Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[CH:8]([CH3:10])[CH3:9])[CH3:7]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: COc1ccc(S)cc1
Product: CCOC(=O)C(Sc1ccc(OC)cc1)C(C)C
Yield: 99 %

Procedure:
2-(4Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product was isolated. Yield 99%; Light yellow oil; MS: 271 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[O:36])[CH3:35].[OH-].[Na+].O>C(O)C>[O:36]=[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[NH2:27])/[CH:35]=[CH:13]/[C:9]1[N:8]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1C(=O)/C=C/c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
1-Triphenylmethyl-2-imidazole carbaldehyde (4) (25.0 g, 74 mmol) and 2'-aminoacetophenone (10.0 g, 74 mmol) were suspended in 700 ml of ethanol, and a 25% aqueous solution (120 ml) of sodium hydroxide was added to the suspension, The mixture was stirred at room temperature for 12 hours. Water (3,000 ml) was added to the resultant reaction mixture, and crystals deposited were collected by filtration, washed with water and dried. The thus-obtained crystals were recrystallized from ethanol to obtain 17.6 g (yield: 52%) of 2-[(E)-3-oxo-3-(2-aminophenyl)-1-propenyl]-1-triphenylmethylimidazole.
Reaction SMILES: [NH:1]1[C:6]2=[N:7][C:8]([CH:11]=O)=[CH:9][CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:20]([NH2:23])([CH3:22])[CH3:21].C(O)(=O)C>ClCCl>[CH3:21][CH:20]([NH:23][CH2:11][C:8]1[N:7]=[C:6]2[NH:1][CH2:2][CH2:3][CH2:4][C:5]2=[CH:10][CH:9]=1)[CH3:22]
Reactant: O=Cc1ccc2c(n1)NCCC2
Reactant: CC(C)N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)NCc1ccc2c(n1)NCCC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-tetrahydropyridino[2,3-b]pyridine-7-carbaldehyde in dry dichloromethane (32 mL) were added 4° A seives, sodium sulfate and isopropyl amine. The mixture was cooled to 0° C. followed by the addition of acetic acid (300 μL). The resulting mixture was stirred at room temperature under nitrogen for 18 hrs. The mixture was filtered through celite, diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, evaporated concentrated in vacuo and purified by flash chromatography(10% MeOH/CH2Cl2 ). EI-MS m/z 206 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>ClC1C(Cl)=C(Cl)C=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]2[C:6]1=[O:8]
Reactant: Nc1ccccn1
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Agent: Clc1cccc(Cl)c1Cl
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccccn1
Reaction time: 9 h
Yield: 84 %

