Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18]Br)=[CH:13][C:12]=1[F:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:13][C:12]=1[F:20]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Fc1cc(CBr)c(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Fc1cc(COc2ccc(Cl)c(Cl)c2)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 110.3 %

Procedure:
A mixture of 3,4 dichlorophenol (730 mg, 4.48 mmol), 1-bromo-4-(bromomethyl)-5-chloro-2-fluorobenzene (Preparation 2, 1.35 g, 4.48 mmol), and potassium carbonate (1.87 g, 13.5 mmol) in acetone (56 mL) was stirred for 72 hours at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through Arbocel™. The Arbocel™ was washed with ethyl acetate (2×50 mL) and the combined organic extracts were concentrated in vacuo to afford a pale yellow solid. The solid was then dissolved in ethyl acetate (150 mL) and washed successively with aqueous sodium hydroxide solution (0.5 M, 100 mL), brine (3×100 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford an off white solid (1.90 g). Recrystallisation from hot heptane afforded the title compound (920 mg, 53%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:27][Mg]I>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]([OH:24])[CH3:27])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)O)cc(OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.7 %

Procedure:
A solution of 150 mg (0.426 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde in 2 ml THF is treated with excess methylmagnesiumiodide (prepared from 207 mg methyliodide and 35 mg magnesium in 5 ml diethyl ether). The resulting mixture is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo to afford 180 mg of the title compound as an oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][CH:13]=[C:9]3[N:8]=[C:7]([S:14][CH3:15])[N:6]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN([CH:27]=[O:28])C>>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:27]=[O:28])=[C:9]3[N:8]=[C:7]([S:14][CH3:15])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CSc1nc(NC2CC2)n2nccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1nc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
N-Cyclopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 eq, 3.10 g, 14.00 mmol) was dissolved in anhydrous DMF (50 ml) under nitrogen atmosphere. Phosphorus oxychloride (5.0 eq, 6.4 ml, 69.9 mmol) was added dropwise over 5 minutes. Internal temperature rose to 45° C. The reaction was stirred in an oil bath at 70° C. for 4.5 hours. The mixture was cooled down and added dropwise into a solution of 6N NaOH (150 ml) chilled with an ice bath. The rate of addition was adjusted to maintain the internal temperature of the aqueous NaOH below 16° C. At the end of the addition, the mixture was neutralized by slow addition of 6N HCl to reach pH=5-6. The resulting solid was filtered, washed with water and dried in a vacuum oven overnight. 4-(cyclopropylamino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde was isolated as tan solid (9.26 g, 93%). LCMS (ES):>95% pure, m/z 250 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O:21][CH2:22][CH3:23])(=[O:20])/[CH:13]=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CCOC(=O)/C=C\C(=O)OCC
Product: CCOC(=O)CC(NCCC[Si](OC)(OC)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl N-(3-trimethoxysilylpropyl)aminosuccinate was prepared as follows: 51.0 g of 3-aminopropyltrimethoxysilane (Silquest®A-1110, Momentive Performance Materials Inc., USA) were introduced as an initial charge. With thorough stirring, 49.0 g of diethyl maleate (Fluka Chemie GmbH, Switzerland) were added slowly at room temperature and the mixture was stirred at room temperature for 2 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[Cu](C#N)[C:11]#[N:12].[NH4+].[Cl-]>N1C=CC=CC=1.N>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([C:11]#[N:12])[CH:7]=[N:6][CH:5]=1
Reactant: OCc1cncc(Br)c1
Reactant: N#C[Cu]C#N
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: N#Cc1cncc(CO)c1
Temperature: 160 °C
Yield: 71.1 %

Procedure:
A mixture of 4.2 g (22.34 mmol) of (5-bromopyridin-3-yl)methanol and 5 g (55.84 mmol) of copper cyanide in 22 mL of pyridine is heated for 20 hours in a sealed tube at 160° C. After cooling to room temperature, the medium is taken up in 10 mL of concentrated aqueous ammonia and 30 mL of saturated NH4Cl solution and then stirred for 2 hours. The medium is then extracted with 200 mL of a DCM/iPrOH mixture (85/15), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 2.13 g of 5-(hydroxymethyl)pyridine-3-carbonitrile are obtained in the form of a white solid.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[N:19][C:20]=1[CH:21](OC)[O:22]C)[N:17]([C:26]([NH:28][C:29]1[CH:34]=[C:33]([NH:35][CH2:36][C:37]([OH:43])([CH3:42])[CH2:38][N:39]([CH3:41])[CH3:40])[C:32]([C:44]#[N:45])=[CH:31][N:30]=1)=[O:27])[CH2:16][CH2:15][CH2:14]2)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:44]([C:32]1[C:33]([NH:35][CH2:36][C:37]([OH:43])([CH3:42])[CH2:38][N:39]([CH3:40])[CH3:41])=[CH:34][C:29]([NH:28][C:26]([N:17]2[C:18]3[C:13](=[CH:12][C:11]([CH2:10][OH:9])=[C:20]([CH:21]=[O:22])[N:19]=3)[CH2:14][CH2:15][CH2:16]2)=[O:27])=[N:30][CH:31]=1)#[N:45]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(NCC(C)(O)CN(C)C)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC(C)(O)CNc1cc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)ncc1C#N

