Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:39]([N:41]([CH2:49][CH3:50])[CH:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)[CH3:40]>S([O-])(O)(=O)=O.[K+].FC(F)(F)C(O)=O>[CH2:49]([N:41]([CH2:39][CH3:40])[CH:42]1[CH2:47][CH2:46][CH:45]([NH:48][C:2]2[C:12]([F:13])=[CH:11][C:10]([C:14]3[CH:15]=[C:16]4[C:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[N:21][NH:20][C:17]4=[N:18][CH:19]=3)=[CH:9][C:3]=2[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[CH2:44][CH2:43]1)[CH3:50]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(F)c(F)c(C(=O)N(C)C)c3)cc12
Reactant: CCN(CC)C1CCC(N)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C1CCC(Nc2c(F)cc(-c3cnc4[nH]nc(-c5ccccc5OC)c4c3)cc2C(=O)N(C)C)CC1
Reaction time: 48 h

Procedure:
Into a 5 mL screw-cap vial were added 2,3-difluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (266 mg, 0.46 mmol) and 4-diethylamino-cyclohexylamine (468 mg, 2.74 mmol, mixture of cis/trans isomers). The vial was sealed and placed in heated block at 120° C. for 48 h. The reaction solution was suspended in 1 N aqueous potassium hydrogensulfate solution and loaded onto a 5 g C18 functionalized silica gel cartridge. The plug was washed with 1 N aqueous potassium hydrogensulfate and water. Elution with acetonitrile and evaporation of the solvent afforded a brown oil which was dissolved in 5 mL trifluoroacetic acid. The resulting mixture was stirred for 1 h and then the reaction mixture was concentrated. The residue was dissolved in 2 mL of methanol and 200 μL ethylenediamine were added. The mixture was diluted with 2 mL of DMSO and purified by reverse-phase HPLC to afford 43.4 mg (0.63 mmol, 14%) of both diastereomers of 2-(4-diethylamino-cyclohexylamino)-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide separately as colorless powders. More polar diastereomer (21.3 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.81 (d, J=1.5 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 7.62 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.58 (dd, J1=14 Hz, J2=2 Hz, 1H), 7.45 (m, 1H), 7.30 (d, J=2 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.08 (td, J1=7.5 Hz, J2=1 Hz, 1H), 4.53 (dd, J1=8 Hz, J2=1.5 Hz, 1H), 3.82 (s, 3H), 3.12 (m, 1H), 2.75-3.05 (m, 7H), 2.44 (q, J=7 Hz, 4H), 1.89 (m, 2H), 1.69 (m, 2H), 1.19 (m, 4H), 0.93 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+). Less polar diastereomer (22.1 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.76 (s, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 7.64 (dd, J1=4.5 Hz, J2=1.5 Hz, 1H), 7.61 (t, J=2 Hz, 1H), 7.45 (m, 1H), 7.42 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 4.99 (dd, J1=10 Hz, J2=1 Hz, 1H), 3.82 (s, 3H), 3.68 (m, 1H), 3.32 (m, 1H), 2.97 (bs, 6H), 2.46 (q, J=7 Hz, 4H), 1.70 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.35 (m, 2H), 0.94 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH2:18].C(O)(=O)C>O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 40 °C

Procedure:
Acetic anhydride (8.0 mL) was added dropwise over a period of 10 minutes to a mixture of 2-fluoro-5-nitrophenylamine (7.8 g) and acetic acid (50 mL) at reflux. The resulting mixture was heated at reflux for 30 minutes and cooled to 40° C. The mixture was poured into cold water (800 mL) and the resulting precipitate collected by filtration, washed with 1.0 M aqueous hydrochloric acid and water and dried to give title compound as a light brown solid, 9.2 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[C:7]([O:14][CH3:15])[C:5]=2[N:6]=1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[S:3][C:4]3[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[C:7]([O:14][CH3:15])[C:5]=3[N:6]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc(C(=O)O)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole-7-carboxylic acid methyll ester and 4-fluoro-benzoyl chloride the title compound was obtained as a white solid (91% yield), MS: m/e=361.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(Nc2ccc(Cl)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4-chloroaniline according to general procedure A provided methyl ester of Compound 8 as a yellow oil (52% yield). 1H NMR (CDCl3, 500 MHz): δ=7.70 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.21-7.27 (m, 3H), 7.01 (d, J=8.8 Hz, 2H), 5.78 (s, 1H), 3.91 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.2, 143.4, 141.4, 131.7, 129.7, 126.7, 122.5, 122.0, 119.8, 118.7, 52.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:17]=2[O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cccc(C)c1-c1cccc2c1OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 87.2 %

