Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][C:5](O)=[O:6].N1C=CC=CC=1.S(Cl)([Cl:23])=O>CCOCC>[O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][C:5]([Cl:23])=[O:6]
Reactant: CCCCCCCC(=O)CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCC(=O)CCC(=O)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 50 g 4-oxo-undecanoic acid (Synthesis, 1987, 408) in 350 ml of ether, 22.15 g pyridine was added in at 0° C. Then a solution of 32.72 g thionyl chloride in 50 ml of ether was added in at 0-5° C. and then the reaction mixture was stirred for 20 hours at room temperature. Then the reaction mixture was filtered and evaporated to dryness. The residue (53.83 g yellow oil) was not further purified.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC[Si](C)(C)C)=O)[CH2:10][CH:9]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43]COCC[Si](C)(C)C)[CH:38]=3)[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>FC1C=CC(C2CCNCC2OCC2C=C(OCC3C=CC=C(OCOCC[Si](C)(C)C)C=3)C3C(=CC=CC=3)C=2)=CC=1.O1CCCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:23][CH2:24][C:25]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([OH:43])[CH:38]=3)[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCOc1cccc(COc2cc(COC3CN(C(=O)OCC[Si](C)(C)C)CCC3c3ccc(F)cc3)cc3ccccc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)CCOCOc1cccc(COc2cc(COC3CNCCC3c3ccc(F)cc3)cc3ccccc23)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Oc1cccc(COc2cc(COC3CNCCC3c3ccc(F)cc3)cc3ccccc23)c1

Procedure:
From 2-trimethylsilylethyl (3RS,4RS)-4-(4-fluorophenyl)-3-[4-[3-(2-trimethylsilyl-ethoxymethoxy)-benzyloxy]-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate there was obtained in analogy to the procedure described in Example 1 (e) by cleavage of the 2-trimethylsilylethyl carbamate with tetrabutylammonium fluoride in tetrahydrofuran (3RS, 4RS)-4-(4-fluorophenyl)-3-[4-[3-(2-trimethylsilyl-ethoxymethoxy)-benzyloxy]-naphthalen-2-ylmethoxy]-piperidine, MS: 588 (M+H)+, as a light yellow oil, from which by cleavage of the SEM group by means of a 2N solution of hydrogen chloride in methanol analogously to the procedure described in Example 5 (g) there was obtained (3RS,4RS)-4-(4-fluorophenyl)-3-[4-[3-hydroxy-benzyloxy]-naphthalen-2-ylmethoxy]-piperidine as a colourless solid; MS: 458 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].CS([C:31]1[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[N:32]=1)(=O)=O>CN(C=O)C>[CH3:40][O:39][C:33]1[CH:34]=[C:35]([O:37][CH3:38])[N:36]=[C:31]([O:1][CH:2]([C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[C:3]([O:5][CH3:6])=[O:4])[N:32]=1
Reactant: COC(=O)C(O)C(C)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
1.2 g (4.4 mmol) of methyl 2-hydroxy-3,3-diphenylbutyrate were dissolved in 10 ml of absolute DMF and, under nitrogen, 1.2 g (8.8 mmol) of K2CO3 and 0.97 g (4.4 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture was stirred at room temperature for 16 hours. It was then evaporated, and the residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated. 1.8 g of crude product were obtained and were reacted further without purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N:7]#[C:8]Br.[N:10]1([C:19](=[O:34])[CH2:20][C:21]2[NH:26][C:25](=[O:27])[CH:24]=[C:23]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>O1CCOCC1>[N:10]1([C:19](=[O:34])[CH2:20][C:21]2[N:26]([C:8]#[N:7])[C:25](=[O:27])[CH:24]=[C:23]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: N#CBr
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cn1c(CC(=O)N2CCc3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 40 °C