Procedure:
Concentrated hydrochloric acid (0.17 ml) was added to a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((3-(dimethylamino)-2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 78D, 33 mg, 0.053 mmol) in THF (1 ml) and water (0.5 ml) at room temperature. After stirring for 18 h at room temperature saturated aqueous NaHCO3 was then added, the mixture extracted with DCM (2×), the organic layers dried over Na2SO4 and evaporated. The residue was triturated with Et2O to give the title compound.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][CH2:19][C:20]2[C:25]([N+:26]([O-])=O)=[CH:24][N:23]=[C:22]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[CH2:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:25]1[C:20]([CH2:19][NH:18][CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:10])=[CH:21][C:22]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:23][CH:24]=1
Reactant: [H][H]
Reactant: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1N)C1CCCCC1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
In a Parr bottle 10% Pd/C (0.42 g) was added and cooled to −78° C., then a solution of 3-cyclohexyl-N-(3,3-dimethyl-butyl)-3-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-propionamide (0.42 g, 0.87 mmol) in ethyl acetate (5 mL) and ethanol (20 mL) was added. The resulting mixture was subjected to hydrogen atmosphere and shaken for 3.5 h. The hydrogen was purged with nitrogen, then the reaction mixture was filtered (glass fiber filter paper) and the solvent was evaporated under reduced pressure to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]4OCC[O:27]4)[CH:21]=3)=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[CH:26]=[O:27])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)c1cccc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1cccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)c1
Yield: 95.2 %

Procedure:
To a stirred solution of the product of Example 150 (73 mg, 0.13 mmol) in acetone (4 mL) and water (1 mL) was added pyridinium p-toluenesulfonate (33 mg, 0.13 mmol) and the mixture refluxed for 3.5 h. The acetone was evaporated and the residue diluted with water (10 mL) and extracted into ethyl acetate (2×10 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (10 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave the desired product (64 mg). MS (ES+) 539 ([MNa]+).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3[N+](=O)[O-])CC2)cc1

Procedure:
Ethyl 4-(piperazin-1-yl)benzoate (1.5 g), 1-(bromomethyl)-2-nitrobenzene (1.383 g) and sodium carbonate (2.036 g) were suspended in anhydrous N,N-dimethylformamide (20 mL) at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and concentrated. The residue was purified by flash column purification with 10-40% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[CH3:11].[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[Cl:10][C:4]1[C:5]([Cl:9])=[CH:6][C:7]2[C:2](=[N:1][C:12](=[O:16])[C:13](=[O:14])[N:8]=2)[C:3]=1[CH3:11]
Reactant: O=C(O)C(=O)O
Reactant: Cc1c(N)c(N)cc(Cl)c1Cl
Agent: Cl
Product: Cc1c(Cl)c(Cl)cc2c1=NC(=O)C(=O)N=2
Yield: 66.3 %

Procedure:
A mixture of 2,3-diamino-5,6-dichlorotoluene (from step (c), 21.6 g, 0.137 mol) and oxalic acid (18.45 g, 0.206 mol) in hydrochloric acid (4M, 900 ml) was heated at reflux for 6 hours, cooled and filtered. The dark brown solid was suspended in diethyl ether, filtered and washed with more ether to give 6,7-dichloro-5-methyl-quinoxalin-2,3-dione (22.06 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[CH2:14][C@H:13]([CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:12][C:11](=[O:26])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].[C:51]([CH2:55]OS(C(F)(F)F)(=O)=O)([F:54])([F:53])[F:52]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:16]([CH2:55][C:51]([F:54])([F:53])[F:52])[C:15]3[CH2:14][CH:13]([CH2:17][O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:12][C:11](=[O:26])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Nc1nccc(-c2cc3c([nH]2)C[C@H](COCc2ccccc2)NC3=O)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc(-c2cc3c(n2CC(F)(F)F)CC(COCc2ccccc2)NC3=O)n1
Temperature: 50 °C
Yield: 70.6 %

