Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH:28]([CH3:30])[CH3:29])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:7]2[CH2:8][CH2:9][C:5]3([N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4]3)[CH2:6]2)=[CH:19][C:20]=1[O:27][CH:28]([CH3:30])[CH3:29])([O-:26])=[O:25]
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC12CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(N2CCC3(CCCN3C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A mixture of 3.0 g of tert-butyl 1,7-diazaspiro[4.4]nonane-1-carboxylate and 2.64 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene (obtained according to method 6), and 2.75 g of potassium carbonate in DMSO is stirred at ambient temperature overnight. The mixture is taken up with ethyl acetate and washed twice with 10 volumes of water. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The crude product is purified on 120 g of silica, elution being carried out with dichloromethane, so as to obtain 3.40 g of 2-methylpropan-2-yl 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate in the form of a dark yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([OH:19])=O)[CH2:11]2)[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:19])[CH2:11]2)[CH:3]=1
Reactant: NCc1ccccc1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 0 °C
Yield: 105.5 %

Procedure:
To a suspension of (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (2.2 g, 7.73 mmol) in CH2Cl2 (30 mL) at room temperature was added Hunig's base (1.75 mL, 10.04 mmol, 1.3 equiv) and benzylamine (1.01 mL, 9.27 mmol, 1.2 equiv), and the resulting mixture was chilled in an ice bath. To this stirred solution was added HATU (3.23 g, 8.50 mmol, 1.1 equiv) in one portion, and the resulting suspension was stirred in the ice bath for 30 minutes. LCMS showed conversion complete. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. Silica gel column chromatography using a gradient elution of 1% EtOAc in CHCl3 to 40% EtOAc in CHCl3 afforded the title compound (3.05 g) as a gum. LC-MS (ES) m/z=374 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:39]1[CH2:45][CH2:44][CH2:43][C@H:40]1[CH2:41][OH:42]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:39]1[CH2:45][CH2:44][CH2:43][C@H:40]1[CH:41]=[O:42])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C[C@@H]1CCCN1C(=O)CNC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 17.7 g of N-benzyloxycarbonyl-glycin. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 600 ml of THF. To this solution was added 9.2 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of a 1-M Na2CO3 solution, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 38.7 g of WSCD.HCl and 155 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Successively, 7.7 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 360 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 250 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 300 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 4.5 g (15.6%).
Reaction SMILES: C[Si](C)(C)C#C[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:9]([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]4)[CH2:21]2)[CH2:27]3)[CH:8]=1)[OH:6].[CH2:32]1COC[CH2:33]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:32]([CH:16]([O:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:5][OH:6])=[CH:8][C:9]=1[C:20]12[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2)[CH2:17][O:18][CH3:19])#[CH:33]
Reactant: COCCOCOc1ccc(C(O)C#C[Si](C)(C)C)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C#CC(COC)OCOc1ccc(CO)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.7 g (10.5 mmol) of a-trimethylsilylethynyl-3-(1-adamantyl)-4-methoxyethoxymethoxyphenylmethanol and 50 ml of THF were introduced into a round-bottomed flask and 11.4 ml (12.6 mmol) of tetrabutylammonium fluoride solution (1.1M in THF) was added dropwise. The reaction medium was stirred at room temperature for one hour and was then poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of ethyl acetate and heptane (30/70). After evaporation of the solvents, 2.5 g (64%) of a-ethynyl-3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl-methanol were recovered.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:18](Cl)([Cl:20])=[O:19]>C1C=CC=CC=1>[Cl:20][C:18]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:19]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C(C#N)=NO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=NOC(=O)Cl
Reaction time: 2 h

Procedure:
In dry benzene (50 ml), ethyl 2-hydroxyimino-2-cyanoacetate (7.2 g) and triethylamine (7.0 ml) are dissolved, and the resulting solution is dropwise added to a solution of phosgene (0.05 mol) in benzene (52.5 ml) at 5°C. The mixture is stirred at the same temperature for 2 hours and allowed to stand at room temmperature over night to give a solution of ethyl 2-chlorocarbonyloxyimino-2-cyanoacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:20])[CH2:17][NH:18][CH3:19])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:20])[CH2:17][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:19])=[CH:14][CH:15]=1)[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CNCC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)CN(C)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound [2-3] was dissolved in 3 mL of chloroform, and 76 μL of benzaldehyde and 158 mg of sodium triacetoxyborohydride were added thereto. After an overnight stirring at room temperature, to the mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The resulting organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the resulting residue was purified by preparative thin-layer chromatography, to obtain 64 mg of tert-butyl{(1S)-1-[4-(N-benzyl-N-methylglycyl)phenyl]ethyl}carbamate [24] (hereinafter, referred to as the compound [2-4]) as a colorless oily product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:32][CH:31]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)cc3)ccn2c1=O
Yield: 107.5 %