Procedure:
330 mg of cesium carbonate and 404 mg of cyanogen bromide are successively added to a solution of 1 g of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one (which can be obtained according to example 41d, step 1d) in 40 ml of dioxane with 4 Å molecular sieve. The reaction mixture is heated at 40° C. for 2 hours and then cooled to ambient temperature. The suspension is filtered through sintered glass and then rinsed with dioxane, and the filtrate is concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05). The fractions of interest containing the product are combined and then evaporated under reduced pressure. The residue is taken up with a mixture of 3 ml of methanol and 10 ml of ethyl ether. After stirring and filtration, the precipitate obtained is rinsed with ethyl ether (3×2 ml) and 22 mg of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-4-(morpholin-4-yl)-6-oxopyrimidine-1(6H)-carbonitrile are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8].Br[CH2:18][C:19]#[CH:20]>CC(C)=O>[C:7]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:20][C:19]#[CH:18])[CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: C#CCBr
Reactant: CC(C)(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCC(C(C)(C)C)CC1
Temperature: 0 °C
Yield: 83.6 %

Procedure:
Anhydrous potassium carbonate (196 g) was added to a solution of 4-tert-butylpiperidine (98.9 g) in anhydrous acetone (1.2 liters) and the resulting suspension was cooled to 0° C., with stirring under an inert atmosphere. A solution of 1-bromoprop-2-yne (87.5 g) in anhydrous acetone (100 ml) was then added dropwise, the temperature being maintained below 5° C. The reaction mixture was then stirred at ambient temperature for 24 hours, filtered and the filtrate was evaporated under reduced pressure (water-pump). The residual oil thus obtained was extracted with petroleum spirit (b.p. 40°-60° C.). The resulting solution was treated with decolourizing charcoal, filtered and the filtrate was evaporated to give 4-tert-butyl-1-(prop-2-ynyl)piperidine (105 g), m.p. 48°-49° C., which may be further purified by distillation under reduced pressure (water-pump) (b.p. 108°-110° C./15 mm Hg) or by sublimation under reduced pressure (water-pump) at 80° C./20 mm Hg.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][N:8]([CH2:11][CH3:12])[C:4]=2[N:5]=[N:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([N:8]1[C:4]2[N:5]=[N:6][CH:7]=[C:2]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:3]=2[N:10]=[CH:9]1)[CH3:12]
Reactant: CCn1cnc2c(Cl)cnnc21
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cnc2c(-c3ccc(F)cc3)cnnc21
Yield: 55 %

Procedure:
To a room temperature solution of 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8, 9.6 g, 52.4 mmol) in dioxane (300 mL) was added 4-fluorobenzene boronic acid (8.8 g, 63 mmol) and an aqueous solution of Na2CO3 (1M, 260 mL, 262 mmol). The reaction mixture was degassed and purged with nitrogen gas 3 times. Tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) was then added and the mixture was heated to reflux for 4 hours. The organic solvent was removed in vacuo and the resulting aqueous mixture filtered. The filter cake was dried under vacuum to afford the title compound as a yellow solid in 55% yield, 7 g.
Reaction SMILES: P(=O)(O)(O)O.C(OC([NH:13][CH:14]1[CH2:17][N:16]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:15]1)=O)(C)(C)C.O.[OH-].[Na+]>ClCCl>[NH2:13][CH:14]1[CH2:15][N:16]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17]1
Reactant: CCOC(=O)c1cccc(N2CC(NC(=O)OC(C)(C)C)C2)c1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(N2CC(N)C2)c1
Reaction time: 27 h
Yield: 83.5 %