Procedure:
To a stirred mixture of (R)-2-(2-amino-pyrimidin-4-yl)-6-benzyloxymethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (73 mg, 0.21 mmol) in dry DMF (2 mL) were added 18-crown-6 ether (110.5 mg, 0.42 mmol), K2CO3 (115.5 mg, 0.84 mmol) and CF3CH2OSO2CF3 (0.21 mmol). The reaction mixture was heated at 50° C. for 7 hours, then treated with water and extracted with AcOEt. The organic phase was dried over anh. Na2SO4 and evaporated to yield a crude product that was purified by flash chromatography (eluant: DCM/MeOH 95:5) to provide 64 mg of the title product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[CH3:12][C:13]([Si:16]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)([CH3:15])[CH3:14]>>[CH3:15][C:13]([Si:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]([OH:23])[CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[CH:20][CH:19]=1)([CH3:12])[CH3:14]
Reactant: Clc1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(C=O)cc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](Oc1ccc(C(O)CCCc2ccc(Cl)cc2)cc1)(c1ccccc1)c1ccccc1

Procedure:
Using the procedure of Example 1, Step 2, the Grignard reagent prepared from 1-(3-bromopropyl)-4-chlorobenzene was added to the benzaldehyde of Step 1. The title compound so obtained was used as such in the next step.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21]Cl)=[CH:19][C:18]([Cl:23])=[CH:17][N:16]=2)[C:6]1=[O:24])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C@:7]2([CH2:14][C:15]3=[N:16][CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]3[CH2:21]2)[C:6]1=[O:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CCl)c2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N1C(=O)[C@]2(Cc3cc(Cl)cnc3C2)c2cccnc21
Temperature: -3.299999952316284 °C
Reaction time: 0.25 h

Procedure:
A solution of 6 (2.39 g, 6.56 mmol) in toluene (50 mL) was cooled to −2.5° C. under nitrogen atmosphere. Compound 10 (17 mg, 0.020 mmol) was charged, and the resulting solution was aged for about 15 min while cooled to −3.3° C. A pre-cooled (−1° C.) aqueous NaOH (26.2 mL, 0.3 N) was charged in over 4 min below −0.6° C. The reaction was aged at −1.3° C. for 3 h. The reaction was quenched with water (10 ml). The organic layer was washed with water (10 mL), concentrated, flushed with IPA to give crude product 7 (2.59 g, 94.4% ee, 83% wt by NMR against 1,3,5-trimethoxybenzene as an internal standard).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].Cl.[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.N>>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[N:5]=[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[O:7][N:6]=1
Reactant: NC(=NO)c1cccc(F)c1F
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: N
Product: Fc1cccc(-c2noc(-c3cccnc3)n2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2,3-difluoro-N′-hydroxybenzimidamide (Tyger Scientific) and nicotinoyl chloride hydrochloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.42-7.61 (m, 1H), 7.67-7.85 (m, 2H), 7.91-8.04 (m, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.92 (dd, J=4.8, 1.6 Hz, 1H), 9.36 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[F:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([OH:14])[CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[CH2:22][CH2:23]2)=[CH:8][CH:9]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: OC(CCCl)COc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: OC(CCN1CCN(c2ccccn2)CC1)COc1ccc(F)cc1

Procedure:
A mixture of 9.0 g (0.0413 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 6.8 g (0.0414 mole) of 1-(2-pyridinyl)piperazine, 14.5 g (0.1374 mole) of anhydrous sodium carbonate and 0.24 g of potassium iodide in 200 ml of 1-butanol was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between 200 ml of water and 200 ml of benzene. The benzene layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give a thick yellow oil. Upon trituration with petroleum ether (30°-60° C.), the oil solidified. The collected solid was recrystallized from ligroin to yield 8.2 g (57%) of white, crystalline solid, m.p. 72°-73° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[NH:54][C:55]([C@@H:57]([NH2:64])[CH2:58][N:59]3[N:63]=[N:62][CH:61]=[N:60]3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[NH:54][C:55]([C@@H:57]([NH:64][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][N:59]3[N:63]=[N:62][CH:61]=[N:60]3)=[N:56][C:52]=2[CH:51]=1
Reactant: N[C@@H](Cn1ncnn1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](Cn2ncnn2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 22 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-tetrazol-2-yl-ethylamine in tetrahydrofuran. Yield: 22%; Rf value: 0.64 (silica gel; dichloromethane/ethanol=9:1); C23H23ClN8O2 (478.94); mass spectrum: (M+H)+=479/481 (chlorine isotope).
Reaction SMILES: [CH2:1]([N:3]([CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][CH3:5])[CH3:2].C([OH:19])C>>[CH2:1]([N+:3]([O-:19])([CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][CH3:5])[CH3:2]
Reactant: CCCCC/C=C\C/C=C\CN(CC)CC
Reactant: CCO
Product: CCCCC/C=C\C/C=C\C[N+]([O-])(CC)CC
Reaction time: 1 h
Yield: 95 %

