Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=[C:4]([CH3:15])[CH:3]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(Cl)(Cl)Cl>[CH3:15][C:4]1[CH:3]=[C:2]([O:25][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=1
Reactant: Cc1cc(Cl)c2cc3c(cc2n1)OCO3
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)c2cc3c(cc2n1)OCO3
Temperature: 145 °C

Procedure:
A mixture of known 8-chloro-6-methyl[1,3]dioxolo[4,5-g]quinoline (2.216 g, 10 mmol)56 and 4-nitrophenol (2.08 g, 15 mmole) was heated at 140-150° C. for 2 h. The resulting solution was dissolved in chloroform and washed with 10% aq. solution of NaOH and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduce pressure. The resulting solid was collected by filtration, washed with ether and dried to 6-methyl-8-(4-nitrophenoxy)[1,3]dioxolo[4,5-g]quinoline, 2.94 g of (90.60%); mp 210-212° C.; 1H NMR (DMSO-d6) δ 2.52 (3H, s, Me), 6.21 (2H, s, CH2), 6.86 (1H, s, ArH), 7.30 (1H, s, ArH), 7.34-7.38 (3H, m, ArH), 8.29-8.33 (2H, m, ArH). Anal. Calcld. for (C17H12N2O5): C, 62.96; H, 3.73; N, 8.64. Found: C, 62.27; H, 3.84; N, 8.58.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)COCCO.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)CNc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 0.1 %

Procedure:
26.2 g (0,137 mol) of 2,5-dichloro-1-nitrobenzene, 20.6 g (0,274 mol) of glycine and 18.9 g (0.137 mol) of potassium carbonate in 200 ml of diethylene glycol were heated at 120° C. for 1 h. After cooling, 100 ml of water were added and the solution was acidified with 1M hydrochloric acid. The precipitate was filtered off with suction to yield 17.1 g (54%) of the product.
Reaction SMILES: [C:1]([C:5]1[C:14](=O)[C:13]2[C:8](=[C:9]([O:16][CH3:17])[CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].P(Cl)(Cl)([Cl:20])=O>>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[Cl:20])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH3:17])(=[O:4])[CH2:2][CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Product: CCC(=O)c1cnc2c(OC)cccc2c1Cl

Procedure:
3-Propanoyl-8-methoxy-4(1H)-quinolone (35.4 g, 0.15 mol) was dissolved in phosphoryl chloride (400 ml) and heated at reflux for 1 hour, then the excess phosphoryl chloride evaporated. The residue was mixed with ice, then diluted with water and extracted into dichloromethane. Drying and evaporation gave 3-propanoyl-4-chloro-8-methoxyquinoline (39.7 g) as a dark oil which was used without further purification.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[C:6](=[CH:11][CH:12]=1)[CH2:7][C:8]([OH:10])=O)[CH3:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[O:1]([C:3]1[CH:4]=[C:5]2[C:13](=[O:14])[O:15][C:8](=[O:10])[CH2:7][C:6]2=[CH:11][CH:12]=1)[CH3:2]
Reactant: COc1ccc(CC(=O)O)c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(=O)OC(=O)C2
Temperature: 25 °C
Yield: 110.1 %

