Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)(Cl)Cl.O.[CH2:22]([OH:24])C>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([CH:13]=1)[CH:22]=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1cc(Oc2ccccc2)ccc1O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The starting material is prepared as follows: 4-Phenoxyphenol (20.0 g, 107 mmol) and sodium hydroxide (3.8 g, 845 mmol) are dissolved in a water/ethanol (130 ml/26 ml) mixture and heated at 70° C. To this reaction mixture is added chloroform (24.6 g, 215 mmol) dropwise over 45 minutes, and heating is continued for 3 hours. The mixture is cooled to room temperature, and then evaporated. The aqueous phase is acidified with conc. HCl to pH 1-3, and extracted twice with ether. The extracts are dried (MgSO4) and evaporated. Silica gel chromatography (10% ethyl acetate/hexane) of the residual oil yields 5-phenoxy-2-hydroxybenzaldehyde as a yellow solid, m.p. 54°-55° C., which is converted to 3-(N-hydroxyaminomethyl)-6-phenoxy-2H-1-benzopyran as described under (a).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]2[CH2:19][N:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:21][CH2:22][S:23][C:17]=2[CH:16]=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[C:18]2[CH2:19][N:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:21][CH2:22][S:23](=[O:9])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)N1CCSc2cccc(Cl)c2C1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCS(=O)c2cccc(Cl)c2C1
Reaction time: 0.25 h

Procedure:
A solution of 3-chloroperbenzoic acid (2.26 g) in dichloromethane (150 ml) was added dropwise with cooling from 0° C. to -2° C. to a stirred solution of 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.05 g, prepared as Example 19 above) in dichloromethane (100 ml). The reaction mixture was stirred for 15 minutes, washed with water and dried, and the solvent was removed by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethyl acetate. Yield 2.86 g (m.p. 167°-169° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=[O:18])[C:16]2=[C:19]([N+]([O-])=O)[CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:26])([CH3:3])[CH3:2].[F-:27].[K+]>CS(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=[O:18])[C:16]2=[C:19]([F:27])[CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:26])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc(F)c2C1=O
Temperature: 100 °C
Yield: 34.8 %

Procedure:
In 300 ml of dimethylsulfoxide was dissolved 14.0 g of N-(2',6'-diisopropylphenyl)-3-nitrophthalimide, and 10.0 g of potassium fluoride was added to the solution. The mixture was heated on an oil bath at 100° C. for 3 hours. The liquid reaction mixture was concentrated under reduced pressure below 80° C., and the residue was extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried and concentrated. Then, 20 ml of methanol was added to the residue, and the mixture was cooled and allowed to stand still. The compound 3 was precipitated in the form of colorless crystals. The amount obtained of the crude product was 10.1 g, yield: 77.6%. The crude crystals were recrystallized from methanol two times to obtain 4.5 g of pure crystals.
Reaction SMILES: C(Cl)=NN.IC1C=CC(N2CCC=C(N3CCOCC3)C2=O)=CC=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[C:43]3(N4CCOCC4)[C:44](=[O:55])[N:45]([C:48]4[CH:53]=[CH:52][C:51]([I:54])=[CH:50][CH:49]=4)[CH2:46][CH2:47][CH:42]3[C:41]([S:62]([CH3:65])(=[O:64])=[O:63])=[N:40]2)[CH:36]=[CH:37][CH:38]=1>C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[C:43]3[C:44](=[O:55])[N:45]([C:48]4[CH:49]=[CH:50][C:51]([I:54])=[CH:52][CH:53]=4)[CH2:46][CH2:47][C:42]=3[C:41]([S:62]([CH3:65])(=[O:64])=[O:63])=[N:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: CS(=O)(=O)C1=NN(c2cccc(Cl)c2)C2(N3CCOCC3)C(=O)N(c3ccc(I)cc3)CCC12
Agent: NN=CCl
Agent: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 70 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
The methanehydrazonoyl chloride (8.47 g, 31.7 mmol) and 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (12.17 g, 31.7 mmol) were combined in anhydrous toluene. The solution heated to 70° C. and triethylamine (13.2 mL, 95.1 mmol) was added dropwise. After the addition was complete the reaction was warmed to 90° C. and stirred at this temperature for 14 h. Analysis by LC/MS indicated formation of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-7a-morpholin-4-yl-1,3a,4,5,6,7a-hexahydro-pyrazolo[3,4-c]pyridin-7-one complete with less than 5% of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one remaining. The solvent was removed in vacuo. To the viscous oil was added dichloromethane (50 mL) then trifluoroacetic acid (30 mL) and heated to reflux for 4 h. The solvent was evaporated and the residue purified by flash column chromatography eluting with a gradient of hexane to 40% ethylacetate/hexane to give 10.65 g (64%) of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][CH2:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][CH2:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH:13]([CH3:19])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(CNc2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
In 50 ml of dried methanol are dissolved 10.0 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]propionate and 1.68 g of potassium hydroxide. The mixture is stirred at room temperature for 5 hours. After concentrating the reaction mixture, water is added to the residue, and the resulting solution is washed with ether. The aqueous layer is acidified with hydrochloric acid and extracted with ether. The extract is washed with water, then dried over magnesium sulfate and thereafter the solvent is distilled off. The resulting crystalline residue is recrystallized from benzene to give 8.0 g of 2-[4-(4-chloroanilinomethyl)phenoxy]propionic acid, mp 148° to 149° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10][Cl:11])=[C:6]([CH3:13])[N:5]=[CH:4][N:3]=1.[CH2:14](Br)[C:15]#[CH:16].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[CH2:16]([N:8]([C:7]1[C:6]([CH3:13])=[N:5][CH:4]=[N:3][C:2]=1[CH3:1])[C:9](=[O:12])[CH2:10][Cl:11])[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: Cc1ncnc(C)c1NC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C#CCN(C(=O)CCl)c1c(C)ncnc1C
Reaction time: 2 h