Procedure:
4 G (18 mmole) of N,N-diethyl-undeca-2Z,5Z-dienyl-amine in 10 ml of ethanol were placed in a 25 ml flask under nitrogen and 4 ml of 70% oxygenated water were added thereto. The reaction mixture was maintained under stirring for 1 h and then left to rest at room temperature for 18 h. After evaporation, it was retaken with ethyl acetate and the organic phase, once separated, was washed with a saturated solution of NaCl, dried over Na2SO4 and evaporated to provide 4.09 g of N,N-diethyl-undeca-2Z,5Z-dienyl-amine N-oxide (yield: 95%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)=[C:5]([NH2:19])[CH:4]=1)#[N:2].[CH2:20](OC=C(C#N)C#N)C>C(O)CC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[CH:13]4)[CH:20]=[N:19][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2ccc3[nH]ccc3c2)c(N)c1
Reactant: CCOC=C(C#N)C#N
Solvent: CCCO
Product: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Yield: 94 %

Procedure:
5-(4-Cyano-2-nitrophenylamino)-1H-indole (0.56 g, 2.0 mmoles) was reduced by catalytic hydrogenation, to form 5-(4-cyano-2-aminophenylamino)-1H-indole (0.50 g, 2.0 mmole). The 5-(4-cyano-2-aminophenylamino)-1H-indole was cyclized using ethoxymethylenemalononitrile (0.49 g, 2.0 mmoles) in propanol, and the cyclization reaction was heated for 24 hours. Column chromatography using ethyl acetate/hexanes [1:1] afforded the title compound (94%) as a yellow solid. Mp, 263.0°-264.0° C.; 13C NMR (DMSO-d6) δ147.2, 143.5, 137.5, 135.8, 128.5, 128.1, 127.3, 127.0, 125.3, 120.2, 118.2, 116.7, 113.1, 112.6, 104.8, 102.2; HRMS calculated for C16H10N4 258.0904, found 258.0904. Analytical calculated for C16H10N4 : C, 74.40; H, 3.90; N, 21.69. Found: C, 74.20; H, 3.92; N, 21.69.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:52])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([N:34]3[CH2:38][CH2:37][CH2:36][C@H:35]3[C:39](=[O:45])[NH:40][CH:41]3[CH2:44][CH2:43][CH2:42]3)=[O:33])[N:27]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:26]=2)=[O:24])[CH2:14][CH:15]2[CH2:19][O:18]C(C)(C)[O:16]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:52])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([N:34]3[CH2:38][CH2:37][CH2:36][C@H:35]3[C:39](=[O:45])[NH:40][CH:41]3[CH2:42][CH2:43][CH2:44]3)=[O:33])[N:27]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:26]=2)=[O:24])[CH2:14][CH:15]([OH:16])[CH2:19][OH:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC2COC(C)(C)O2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(O)CO)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 15 mg 4-[(S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-propionyl]-piperazine-1-carboxylic acid ethyl ester in 5 ml MeOH were added 5 mg pyridinium p-toluenesulfonate and the solution was stirred for 2 h before being concentrated in vacuo. The residue thus obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [CH2:1]([N:3](C(C)C)[CH:4](C)C)C.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][N:12]=1.CNC.CCN=C=NCCCN(C)C>C1COCC1>[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:3]([CH3:4])[CH3:1])=[O:16])=[CH:13][N:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (12.61 mL, 72.40 mmol) was added to 6-aminonicotinic acid (CAS no. 3167-49-5) (5 g, 36.20 mmol), dimethylamine (2M in THF) (21.72 mL, 43.44 mmol) and EDCI (9.02 g, 47.06 mmol) in THF (150 mL) under nitrogen. The resulting suspension was stirred at r.t. for 18 hours. The reaction mixture was dry loaded onto silica and purified by flash silica chromatography, eluting with 0 to 10% MeOH in ethyl acetate to the product (4.50 g, 75%). 1H NMR (400 MHz, DMSO) δ 2.95 (6H, s), 6.28 (2H, s), 6.38-6.44 (1H, m), 7.42-7.47 (1H, m), 7.99-8.04 (1H, m)