Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[OH-].[Na+].[CH3:12][C:13]([CH3:18])=[CH:14][C:15](Cl)=[O:16]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[CH:14]=[C:13]([CH3:18])[CH3:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: CC(C)=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a biphasic mixture of 3-bromo-4-methylaniline (50 g, 0.269 mol), 10% NaOH (270 mL) and dichloromethane (160 mL) was added dropwise over a period of 2 hours 3,3-dimethylacryloyl chloride (36 mL, 0.322 mol) in dichloromethane (95 mL). The solution was stirred at room temperature for 48 hours then diluted with water (100 mL). The aqueous layer was further extracted with dichloromethane. The organic layers were combined and washed with water and brine, dried (MgSO4), filtered and evaporated. The white solid was triturated with hexane and collected to give 70 g (97%) of 3-Methyl-but-2-enoic acid (3-bromo-4-methyl-phenyl)-amide. 1H NMR (300 MHz; CDCl3): 1.89 (s, 3 H), 2.21 (s, 3 H), 2.33 (s, 3 H), 5.68 (s, 1 H), 7.14 (d, J=8.0 Hz, 1 H), 7.17 (br s, 1 H), 7.33 (d, J=8.0 Hz, 1 H), 7.79 (s, 1 H).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13].[P:15]([O-:23])([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([O:23][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13])=[O:16])[CH3:19]
Reactant: CCOP(=O)([O-])OCC
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1C(=O)N(COP(=O)(OCC)OCC)S(=O)(=O)N1C
Yield: 66 %

Procedure:
A mixture of 2-chloromethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 4.16 mmol), diethyl phosphate (Formula III: A=B=Et) (0.96 g, 6.63 mmol), tetrabutylammonium bromide (94 mg, 0.29 mmol) and triethylamine (0.63 g, 6.23 mmol) in methylene chloride (20 ml) was allowed to reflux for 24 hours. After adding an additional tetrabutylammonium bromide, the mixture was refluxed for an additional 48 hours, and then cooled. The mixture was purified by silica gel flash chromatography (ethyl acetate/hexane) to afford 0.98 g (66%) of 2-(diethoxyphosphinyloxymethyl)-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: A=B=Et; R1 =H; R2 =propyl; R3 =CH3) as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:29][CH2:28][CH2:27][CH2:26]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].N1CCNCC1.[OH-].[Na+]>CN1CCCC1=O.O>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:32]=[N:31][NH:30][N:24]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:26][CH2:27][CH2:28][CH2:29]2)[N:6]=1
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine (10.2 g) in 1-methylpyrrolidin-2-one (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.5 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (2.5 g, 94.4% purity by HPLC).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][CH:61]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[CH2:62][CH2:63][NH:64][C:65](=[O:67])[CH3:66]>CN1C(=O)CCC1.C(OC(NC1(C(O)=O)CCN(C2C3C=CNC=3N=CN=2)CC1)=O)(C)(C)C.NC(C1C=CC(Cl)=CC=1)CCNC(=O)C>[C:65]([NH:64][CH2:63][CH2:62][CH:61]([NH:60][C:48]([C:33]1([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1)=[O:50])[C:68]1[CH:69]=[CH:70][C:71]([Cl:74])=[CH:72][CH:73]=1)(=[O:67])[CH3:66]
Reactant: CC(=O)NCCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)NCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (98 mg, 0.26 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (62.2 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.085 mL, 0.52 mmol) in NMP (2 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. N-(3-amino-3-(4-chlorophenyl)propyl)acetamide (Intermediate 27) (39 mg, 0.17 mmol) in NMP (2 mL) was then added to the reaction and stirred for 1 hour. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(3-acetamido-1-(4-chlorophenyl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (1.04 g, 86%) as a white solid. m/z (ESI+) (M+H)+=570; HPLC tR=1.95 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([NH:37][CH3:36])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: CNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Yield: 55 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with methylamine to give the title compound as a white solid (110 mg, 55%) except that the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum 1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.71 (s, 2H), 7.00 (d, 1H), 7.04-7.10 (m, 3H), 7.36 (dd, 2H), 7.71-7.77 (m, 3H), 8.17 (s, 1H), 8.37 (m, 1H), 8.53 (s, 1H), 8.55 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 471.