Procedure:
A mixture of 5.0 g (0.025 mol) N-(4,6-dimethylpyrimidin-5-yl)-chloroacetamide and 1.0 g tetrabutylammoniumchloride in 150 ml CH2Cl2 and 6.0 g propargylbromide is cooled to 8°, and 15 ml 50% aqueous NaOH are added dropwise thereto, whereby the temperature gradually rises to 20°. The reaction temperature is maintained at 18° to 20° with cooling. The mixture is stirred during 21/2 hours and then diluted with 100 ml H2O. The organic phase is separated off and dried over Na2SO4. The dried solution is evaporated to give a brown powder that is chromatographed on silica gel with the aid of diethylether (Rf=0.15), yielding the title compound in the form of white crystals m.p. 122°-123°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:12](=[CH:15]NC2C=CC=CC=2)[C:13]#[N:14])[CH:2]=1.[NH2:23][C:24]([NH2:26])=[NH:25]>>[NH2:25][C:24]1[N:26]=[C:13]([NH2:14])[C:12]([CH2:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:15][N:23]=1
Reactant: N=C(N)N
Reactant: N#CC(=CNc1ccccc1)Cc1cnc2ccccc2c1
Product: Nc1ncc(Cc2cnc3ccccc3c2)c(N)n1
Yield: 87 %

Procedure:
2-(3-Quinolylmethyl)-3-anilinoacrylonitrile (6.38 g) was treated with guanidine in the manner of Example 5B. There was isolated 4.90 g (87%) of 2,4-diamino-5-(3-quinolylmethyl)pyrimidine which was recrystallized from methyl cellosolve with the aid of decolorizing charcoal; m.p. 279°-282° C. (dec). Anal. Calcd. for C14H13N5 : C, 66.92; H, 5.21; N, 27.87. Found: C, 66.57; H, 5.36; N, 27.54.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:36]([O:35][CH2:34][C@@H:21]1[C@@H:20]([CH2:19][OH:18])[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO
Yield: 56.6 %

