Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[H-].[Na+].[C:33](Cl)(=[O:43])[O:34][CH:35]([Cl:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC1CCCO1.C(OCC)(=O)C>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[C:24]3[C:23]([CH2:30][CH2:29][C:27](=[O:28])[N:26]3[C:33]([O:34][CH:35]([Cl:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:43])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: O=C(Cl)OC(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of aripiprazole (1 g, 2.23 mmol) in 2-methyltetrahydrofuran (20 mL) was added NaH (178 mg, 4.46 mmol). The reaction was heated to reflux for 1.5 hours then cooled to room temperature. Chloro(phenyl)methyl carbonochloridate (1.37 g, 6.69 mmol) was then added and the reaction stirred overnight at room temperature. The reaction was cooled to 0° C., diluted with ethyl acetate (20 mL) and quenched with aqueous saturated NaHCO3 (20 mL) solution. The reaction was extracted with ethyl acetate (3×20 mL) and the combined organics washed with brine (50 mL), then dried (MgSO4) and concentrated to give chloro(phenyl)methyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (crude yield 2.10 g) as a 1:3 mixture of product/aripiprazole. The product was taken onto the next step crude.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.C(O)(=O)C[C:29](CC(O)=O)([C:31](O)=[O:32])[OH:30]>C(O)CO.O>[OH:30][CH2:29][CH2:31][O:32][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)CCc2ccccc2)cc1
Solvent: O
Solvent: OCCO
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCO)cc1
Temperature: 120 °C
Reaction time: 27 h

Procedure:
2-Phenyl-ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (850 mg) was added to a solution of K-tert. butylate (1.1 g) in ethylene glycol (15 ml). The mixture was stirred at 120° C. for 27 h before it was diluted with water (100 ml), acidified with 10% aq. citric acid (13 ml). The resulting precipitate was collected, washed with water and diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (716 mg) as a beige powder. LC-MS: tR=4.44 min, [M+1]+=414.18, [M−1]−=412.13.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][NH:18][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)CCN
Solvent: CN(C)C=O
Product: CC(C)CCNc1ccc(C#N)cc1[N+](=O)[O-]
Yield: 90 %

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (18.3 g, 0.10 mol) and isoamylamine (19.2 g, 0.22 mol) in DMF (250 mL) was heated to 90° C. for 4 h under nitrogen then cooled and the solvent evaporated. The residue is triturated with EtOAc (300 mL) and solids removed by filtration. The filtrate was washed with water and brine. The organic layer was dried over MgSO4 and evaporated. The residue was recrystallized from MeOH to give 21.0 g (90%) of 4-(3-methyl-butylamino)-3-nitro-benzonitrile as a yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2SC.C([NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH3:20])C.CSC1N2C=NC=[C:27]2[CH:26]=NN=1.CNCCNC>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[NH:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:26][CH3:27]
Reactant: CCNCCNCC
Reactant: CSc1nncc2c(C)ncn12
Reactant: CSc1nncc2cncn12
Agent: CNCCNC
Product: CCN(CC)CCNc1nncc2c(C)ncn12

Procedure:
The procedure of Example 41 is repeated substituting equimolecular amounts of 8-methyl-4-(methylthio)-imidazo[1,5-d]-as-triazine and unsymmetrical diethylethylenediamine for the 4-(methylthio)-imidazo[1,5-d]-as-triazine and unsymmetrical dimethylethylenediamine employed in that example.
Reaction SMILES: [C:1](=O)([OH:3])[O-:2].[Na+:5].[C:6]([OH:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([OH:16])=[O:15])([C:10]([OH:12])=[O:11])[OH:9]>O>[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Na+:5].[Na+:5].[Na+:5].[C:1](=[O:3])=[O:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: O=C=O

Procedure:
The material selected for powder particles 16 should be inert with respect to the cellulosic material and reactive with respect to the moisture (e.g., water) to be absorbed. Preferably, the material selected for powder particles 16 should also generate water as a product of its chemical reaction with water. For example, if powder particles 16 comprise a mixture of sodium bicarbonate (NaHCO3) and citric acid (H3C6H5O7), a reaction of this mixture with water yields sodium citrate (Na3C6H5O7), carbon dioxide (CO2) and water (H2O). Another preferred example for powder particles 16 is a mixture of sodium bicarbonate (NaHCO3) and potassium hydrogen tartrate (KHC4H4O6). A reaction of this mixture with water yields potassium sodium tartrate (KNaC4H4O6), carbon dioxide and water. Note that any amount of water is sufficient to start the reaction. Once started, no additional water is needed as the reaction self-produces water.
Reaction SMILES: C([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.[ClH:16].[NH2:17][N:18]1[C:24](=[O:25])[CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[C:20]2[CH:36]=[CH:37][CH:38]=[CH:39][C:19]1=2>>[ClH:16].[NH2:8][C@H:9]([C:13]([NH:17][N:18]1[C:24](=[O:25])[CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[C:20]2[CH:36]=[CH:37][CH:38]=[CH:39][C:19]1=2)=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCC1C(=O)N(N)c2ccccc2-c2ccccc21
Agent: Cl
Product: CCCCCCC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 11), the title compound was prepared.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1F.[CH:21]12[CH2:26][CH:25]1[CH2:24][NH:23][CH2:22]2.Cl>CN(C=O)C.C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1[N:23]1[CH2:24][CH:25]2[CH:21]([CH2:26]2)[CH2:22]1
Reactant: C1NCC2CC12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CC3CC3C2)c(F)c1
Temperature: 45 °C