Procedure:
1.1 g (5.2 mmol) of 4-methoxylhomophthalic acid (IIb) was dissolved in 20 ml toluene, and 0.7 ml (7.9 mmol) of acetic anhydride was added. The mixture was heated to the reflux temperature and reacted for 0.5 h. Then, the reaction mixture was cooled to the room temperature and concentrated to dry in a reduced pressure to obtain 1.1 g of a pale yellow solid with the yield of 100%. m.p. 142-143° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[I:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1.Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C>[I:16][C:17]1[CH:21]=[CH:20][N:19]([C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:18]=1
Reactant: Ic1cc[nH]n1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)n1ccc(I)n1
Temperature: 40 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
A stirred solution of NaHMDS in THF (1.0 M, 3.1 mL, 3.1 mmol) was cooled in an ice water bath under Ar. 3-iodo-1H-pyrazole (500 mg, 2.6 mmol) was added as a solution in DMF (1 mL), washing with additional DMF (2×1 mL). tert-butyl 2-bromo-2-methylpropanoate (0.58 mL, 3.1 mmol) was added and the reaction mixture was removed from the cold bath and heated to 40° C. After 16 h, the reaction mixture was cooled and diluted with water and EtOAc. The phases were separated, and the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to afford tert-butyl 2-(3-iodo-1H-pyrazol-1-yl)-2-methylpropanoate 7.03 (649 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.36 (d, J=2.4 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 1.79 (s, 6H), 1.38 (s, 9H).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[F:53])(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[F:53])(=[O:43])=[O:44])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3c(F)cccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3c(F)cccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 96 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (white-yellow solid) in 96% yield. HRMS calc for [C39H33ClF2N2O6S2—H] 761.13638 found 761.13565.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[O-]CC.[Na+].[Na].[C:17](Cl)(=O)[C:18](C)([CH3:20])[CH3:19]>C1(C)C(C)=CC=CC=1.C(O)C>[C:3]([CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[C:18]([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CCOC(=O)CC(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
Ethyl pivaloylacetate was prepared from diethyl malonate in the following manner. Diethyl malonate (64 g, 0.4 mol) was dissolved in 350 ml of a mixture of xylene isomers. A solution of sodium ethoxide, prepared by dissolving sodium (9.66 g, 0.42 g at) in absolute ethanol (150 ml), was then added with stirring at ambient temperature. Ethanol was removed by distillation. After the mixture was cooled to 50° C., pivaloylchloride (53 g, 0.4 mol) was added with stirring over a period of one hour and the resulting slurry stirred for a further hour. The mixture obtained was then filtered to remove sodium chloride and the filtrate added to dry sodium ethoxide, which had been prepared by dissolving sodium (9.29 g; 0.4 g at) in 250 ml of absolute ethanol and evaporating to dryness. After stirring for 90 minutes at 50° C., the mixture was acidified with dilute hydrochloric acid and the organic phase separated and dried over anhydrous magnesium sulphate. Evaporation of the solvent in a rotary evaporator followed by vacuum distillation afforded essentially pure ethyl pivaloylacetate product as a colorless liquid (b.p. 167° C. at 65 mbar). Structure of the product was confirmed with NMR analysis. The product yield, determined by GLC, was 0.343 mol (86%).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Br:11][C:12]1[C:13]([NH2:20])=[C:14]([NH2:19])[CH:15]=[C:16]([Br:18])[CH:17]=1.C>[OH-].[Na+]>[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:14]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:19]2
Reactant: Nc1cc(Br)cc(Br)c1N
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Br)cc(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.19 g, 15.0 mmol) and 3,5-dibromo-1,2-diaminobenzene (400 mg, 1.50 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale brown shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 264 mg (55%). A portion of this solid (150 mg) was taken and dissolved in 20 mL 1N NaOH with heating. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 2N HCl (pH=1). Pale yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 20 mL of H2O) and dried under vacuum (0.1 torr, 78° C.) to yield 50.0 mg of powdery white solid, mp 356°-358° C. (dec). 1H NMR (d6 -DMSO) δ7.21 (d, 1H, J=2.1, H-8), 7.53 (d, 1H, J=2.1, H-6), 11.1 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/z 322 (M+4, 51.3), 320 (M+2, bp), 318 (M+, 53.9), 294 (32.2), 292 (62.6), 290 (28.7), 185 (24.3), 183 (25.2). EIHRMS calc. for C8H4Br2N2O2 317.8641, found 317.8642.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[NH2:2].[F:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[CH2:14][CH2:15][C:16](=O)[CH3:17]>>[CH3:17][C:16](=[N:2][NH:1][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[CH2:15][CH2:14][C:13]1[CH:19]=[CH:20][CH:21]=[C:11]([F:10])[CH:12]=1
Reactant: CC(=O)CCc1cccc(F)c1
Reactant: NNc1cc[nH]c(=O)c1
Product: CC(CCc1cccc(F)c1)=NNc1cc[nH]c(=O)c1

Procedure:
In accordance with the same procedures as in Step 2 of Preparation 1, except for using 4-hydrazino-1H-pyridin-2-one (5.39 g, 43.1 mmol) prepared in Step 1 of Preparation 1 and 3-fluorobenzylacetone (9.82 ml, 65.1 mmol), the titled compound was obtained as a white solid. (Yield: 63.4%) The product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([OH:10])[CH3:9])[CH2:3]1.[Cl:12][CH2:13][C:14](O)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([O:10][C:14](=[O:15])[CH2:13][Cl:12])[CH3:9])[CH2:3]1
Reactant: O=C(O)CCl
Reactant: CC(O)C1CCCC(C)(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)CCl)C1CCCC(C)(C)C1
Yield: 88.1 %