Procedure:
Compound 183 (2.00 g, 3.73 mmol) was dissolved in dry THF (36 ml) and tetrabutylammonium fluoride (8.8 ml, 1.0 M solution in THF, 2.4 equiv.) was added via syringe at room temperature under an atmosphere of argon. After completion of the reaction (1.5 hours), as was monitored by tlc in EtOAc (Rf 0.42), the solvent was removed in vacuo. The residue was purified by silica gel flash column chromatography in EtOAc/Hexane (4:6-9:1, v/v) to afford 184 (0.63 g, 57%) 1H NMR (CDCl3): δ8.89 (br, 1 H, NH), 7.55 (d, 1 H, J=1.1 Hz, H6), 6.13 (dd, 1 H, J=4.9, 6.6 Hz, H-1'), 4.17 & 4.09 (m, 2 H, CH2 -OAc), 4.07 (d, 1 H, J=11.7 Hz, H-5' & H-5'), 3.94-3.90 (m, 1 H, H-4'), 3.76 (d, 1H, J=11.7 Hz, H-5), 2.80-2.76 (m, 1 H, H-3'), 2.60 (br, 1 H, OH), 2.29-2.25 (m, 2 H, H2' & H-2"), 2.09 (s, 3 H, COCH3), 1.91 (s, 9 H, C(CH3)3); 13C NMR (CDCl3): 170.8 (C=O), 163.8 (C4), 150.3 (C2), 136.3 (C6), 110.8 (C5), 85.4 (C1'), 83.5 (C4'), 64.2 (C5'), 36.8 (C3'), 35 35.6 (C2'), 20.8, 12.5;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[I:23][CH2:24]I>O.CCOCC.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:24][I:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: ICI
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: O=S(=O)(CI)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 4-bromo-benzenesulfonyl chloride (5.12 g, 20 mmol), sodium sulfite (4.69 g, 37.3 mmol) and sodium bicarbonate (3.07 g, 36.6 mmol) in water (20 mL) is heated at 100° C. for 1 h. The crude sodium sulfinate solution is allowed to cool for 30 min and then treated with diiodomethane (25 mL) and tetra-N-butyl ammonium bromide (0.65 g, 2.0 mmol). The resulting mixture is heated at 75° C. overnight. The organic layer was separated. The aqueous solution was extracted with CH2Cl2 (×2). The combined organics were washed with water and brine, and dried over anhydrous MgSO4. The filtration through Celite-silica gel pad and concentration in vacuo gave light yellow liquid residue. Et2O/hexane (1:1) was added to the residue and the mixture was stirred to make homogenous and sit at 0 C for 20 min. The product was crushed out of the solution, filtered and washed with Et2O/hexanes. 1H NMR (300 MHz, CDCl3) 7.83 (d, 2H), 7.75 (d, 2H), 4.48 (s, 2H).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>CC#N.O>[C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)c1cccc(N(c2ccccc2)C2CCNCC2)c1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(N(c2ccccc2)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To solution of N-phenyl-N-(3-(trifluoromethyl)phenyl)piperidin-4-amine (1.3 g, 4.1 mmol) in MeCN (15 mL) was added ethyl bromoacetate (0.50 ml, 4.5 mmol) followed by triethylamine (1.1 ml, 8.1 mmol). The reaction mixture was stirred at RT for 4 h, diluted with water and extracted with DCM. The combined DCM layer was dried (Na2SO4), and concentrated. The product was purified with ISCO using 0-15% EtOAc in DCM to give ethyl 2-(4-(phenyl(3-(trifluoromethyl)phenyl)amino)piperidin-1-yl)acetate (1.2 g, 73% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Br)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 558.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Reactant: OC[C@@H]1CCCN1
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one and (S)-1-pyrrolidin-2-yl-methanol in direct analogy to the general procedure used in example 129. MS: 477.3 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C[O-].[Na+].O.O.C([O-])(=O)C.[Zn+2:19].C([O-])(=O)C>CO>[Zn:19].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: C[O-]
Solvent: CO
Solvent: O
Product: [Zn]

Procedure:
L-isoleucine (2.00 g, 15.3 mmol) was added to an MeOH solution of NaOMe (prepared with Na: 0.35 g, MeOH: 50 ml) at 0° C. and stirred. An MeOH solution (30 ml) of zinc acetate dihydrate (1.67 g) was then slowly dropwise added thereto at room temperature. After stirring for hours at the same temperature, the solution was concentrated to half its original volume, followed by the addition of an equal volume of water. The precipitated crystal was recovered by filtration, air dried, and then dried under a reduced pressure (5 mmHg, 80° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:15]=[CH:16][C:17]=1[NH2:18]
Reactant: [H][H]
Reactant: COc1cc(OCCN2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCCCC2)ccc1N
Yield: 81.4 %