Procedure:
Treatment of (±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.947 g, 3.73 mmol) with diisopropylethylamine (0.725 g, 5.60 mmol) and benzyl chloroformate (0.7647 g, 4.48 mmol) generally according to the procedure described for Intermediate 12 gave 1.26 g (87%) of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil Rf=0.56 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C25H25NO3: C, 77.49; H, 6.50; N, 3.61. Found: C, 77.42H, 6.57; N, 3.62. Chiral HPLC separation of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, methanol:carbon dioxide 4:6) provided two fractions. Fraction 1 (Rt=2.89 min, Chiralcel OJ, methanol:carbon dioxide 4:6); Fraction 2 (Rt=3.84 min, Chiralcel OJ, methanol:carbon dioxide 4:6).
Reaction SMILES: [CH3:1][N:2]([C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4].C(OO)(=[O:22])C>>[CH3:1][N:2]([C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1)[S:3]([C:6]1[N+:7]([O-:22])=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CC(=O)OO
Reactant: CN(c1ncc(Cl)cc1Cl)S(=O)(=O)c1ccccn1
Product: CN(c1ncc(Cl)cc1Cl)S(=O)(=O)c1cccc[n+]1[O-]

Procedure:
Following the procedures of Example 1, N-methyl-N-(3,5-dichloro-2-pyridyl)-2-pyridinesulfonamide is oxidized with 40% peracetic acid to give the title compound, MS m/e 334.00 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:31])[N:14]([CH2:16][CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]O.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>C(Cl)Cl.O>[N:37]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:31])[N:14]([CH2:16][CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:3][C:2]=1[Cl:1])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(CO)c(Cl)c4)ccc3=O)ccnc2c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(OCCn3nc(-c4ccc(CN=[N+]=[N-])c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 6-(3-chloro-4-(hydroxymethyl)phenyl)-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (1060 mg, 2421 μmol) and TEA (337 μL, 2421 μmol) in DCM (10 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (187 μL, 2421 μmol) in DCM (1 mL). After 3 hours, the mixture was partitioned between DCM (25 mL) and 5% NaHCO3 (25 mL). The aqueous layer was further extracted with DCM (2×10 mL). The combined organics were dried over MgSO4, then concentrated to a solid. Solid was then dissolved in DMF (5 mL) and sodium azide (787 mg, 12104 μmol) in water (5 mL) was then added. The biphasic solution was then heated to 60° C. overnight. The reaction was then partitioned between DCM (25 mL) and 5% NaHCO3 (25 mL). The aqueous layer was then further extracted with DCM (2×10 mL). The combined organics were then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with 1 to 4% of MeOH/DCM. MS (ESI pos. ion) m/z: 463 (MH+); calc'd for C23H19ClN6O3: 462.
Reaction SMILES: [CH:1]([N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[C@@H:7]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)=[O:27])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH2:3][CH3:4])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([N:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)=[O:27])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)N1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
tert-Butyl (2R)-4-sec-butyl-2-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]piperazine-1-carboxylate (75 mg) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added and the mixture stirred at room temperature overnight. The mixture was partitioned between dichloromethane (75 ml) and saturated aqueous sodium bicarbonate (15 ml) and the organic layer concentrated in vacuo and adsorbed onto silica for purification by chromatography eluting with 0-20% methanol/dichloromethane. This gave the product as a brittle white solid (41 mg).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:50][O:51][CH:52]1[CH2:57][CH2:56][CH2:55][N:54]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([CH2:65][NH:66][CH3:67])=[CH:61][CH:60]=2)[CH2:53]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:66]([CH2:65][C:62]3[CH:61]=[CH:60][C:59]([CH2:58][N:54]4[CH2:55][CH2:56][CH2:57][CH:52]([O:51][CH3:50])[CH2:53]4)=[CH:64][CH:63]=3)[CH3:67])=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (28 mg, 0.16 mmol), HOBt (21 mg, 0.16 mmol) DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (36 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [CH2:1]1[CH2:5][Si:4]([Cl:7])(Cl)[CH2:3][CH2:2]1.NC(N)=O.[C:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH2:13][OH:14]>C1COCC1>[Cl:7][Si:4]1([O:14][CH2:13][C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:5][CH2:1][CH2:2][CH2:3]1
Reactant: Cl[Si]1(Cl)CCCC1
Reactant: O=C(CO)OCc1ccccc1
Agent: NC(N)=O
Solvent: C1CCOC1
Product: O=C(CO[Si]1(Cl)CCCC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of cyclotetramethylenedichlorosilane (0.5 mL; 3.82 mMol) in dry THF (5 mL) was added urea (0.275 g; 4.58 mmol). The mixture was then cooled to 0° C. and benzyl glycolate (0.54 mL; 3.82 mmol) was then added dropwise over a 7 minute span. The mixture was then taken off the ice bath and allowed to stir at room temperature for 1 hour. The biphasic mixture was then concentrated under high vacuum and diluted with chloroform. The aqueous layer was then soaked up with excess Na2SO4 and the mixture was filtered. The filtrate was concentrated to a light yellow crude liquid which was used without further purification.
Reaction SMILES: [CH2:1]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=[C:3]2[CH2:2]1.CO[CH2:11][Cl:12].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:12][CH2:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[CH2:1][CH2:2][C:3]=12
Reactant: COCCl
Reactant: c1ccc2c(c1)CC2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccc2c1CC2
Temperature: 0 °C
Yield: 41 %