Procedure:
Following our general procedure, 15.6 g (100 mmol) of 1-(3′,3′-dimethylcyclohexyl)ethanol were esterified with 9.45 g (100 mmol) of chloroacetic acid in anhydrous dichloromethane in the presence of 1.22 g (10 mmol) of 4-(dimethylamino)pyridine and 22.7 g (110 mmol) of N,N′-dicyclohexylcarbodiimide. The usual work-up provided 28.4 g of crude product, which was purified by flash chromatography (600 g silica gel, pentane/ether, 19:1, Rf=0.77) to provide 20.5 g (88%) of chloroacetic acid 1-(3,3-dimethylcyclohexyl)ethyl ester, 4.80 g (20.6 mmol) of which were dissolved in 50 ml of diethyl ketone and 13 ml of 1,4-dioxane. To this solution, 1.77 g (20.6 mmol) of cyclopropanecarboxylic acid and 5.69 g (41.2 mmol) of potassium carbonate were added, and the resulting mixture was refluxed for 20 h. The reaction mixture was then poured onto 100 g of ice, and the product was extracted twice with 150 ml of ether. The combined ethereal extracts were washed with 100 ml of water and 50 ml of brine, dried with sodium sulphate, and concentrated under reduced pressure to furnish 26.0 g of crude material. This was purified by flash chromatography (175 g silica gel, pentane/ether, 9:1, Rf=0.52) to provide 3.56 g (61%) of the target compound cyclopropanecarboxylic acid 1-(3,3-dimethylcyclohexyl)ethoxycarbonylmethyl ester (12).
Reaction SMILES: ClC[C:3]([N:5]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]#[N:22])[CH:15]=1)[CH2:6][CH2:7][NH:8][C:9](=O)[O-])=[O:4].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C:3]2=[O:4])=[CH:15][C:16]=1[C:21]#[N:22]
Reactant: N#Cc1cc(CCN(CCNC(=O)[O-])C(=O)CCl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CCN2CCNCC2=O)ccc1F
Temperature: 25 °C

Procedure:
A solution of (2-{(chloroacetyl) [2-(3-cyano-4-fluorophenyl)ethyl]amino}ethyl)carbamate (0.12 g, 0.31 mmol) and TFA in 5 mL of DCM was stirred at room temperature for 1 h. The solvent was evaporated. The residue was dissolved in 40 mL of ethanol and K2CO3 (0.13 g, 0.93 mmol) was added. The resulting mixture was refluxed under N2 overnight, cooled to room temperature, and filtered. The filtrate was evaporated and the residue was purified with preprep-HPLC to give 2-Fluoro-5-[2-(2-oxopiperazin-1-yl)ethyl]benzonitrile. 1H-NMR (400 MHz, CDCl3) δ: 7.41˜7.44 (m, 2H), 7.07˜7.12 (m, 1H), 3.51˜3.53 (m, 4H), 3.18˜3.22 (m, 2H), 2.99˜3.04 (m, 2H), 2.75˜2.86 (m, 2H).
Reaction SMILES: [S].[N+:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7][CH:6]=1)([O-])=O.[OH-:16].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:2][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1
Reactant: Cc1ccc([N+](=O)[O-])c2ccccc12
Reactant: [OH-]
Agent: [Na+]
Agent: [S]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C=O)c2ccccc12

Procedure:
To a stirring boiling solution of sulfur (3.7 g) in 12% aqueous NaOH (50 mL) was added a solution of 4-nitro-1-methylnaphthalene (8 g) in ethanol (50 mL). After refluxing the solution for one hour, the reaction was diluted with 500 mL of ethyl acetate and washed with water and brine, dried over MgSO4, and concentrated. The product was purified via silica gel column chromatography using ethyl acetate:hexane (5:95 to 10:90). The product (2.54 g, 34%) was stored at −78° C.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]#N)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[OH2:24]>>[CH3:1][N:2]1[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[O:24])[C:4]2[CH:5]=[C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:8][C:3]1=2
Reactant: CCOC(=O)Cc1ccc(N(C)Cc2ccccc2C#N)cc1
Reactant: O
Product: CCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Reaction time: 2 h