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[C:10](=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])/[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].C[Si]([C:25]#[N:26])(C)C>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])([C:25]#[N:26])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: C/C(COCc1ccccc1)=N\S(=O)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C#N)(COCc1ccccc1)NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of (E)-N-(1-(benzyloxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide (CAN 393536-49-7, 3.1 g, 11.6 mmol) in dry THF (55 ml) under an argon atmosphere was added cesium fluoride (1.94 g, 12.8 mmol) followed by addition of trimethylsilyl cyanide (1.27 g, 1.71 ml, 12.8 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and poured into a separatory funnel. Organic phase was extracted with a 1M aqueous solution of sodium bicarbonate and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (2.53 gr, 74%); MS (ESI, m/z): 295.6 (M+H+).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)=[C:11]([NH:24][CH3:25])[CH:10]=1>C(O)=O>[F:8][C:9]1[CH:10]=[C:11]2[C:12]([C:15](=[O:23])[C:16]([C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)=[CH:25][N:24]2[CH3:1])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNc1cc(F)ccc1C(=O)Cc1nnnn1C
Solvent: O=CO
Product: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of acetic anhydride (0.8 ml) and formic acid (0.4 ml) was stirred at 50°-60° for 2 hours, then cooled to ambient temperature. 1-(4-Fluoro-2-methylaminophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone (1.03 g) was added. The mixture was stirred at ambient temperature for 5 hours, then kept at this temperature for 16 hours. The mixture was triturated under light petroleum to give a solid product. This product was extracted with boiling ethyl acetate (100 ml) and the extract cooled to give a solid product which was recrystallised from industrial methylated spirit to give the novel compound 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 264°-267°, identical to the product of Example 2(d).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:7]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[N:6][CH:5]=[N:4]1.[CH2:13]([OH:15])[CH3:14]>>[CH3:2][N:3]1[C:7]([C:8]2([C:11](=[NH:12])[O:15][CH2:13][CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:5]=[N:4]1
Reactant: Cn1ncnc1C1(C#N)CC1
Reactant: CCO
Agent: [Na]
Product: CCOC(=N)C1(c2ncnn2C)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Sodium metal (37 mg, 1.61 mmol) was added to anhydrous ethanol (5 mL) at room temperature. The mixture was stirred for 30 min. A solution of 1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclopropanecarbonitrile (0.3 g, 2.0 mmol) in ethanol (5 mL) was added and the reaction mixture was heated to 60° C. for 1 h. The resulting mixture was used without further purification. MS (ES+APCI) (M+H) 195.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Cn1ccc(N)n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1ccc(Nc2nc(Cl)ncc2Cl)n1

Procedure:
The mixture 1-methyl-1H-pyrazol-3-amine (48 mg, 0.50 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and sodium carbonate (53 mg, 0.5 mmol) in 3 mL of EtOH is heated at 40° C. over night. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford 2,5-Dichloro-N-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z 244.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[C:17]3[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:12]=3[C:11]3[CH2:20][C@H:21]([NH:23][C:24](=[O:29])[O:25][CH:26]([CH3:28])[CH3:27])[CH2:22][C:10]2=3)[C:3]=1[O:30][CH3:31]>[Pd].CO.O>[CH:26]([O:25][C:24](=[O:29])[NH:23][C@@H:21]1[CH2:22][C:10]2[N:9]([CH2:8][C:4]3[C:3]([O:30][CH3:31])=[CH:2][CH:7]=[CH:6][N:5]=3)[C:17]3[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:12]=3[C:11]=2[CH2:20]1)([CH3:28])[CH3:27]
Reactant: COc1c(Cl)ccnc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1cccnc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of (S)-isopropyl 4-((4-chloro-3-methoxypyridin-2-yl)methyl)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamate (12.53 g, 28.55 mmol) and 10% palladium on carbon (1.00 g) in methanol (150 mL) is hydrogenated at 50 psi at room temperature overnight. A fresh batch of 10% palladium on carbon (1.2 g) is slurried in water (˜2 mL) and added to the reaction mixture, which is hydrogenated (50 psi) at room temperature overnight. The catalyst is filtered off and the solution is concentrated under reduced pressure to obtain a pale yellow solid. The solid is triturated with ether twice and dried under high vacuum to afford a yellow solid (10.80 g, 94%). LC-ES/MS m/z 405.2 [M+H]+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[N:2]1.[NH2:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:34]=[C:35](I)[C:28]=12.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:34]=[C:35]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[CH:16][CH:15]=3)[C:28]=12
Reactant: CC1(C)OB(c2ccc(Nc3noc4ccccc34)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Nc4noc5ccccc45)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C

Procedure:
A mixture of N-benzo[d]isoxazol-3-yl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.087 g, 0.000258 mol), tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.088 g, 0.000198 mol), tetrakis-(triphenylphosphine)palladium (0.014 g, 0.000012 mol) and sodium carbonate (0.053 g, 0.000495 mol) was heated in a mixture of ethylene glycol dimethyl ether (4 mL) and water (2 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure and the residue partitioned between water and dichloromethane. The organic phase was dried with magnesium sulfate and concentrated under reduced pressure to yield crude tert-butyl 4-{4-amino-3-[4-(benzo[d]isoxazol-3-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-1-piperidinecarboxylate which was used without further purification. It was dissolved in ethyl acetate (5 mL) and treated with a 4N aqueous solution of hydrochloric acid (1 mL). The resulting emulsion was vigorously stirred for 1 hour; the water layer was neutralized with saturated solution of sodium bicarbonate in water and the layers were separated. The organic phase was concentrated under reduced pressure and residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield N3-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}benzo[d]isoxazol-3-amine acetate (0.009 g, 0,0000185 mol) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:13](=[O:17])[N:14]([CH2:15][CH3:16])[C:7]=12)(=O)C.[OH-].[Na+].[NH4+:27].[Cl-]>CCO>[CH2:15]([N:14]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[CH2:5][OH:4])[N:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:13]3[N:12]([CH3:18])[C:8]4=[N:9][CH:10]=[CH:11][CH:6]=[C:7]4[N:27]=3)=[CH:20][CH:19]=2)[C:13]1=[O:17])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(COC(C)=O)c21
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(CO)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of [1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (150 mg) and EtOH (3 mL) was added 1 N NaOH (2 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, treated with saturated NH4Cl solution, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMA (4 ml) and KOtBu (52 mg) was added at room temperature. The mixture was stirred for 2 min, and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (97 mg) was added. The mixture was stirred at 150° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/MeOH=20/1. The product was crystallized from AcOEt/Hexane to give 1-ethyl-7-(hydroxymethyl)-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 (46 mg).
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 74 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 74% of theory, Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1) C27H28N6O3 (484.6) ##EQU23##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])=[CH:23][CH:22]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc(F)cc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)cc3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 4-fluoroaniline gave the title compound as a tan solid, mp 177-181° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.C(OCC)(=O)C>C1COCC1>[CH2:1]1[CH2:2][CH2:3][CH:4]([CH2:7][O:8][C:9]([C:11]2([CH2:33][C:34]3[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=3)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCC2CCCCC2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C#N)cc2)(C(=O)OCC2CCCCC2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester (6.61 mmol; 2.15 g) in dry THF (30 mL) under argon at −78° C. was added, dropwise, a 2M solution of lithium diisopropylamide (2M solution in heptanes/THF/ethylbenzene; 8.59 mmol; 4.29 mL). The resulting solution was stirred at −78° C. for 2 hours. 4-Bromomethyl-benzonitrile (6.61 mmol; 1.30 g) was added and the resulting solution was stirred at −78° C. for 2 hours, then allowed to warm to room temperature overnight. Ethyl acetate (150 ml) was added. The resulting solution was washed with a 1M aqueous hydrochloric acid solution (2×50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-(4-cyano-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester. MS (ESI) m/z 436.38 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br.O>ClCCl>[Br:16][C:9]1[C:2]([CH3:1])=[C:3]([CH:6]=[C:7]([CH3:11])[C:8]=1[CH3:10])[CH:4]=[O:5]
Reactant: BrBr
Reactant: Cc1cc(C)c(C=O)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C=O)c(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
To a solution of 2,4,5-trimethylbenzaldehyde (21.3 g, 144 mmol) in dichloromethane (200 mL) was added aluminum chloride (48.0 g, 360 mmol) with ice-cooling, and the mixture was warmed to room temperature. Bromine (7.80 mL, 151 mmol) was added dropwised to the reaction solution at room temperature, the mixture was stirred for 4 hours, water was added to the reaction solution, and dichloromethane was distilled off under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was washed with water, a saturated sodium hydrogen carbonate solution, 5% sodium sulfite aqueous solution, water and a saturated brine. The organic layer was dried over anhydrous sodium sulfate and then was concentrated under reduced pressure to obtain 32.5 g (yield 100%) of the title compound. Melting point: 108-110° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[CH3:11]
Reactant: Cc1cn2ccnc(Cl)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1nc2c(Cl)nccn2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of 8-Chloro-2-methyl-imidazo[1,2-a]pyrazine (0.7 g, 4.18 mmol) in DCM (20 ml) is added N-bromosuccinimide (0.74 g, 4.18 mmol) and the reaction stirred at room temperature for 2 h. After this time the solution is washed with saturated aqueous solution of Na2CO3 (2×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 3-bromo-8-chloro-2-methyl-imidazo[1,2-a]pyrazine (0.771 g, 75%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)N)=[CH:6][CH:5]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:27]3[CH:26]([CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:31][CH2:30][CH2:29][C:28]=3[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)=[CH:6][CH:5]=1
Reactant: COc1ccc(CN(N)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(OC)cc1)c1ccc(F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-methoxybenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.