Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(COC(=O)C2CCC(O)CC2)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2CCC(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled solution of 4-methoxybenzyl 4-hydroxycyclohexanoate (7.5 g, 28 mmole), 4-dimethylaminopyridine (0.73 g, 6 mmole) and N-benzyloxycarbonyl-L-valine (7.54 g, 30 mmole) in dichloromethane (90 ml) was added dicylohexyl-carbodiimide (6.8 g, 33 mmole) and the mixture was stirred for 2 days at room temperature. The mixture was cooled and the urethane was filtered. The solution was evaporated and 250 ml ethyl acetate was added. The organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 13 g=93%
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:8]=1[C:9]([NH:11][CH:12]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:13][CH2:14][OH:15])=O.C(N(CC)CC)C>O1CCCC1>[F:6][C:7]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:8]=1[C:9]1[O:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:11]=1
Reactant: O=C(NC(CCO)c1ccc(Cl)cc1)c1c(F)cccc1F
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1cccc(F)c1C1=NC(c2ccc(Cl)cc2)CCO1
Yield: 73 %

Procedure:
A mixture of 1.74 g (15.2 mmol) of methanesulfonyl chloride and 10 ml of tetrahydrofuran is added dropwise to a mixture of 4.5 g (13.8 mmol) of N-(2,6-difluorobenzoyl)-3-amino-3-(4-chlorophenyl)-1-propanol, 1.54 g (15.2 mmol) of triethylamine and 50 ml of tetrahydrofuran, while cooling with ice and stirring. The mixture is stirred at room temperature for 2 hours and filtered, and the filtrate is concentrated in vacuo. The residue is taken up in 50 ml of methanol, 2 g of potassium hydroxide are added and the mixture is stirred at 70° C. for 30 minutes. After customary working up, the crude product is purified by column chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 8/2. 3.1 g (72.9%) of 2-(2,6-difluorophenyl)-4-(4-chlorophenyl)-5,6-dihydro-(4H)1,3-oxazine are obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.I[CH:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:13]([CH3:15])[CH3:14])[CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[CH:3]=1
Reactant: Clc1cc(Cl)c2nc[nH]c2n1
Reactant: CC(C)I
Product: CC(C)n1cnc2c(Cl)cc(Cl)nc21

Procedure:
Following the procedure of Example 15b, 5,7-dichloro-3H-imidazo[4,5-b]pyridine (J. Med. Chem., 2007, 50, 828-834) (0.118 g, 0.624 mmol) was reacted with 2-iodopropane. The crude product mixture was purified by silica gel chromatography (25 to 35% ethyl acetate in hexane eluant) to afford a mixture of the title compound (major) and an isomeric product as a solid. MS m/z 230.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@@H:13]([C:17]([NH2:19])=[O:18])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>C(C#N)(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([CH:14]([CH3:16])[CH3:15])[C:17]([NH2:19])=[O:18])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: CC(C)[C@@H](N)C(N)=O
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: CC(=O)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.7 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (500 mg, 2.84 mmol) and D-valinamide HCl salt (476 mg, 3.12 mmol) in AcCN (10 mL) was added DIPEA (1.11 mL, 6.25 mmol). After stirring at room temperature for 4 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-methylbutanamide (740 mg). Step 2: To a mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-methylbutanamide (100 mg, 0.394 mmol) in Dioxane (2 mL) was added 3-aminoquinoline (71 mg, 0.492 mmol), Pd(OAc)2 (18 mg, 0.079 mmol), BINAP (49 mg, 0.079 mmol) and K2CO3 (163 mg, 1.18 mmol). After heating at 95° C. for 5 h, the mixture was filtered, the filtrate was concentrated and purified by preparative HPLC to give (R)-2-(5-cyano-6-(quinolin-3-yl)pyrazin-2-ylamino)-3-methylbutanamide (113 mg).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:6]=[C:7]([C@@H:11]2[CH2:20][CH2:19][CH2:18][C@H:17]3[N:12]2[C:13](=[O:29])[CH:14](P(=O)(OCC)OCC)[CH2:15][CH2:16]3)[CH:8]=[CH:9][CH:10]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]1)[CH:35]=O.C(OCC)(=O)C>O1CCCC1.C(O)C>[F:4][C:5]1[CH:6]=[C:7]([C@@H:11]2[CH2:20][CH2:19][CH2:18][C@H:17]3[N:12]2[C:13](=[O:29])/[C:14](=[CH:35]/[C:34]2[CH:37]=[CH:38][C:39]([N:40]4[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]4)=[C:32]([O:31][CH3:30])[CH:33]=2)/[CH2:15][CH2:16]3)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3cccc(F)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CCC[C@@H](c4cccc(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
Lithium hydroxide monohydrate (220 mg) was added to a mixed solution of diethyl [(6S*,9aR*)-6-(3-fluorophenyl)-4-oxooctahydroquinolizin-3-yl]phosphonate (670 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (378 mg) in tetrahydrofuran (15 mL) and ethanol (5 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 583 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:26]([CH3:28])[CH3:27])=[NH:15])([CH3:3])[CH3:2].[Br:29][CH:30](Br)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:17]=1[NH:16][C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[N:15][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][Br:29])=[CH:32][CH:33]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)Nc1c(C(C)C)cccc1C(C)C
Reactant: Cc1ccc(C(Br)Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=NCc1ccc(CBr)cc1)Nc1c(C(C)C)cccc1C(C)C
Yield: 39.1 %