Procedure:
85% phosphoric acid (0.18 mL, 1.57 mmol) was added to a solution of ethyl 3-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}benzoate obtained in Example (223a) (200 mg, 0.62 mmol) in dichloromethane (0.8 mL) at room temperature, followed by stirring for 27 hours. Water and a 50% aqueous sodium hydroxide solution were added to the reaction solution, and then the mixture was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was evaporated under reduced pressure to obtain 114 mg of the title compound as a colorless oily substance (83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7](N)[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12]>O1CCCC1>[CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[CH2:7][C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 50 ml of anhydrous tetrahydrofuran were added 447 mg (1 mmol) of 2,3,4,5,6-penta-O-acetyl-D-gluconyl isothiocyanate and 216 mg (1 mmol) of 6-aminopenicillanic acid and the mixture was stirred at room temperature for 24 hours. The solvent was then distilled off under a reduced pressure and the residue was crystallized by the addition of dimethylformamide. Recrystallization from dimethylformamide gave colourless needles melting at 63° C. (uncorrected). Yield: 630 mg (95%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][S:9][C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:12]([C:11]4[C:2]([Cl:1])=[CH:3][C:4]5[S:9][CH2:8][CH2:7][NH:6][C:5]=5[CH:10]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2c(cc1Cl)SCCN2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCCN5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white solid (37 mg, 51% yield) following Scheme 3 and in analogy to Example 35 using 7-chloro-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (29 mg, 0.12 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine as starting materials.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12](O)=[O:13])=[CH:10][O:9][N:8]=1.CC1ON=C(C2C=CN=CN=2)C=1C(O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][OH:13])=[CH:10][O:9][N:8]=1
Reactant: O=C(O)c1conc1-c1ccccn1
Agent: Cc1onc(-c2ccncn2)c1C(=O)O
Product: OCc1conc1-c1ccccn1
Yield: 76.1 %

Procedure:
As described for example 114g, 3-pyridin-2-yl-isoxazole-4-carboxylic acid (39.0 g, 200 mmol) was converted, instead of 5-methyl-3-pyrimidin-4-yl-isoxazole-4-carboxylic acid, to the title compound (26.8 g, 76%) which was obtained as a white solid. MS: m/e=177.2 [M]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:23]1[C:24]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][NH:37][C:36](=[O:40])[CH:35]=2)=[CH:25][N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([N:37]4[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:24]5[N:23]=[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][N:26]6[CH:25]=5)=[CH:35][C:36]4=[O:40])=[CH:15][CH:16]=3)[N:11]([CH3:22])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1cc(OCc2cn3ccccc3n2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5cn6ccccc6n5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
tert-Butyl-7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.328 g, 0.898 mmol), 4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine-2(1H)-one (0.240 g, 0.998 mmol) and Cs2CO3 (0.358 g, 1.09 mmol) were suspended in DMSO (4.0 mL), and argon was bubbled through the system for 10 minutes. 8-Hydroxyquinoline (43.4 mg, 0.299 mmol) and copper iodide (228 mg, 1.20 mmol) were added, and resulting suspension was placed under vacuum for 15 min. The system was flushed with argon. The evacuation/argon flushing process was repeated a total of three times. The reaction mixture was heated at 130° C. for 18 h under argon. The mixture was cooled, and a solution of 20% NH4OH in MeOH (40 mL) was added. The resulting mixture was stirred for 1 h. The mixture was diluted with CH2Cl2 and filtered through a silica gel plug. The filtrate was collected and concentrated. The residue was diluted with CH2Cl2, washed with brine (3×25 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (80 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 80:20 to 0:100:0 over 10 column volumes and then hold for 8 column volumes) gave the title compound (0.190 g, 40%) as a yellow foam: 1H NMR (500 MHz, DMSO-d6) δ 8.12 (d, J=6.8 Hz, 1H), 7.69 (s, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31-7.29 (m, 2H), 7.22-7.19 (m, 1H), 7.02 (dd, J=8.3, 1.7 Hz, 1H), 6.83-6.80 (m, 1H), 6.17 (d, J=2.7 Hz, 1H), 6.07 (dd, J=7.6, 2.7 Hz, 1H), 5.25 (s, 2H), 4.64 (m, 2H), 3.75 (m, 2H), 3.63 (s, 3H), 2.80 (m, 2H), 1.52 (s, 9H)— ESI MS m/z 526 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:8]([C@@:9]2([CH3:15])[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:7][CH:6]=[C:5]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[CH:20]=[CH:19]3)[N:4]=1.C([S-])CC.[Na+].CN(C=O)C>CCO>[CH3:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([C:5]3[NH:4][C:3](=[O:2])[C:8]([C@@:9]4([CH3:15])[CH2:13][CH2:12][NH:11][C:10]4=[O:14])=[CH:7][CH:6]=3)=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: COc1nc(-c2ccc3c(ccn3C)c2)ccc1[C@@]1(C)CCNC1=O
Agent: CCC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1ccc2cc(-c3ccc([C@@]4(C)CCNC4=O)c(=O)[nH]3)ccc21
Temperature: 110 °C
Reaction time: 17 h
Yield: 96.9 %