Procedure:
To a stirred solution of 10 g of benzocyclobutene and 18.25 mL of chloromethyl methyl ether in 100 mL of methylene chloride at -78° C. under a nitrogen atmosphere, 11.1 g tin tetrachloride was added slowly over a period 1 hour and stirring was continued for 6 more hours at -78° C. The reaction mixture was then poured into an ice cold sodium hydroxide solution (10%) and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Removal of the solvent followed by purification by flash chromatography afforded 6 g of 4-chloromethylbenzocyclobutene (41%) as a colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH:10]2[CH2:12][O:11]2)[CH:8]=1)([O-:3])=[O:2].[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[CH2:12][CH:10]([OH:11])[CH2:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]1
Reactant: O=[N+]([O-])c1cnn(CC2CO2)c1
Reactant: CNC
Product: CN(C)CC(O)Cn1cc([N+](=O)[O-])cn1

Procedure:
4-nitro-1-(oxiran-2-ylmethyl)-1H-pyrazole (200 mg, 1.2 mmol) was stirred overnight at rt in dimethylamine (2M in methanol, 5 mL). The solution was concentrated to give 1-(dimethylamino)-3-(4-nitro-1H-pyrazol-1-yl)propan-2-ol as a yellow solid (quantitative). LC-MS (UPLC, high pH), (ES+) 215.2, RT=0.75 min.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[N:20]1([CH2:26][CH2:27][NH:28][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCN2CCOCC2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-morpholin-4-yl-ethylamine and DIEA to give 2-(2-morpholin-4-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 368 (MH+).
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: [NH4+]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(COC(C)=O)c21
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: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[NH:16])[NH:14][CH3:15])=[O:11].[C:17](#N)C>CN(C=O)C.CC(N(C)C)=O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH:15]=[N:14][C:13]([NH:16][CH3:17])=[N:12][C:10]1=[O:11]
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Reactant: CC#N
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Temperature: 105 °C

Procedure:
About 200 mg. of 1-(2',6'-dimethylphenyl)-3-methylamidinourea is introduced into a gas chromatograph hypo vial and dissolved in 1 ml. of acetonitrile. To the solution is added 0.2 ml. of DMF DMA reagent. The vial is sealed with crimper and heated at 105° C. for 15 minutes in an oven. Seven vials are made. The contents of the vials are then put into a long-neck round bottom flask and evaporated to dryness by a flask evaporator. The solid mass is dissolved in a mixture of 30 ml. of CH Cl3 and 20 ml. of water and shaken vigorously in a 60 ml. separatory funnel. The aqueous layer is discarded and 20 ml. of water is added and shaken. The CH Cl3 layer is then taken off and about 10 g. of anhydrous Na2SO4 is added, the CH Cl3 solution is decanted into a flask and evaporated to dryness. The solid material is dissolved in pentanone-2 (about 80 ml.) at 70° C. The solution is concentrated and crystallizes upon cooling. The crystals are collected and dried in a desiccator with P2O5 with vacuum for one hour.
Reaction SMILES: [CH2:1]([C:3]1([CH3:22])[CH:8]([CH3:9])[CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][C:5]([CH2:20][CH3:21])([CH3:19])[NH:4]1)[CH3:2].Cl.[CH2:24]1[O:26][CH2:25]1>CO>[OH:26][CH2:25][CH2:24][N:4]1[C:5]([CH2:20][CH3:21])([CH3:19])[CH2:6][CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:22]
Reactant: C1CO1
Reactant: CCC1(C)CC(NC(=O)c2ccccc2)C(C)C(C)(CC)N1
Agent: Cl
Solvent: CO
Product: CCC1(C)CC(NC(=O)c2ccccc2)C(C)C(C)(CC)N1CCO
Temperature: 130 °C