Procedure:
5.2 grams of 4-chlorotetrahydrophthalic anhydride, 2.6 grams of 2-aminopyridine, 50 milliliters of trichlorobenzene and 6.0 grams of Calgon Carbon S-Sorb was combined in a 3 neck flask. The flask was fitted with a reflux condenser and an inlet tube adjusted to deliver air as bubbles below the surface. The third neck was fitted with a drying tube to remove water. After about 9 hours, N-(2-pyridyl)-4-chlorophthalimide was formed in about 84% yield as determined by GC-MS.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[C:28]([O:31][CH2:32]Br)(=[O:30])[CH3:29]>CN(C)C=O>[CH3:32][O:31][C:28](=[O:30])[CH2:29][O:8][C:7]1[C:6]([Br:9])=[CH:5][C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])=[CH:3][C:2]=1[Br:1]
Reactant: CC(=O)OCBr
Reactant: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ccncc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(Br)cc(C(=O)N2CCOc3ccncc32)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
In a 25 ml flask, (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (100 mg, 0.24 mmol) was dissolved in N,N-dimethyl formamide (2.4 ml), and potassium carbonate (37 mg, 0.266 mmol) was added thereto dropwise at room temperature. After stirring at room temperature for 10 minutes, bromo-methyl acetate was added dropwise and then stirred for 40 minutes at room temperature. The reaction mixture was filtered on celite and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=20:1 to obtain the target compound 24 as white foam (48 mg, 41.0%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15].[OH-].[Na+].O.[ClH:20]>CO>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH3:15])=[C:4]([CH:9]=1)[C:3]([Cl:20])=[O:2])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)c1cc(C(C)(C)C)ccc1OC
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.8 g of 5-(tert-butyl)-2-methoxybenzoic acid methyl ester in MeOH (30 mL) was added 50% NaOH-water solution (1 mL). The resulting solution was stirred at room temperature for 3 hr. After the reaction was complete, the pH was adjusted to pH=2–3 using 1M HCl. The reaction mixture was collected by extraction with ethylacetate and water three times. The organic layer was dried over anhydrous magnesium sulfate (MgSO4) and evaporated under reduced pressure. After recrystallization, the final product yielded 3.4 g (96%). Without further purification a solution of 3.4 g of 5-(tert-butyl)-2-methoxybenzoic acid in 20 mL CH2Cl2 was slowly treated with SOCl2 (1.2 eq). The resulting solution was stirred at room temperature for 2 hr. The reaction mixture was evaporated under reduced pressure and dried in a vacuum oven overnight to yield 3.4 g (91.9%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH:16]([CH3:19])[C:17]#[N:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:16]([CH3:19])[C:17]#[N:18])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, Cat. No. 525057)(0.22 g, 1.1 mmol), 2-chloropropanenitrile (Aldrich, Cat. No. 192406) (0.12 g, 1.4 mmol), and cesium carbonate (0.82 g, 2.5 mmol) in acetonitrile (4.0 mL) was stirred at 80° C. for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product. LCMS (M+H)+=248.1.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:22]2[CH:23]=[N:24][CH:25]=[CH:17][C:18]=2[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccc(Oc2ccccc2)cc1
Product: O=C(O)c1ccncc1NCc1ccc(Oc2ccccc2)cc1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 4-phenoxybenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.42 (br s, 1H), 8.18 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.35-7.40 (m, 4H), 7.13 (t, 1H, J=7.2), 6.97-7.02 (m, 4H), 4.55 (s, 2H). [M+H] calc'd for C19H16N2O3, 321; found 321.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7](Cl)[C:6]([CH:10]=[O:11])=[C:5]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1.[CH:27]1([CH2:33][OH:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:2][C:3]1[N:8]=[C:7]([O:34][CH2:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:6]([CH:10]=[O:11])=[C:5]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1
Reactant: Nc1nc(Cl)c(C=O)c(N(Cc2ccccc2)Cc2ccccc2)n1
Reactant: OCC1CCCCC1
Agent: [Na]
Product: Nc1nc(OCC2CCCCC2)c(C=O)c(N(Cc2ccccc2)Cc2ccccc2)n1
Reaction time: 1.5 h

Procedure:
Cyclohexylmethanol (10 ml) and sodium (5 eq; 0.163 g) were reacted at 90° C. for 1 h. 2-Amino-4-chloro-6dibenzylamino-5-pyrimidine carbaldehyde (0.5 g; 1.42 mmol) was added and heating continued for 90 mins. Excess alcohol was removed by short path distillation under reduced pressure, and the product purified further by column chromatography. Product was shown to be contaminated with cyclohexylmethanol by visualisation of the alcohol with sulfuric acid spray (2%).
Reaction SMILES: [O:1]([C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[O:1]([C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 92.1 %

Procedure:
A slurry of 5.00 g (15.6 mmoles) of methyl 4-(4-phenoxyphenoxy)benzoate from Example A, 0.28 g (50.0 mmoles) of potassium hydroxide, 50 ml of methanol and 50 ml of deionized water is refluxed for 48 hours. Methanol is added until the mixture is homogeneous. Aqueous hydrochloric acid is added until the solution is strongly acidified, and the slurry is cooled. The resulting precipitate is filtered, washed with 300 ml of deionized water and dried in air. It is recrystallized from a minimum volume of hot 2-1 by volume methanol and water solution to yield 4.40 g (92 percent yield) of 4-(4-phenoxyphenoxy)benzoic acid having a melting point of 185° C. as measured by DSC.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:1][CH:2]([CH2:5][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH2:3][OH:4]
Reactant: C1=COCCC1
Reactant: CC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(CO)COC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
Into a 50-mL 3-necked round-bottom flask was placed 2-methylpropane-1,3-diol (20 g, 221.92 mmol, 1.00 equiv) and 4-methylbenzene-1-sulfonic acid (11 mg, 0.06 mmol). Then 3,4-dihydro-2H-pyran (5 g, 59.44 mmol, 0.27 equiv) was added at 0° C. The resulting solution was stirred for 3 h at room temperature. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). Purification afforded 6.9 g (18%) of 2-methyl-3-(oxan-2-yloxy)propan-1-ol as a light yellow liquid.
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[CH3:7][C:8]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)([CH3:11])[CH2:9][OH:10].[C:21](=O)(O)[O-].[Na+].CI>CN(C)C(=O)C>[CH3:21][O:17][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([C:8]([CH3:7])([CH3:11])[CH2:9][OH:10])=[CH:20][CH:19]=1
Reactant: CC(C)(CO)c1ccc(C(=O)O)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(C(C)(C)CO)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
The following reagents were placed in a flask equipped with a magnetic stirrer, oil bath and reflux condenser protected with a guard tube containing anhydrous calcium sulfate ("Drierite"): p-(1,1-dimethyl-2-hydroxyethyl)benzoic acid, 20 g, 0.103 mole; sodium bicarbonate, 9.4 g, 0.112 mole; N,N-dimethylacetamide, 100 mL; and methyl iodide, 28.4 g, 0.2 mole. The mixture was heated at 80° C. for 2.5 hours, cooled to room temperature and filtered to remove any unreacted hydroxyacid. The clear solution was then poured into 600 mL water and stirred for 10 minutes. 50 mL of 5% aqueous sodium bicarbonate was added and the resultant solution extracted 3 times with 120 mL portions of ether. The ether layers were combined, washed with dilute aqueous bicarbonate, dilute aqueous sodium thiosulfate and finally water, and dried over anhydrous potassium carbonate. The ether solution was evaporated to give a colorless liquid which crystallized upon standing at room temperature. Yield 99%. The compound was purified by distillation, bp 135°- 140° C. at 0.3 to 0.5 mm Hg, (0.04 to 0.667 kPa) followed by recrystallization from ether/pentane (1/4 vol.) at -20° C., mp 44°-45° C. Elemental analysis, IR and NMR spectra were all consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][N:8]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([NH2:24])[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][N:8]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=3)(=[O:35])=[O:34])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Reaction time: 2 h
Yield: 81 %