Procedure:
11.4 g (0.03 mole) of N,N'-bis-(2,6-diisopropylphenyl) guanidine, 8.7 g (0.033 mole) of α,α-dibromo-p-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of toluene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent to obtain a slightly brown powder. The powder was then recrystallized from acetone to obtain 6.6 g of white powder.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][N:21]([C:23]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[O:24])[CH2:20][CH:19]([C:31]([O:33]C)=[O:32])[CH2:18]2)=[CH:13][CH:12]=1)([F:10])[CH3:9]>CO>[F:10][C:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][N:21]([C:23]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[O:24])[CH2:20][CH:19]([C:31]([OH:33])=[O:32])[CH2:18]2)=[CH:13][CH:12]=1)([F:7])[CH3:9]
Reactant: COC(=O)C1CC(c2ccc(C(C)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CC(F)(F)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.44 g (12.8 mmol) of potassium tert-butoxide were added at RT to a solution of 528 mg (1.28 mmol) of the compound from Example 52A in 15 ml of methanol. The mixture was stirred at 60° C. overnight. For workup, the methanol was removed under reduced pressure, the residue was admixed with water and the mixture was acidified (pH 1) with aqueous 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried with magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 471 mg (91% of theory, 2:1 cis/trans isomer mixture)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)[CH2:7][C:8](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:9])=[N:2]1.[OH:37]O.[Li+].[OH-].Cl>C1COCC1.O>[O:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)[CH2:7][C:8]([OH:9])=[O:37])=[N:2]1
Reactant: O=C(C[C@H](c1cccc(OCc2ccccc2)c1)c1ccon1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H](c1cccc(OCc2ccccc2)c1)c1ccon1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (R)-4-benzyl-3-((R)-3-(3-(benzyloxy)phenyl)-3-(isoxazol-3-yl)propanoyl)oxazolidin-2-one (94.1C) (0.558 g, 1.16 mmol) in THF (12 mL) was cooled to 0° C. H2O2 (30% w/w, 0.50 mL) was added, and was followed by addition of LiOH, monohydrate (0.0643 mL, 2.31 mmol) in water (4 mL). The resulting mixture was stirred at 0° C. for 2 hours. The organic solvent was blown away by nitrogen, and the aqueous mixture was acidified with 1N HCl to pH 3-5. The mixture was extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4. After removing solvent, crude product (94.1D) (491 mg) was obtained.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:22][C:21]=2[O:34][CH2:35][C@@H:36]2[CH2:38][O:37]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:22][C:21]=2[O:34][CH2:35][C@@H:36]([OH:37])[CH2:38]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCc4ccccn4)cc3OC[C@@H]3CO3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1cc(OCc2ccccn2)ccc1-3
Yield: 62 %

Procedure:
Methyl 3-cyclohexyl-2-[2-[(2S)-oxiran-2-ylmethoxy]-4-(pyridin-2-ylmethoxy)phenyl]-1H-indole-6-carboxylate was dissolved in DMF (0.1 M) and the solution was added slowly to a suspension of Cs2CO3 (0.5 eq) in DMF at 65° C. After 1 h the mixture was diluted with Et2O. The solution was extracted with H2O, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo to leave an orange amorphous solid. The product was purified by FC (PE:EtOAc, 1:1+1% NEt3 to wash away remaining starting material, then EtOAc:MeOH, 9:1+1% NEt3). The product was obtained as a yellowish amorphous solid (62%). (ES+) m/z 513 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[Cl:27][C:28]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:29]=1[CH:30]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:30][C:29]4[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:28]=4[Cl:27])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccc(O)cc1Cl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(O)cc3Cl)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 2-chloro-4-hydroxybenzaldehyde to provide 22 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C=O)[CH2:8][CH2:7]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25](N)[CH2:26][NH2:27].CO[Na]>C(O)C>[NH:27]1[CH2:26][CH2:25][N:2]=[C:1]1[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: N#CCCCC1CCN(C=O)CC1
Reactant: NCCN
Agent: CO[Na]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C(CC1=NCCN1)CC1CCNCC1
Temperature: 200 °C
Yield: 72.5 %