Procedure:
Diisopropylethylamine (0.56 mL, 3.2 mmol) and 3,4-difluoronitrobenzene (0.184 g, 1.16 mmol) were added to a solution 3-aza-bicyclo[3.1.0]hexane (0.152 g of HCl salt, 1.28 mmol; prepared as described in U.S. Pat. No. 4,183,857) in DMF (3.2 mL). The mixture was heated for three days at 45° C. and then cooled to room temperature. The solution was diluted with ethyl acetate and washed with 0.5 M HCl, saturated NaHCO3, brine, and dried (MgSO4). The mixture was filtered and concentrated to give 3-(2-fluoro-4-nitro-phenyl)-3-aza-bicyclo[3.1.0]hexane as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Solvent: CCO
Product: Cc1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 66 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.130 g, 0.38 mmol) in ethanol (10 mL) was added 4-chloro-2-picoline (0.1 mL). The reaction mixture was heated in a sealed tube for 24 hours. The reaction mixture was concentrated and the residue was purified by RPHPLC. The pure product containing fractions were combined and lyophilized to give 155 mg (66%) of a tan powder.
Reaction SMILES: [C:1]([CH2:9][N+:10]([O-:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:14](=[N:20]O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15]([C:14]1[C:9]([N+:10]([O-:12])=[O:11])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][N:20]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Product: CCOC(=O)c1noc(-c2ccccc2)c1[N+](=O)[O-]

Procedure:
4-Nitro-5-phenyl-isoxazole-3-carboxylic acid ethyl ester is prepared from benzoylnitromethane and ethyl chlorooximinoacetate, using the condition described in Dal Piaz, V.; Pinzauti, S.; Lacrimini, P. Synthesis 1975, 664; 1H NMR (CDCl3, 400 MHz) δ 7.93 (d, 2H), 7.65 (t, 1H), 7.58 (t, 2H), 4.53 (q, 2H), 1.44 (t, 3H); HPLC-MS calculated for C12H10N2O5 (M+H+) 263.1. Found 263.1.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].Br[CH2:20][CH2:21]Br>CCOCC>[C:1]1([CH:16]([C:15]2[C:14]3[CH2:21][C:20]4[C:3](=[CH:2][CH:1]=[CH:13][CH:12]=4)[C:4]=3[CH:5]=[CH:6][CH:7]=2)[CH3:17])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:17][CH2:16][C:15]2[C:14]3[CH2:21][C:20]4[C:3](=[CH:2][CH:1]=[CH:13][CH:12]=4)[C:4]=3[CH:5]=[CH:6][CH:7]=2)[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: BrCCBr
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CC(c1cccc2c1Cc1ccccc1-2)c1cccc2c1Cc1ccccc1-2
Product: c1ccc2c(c1)Cc1c(CCc3cccc4c3Cc3ccccc3-4)cccc1-2
Reaction time: 1 h