Procedure:
A mixture of 1-[2-(3-methoxy-4-nitro-phenoxy)-ethyl]-piperidine (1.5 g, 5.4 mmol) and 5% Pd—C (0.5 g) in ethyl acetate (70 mL) was shaken under 50 psi of hydrogen for 18 hours. The mixture was filtered through Celite and evaporated, providing 1.1 g of the product, in 81% yield: 1H NMR (DMSO-d6) δ 1.45-1.53 (m, 6H), 2.35-2.41 (m, 4H), 2.59 (t, J=6.0 Hz, 2H), 3.74 (s, 3H), 3.93 (t, J=6.0 Hz, 2H), 6.28 (dd, J=8.3 Hz, J=2.6 Hz, 1H), 6.45 (d, J=2.6 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:11]=[C:12]2[N:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[N:16]([CH3:29])[C:13]2=[N:14][CH:15]=1)=[O:9].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].C(OCC)(=O)C.C(O)C.N>CO>[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:11]=[C:12]2[N:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27](=[NH:41])[NH2:28])=[CH:25][CH:26]=3)[N:16]([CH3:29])[C:13]2=[N:14][CH:15]=1)=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 75 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide, methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 75% of theory, C26H27N7O3 (485.55) Rf value: 0.31 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) EKA mass spectrum: (M+H)+ =486
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.O[CH2:81][CH2:82][N:83]1[CH2:87][CH2:86][CH2:85][C:84]1=[O:88]>CN(C=O)C.C(O)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:81][CH2:82][N:83]5[CH2:87][CH2:86][CH2:85][C:84]5=[O:88])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: O=C1CCCN1CCO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCCN4CCCC4=O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 45 mg (0.14 mmol) TBTU and 32 μL (0.23 mmol) triethylamine in 1.2 mL DMF was stirred for 1 h at RT. Then 26 mg (0.23 mmol) 1-(2-hydroxy-ethyl)-pyrrolidin-2-one were added and the reaction mixture was stirred overnight at RT. The reaction solution was mixed with 5 drops of formic acid, filtered through a syringe filter and purified directly by HPLC without any further working up. The fractions containing the product were combined, extracted with 30 mL EtOAc, the organic phase was made alkaline with 5% NaHCO3 solution, separated off and dried on Na2SO4. After the elimination of the desiccant and solvent the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:19][O:20][CH2:21][CH2:22][NH:23][CH3:24]>CN(C=O)C.O>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:24])[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CNCCOC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCCN(C)c1cc(N)c([N+](=O)[O-])cn1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-5-nitropyridin-4-amine (500 mg, 2.88 mmol, 1.00 equiv), triethylamine (1.167 g, 11.53 mmol, 4.00 equiv), and (2-methoxyethyl)(methyl)amine (514 mg, 5.77 mmol, 2.00 equiv) in DMF (20 mL) was stiffed in a sealed tube at 55° C. behind a blast shield overnight. After cooling to room temperature, the mixture was diluted with 100 mL of water and extracted with 3×150 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 723 mg (crude) of the title compound as a dark red oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[N:9]O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.O=S(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: ON=Cc1c(Cl)ncnc1Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: N#Cc1c(Cl)ncnc1Cl

Procedure:
4,6-Dichloropyrimidine-5-carbaldehyde oxime (8g) was dissolved in CHCl3 (40 mL) and treated with SOCl2 (6 mL) for 2 h at rt. The solvent was removed and redissolved in DCM (5 mL). The solid was filtered and washed with DCM (5 mL). The filtrate was concd and purified by column chromatography on silica gel (dry loading, DCM/hexane, 3/1) to give 4,6-dichloropyrimidine-5-carbonitrile as a white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:10]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([F:19])=[C:7]([NH:20]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1)C.OS(O)(=O)=O.CC#N>O>[NH2:20][C:7]1[C:8]([F:19])=[C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:10]=[C:5]([CH:4]=[O:3])[CH:6]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(Cc2ccc(F)cc2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: Nc1cc(C=O)nc(Cc2ccc(F)cc2)c1F
Yield: 84.6 %

Procedure:
Using the procedure for Example 12, 6-(diethoxymethyl)-3-fluoro-2-(4-fluorobenzyl)-N-tritylpyridin-4-amine (2.82 g, 5 mmol), conc H2SO4 (1 mL), CH3CN (35 mL) and H2O (35 mL) gave 4-amino-5-fluoro-6-(4-fluorobenzyl)picolinaldehyde (1.05 g, 83%) as a white solid: mp 130-131° C.; 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.29 (m, 2H), 7.25 (d, J=6.7 Hz, 1H), 6.97 (m, 2H), 4.45 (s, 2H), 4.14 (d, J=3.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 192.85, 161.67 (d, J=244.6 Hz), 148.87 (d, J=5.4 Hz), 148.70 (d, J=254.7 Hz), 148.03 (d, J=13.7 Hz), 141.77 (d, J=12.3 Hz), 133.71 (d, J=2.7 Hz), 130.32 (d, J=8.1 Hz), 115.30 (d, J=21.3 Hz), 108.09 (d, J=3.9 Hz), 37.09; 19F NMR (376 MHz, CDCl3) δ−116.54 (m), −143.54 (dt, J=6.1, 2.7 Hz); HRMS-ESI (m/z) [M+H]+ calcd for C13H10F2N2O, 248.0761. found, 248.0763.