Procedure:
30.3 g of 2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine (compound no. 9), 200 ml of methanol and 2 ml of concentrated hydrochloric acid are introduced into an autoclave. About 9 g of ethyleneoxide are added, and the contents of the autoclave are heated to 130° C. for 30 hours. After cooling, the contents of the autoclave are purified by filtration, and the methanol is evaporated. Crystallization of the residue from toluene yields 1-β-hydroxyethyl-2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine (compound no. 27); m.p. 212°-214° C. If, instead of 30.3 g of 2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine an equimolar amount of N,N'-diacetyl-N,N'-bis-(2,6-diethyl-2,3,6-trimethyl-4-piperidyl)-hexamethylene-1,6-diamine (compound no. 22), 12 g instead of 9 g of ethyleneoxide are used and otherwise the procedure described above is followed, N,N'-diacetyl-N,N'-bis-(1-β-hydroxyethyl-2,6-diethyl-2,3,6-trimethyl-4-piperidyl)-hexamethylene-1,6-diamine (compound no. 28) is obtained as a yellowish viscous resin.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].[C:10]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>O1CCCC1.C(OCC)(=O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:9])[C:5]([F:7])([F:6])[C@H:23]([OH:24])[C@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[NH:17][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:2]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.45 g zinc powder are suspended in 30 ml tetrahydrofuran and heated to reflux temperature. 4.4 g ethylbromodifluoroacetate are added at once and as soon as a vigorous reaction is initiated 2 g of N--BOC--L--leucinal dissolved in 5 ml tetrahydrofuran are added dropwise. After 30 minutes the reaction mixture is allowed to cool, then taken up in ethyl acetate and washed with 2N tartaric acid. The organic phase is dried over magnesium sulfate, evaporated to dryness and chromatographed over silicagel using ether/hexane 2:8 as an eluent. N--BOC--(4S,3R)-2,2-difluorostatine ethyl ester is obtained ([α]D20 =-12.2°, c=0.29 in ethanol).
Reaction SMILES: [N:1]1([N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[CH3:15])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Se](=O)=[O:17]>O1CCOCC1>[N:1]1([N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[CH:15]=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: Cc1nc2ccccc2n1-n1cccc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1nc2ccccc2n1-n1cccc1

Procedure:
Using the procedure of Example 10B and starting with 1.9 g of 1-(1-pyrrolyl)-2-methylbenzimidazole [Synthesis, 757 (1983)]and 1.07 g of selenium dioxide in 35 ml of dioxane, there was obtained 1.3 g of the product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[CH2:33][NH:34][C:35]([NH:37][C:38]4[O:42][N:41]=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=4)=[O:36])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:43]([C:40]1[CH:39]=[C:38]([NH:37][C:35]([NH:34][CH2:33][C:27]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=2[O:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:17]=[CH:18]3)=[O:36])[O:42][N:41]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4CNC(=O)Nc4cc(C(C)(C)C)no4)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCN3CCNCC3)c2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
4-[2-(5-{2-[3-(3-tert-Butyl-isoxazol-5-yl)-ureidomethyl]-4-fluorophenoxy}-indazol-1-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (0.056 g, 0.088 mmol) was treated with TFA/CH2Cl2 (1:1, 2 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and azeotroped with toluene. The residue was diluted with ethyl acetate (40 mL) and washed with 1N NaOH and brine. The solution was concentrated under reduced pressure to afford 0.038 g of the product (80% yield). MS (ESI+) m/z 536 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 7.81 (s, 1H), 7.35 (d, 1H), 7.15 (dd, 1H), 7.08 (s, 1H), 7.05 (d, 1H), 6.88 (m, 1H), 6.76 (m, 1H), 6.28 (m, 1H), 5.99 (s, 1H), 4.46 (m, 4H), 2.86 (m, 2H), 2.79 (m, 4H), 2.43 (m, 4H), 1.26 (s, 9H).