Procedure:
The ligand bis(fluorenyl)ethane was prepared as follows. To 0.2 mole fluorene in 200 mL ether was added 0.2 mole butyllithium (1.6M in hexane) at a rate of 0.15 mL/min. at room temperature. The reaction mixture was stirred for one hour, and 0.1 mole 1,2 dibromoethane was added slowly and stirred for 3 hours. The volume was reduced to 150 mL, filtered and the pale yellow solid was washed 2 times with 50 mL distilled water. The pale yellow solid was dried and washed with 100 mL of pentane to yield white 1,2-bis(fluorenyl)ethane. The yield was 80%.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:4]=2[N:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>ClCCl>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:4]=2[N:3]=1
Reactant: CCOc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cnccc1-3
Reactant: CN(C)CCN
Solvent: ClCCl
Product: CCOc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1cnccc1-3
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-3-ethoxy-5,9-diaza-benzo[c]fluoren-7-one (Example 34b) (14 mg) was suspended in N,N-dimethylethylenediamine (0.3 ml) and the mixture was stirred at 70° C. for 30 min. The reaction mixture was diluted with dichloromethane and washed with saturated ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography developed by dichloromethane-methanol-ammonia water (28%)=15:1:0.1. The desired product was obtained as a reddish powder (16 mg). ESI−MS: m/z 363 (MH+); 1H-NMR (CDCl3): δ1.50 (3H, t, J=7 Hz), 2.36 (6H, s), 2.65 (2H, t, J=6.5 Hz), 3.78 (2H, quartet like, J=ca 6 Hz), 4.20 (2H, q, J=7 Hz), 6.97 (1H, dd, J=9 Hz, 2.5 Hz), 7.06 (1H, d, J=2.5 Hz), 7.34 (1H, brt, J=ca 5 Hz), 7.87 (1H, dd, J=5 Hz, 1 Hz), 8.04 (1H, d, J=9 Hz), 8.83 (1H, d, J=5 Hz), 8.86 (1H, d, J=1 Hz).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[OH:28][CH2:29][CH2:30][NH:31][NH2:32]>CO.ClCCl>[OH:28][CH2:29][CH2:30][NH:31][N:32]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:6][CH2:7]1
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reactant: NNCCO
Solvent: CO
Solvent: ClCCl
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC(=NNCCO)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5 ml), 2-hydroxyethylhydrazine (29 mg, 0.37 mmol) added, and the mixture stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue purified by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 1.5% MeOH in dichloromethane. Relevant fractions were combined to give the desired product (98 mg). MS (ESP): 434 (MH+) for C20H24FN5O5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13]I)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1>C1COCC1.[Zn]>[Cl:15][C:16]1[N:17]=[C:18]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=[C:20]([CH2:13][CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1ccc(CCCI)cc1OC
Agent: [Zn]
Solvent: C1CCOC1
Product: COc1ccc(CCCc2nc(Cl)nc(N3CCOCC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-propyl iodide (1.224 g, 4.00 mmol, 1.00 equiv.) in 20 mL dry THF was added highly active zinc (suspension in THF, Rieke metal from Aldrich, 5.2 mL 0.05 g/mL, 4.00 mmol, 1.00 equiv.). The mixture was stirred at room temperature overnight. 2,4-dichloro-6-morpholin-4-yl-1,3,5-triazine (0.936 g, 4.0 mmol, 1.00 equiv.) and trans-benzyl-(chloro)-bis-(triphenylphosphine)palladium(II) (0.03 g, 0.04 mmol, 0.01 equiv.) were added, and the reaction mixture was stirred at room temperature for 8 hours. Usual workup and flash chromatography purification gave 4-chloro-2-[3-(3,4-dimethoxyphenyl)propyl]-6-morpholin-4-yl-1,3,5-triazine as a light yellow solid which was treated with hydrazine following the typical procedure to yield {4-[3-(3,4-Dimethoxy-phenyl)-propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-hydrazine as a white solid (0.85 g, 2.27 mmol, 57%). MS (ESI): m/z 375.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:18]=3)[O:14][N:13]=2)=[CH:7][C:6]=1[CH2:29][CH3:30].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.CC(=O)OCC>[CH2:27]([N:24]([CH2:25][CH3:26])[C:19]1[CH:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:8]3[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][NH:1][S:41]([CH3:40])(=[O:43])=[O:42])=[C:6]([CH2:29][CH3:30])[CH:7]=3)[N:16]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1)[CH3:28]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of crude (4-{3-[4-(2-amino-ethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-6-methyl-pyridin-2-yl)-diethyl-amine (70 mg, 0.17 mmol) and DIPEA (44 mg, 0.342 mmol) in DCM (2 mL), methane sulfonyl chloride (23 mg, 0.205 mmol) is added. The mixture is stirred at rt for 30 min before it is diluted with EA and washed with sat. aq. NaHCO3-solution. The washing is extracted back three times with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give the title compound (34 mg) as a pale yellow oil; LC-MS*: tR=1.12 min; [M+1]+=488.05; 1H NMR (CDCl3): δ 1.25 (t, J=6.8 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.50 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.09 (s, 3H), 3.57-3.67 (m, 6H), 3.99 (t, J=4.8 Hz, 2H), 4.91 (t, J=5.5 Hz, 1H), 7.01 (s, 1H), 7.10 (s, 1H), 7.88 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:19])=[N:4][C:5]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:7]=1.[CH3:20][O-:21].[Na+]>CO>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:5]1[N:4]=[C:3]([NH2:19])[C:2]([O:21][CH3:20])=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)nc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Temperature: 70 °C
Yield: 46 %

Procedure:
3-Bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 62, 160 mg, 0.5 mmol) was suspended in methanol (5 mL), sodium methoxide was added (0.12 mL, solution 30% in methanol, 0.5 mmol) and the solution was heated to 70° C. for 2 hours. The mixture was cooled, the solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane. The organic layer was dried and concentrated. The residue was triturated with diethyl ether to provide the target compound as a brownish solid (62 mg, 46%)
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[CH:15][C:3]=12.[N+:16]([O-])([OH:18])=[O:17]>>[F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:3]=12
Reactant: COCCOc1cnc2[nH]ccc2c1F
Reactant: O=[N+]([O-])O
Product: COCCOc1cnc2[nH]cc([N+](=O)[O-])c2c1F
Reaction time: 0.25 h
Yield: 67 %

