Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[N:3]1[C:12]2[NH:11][C:10]3[CH:13]=[C:14]([CH:17]([OH:21])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[N:6]=[CH:5][CH:4]=1.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][O:19][C:18](=[O:20])[CH:17]([C:14]1[CH:15]=[CH:16][C:9]2[S:8][C:7]3[N:6]=[CH:5][CH:4]=[N:3][C:12]=3[NH:11][C:10]=2[CH:13]=1)[OH:21]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(O)c1ccc2c(c1)Nc1nccnc1S2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(O)c1ccc2c(c1)Nc1nccnc1S2
Yield: 64.7 %

Procedure:
150 mg of methyl iodide was added to a solution of 100 mg of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)hydroxyacetic acid in N,N-dimethylformamide (8 ml) in the presence of 260 mg of potassium carbonate. After purifying by silica gel column chromatography (eluted with dichloromethane/methanol) and recrystallizing from ethyl acetate/diisopropyl ether, 68 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[CH:16]=[CH:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(Cl)cc32)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3ccc(Cl)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
Dissolve 4-(6-chloro-2,3-dihydroindol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 9.2 mmol) in tetrahydrofuran (50 mL) and cool to 0° C. under nitrogen. Dissolve DDQ (2.1 g, 1 eq) in tetrahydrofuran (25 mL) and add dropwise to the reaction over 15 minutes. Stir for 30 minutes at 0° C. Dilute with ethyl acetate then wash with saturated sodium bicarbonate followed by brine. Dry over magnesium sulfate, filter and concentrate to give 3.15 g (102%) crude product. MS (ES, m/z): 279.1 (M+1, product—tert butyl).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].[C:14](#[N:16])[CH3:15]>C1(C)C=CC=CC=1>[O:9]=[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][C:14]#[N:16]
Reactant: CC#N
Reactant: CCOC(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCC(=O)c1cccnc1
Temperature: 90 °C

Procedure:
To a solution of ethyl nicotinate (30.24 g, 0.20 mol) in toluene (anhydrous, 200 mL) was added NaH (18.64 g, 0.47 mol, 60% in mineral oil). The resulting suspension was heated at 90° C. and acetonitrile (anhydrous, 24.74 ml, 0.47 mol) was added into this suspension via syringe under nitrogen and the reaction was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature and the resulting solid material was collected by filtration. The crude product was dried in vacuo and used directly in the next step. For analytical purposes, the solid was dissolved in water. The pH was adjusted to 5 by aqueous HCl and the solution extracted with DCM. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo to afford a sample of the product for characterization. 1H NMR (CDCl3): δ 9.2 (s, 1H), 8.8 (d, 1H), 8.2 (d, 1H), 7.5 (dd, 1H), 4.1 (s, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[O-].[Na+]>[Cu].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][N:3]=1
Reactant: Nc1ccc(I)cn1
Reactant: Sc1ccccn1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(Sc2ccccn2)cn1

Procedure:
11.0 G. (0.05 moles) of 2-amino-5-iodo pyridine, 6.1 g. (0.055 moles) of 2-mercapto pyridine, 2.97 g. (0.055 moles) of sodium methoxide and 1.0 g. of copper powder are combined in 200 ml. of methanol and heated at 150° C for 12 hours in a glass lined bomb. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo. The residue is dissolved in 300 ml. of methylenechloride and washed 5 times with 2.5 N sodium hydroxide and 3 times with saturated sodium chloride solution. The methylene chloride is dried over magnesium sulfate, and evaporated to dryness. The residue is dissolved in boiling methanol, treated with decolorizing carbon, filtered and evaporated to dryness affording 2-amino-5-(2-pyridylthio) pyridine, m.p. 121° C.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.P(C#N)(OCC)(OCC)=O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Reactant: C1CCNC1
Agent: CCOP(=O)(C#N)OCC
Product: O=C(c1cc2c(O)cccc2s1)N1CCCC1
Yield: 92 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 16 using 4-(methoxymethyloxy)-benzo(b)thiophene-2-carboxylic acid (3.0 g), pyrrolidine (0.75 g) and diethyl cyanophosphate (2.5 g), 1-(4-hydroxybenzo(b)-thiophene-2-carbonyl)pyrrolidine (2.4 g) was obtained as a brown oil. By the reactions in the same manner as in Starting Material Synthesis Example 1 using the brown oil (2.0 g) and (S)-glycidyl nosylate (2.0 g), the title compound (0.45 g) was obtained as brown crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15](=[O:16])[N:5]2[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH:10]=[O:11])[CH2:8][S:9][C@H:4]12.N1C=CC=CC=1>CO>[NH2:2][C@@H:3]1[C:15](=[O:16])[N:5]2[C@@H:4]1[S:9][CH2:8][C:7]([CH:10]=[O:11])=[C:6]2[C:12]([OH:14])=[O:13]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12

