>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[CH:9]=[O:31])[CH3:2]
Reactant: C=Cc1c(CC)nc(CCC)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CCCc1nc(CC)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of 4′-[(4-ethyl-6-oxo-2-propyl-5-vinylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (5.9 g) and sodium periodate (16 g) in acetone (100 mL)-acetonitrile (100 mL)-water (100 mL) was added osmium tetroxide (5 g, 7% polymer-bound catalyst), and the mixture was stirred for 4 hr. The insoluble material was filtered off through celite, and the filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.8 g, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][CH2:13][Br:14])[NH:7][CH2:6][CH2:5]2.[F:15][C:16]([F:21])([F:20])[C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].O>CN(C)C=O>[CH3:28][N:29]([CH3:33])[C:30]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][CH2:13][Br:14])[NH:7][CH2:6][CH2:5]2)=[O:31].[F:15][C:16]([F:21])([F:20])[C:17]([NH2:19])=[O:18]
Reactant: Oc1ccc2c(c1)CCN[C@@H]2CCBr
Reactant: CN(C)C(=O)Cl
Agent: NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Oc1ccc2c(c1)CCN[C@@H]2CCBr
Yield: 50.1 %

Procedure:
To a solution of 6-hydroxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide (270 mg, 0.77 mmol) obtained in step (d) of Example 190 and potassium carbonate (268 mg, 1.94 mmol) in dimethylformamide (3 ml) was added dimethylcarbamyl chloride (0.2 ml, 1.55 mmol) gradually with stirring under cooling in an ice bath. Subsequently, the resulting mixture was stirred at 40° C., and after confirming the disappearance of the starting material by thin layer chromatography, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (80:20) as the eluent to afford the title compound (170 mg, yield: 52%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([O:19]C)=O)[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25][O:26][NH2:27].C(O)(=O)C>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([NH:27][O:26][CH3:25])=[O:19])[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:21][CH:22]=1
Reactant: CON
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CONC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Temperature: 63 °C
Reaction time: 28 h
Yield: 5.6 %

Procedure:
To methyl 1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.6 g, 2 mmol) in methanol (10 ml) and water (1 ml) were added sodium hydroxide (0.56 g, 14 mmol) and O-methylhydroxylamine (0.668 g, 8 mmol). The resulting mixture was stirred for 28 hours at 63° C. Acetic acid (2 mL) was added to precipitate undesired byproduct, 1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid, which was removed by filtration. The filtrate was concentrated in under reduced pressure; the residue was dissolved in methanol and purified by preparative HPLC to provide the title compound as a white powder (0.035 g, 5.6% yield). 1H NMR (300 MHz, DMSO-d6) d ppm 3.76 (s, 3H) 5.60 (s, 2H) 6.75 (d, J=2.83 Hz, 1H) 7.17-7.24 (m, 2H) 7.32-7.39 (m, J=5.46 Hz, 2H) 7.76 (d, J=3.20 Hz, 1H) 8.47 (s, 1H) 12.08 (s, 1H) 12.89 (s, 1H). LC-MS (APCI, M+H+): 316.1. HPLC: 95% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.[H-].[Na+].CS(C)=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Yield: 14 %

Procedure:
2-Amino-4-chloropyridine (2.0 g), 5-hydroxyindole (4.1 g), sodium hydride (60% in oil, 1.25 g) and dimethylsulfoxide (20 ml) were stirred at 160° C. for 9.5 hours. Water was added, extraction was performed with ethyl acetate, and purification was performed by silica gel column chromatography (hexane:ethyl acetate=1:1, ethyl acetate). The solvent was distilled off under reduced pressure, a small amount of ethyl acetate was added to the residue and the solid was filtered out to obtain 490 mg of a light brown solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C(Cl)Cl>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:3](=[O:4])[CH2:2][Br:1])=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: O=C(Br)CBr
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(CBr)NCCc1ccc([N+](=O)[O-])cc1