Procedure:
To a flask was added (R)-3-(2-methoxy-6-(1-methyl-1H-indol-5-yl)pyridin-3-yl)-3-methylpyrrolidin-2-one (534 mg, 1.59 mmol), sodium n-propanethiolate (1287 mg, 13.11 mmol), and DMF (9.5 mL). The mixture was stirred for 17 h at 110° C. Due to incomplete reaction, additional sodium n-propanethiolate (667 mg) was added. The reaction was stirred for 30 h at 110° C. The mixture was diluted with EtOH, concentrated and partitioned between 15% EtOH/DCM and pH 7 phosphate buffer. The aqueous phase was extracted 2× and the combined organic layers were dried over Na2SO4 to provide a crude product. Purification by slurrying at r.t. overnight (3.3 mL EtOAc/0.33 mL EtOH) followed by filtration, wash with EtOAc several times and dried under reduced pressure for 3 days at 60-80° C. provided (R)-6-(1-methyl-1H-indol-5-yl)-3-(3-methyl-2-oxopyrrolidin-3-yl)pyridin-2(1H)-one (495 mg, 97%) as a yellow solid. 1H NMR (600 MHz, methanol-d4) δ: 1.54 (s, 3H), 1.91-1.98 (m, 1H), 2.68-2.79 (m, 1H), 3.48 (dd, 2H), 3.85 (s, 3H), 6.55 (d, 1H), 6.62 (d, 1H), 7.26 (d, 1H), 7.47 (dd, 1H), 7.49-7.51 (m, 1H), 7.63 (d, 1H), 7.89 (d, 1H); MS (ES+)(M+H) 322.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]1[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=1)[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:34]=[CH:35][C:36]=1[CH3:37])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20])=[O:14].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:37][C:36]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1[NH:15][C:13](=[O:14])[C:12]1[CH:38]=[CH:39][CH:40]=[C:10]([CH2:9][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 60 °C
Yield: 41.6 %

Procedure:
N-Methylpiperazine (0.036 g) was added to a mixture of 3-(3-chloromethylbenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide (0.15 g), potassium carbonate (0.09 g) and acetone (5 ml) and the resultant mixture was stirred and heated to 60° C. for 16 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using methanol as eluent. The product so obtained was dissolved in ethyl acetate and precipitated by the addition of isohexane. There was thus obtained the title compound (0.071 g); NMR Spectrum: (DMSOd6) 2.1 (s, 3H), 2.3 (s, 3H), 2.2-2.4 (m, 8H), 3.1 (t, 4H), 3.55 (s, 2H), 3.75 (t, 4H), 6.65-6.7 (m, 1H), 7.18 (t, 1H), 7.3-7.35 (m, 1H), 7.38-7.55 (m, 4H), 7.78-7.8 (m, 1H), 7.85-7.9 (m, 2H), 7.95 (s, 1H); Mass Spectrum: M+H+ 528.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:24]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[C:36]([C:38]([CH2:41][C:42](C)(C)C)([CH3:40])[CH3:39])[C:35]([OH:46])=[C:34]([C:47]([CH2:50][C:51](C)(C)C)([CH3:49])[CH3:48])[CH:33]=3)[CH:28]3[S:55][CH:25]2[CH2:26][CH2:27]3)[CH:12]=[C:13]([C:16]([CH2:19][C:20](C)(C)C)([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH2:4][C:5](C)(C)C)([CH3:3])[CH3:2].C(C1C=CC=C(C(CC)(C)C)C=1O)(CC)(C)C.C(C1C=C(C2CCC3SC2CCC3C2C=C(C(CC)(C)C)C(O)=C(C(CC)(C)C)C=2)C=C(C(CC)(C)C)C=1O)(CC)(C)C>>[C:16]([C:13]1[CH:12]=[C:11]([CH:24]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[C:36]([C:38]([CH2:41][CH3:42])([CH3:40])[CH3:39])[C:35]([OH:46])=[C:34]([C:47]([CH2:50][CH3:51])([CH3:48])[CH3:49])[CH:33]=3)[CH:28]3[S:55][CH:25]2[CH2:26][CH2:27]3)[CH:10]=[C:9]([C:1]([CH2:4][CH3:5])([CH3:2])[CH3:3])[C:14]=1[OH:15])([CH2:19][CH3:20])([CH3:17])[CH3:18]
Reactant: CC(C)(C)CC(C)(C)c1cc(C2CCC(c3cc(C(C)(C)CC(C)(C)C)c(O)c(C(C)(C)CC(C)(C)C)c3)C3CCC2S3)cc(C(C)(C)CC(C)(C)C)c1O
Agent: CCC(C)(C)c1cc(C2CCC3SC2CCC3c2cc(C(C)(C)CC)c(O)c(C(C)(C)CC)c2)cc(C(C)(C)CC)c1O
Agent: CCC(C)(C)c1cccc(C(C)(C)CC)c1O
Product: CCC(C)(C)c1cc(C2CCC(c3cc(C(C)(C)CC)c(O)c(C(C)(C)CC)c3)C3CCC2S3)cc(C(C)(C)CC)c1O