Procedure:
2.64 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine (hydroxylactone of the hydrochloride of 7-amino-3-formyl-3-cephem-4-carboxylic acid) are dissolved in 50 ml of methanol. A solution of 0.78 g of pyridine in 10 ml of methanol is added dropwise to this solution whilst stirring and cooling with ice. The precipitated product is filtered off under nitrogen whilst excluding moisture, washed with a little methanol and dried over a drying agent in vacuo at room temperature. (6R-trans)-7-amino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is thus obtained in the form of a light brown powder. IR (KBr): 1799 cm-1 (β-lactam), 1672 cm-1 (CHO), 1606 and 1542 cm-1 (carboxylate) UV spectrum: λmax in H2O=302 nm.
Reaction SMILES: C[Si](C)(C)C#[C:4][O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1.[F-].[CH2:20]([N+](CCCC)(CCCC)CCCC)[CH2:21]CC.Cl>O1CCCC1>[C:20]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([O:5][CH3:4])=[O:16])=[CH:8][C:9]=1[N+:13]([O-:15])=[O:14])#[CH:21]
Reactant: C[Si](C)(C)C#COC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: -22.5 °C
Yield: 65.8 %

Procedure:
15 g (0.054 mol) Methyl 4-(2-trimethylsilyl)ethynyl-3-nitrobenzoate (Compound III) and 225 ml tetrahydrofuran were added into a reaction flask, and started to stir, and cooled to −20 to −25° C., then 35 ml solution of 7.1 g (0.027 mol) tetrabutylammonium fluoride in tetrahydrofuran was added dropwise, and continued to react for 20 min after completing the dropwise addition. After the completion of the reaction monitored by TLC, the pH was adjusted to 4˜5 by adding 0.5 M hydrochloric acid. The mixture was concentrated under reduced pressure to evaporated most of the tetrahydrofuran, and then extracted with 300 ml ethyl acetate, the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, to obtain about 10.5 g crude product, which was separated by column chromatography to obtain methyl 4-ethynyl-3-nitrobenzoate (compound II-1), 7.3 g (0.036 mol), yield 65.8%.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([NH:24][CH2:25][CH2:26][CH:27]=C)=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOC[CH2:30]1.CO>O>[CH2:25]([N:24]([CH3:30])[C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:3])=[O:5])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=1)[CH:26]=[CH2:27]
Reactant: C1COCCO1
Reactant: C=CCCNc1ncccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Solvent: O
Solvent: CO
Product: C=CCN(C)c1ncccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 38 h
Yield: 100 %

Procedure:
A 100 mL round bottom flask which contains 2-{[2-(allyl-methyl-amino)-pyridine-3-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester (339, 280 mg, 0.74 mmol) is charged with 1,4-dioxane (2 mL) and MeOH (2 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1 mL) is added followed by the LiOH monohydrate (78 mg, 1.86 mmol). After 38 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 15 days, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.26 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][N:13]([CH3:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH3:21])[CH3:12])=[CH:15][CH:16]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CN(C)c1ccc(N)cc1
Solvent: CCCCO
Product: CN(C)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 85.5 %