Procedure:
4-Fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridine (440 mg, 2.09 mmol) was added to HNO3 fuming (4 mL) at 0-5° C., and the reaction was stirred for 15 minutes. Ice was added, and the resulting solid was filtered and dried to yield 4-fluoro-5-(2-methoxyethoxy)-3-nitro-1H-pyrrolo[2,3-b]pyridine (360 mg, 67% yield) as a solid.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][N:4]=1.C(OCC=[N+]=[N-])(=O)C.C([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#C>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][N:4]=1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Reactant: C#Cc1ccccn1
Agent: CC(=O)OCC=[N+]=[N-]
Product: CCOC(=O)c1cc(-c2ccccn2)n[nH]1

Procedure:
Was prepared in a similar way as ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate using diazoethyl acetate (Purchased from Aldrich) and 2-ethynyl-pyridine (Purchased from Aldrich).
Reaction SMILES: C=O.N1CCNC[CH2:4]1.C(O)(=O)C.[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[O:30])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[CH2:4])[CH:29]=[O:30])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CCCCCCNC(=O)OCc1ccccc1
Reactant: C1CNCCN1
Agent: C=O
Solvent: O
Solvent: CC(=O)O
Product: C=C(C=O)CCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2.44 g (30 mmol) of 37% aqueous formaldehyde solution are added to a solution of 1.5 g (17 mmol) of anhydrous piperazine and 2.03 g (34 mmol) of acetic acid in 18.7 ml of water. The mixture is stirred at 25° for 15 minutes, and then 7.48 g (30 mmol) of 6-(N-benzyloxycarbonylamino)hexanal are added thereto. The reaction mixture is heated under reflux for 2 hours and then cooled with ice-water and extracted twice with 50 ml of methylene chloride each time. The extracts are combined, washed twice with 25 ml of saturated sodium hydrogen carbonate solution each time and with 25 ml of saturated sodium chloride solution, dried and concentrated to dryness by evaporation. 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal is obtained in the form of a yellowish liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:16])[N:14]2[CH:10]([S:11][CH2:12][CH:13]2[C:17](=O)[NH2:18])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15](=[O:16])[N:14]2[CH:10]([S:11][CH2:12][CH:13]2[C:17]#[N:18])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CC2SCC(C(N)=O)N2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)NC1(c2ccccc2)CC2SCC(C#N)N2C1=O
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of compound 17 (380 mg, 1.0 mmol) in CH2Cl2 (50 mL) was added TFAA (252 uL, 1.2 mmol) dropwise at room temperature, followed by the addition of Et3N (404 mg, 4 mmol). After stirring for 1 h, the mixture was washed with brine, dried over Na2SO4. After concentration, the residue was purified by column chromatography on silica gel (PE: EA=15:1) to give compound 18 (300 mg, 83.6%). 1 H NMR (400 MHz, CDCl3) δ 1.40 (s, 9 H), 3.26-3.27 (m, 1 H), 3.30-3.31 (m, 1 H), 3.31-3.34 (m, 1 H), 3.43-3.47 (m, 1 H), 5.06 (bs, 1 H), 5.22 (bs, 1H), 5.50 (bs, 1H), 7.37-7.49 (m, 5H). MS (M+1): 360.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=2)[N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])[N:25]=1)=[O:15]
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)nc1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
4-(6-bromo-pyridin-3-yl)-2-oxo-3-butenoic acid methyl ester (615.0 mg, 2.3 mmol) prepared in Step 1 and 2-chlorophenylhydrazine hydrochloride (450.0 mg, 2.5 mmol) were added to acetic acid (10.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 650.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][CH2:10][C:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][OH:13])(=[O:8])=[O:7])C.Cl[C:19]1[C:20]([CH3:28])=[CH:21][C:22]2[N:23]([N:25]=[CH:26][N:27]=2)[N:24]=1>>[CH2:16]([C:11]([CH2:14][CH3:15])([CH2:10][CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:12][O:13][C:19]1[C:20]([CH3:28])=[CH:21][C:22]2[N:23]([N:25]=[CH:26][N:27]=2)[N:24]=1)[CH3:17]
Reactant: CCC(CC)(CO)CCS(=O)(=O)N=CN(C)C
Reactant: Cc1cc2ncnn2nc1Cl
Product: CCC(CC)(CCS(N)(=O)=O)COc1nn2ncnc2cc1C

Procedure:
Using 4-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-butanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 148°-149° C.