Procedure:
When in Example 1, the 2,6-di-tert-butylphenol is replaced by an equivalent amount of 2,6-di-tert-amylphenol, a mixture of 2,6-bis(3,5-di-tert-amyl-4-hydroxyphenyl)-9-thiabicyclo[3.3.1]nonane and 2,5-bis(3,5-di-tert-amyl-4-hydroxyphenyl)-9-thiabicyclo[4.2.1]nonane is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][NH:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)CCCC(C)(C)N1.Cl[C:30]1([C:36]([O:38][CH3:39])=[O:37])[C:34](=[O:35])[CH:33]=[CH:32][S:31]1>ClCCl.C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:32]3[S:31][C:30]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([OH:35])[CH:33]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2[nH]cnc2cn1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reaction time: 12 h

Procedure:
To a mixture of 21.2 g of 6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridine and 11.36 g of 2,2,6,6-tetramethylpiperidine in 2 l dichloromethane was slowly added a solution of 8.77 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 300 ml chloroform at 30-40° C. The reaction mixture was stirred for 12 h, washed with water (2×200 ml) and concentrated under vacuum. The residue was purified by flash chromatography (eluents: ethyl acetate/methanol/triethylamine) two times and after precipitation from ethyl acetate/n-hexane the title compounds were obtained as a mixture of regioisomers.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([S:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)(=[O:54])=[O:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([S:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)(=[O:54])=[O:53])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(S(=O)(=O)c3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc3c(N4CCN(S(=O)(=O)c5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 18 h
Yield: 23 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(phenylsulfonyl)piperazin-1-yl)pyridin-2-amine (40 mg, 0.090 mmol), DMF (1 mL), 1M Na2S2O4 (3 eq, 0.27 mmol, 0.27 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.1 eq, 0.099 mmol, 15 mg). After 18 h, the reaction was quenched with NH4OH and extracted with EtOAc (5×5 mL). The organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the product (11 mg, 23%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 3.01 (s, 6H, N(CH3)2), 3.17-3.27 (m, 4H, piperazine N(CH2)2), 3.65 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 6.82 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl), 7.68-7.70 (m, 2H, phenyl H-3 & H-5), 7.73-7.76 (m, 1H, phenyl H-4), 7.81 (dd, J=7.1, 1.5 Hz, 2H, phenyl H-2 & H-6), 7.99 (d, J=9.0, 2H, N,N-dimethylaminophenyl), 8.14 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.21 (s, br, 1H, imidazo[4,5-b]pyridine NH);