Procedure:
To 4-(3-cyanopropyl)-1-piperidinecarboxaldehyde (10 g, 0.055 M), there was added ethylenediamine p-toluenesulfonate (30 g, 0.129 M) and the mixture was heated at 200° C. for 41/2 hours. The reaction mixture was dissolved in ethanol (100 ml), basified with MeONa (0.26 M), filtered and stripped to dryness. The residue was distilled at 170° C., 0.025 mmHg to give 4-[3-(4,5-dihydro-1H-imidazol-2-yl)propyl]piperidine (7.86 g, 72% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([F:22])([F:31])[F:32]
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c(Cl)c(Oc2ccccc2C(F)(F)F)cnn1C1CCCCO1
Temperature: 105 °C
Yield: 79.6 %

Procedure:
A solution of 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (4.00 g, 16.05 mmol) (Intermediate 20) in acetonitrile (178 mL, 0.09M) was treated with potassium carbonate (2.21 g, 16.05 mmol) and 2-trifluoromethyl-phenol (2.60 g, 16.05 mmol). The resulting reaction mixture was heated to 105° C. for 18 h and then was allowed to cool to 25° C. The reaction mixture was partitioned between water (150 mL) and methylene chloride (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix) afforded 4-chloro-2-(tetrahydro-pyran-2-yl)-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (4.79 g, 79%) as a white solid; ES+-HRMS m/e calcd for C16H14N2O3F3Cl [M+H+] 375.0718, found 375.0718. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.51 (d, 2H), 1.62-1.77 (m, 2H), 1.87-2.12 (m, 2H), 3.55-3.70 (m, 1H), 3.91-4.03 (m, 1H), 5.90 (dd, J=10.4, 2.0 Hz, 1H), 7.45-7.53 (m, 2H), 7.76 (t, J=7.8 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.91 (s, 1H).
Reaction SMILES: CS(O[CH2:6][C:7]([F:45])([F:44])[CH2:8][CH2:9][C@H:10]([N:20]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])(=O)=O.[N-:46]=[N+:47]=[N-:48].[Na+].C1OCCOCCOCCOCCOCCOC1.N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C>CS(C)=O.CN(C1C=CN=CC=1)C.O>[N:46]([CH2:6][C:7]([F:45])([F:44])[CH2:8][CH2:9][C@H:10]([N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCN([C@@H](CCC(F)(F)COS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CS(C)=O
Product: CCCCCN([C@@H](CCC(F)(F)CN=[N+]=[N-])CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
To a stirred solution of the material from Step 8 (167 mg, 0.233 mmol) in DMSO (2.3 mL) were added sodium azide (23 mg, 0.35 mmol) and 18-crown-6 (3 mg, 0.012 mmol). The reaction mixture was stirred at 125° C. for 24 hours. Upon cooling to room temperature, the reaction mixture was concentrated to dryness in vacuo. LCMS showed that TBS group was removed. The residue was dissolved in dichloromethane (2.3 mL). Imidazole (32 mg, 0.465 mmol), DMAP (1 mg, 0.008 mmol) and TBS—Cl (70 mg, 0.465 mmol) were added. The reaction mixture was stirred at room temperature overnight, poured into water and extracted with dichloromethane (2×). The combined organics were washed with 1 N HCl, saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 60 mg of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=O)=[CH:23][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C=O)=CC=1)(=O)C1C=CC=CC=1.[NH2:43]C1C=C(C=CC=1N)C(O)=O>>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([NH2:43])=[O:26])=[CH:23][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=C(O)c1ccc2[nH]c(-c3ccc(C(=O)c4ccccc4)cc3)nc2c1
Agent: O=Cc1ccc(C(=O)c2ccccc2)cc1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(C(=O)c4ccccc4)cc3)nc2c1