Procedure:
tert-Butyl N-[(1S,3R)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate, 20b, (0.33 g, 0.53 mmol) was dissolved in CH2Cl2 (10 mL) and treated with trifluoroacetic acid (2 mL). After stirring for 2 hours, the solvent was evaporated under reduced pressure and the resulting residue was passed through a polymer supported carbonate column to provide the free base of (1R,3S)—N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (0.25 g, 0.43 mmol, 81%).
Reaction SMILES: [Na].Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][OH:16]>>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1
Reactant: CN(C)CCO
Reactant: Clc1ccc2nccn2n1
Agent: [Na]
Product: CN(C)CCOc1ccc2nccn2n1
Temperature: 130 °C

Procedure:
Sodium metal (0.25 g) and 6-chloroimidazo[1,2-b]pyridazine are added to 25 ml of 2-dimethylaminoethanol and the mixture is heated in a sealed tube for 3 hours at 130° C. After cooling, the solvent is evaporated and the residue is treated with water and extracted with methylene chloride. The organic layer is separated, washed with saturated sodium chloride solution and dried over MgSO4. Evaporation of the solvent gives the title compound as a viscous oil which solidified on standing. The yield is 2.5 g.
Reaction SMILES: COC1C=CC([O:9][C:10](=O)[NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]([CH:34]4[CH2:37][CH2:36][CH2:35]4)[C:20]4[C:25]([C:26]=3[C:27]#[N:28])=[CH:24][CH:23]=[C:22]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:21]=4)=[CH:14][CH:13]=2)=CC=1.[CH3:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[C:27]([C:26]1[C:25]2[C:20](=[CH:21][C:22]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:23][CH:24]=2)[N:19]([CH:34]2[CH2:35][CH2:36][CH2:37]2)[C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]([N:43]2[CH2:44][CH2:45][CH:40]([CH3:39])[CH2:41][CH2:42]2)=[O:9])=[CH:13][CH:14]=1)#[N:28]
Reactant: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)Oc4ccc(OC)cc4)cc3)n(C3CCC3)c2c1
Reactant: CC1CCNCC1
Solvent: ClCCl
Product: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)N4CCC(C)CC4)cc3)n(C3CCC3)c2c1
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a solution of {4-[3-cyano-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 4-methoxy-phenyl ester (40 mg, 0.082 mmol) in DCM (4 mL) is added 4-methylpiperidine (0.16 mmole) and the reaction is stirred for 18 h at reflux temperature. The solvent is removed under reduced pressure. The residue is dissolved in EtOAc and then triturated with hexane. The precipitate is collected by filtration and washed with 50% EtOAc/hexane and dried in vacuo to afford 4-methyl-piperidine-1-carboxylic acid {4-[3-cyano-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indol-2-yl]-phenyl}-amide, compound 1377, (26 mg, 68%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[S:6][CH:7]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3)cs2)cc1
Yield: 76.7 %