Procedure:
A mixture of N-methyl-N-(2-cyanobenzyl)-4-ethoxycarbonylmethylaniline (6 g) and polyphosphoric acid (60 g) was stirred for 2 hours with heating at 130°-140° C. After the reaction, the reaction mixture was poured into iced water (500 ml) to precipitate crystals. The crystals were collected, washed in water, and then vacuum-dried over diphosphorus pentoxide to obtain the desired compound (2.5 g) as yellow prismatic crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:23][O:24][CH:25]([CH3:28])[CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:21][C:17]1[CH:16]=[C:15]([NH:14][C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH2:26][CH:25]([O:24][CH3:23])[CH3:28])[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cccc(Nc2cc(-c3ccnc(Cl)n3)ccn2)c1
Reactant: COC(C)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(C)CNc1nccc(-c2ccnc(Nc3cccc(F)c3)c2)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-chloro-4-pyrimidinyl)-N-(3-fluorophenyl)-2-pyridinamine (i.e., the product of Step C) (55 mg, 0.18 mmol) in toluene (3.0 mL) was added 2-methoxy-1-aminopropane hydrochloride (125 mg, 1.0 mmol) and potassium carbonate (200 mg, 1.5 mmol). The mixture was stirred at 100° C. for 2 h and then allowed to cool to room temperature. The mixture was partitioned with water and ethyl acetate and the water layer was decanted. The organic layer was washed with brine and passed through a Celite® containing drying tube. The solvent was evaporated, and the resulting residue was chromatographed using 5% to 60% ethyl acetate in hexanes as eluant to give an oil which solidified upon standing. This solid was suspended in hexanes, filtered and washed with hexanes to give 25 mg of the title compound as a yellow solid, m.p. 103-105° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>C(O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])[CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1ccc2c(c1)NCC2)c1c[nH]c2ccccc2c1=O
Yield: 27.3 %

Procedure:
A mixture of N-(1-acetylindolin-6-yl)-4-oxo-1H-quinoline-3-carboxamide (233) (43 mg, 0.12 mmol), 1N NaOH solution (0.5 mL) and ethanol (0.5 mL) was heated to reflux for 48 h. The solution was concentrated and the residue was dissolved in DMSO (1 mL) and purified by HPLC (10-99% CH3CN—H2O) to yield the product, N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide (258) (10 mg, 20%). HPLC ret. time 2.05 min, 10-99% CH3CN, 5 min run; ESI-MS 306.3 m/z (MH+).
Reaction SMILES: [C:1]([C:9]1[C:10]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]2[CH:17]=[N:16][N:15](CC3OC=CC=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>>[C:1]([C:9]1[C:10]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1
Agent: O=S(=O)(O)O
Product: CCCCOc1c(C(=O)c2ccccc2)cnc2[nH]ncc12

Procedure:
5-Benzoyl-4-butyloxy-1-(2-furanyl)methyl-1H-pyrazolo[3,4-b]pyridine is treated with concentrated sulfuric acid according to the procedure of Example 4 b to obtain 5-benzoyl-4-butyloxy-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[C:19]([OH:21])=[O:20]>CS(C)=O>[C:19]([CH:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)([OH:21])=[O:20]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Reactant: NC(Cc1cccc(F)c1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1NC(Cc1cccc(F)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(3-fluoro-phenyl)-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][S:2]([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OS(C)(=O)=O)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Oc1ccc(OCCc2cccc(OCc3ccccc3C(=O)O)c2)cc1
Yield: 16 %

Procedure:
Methyl 2-{[3-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (0.109 g, 0.24 mmol) was dissolved in a mixture of THF/water (7/1, 2.5 ml). Lithium hydroxide (23 mg, 0.96 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The mixture was acidified (HCl, 1 ml, 1 M) and the water phase was extracted with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation and gave 17 mg of 2-{[3-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoic acid (yield 16%).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][CH:30]5[O:35][CH2:34][CH2:33][NH:32][CH2:31]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:36])[C:8](=[O:37])[C@H:7]2[CH2:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.O>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][CH:30]5[O:35][CH2:34][CH2:33][N:32]([CH3:42])[CH2:31]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:36])[C:8](=[O:37])[C@H:7]2[CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC4CNCCO4)c4c3OCC4)nc2N1C1CCCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC4CN(C)CCO4)c4c3OCC4)nc2N1C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
The crude compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-(morpholin-2-ylmethyl)-2,3-dihydrobenzofuran-4-carboxamide 2f (163 mg, 0.30 mmol) was dissolved in 60 mL of the mixture solvent of acetonitrile and water (V/V=1:1) in an ice-water bath, the reaction solution was cooled down to 0° C. followed by the addition of formaldehyde (18 mg, 0.60 mmol) and sodium triacetoxyborohydride (191 mg, 0.90 mmol), warmed up slowly to room temperature and stirred for 2 hours. The resulting mixture was added dropwise with saturated sodium bicarbonate solution to adjust pH to 9 to 10, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(4-methylmorpholin-2-yl)methyl]-2,3-dihydrobenzofuran-4-carboxamide 2 (62 mg, yield: 38.0%) as a white solid.