Procedure:
2-(4-Benzoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid. This compound was prepared as described in Example 1 using 4-benzoyl-benzaldehyde (100 mg, 0.47 mmol) and 3,4-diamino-benzoic acid (72 mg, 0.47 mmol) in Step C. The title compound was obtained as a tan solid (135 mg, 85%). MS (ESI): mass calculated for C21H14N2O3, 342.1; m/z found, 342.9 [M+H]+. HPLC (Method A): Rt=7.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]=[C:8]=[O:9].[N+:13](=[C:15]1[N:19]=[CH:18][N:17]=[C:16]1[C:20]([NH2:22])=[O:21])=[N-:14]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]1[C:8](=[O:9])[N:19]2[CH:18]=[N:17][C:16]([C:20]([NH2:22])=[O:21])=[C:15]2[N:13]=[N:14]1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: COc1cccc(CN=C=O)c1
Solvent: CS(C)=O
Product: COc1cccc(Cn2nnc3c(C(N)=O)ncn3c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Meta-methoxybenzyl isocyanate (Sigma Aldrich) (0.390 g, 2.4 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (off-white) removed by filtration, washed with water and ethyl acetate, and recrystallised from chloroform. Yield: 0.335 g, 56%. IR vmax/cm−1 3092, 1730, 1678, 1601. 1H NMR δH (DMSO-d6) 3.76 (3H, s, Me), 5.49 (2H, s, CH2Ar), 6.89-6.92 (1H, m, ArH), 7.00-7.02 (1H, m, ArH), 7.28-7.32 (1H, s, ArH), 7.70 (1H, br s, NH), 7.82 (1H, br s, NH), 8.84 (1H, s, 6-H). δC (DMSO-d6) 52.2, 55.6, 113.7, 114.0, 120.4, 129.5, 130.1, 131.4, 134.9, 137.6, 139.7, 159.9, 162.0. Found 301.1091. Calc for (M+H): 301.1049. Found C, 51.3; H 3.9; N 27.8. Calc. for C13H12N6O3C, 52.0; H, 4.0; N, 28.0%.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].N#N.C([Li])CCC.[N:26](OCCC(C)C)=[O:27]>CC(OC)(C)C.C(Cl)Cl.O>[N:1]1[C:10]2[C:9](=[N:26][OH:27])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CCCC2
Reactant: CC(C)CCON=O
Agent: CC(C)[N-]C(C)C
Agent: N#N
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: ON=C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (10.83 g, 81.3 mmol) and lithium diisopropylamide (LDA) (22.80 mL, 163 mmol) in dry MTBE (tert-butyl methyl ether) (100 mL was stirred for 10 min while dry N2 (nitrogen) was purged through the system. The solution was then cooled in an acetone-dry ice bath to between −30° C. and −20° C. A 2.5 M solution of nBuLi (n-butyllithium) in hexanes (101.0 mL, 253 mmol) was then added over a period of 5 min. The temperature of the cooling bath was maintained below −20° C. throughout the addition. The thus obtained orange/red mixture was then transferred via cannula to a pre-cooled solution of isoamyl nitrite (38.40 mL, 285 mmol) in dry MTBE (100 mL) at −30° C.; the transfer took about 10 min. The resulting mixture was stirred at −30° C. for 40 min at which time water (4.80 mL) was added in one portion. The quenched mixture was slowly warmed to ambient temperature. A brown solid precipitated from the crude mixture and was collected via filtration. The solid isolate was redissolved in CH2Cl2 (300 mL) and then filtered to remove any insoluble material. The solvent was removed in vacuo and the residue was recrystallized from 1:1 MTBE-hexanes to provide 10.05 g (75%) of the title compound as a beige solid. 1H NMR (CDCl3) δ 1.87–1.96 (m, 2H), 2.81 (t, 2H, J=6 Hz), 2.93 (t, 2H, J=8 Hz), 7.18 (dd, 1H, J=9, 6 Hz), 7.48 (dd, 1H, J=9, 1 Hz), 8.52 (dd, 1H, J=6, 1 Hz), 9.63 (br s, 1H); 13C NMR (CDCl3) δ 20.8, 23.8, 28.9, 123.4, 134.5, 136.7, 148.2, 148.9, 152.7. ES-MS m/z 163 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]CN.[C:12](CP(=O)(OCC)OCC)#[N:13].[H-].[Na+].CC1C=CC=CC=1C=O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH2:9])[C:12]#[N:13]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1ccccc1CCCN
Agent: Cc1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C#N)c1ccccc1C
Reaction time: 0.5 h

Procedure:
Procedure for the preparation of 3-(2-Methylphenyl)propylamine ##STR142## 3-(2-Methylphenyl)propylamine: Diethyl cyanomethylphosphonate (5.0 ml, 30.9 mmol) was added to a stirring suspension of sodium hydride (60% oily suspension, 1.24 g, 31 mmol) in tetrahydrofuran (50 ml) under argon. After 30 min, 2-methylbenzaldehyde (3.6 ml, 31.1 mmol) was added and stirring continued for 1 h. The reaction was quenched by the addition of water and extracted with dichloromethane followed by drying and evaporation of the organic solution. Column chromatography (hexane; hexane:ethylacetate=3:1) provided 2-(2-methylphenyl)acrylonitrile as an oil. This material (3.8 g), 10% palladium on carbon (3.8 g) and 12 N hydrochloric acid (11.8 ml, 142 mmol) in methanol (125 ml) were hydrogenated with hydrogen at atmospheric pressure for 2 d. The catalyst was removed by filtration and the solvent was evaporated. The resultant material was partitioned between dichloromethane and water. The aqueous layer was made basic with 10 N sodium hydroxide and extracted with dichloromethane, followed by drying and evaporation. The resultant material was purified on a silica gel column (chloroform:methaol:triethylamine=85:10:5) to provide the title compound as an oil.