Procedure:
Methyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and (4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-boronic acid (516 mg, 2.06 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (850 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@:27]([OH:42])([C@H:34]([S:36][CH:37]([CH2:40]O)[CH2:38][OH:39])[CH3:35])[CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@@:27]([OH:42])([CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)[C@H:34]([S:36][C@@H:37]1[CH2:38][O:39][C@@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=3)=[O:16])=[CH:9][CH:10]=2)[O:15][CH2:40]1)[CH3:35]
Reactant: O=Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(3), a reaction was carried out using 4′-fluoro-4-formylbenzanilide (300 mg, 1.2 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (385 mg, 1.1 mmol) and p-toluenesulfonic acid monohydrate (366 mg, 1.9 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give the trans isomer of the title compound (306 mg, yield 48%) as a colorless oil and the cis isomer (78 mg, yield 12%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][CH2:18][OH:19])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Cl:20]OC(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[Cl:20][C:14]1[C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:13]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)(C)OCl
Reactant: CCOC(=O)COc1ccc(CCO)cc1OCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1cc(Cl)c(CCO)cc1OCC
Reaction time: 0.25 h

Procedure:
To a stirred solution of ethyl 2-[2-ethoxy-4-(2-hydroxyethyl)phenoxy]acetate (1.15 g) in dichloromethane (4.3 ml) was added tert-butyl hypochlorite (478 μl) at room temperature, and the mixture was stirred for 15 minutes. To the reaction mixture was added a solution of sodium sulfite (542 mg) in water (5 ml), and the resulting mixture was stirred for 10 minutes at room temperature. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave ethyl 2-[5-chloro-2-ethoxy-4-(2-hydroxyethyl)phenoxy]acetate (1.28 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:10]1[CH2:11][CH2:1][O:2][CH:3]1[CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8]
Reactant: COC(CNC(=O)CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: OCCO
Product: O=C(CCl)NCC1OCCO1
Temperature: 25 °C

Procedure:
N-(2,2-Dimethoxyethyl)-2-chloroacetamide (18.1 grams; 0.10 mole) ethylene glycol (6.82 grams; 0.11 mole) and 10 drops of a solution of one gram of p-toluenesulfonic acid in 100 ml of diethyl ether were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, distillation head and condenser. The mixture was stirred and heated to about 95° C. to 100° C. Byproduct methanol was distilled off. When no further methanol was evolved, the mixture was cooled to room temperature, sodium carbonate (2 grams) was added and the slurry was stirred for a period of about 1 hour. The slurry was then filtered and the filtrate fractionally distilled under reduced pressure the desired product N-(1,3-dioxolan-2-ylmethyl)-2-chloroacetamide was obtained as a fraction boiling at 109° C.-110° C. at 0.15 mm Hg which, when cooled, solidfied. The solid had a melting point of 61° C.-63° C.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH:22]=O)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12.[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[CH2:33][N:34]([CH3:36])[CH3:35])[C:28]#[N:29].CC(O)=O.[BH4-].[Na+].Cl>ClCCCl>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH2:22][NH:24][C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=4[CH2:33][N:34]([CH3:36])[CH3:35])[C:28]#[N:29])[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CN(C)Cc1ccc(C#N)cc1N
Reactant: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3ncnn3c2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cccc(-c2[nH]c(CNc3cc(C#N)ccc3CN(C)C)nc2-c2ccc3ncnn3c2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
To a stirred solution of 4-((1,2,4)triazolo(1,5-a)pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazole-2-carbaldehyde (0.50 g, 1.64 mmol) in 1,2-dichloroethane (30 mL) were added 3-amino-4-((dimethylamino)methyl)benzonitrile (0.43 g, 2.46 mmol) and AcOH (0.20 g, 3.29 mmol), and the mixture was heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in anhydrous MeOH (30 mL). To a methanolic solution at 0° C. was added NaBH4 (0.25 g, 6.57 mmol), and then the mixture was allowed to warm to room temperature and stirred for an additional 3 h. The pH of the reaction mixture was adjusted to 7-8 at 0° C. with 1 N HCl, and then MeOH was removed under reduced pressure. The aqueous mixture was extracted with CH2Cl2 (2×50 mL), and the CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 (1:19 (v/v)) as eluent to give the titled compound (0.60 g, 79%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.36 (s, 1H), 7.86 (dd, 1H, J=9.2, 1.6 Hz), 7.78 (dd, 1H, J=9.2, 0.8 Hz), 7.47 (t, 1H, J=7.6 Hz), 7.23 (br d, 1H, J=7.6 Hz), 7.09 (d, 1H, J=7.6 Hz), 7.01 (d, 1H, J=7.6 Hz), 6.98 (dd, 1H, J=7.6, 1.6 Hz), 6.93 (br s, 1H), 4.59 (s, 2H), 3.63 (s, 2H), 2.53 (s, 3H), 2.33 (s, 6H); MS (ESI) m/z 464.23 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[C:44]([O:45][CH3:46])=[CH:43][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:24][C:25]2[C:44]([O:45][CH3:46])=[CH:43][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(=O)N1CCOCC1)CC2
Yield: 56 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone. Product isolated as white crystals (60 mg, 56%). mp: 189-191° C., MS (ESI+): 638.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.27 (d, J=8 Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 6.65 (s, 1H), 6.57 (s, 1H), 6.52 (d, J=8 Hz, 1H), 3.93-3.88 (m, 10H), 3.74-3.67 (m, 8H), 3.29 (s, 2H), 3.16 (t, J=5 Hz, 4H), 2.87 (m, 2H), 2.83 (m, 2H), 2.69 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[C:16]([N:21]=2)=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:11][S:12]([C:13]2[NH:14][C:15]3[C:16]([N:21]=2)=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:30])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1c(C)cnc(CSc2nc3ncccc3[nH]2)c1C
Solvent: ClC(Cl)Cl
Product: COc1c(C)cnc(CS(=O)c2nc3ncccc3[nH]2)c1C