Procedure:
The procedure is carried out as in Example 1, starting with 378 mg of 2,6-dichloropurine, 5 ml of butanol and 300 mg of N,N-dimethyl-p-phenylenediamine. 494 mg of the expected product are thus obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl>CN(C)C(=O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: COc1ccccc1S(=O)(=O)c1ccc(N)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: COc1ccccc1S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro2-hydroxy-2-methylpropanoic acid (1.42 g, 9.0 mmol) in N,N-dimethylacetamide (13 mL) was added thionyl chloride (1.13 g, 9.5 mmol) and the mixture stirred at -15° to -5° C. for 1 hour. 4-(2-Methoxyphenyl)sulfonyl-benzeneamine (1.58 g, 6.0 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into 250 mL of 0.5N HCl. The clear supernatient was decanted from the resulting gum. The gum was crystallized from methylene chloride/hexane to yield the title propanamide which contained about 10 mole % of methylene chloride by NMR analysis. The methylene chloride was not removed by heating at 140°/0.1 mm for 40 hours. The yield of white solid was 1.70 g (69%), mp 209°-211° C. 1H--NMR (300 MHz, d6 --DMSO): 1.55 (s, 3H, CH3) 3.72 (s, 3H, OCH3) 5.73 (s, CH2Cl) 7.11-7.17 (m, 2H, aromatic) 7.53 (s, 1H, OH) 7.60-7.63 (m, 1H, aromatic) 7.80-7.83 (m, 2H, aromatic) 0.92-7.97 (m, 3H, aromatic) 10.36 (s, 1H, NH). MS (CI, CH4): 294 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:22]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([Li])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:22]=1)[OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C)c1cccc(C(=O)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C(O)(c2ccccc2)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of (2-(benzyloxy)-3-tert-butylphenyl)(3-(pyridin-2-yl)phenyl)methanone (0.96 g, 2.28 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred at −78° C. under nitrogen and 1.8 M phenyllithium (2 mL, 3.6 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 30 min for 1 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (150 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×100 mL), dried over sodium sulfate and stripped. The crude product was purified by chromatography on silica (60 g) with 5% ethyl acetate in heptane (1 L), then 7.5% (2 L) to afford 6 (1.14 g, 100%). This material contains a minor impurity and it was used as such in the next step.
Reaction SMILES: N1C=CN=C1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C1COCC1.O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.9 %

Procedure:
Imidazole (1.80 g, 26.1 mmol) and p-methoxyphenol (1.62 g, 13.05 mmol) were suspended in THF (30 mL) and placed under nitrogen. Tert-butyldimethylsilyl chloride (2.23 g, 14.36 mmol) was added and the mixture was stirred for 15 hours at room temperature. The thick white mixture was diluted with water (50 mL) and extracted with ether (3×15 mL). The organic solvent was removed under reduced pressure to give the product as a clear liquid (2.33 g, 75%). Characterization matched literature.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3]1.[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:18]1[C:2]2([CH2:3][CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:7]2)[O:1][CH2:16][CH2:17]1
Reactant: COC(=O)C1CC(=O)CC(C(=O)OC)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(C(=O)OC)CC2(C1)OCCO2
Yield: 83 %

Procedure:
To a solution of dimethyl 5-oxocyclohexane-1,3-dicarboxylate (6.0 g, 28 mmol) in toluene (50 ml) was added ethylene glycol (3.73 g, 56.6 mmol) and p-toluenesulfonic acid (65 mg). The reaction was refluxed overnight, using a Dean-Stark trap to remove the excess water. The reaction was worked up by removing the toluene by rotary evaporation, adding brine (10 ml) and extracting with ethyl acetate (3×40 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give the desired product as a thick colorless liquid (6.0 g, 82%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH:21]1[CH3:20])=[O:18]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: CC1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 5 %

Procedure:
The product is prepared according to the procedure described in example 68, using 550 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 400 mg of 2-methylindoline and 500 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 320 μl of pyridine and 8.0 ml of N,N-dimethylformamide. 37 mg of 3-methyl-2-[2-(2-methyl-2,3-di hydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([O:11]C)=O)[CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:18][CH2:19][NH:20][CH3:21].[H-].[Na+].COCCOCCOC>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:18][CH2:19][N:20]([CH3:21])[C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: COC(=O)/C=C/c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: COc1ccc(CCN(C)C(=O)/C=C/c2cccnc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.6 %