Procedure:
Bromoacetyl bromide (806 rag, 4.0 mmol) was added dropwise to a solution of p-nitrophenylethylamine (665 mg, 4.0 mmol, freshly prepared from the hydrochloride salt) in 30 mL CH2Cl2 over 6 rain at 0° C. with stirring. Then, the reaction mixture was stirred at 0° C. for 1 h. The resulting precipitate was filtered off and washed twice with 10 mL CH2Cl2, which was combined with filtrate and rotoevaporated to dryness. Chromatography over 20 g silica gel and elution with 5:3 ethyl acetate:hexane gave crystalline N-(4-nitrophenylethyl)bromoacetamide (compound 74) . Recrystallization from ethyl acetate-hexane gave 290 mg (58% yield) of compound 74 as yellow needles: mp 123°-124° C. IR (nujol) 3276, 1659, 1515, 1343 cm-1 ; NMR δ 2.99 (t, 2H), 3.60 (q, 2H), 3.88 (s, 2H), 6.54 (m, 1H), 7 38°-8 20 (AA'BB' 4H) ppm.
Reaction SMILES: [CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:2].ClCCl.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:13][N:14]([CH3:19])[S:15]([NH:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])(=[O:17])=[O:16]
Reactant: CC=C(C=CCN)CC
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(C=CCNS(=O)(=O)N(C)C)CC
Reaction time: 0.5 h

Procedure:
A mixture of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide (3.0 g), hydrazine monohydrate (0.88 g), and ethanol (30 ml) was refluxed for 40 minutes under nitrogen atmosphere. After cooling, the precipitate was filtered and washed with ethanol. Evaporation of the filtrate gave a crystalline residue which was dissolved in 1N sodium hydroxide solution and extracted with dichloromethane. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to give 4-ethyl-2,4-hexadien-1-ylamine as an oil. To a mixture of crude 4-ethyl-2,4-hexadien-1-ylamine, triethylamine (1.79 g), and dichloromethane (30 ml) at 0° C. was added dropwise dimethylsulfamoyl chloride (2.03 g) during 10 minutes. After 30 minutes, triethylamine (0.6 g) and dimethylsulfamoyl chloride (0.85 g) were added to the reaction mixture. After 1 hour at 0° C., the reaction mixture was washed with water and aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (dichloromethane-hexane, 7:3) to give N,N-dimethyl-N'-(4-ethyl-2,4-hexadien-1-yl)sulfamide (924 mg) as an oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([NH2:39])=[O:38])[CH:17]=2)[CH:13]=[CH:12][N:11]=1>CN(C=O)C.CCOC(C)=O>[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([NH2:39])=[O:38])[CH:17]=2)[C:13]([I:1])=[CH:12][N:11]=1
Reactant: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2ccnc(N)n2)n1COCC[Si](C)(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2nc(N)ncc2I)n1COCC[Si](C)(C)C
Temperature: 65 °C
Yield: 61.1 %

Procedure:
N-iodosuccinimide (720 mg, 3.2 mmol) was added to a solution of 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxamide (1.39 g, 3.0 mmol) in dry DMF (6 mL). The reaction mixture was heated at 65° C. for 7 h, allowed to cool to room temperature and then diluted with EtOAc (30 mL), washed with water (2×20 mL) brine, dried over sodium sulphate, and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 97/3) to afford the title compound as yellow solid (1.07 g, 60%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[C:18]([OH:20])=[O:19].O1CCCC1.CCCCCC.C([Li])CCC>[Cl-].[Na+].O.O>[CH2:13]([O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[C:3]([C:18]([OH:20])=[O:19])[CH:4]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCOc1cc(C(=O)O)c(Br)c2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCOc1cc(C(=O)O)cc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
1-Bromo-4-pentyloxynaphthalene-2-carboxylic acid (400 mg, 1.19 mmol) and tetrahydrofuran (THF, 3 ml) were mixed in a reaction vessel replaced with argon, and this solution was cooled to -78° C. A hexane solution (1.6M, 1.63 ml) of n-butyllithium (2.61 mmol) was added, and the mixture was stirred for 1 hour. Water (0.5 ml) and saturated brine (2 ml) were added, and the aqueous layer was extracted 4 times with ethyl acetate (5 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=3/1-1/2) to give 4-pentyloxynaphthalene-2-carboxylic acid (149.6 mg, 49%) as colorless crystals.