Procedure:
0.4 Gram of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]pyridine was dissolved in 40 ml of chloroform, then this solution was stirred under ice-cooling condition, 0.27 g of m-chloroperbenzoic acid (85%) was added thereto. The whole reaction mixture was stirred at the same temperature for 20 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the residue thus obtained was washed with diethyl ether. Recrystallization from ethanol to yield 1.15 g of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]imidazo[4,5-b]pyridine in the form of light brown powdery crystals. Melting point: 169°-170° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:14]1[CH2:15][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:9][CH:8]=2)[CH2:11][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:13]1)(=[O:29])[CH3:28]
Reactant: COC(=O)C1CNCC(c2ccc(CCO)cc2)C1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(c2ccc(CCO)cc2)CN(C(C)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5.58 g (9.33 mmol, purity 44%) of the compound from Example 56A in dichloromethane (80 ml) was admixed with 2.60 ml (1.89 g, 18.7 mmol) of triethylamine and then cooled to 0° C. At this temperature, 0.33 ml (0.37 g, 4.67 mmol) of acetyl chloride was added dropwise and the mixture was stirred for 2 h. A further 0.13 ml (0.15 g, 1.86 mmol) of acetyl chloride was added and the mixture was stirred for 1 h. Subsequently, the reaction solution was washed with aqueous 1 N hydrochloric acid, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 30:1), and the crude product obtained was purified once more by means of preparative HPLC. Yield: 1.17 g (41% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.[N:23]#CBr.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10]3([CH2:15][CH2:14][N:13]([C:16]#[N:23])[CH2:12][CH2:11]3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CN1CCC2(CC1)CN(c1ccc(Cl)cc1)c1ccccc12
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CN1CCC2(CC1)CN(c1ccc(Cl)cc1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.95 g of 1-(4-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] (Example 2), 0.42 g of cyanogen bromide and 1 g of potassium carbonate in 25 ml of dichloromethane is stirred at ambient temperature for two hours. The reaction mixture is filtered and the filtrate concentrated to dryness leaving an oily residue which is crystallized from an acetone-hexane mixture leaving colorless crystals, mp 178.5-180° C. of 1-(4-chlorophenyl)-1'-cyanospiro[indoline-3,4'-piperidine].
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][C:30]([CH3:31])=[C:25]3[N:24]([CH3:32])[C:23]2=[O:33])=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CC(N(C)C)=O.CO>[CH3:32][N:24]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][C:30]=2[CH3:31])[N:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:21][CH:20]=2)[C:23]1=[O:33]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(Oc2nc3cccnc3n2C)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (600 mg) was added to a solution of 3-(4-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (725 mg) and potassium tert-butoxide (351 mg) in DMA (4 ml) at 20° C. The mixture was stirred at 150° C. under a dry atmosphere for 30 min. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 mg) as colorless crystals.