Procedure:
A mixture of methyl trans-3-(3-pyridyl)acrylate (326 mg), 3,4-dimethoxy-N-methylphenethylamine (390 mg), 60% sodium hydride (80 mg) and diethylene glycol dimethyl ether (2 ml) was stirred at room temperature for 24 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. After the solvent was distilled out under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=50:1) and recrystallized to yield the titled compound (278 mg, 43%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][N:25]([CH3:24])[C:26]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)nc3)CC2)c(C)c1
Yield: 81.6 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 127 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (193 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].ClCCl.[CH3:17][NH2:18]>O1CCCC1>[CH3:17][NH:18][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-nitrobenzenesulfonyl chloride (25 g, 0.113 mol) and dichloromethane (450 mL) at 4° C. was added dropwise 2M methylamine in tetrahydrofuran (68 mL). The mixture was stirred overnight allowing the ice bath to melt. More 2M methylamine in tetrahydrofuran (97 mL) was added and the reaction was stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (500 mL) and was washed with saturated sodium bicarbonate (250 mL). The aqueous layer was extracted with chloroform (250 mL) and all the chloroform layers combined, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography using 0-4% methanol in dichloromethane. 22.63 g of N-methyl-2-nitrobenzenesulfonamide was obtained.
Reaction SMILES: [CH:1]1([N:6]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([OH:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>N1C(C)=CC(C)=CC=1C>[CH:16]1([N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11]([O:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)=[CH:10][CH:9]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(O)cc1OC
Reactant: O=C(c1ccc(Br)cc1)N(C1CCCCC1)C1CCCC1
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Oc2ccc(C(=O)N(C3CCCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-cyclopentyl-N-cyclohexyl amide (2.350 g, 6.71 mmol), 3,4-dimethoxy phenol (1.051 g, 6.81mmol) and cuprous oxide (478 mg, 3.34 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 153.96° C. (DSC).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.N1CCCCC1>C(O)C>[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:21]/[C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]4[C:14]([C:15]=3[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:29][CH:28]=1
Reactant: Cc1cc[n+](CCO)cc1
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCO)cc3)ccc21
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution mixture of 3a (0.13 g, 0.75 mmol), 9 (0.27 g, 0.9 mmol) and piperidine (0.1 mL) in ethanol (30 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed by rotary evaporation. The residue was purified by recrystallization from methanol affording SPOH (0.18 g) as pale red solid in 53% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=6.8 Hz, 2H), 8.55 (s, 1H), 8.19 (m, 4H), 7.84 (d, J=8 Hz, 1H), 7.65 (m, 2H), 7.49 (m, 2H), 7.25 (t, J=7.2 Hz, 1H), 5.66 (s, 1H), 4.57 (m, 4H), 3.79 (m, 4H), 3.43 (m, 2H), 3.27 (m, 2H), 3.08 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.4, 144.4, 142.4, 141.7, 140.8, 126.4, 126.3, 126.2, 122.7, 122.6, 122.1, 121.1, 120.3, 120.0, 119.7, 110.4, 110.2, 71.2, 69.8, 68.8, 61.6, 600.1, 58.1, 42.8. HRMS (MALDI-TOF) m/z Calcd for C26H29N2O3 417.2172 Found 417.2184 [M+].
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[CH:10][S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Li+].CC([N-]C(C)C)C.CN([CH:23]=[O:24])C>C1COCC1.O>[CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:23]=[O:24])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CN(C)C=O
Reactant: CSc1ncnc2sccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncnc2sc(C=O)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
4-(Methylthio)thieno[2,3-d]pyrimidine (J. Heterocycl. Chem. 1975, 12, 921-924) (1 g) in THF (5 mL) was added to a preformed solution of LDA [BuLi (1.6M in hexanes, 3.8 mL) and di-isopropylamine (0.85 mL)] in THF (20 mL) at −78° C. The reaction mixture was allowed to stir for 1 hour at −78° C. and then DMF (1.1 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes then allowed to warm to ambient temperature and stirred for a further 3 hours. The reaction mixture was diluted with water and the product was extracted with EtOAc (4×30 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with DCM afforded the title compound as a white solid (1.17 g, 51%);