Procedure:
Reaction of chloride 51 (402 mg, 1.5 mmol) and sodium 4-methylbenzenesulfinate (294 mg, 1.7 mmol) in dry DMF (10 mL) gave benzoate 52 (446 mg, 77%) as a white powder: mp (EtOAc) 160-161° C.; 1H NMR (CDCl3) δ 8.05 (ddd, J=8.6, 1.9, 1.7 Hz, 2H, H-2, H-6), 7.77 (ddd, J=8.6, 1.9, 1.7 Hz, 2H, H-3, H-5), 7.64 (ddd, J=8.3, 1.9, 1.7 Hz, 2H, H-2″, H-6″), 7.42 (s, 1H, H-5′), 7.27 (br d, J=8.3 Hz, 2H, H-3″, H-5″), 4.60 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.41 (s, 3H, CH3); MS m/z 388.6 (MH+, 100%). Anal. calcd for C19H17NO4S2: C, 58.90; H, 4.42; N, 3.61. Found: C, 58.83; H, 4.33; N, 3.55%.
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]=[N:16][N:17]([CH2:19][CH:20]=O)[CH:18]=3)[S:13][C:6]=12.CC(O)=O.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C([O-])(O)=O.[Na+]>[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]=[N:16][N:17]([CH2:19][CH2:20][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[CH:18]=3)[S:13][C:6]=12
Reactant: CN1CCNCC1
Reactant: O=CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CN1CCN(CCn2cc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cn2)CC1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a solution of 146 (450 mg, 1.13 mmol, Scheme 36) in NMP (10 mL) was added AcOH (0.129 mL, 2.259 mmol) and 1-methylpiperazine (113 mg, 2.259 mmol) and the reaction mixture was stirred at RT for an hour. Sodium triacetoxyborohydride (718 mg, 6.10 mmol) was added and the mixture was stirred at RT overnight. The mixture was diluted with saturated NaHCO3 solution then solid NaHCO3 was added to neutralize the acid. The mixture was extracted with DCM and the extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluent 10% MeOH to 50% MeOH in EtOAc) to afford title compound 152 (250 mg, 27% yield) as a brown oil. MS (m/z)=483.53 (M+H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[C:20]1([C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH2:28][CH2:29][C:30]#[N:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-:39].[Na+]>C(OCC)(=O)C>[C:32]1([C:26]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:31][C:30](=[O:39])[CH2:29][CH2:28][CH2:27]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: N#CCCC=C(c1ccccc1)c1ccccc1
Reactant: O=C([O-])O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCCC(c2ccccc2)(c2ccccc2)N1
Temperature: 0 °C
Yield: 66 %

Procedure:
A stirred mixture of 24. g (0.17 tool) of granular phosphorus pentoxide and 240.g (2.5 mol) of 98% methanesulfonic acid was maintained at 110 ° C. until all the solid dissolved (1 hour) . To this solution was added in portions over several minutes 12 g (0.05 mol) of 5,5-diphenyl-4-pentenenitrile. The resulting dark mixture was heated for 5 minutes longer and then carefully added to an ice-cooled vigorously stirred mixture of 1 liter of saturated aqueous sodium bicarbonate and 1 liter of ethyl acetate. The basic aqueous phase was extracted with 3×500 ml of fresh ethyl acetate, the organic layers were combined, washed with 2×500 ml of water, 1×500 ml brine, and dried over sodium sulfate. The resulting crude solid was recrystallized from toluene to give 8.5 g (66%) of 6,6-diphenyl-2-piperidinone as a white solid (mp 193°-196° C.) .
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:12]=[C:11]([C:13](O)=O)[O:10][N:9]=1)[C:4]([OH:6])=[O:5])C.CCN=C=NCCCN(C)C.Cl.[CH2:28]([N:31]1[C:38]([NH2:39])=[C:37]([NH2:40])[C:35](=[O:36])[N:34]([CH2:41][CH2:42][CH3:43])[C:32]1=[O:33])[CH2:29][CH3:30]>CO>[CH2:41]([N:34]1[C:35](=[O:36])[C:37]2[NH:40][C:13]([C:11]3[O:10][N:9]=[C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])[CH:12]=3)=[N:39][C:38]=2[N:31]([CH2:28][CH2:29][CH3:30])[C:32]1=[O:33])[CH2:42][CH3:43]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CCC(Oc1cc(C(=O)O)on1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)no3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxyisoxazol-3-yl)oxyacetic acid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yl)oxyacetic acid.
Reaction SMILES: ClC([O-])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH2:8]1[CH2:9][CH2:10][N:5]2[C:10](=[N:5][CH2:6][CH2:7][CH2:8]2)[CH2:6][CH2:7]1
Reactant: c1ccncc1
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Product: C1CCC2=NCCCN2CC1

Procedure:
Compounds of Formula (I) wherein R1 is --SO2NHCO2R22 may be prepared by reacting an appropriate chloroformate with the sulfonamide (78) in pyridine or in the presence of DBU in THF to afford the desired compound (80), as outlined in Scheme 22. ##STR40##