Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].Cl.[NH2:15][OH:16].C(N(CC)CC)C>C(O)C>[NH2:2]/[C:1](=[N:15]\[OH:16])/[CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(/C(N)=N/O)C1
Yield: 75.9 %

Procedure:
In a 16 mL vial, tert-butyl 3-cyanoazetidine-1-carboxylate (190 mg, 1.04 mmol; which may be prepared as described in Step 2) was dissolved in ethanol (2.9 mL), then hydroxylamine hydrochloride (101 mg, 1.46 mmol) and triethylamine (247 μL, 1.77 mmol) were added. The reaction mixture was stirred at reflux for 3 h, cooled and concentrated. The residue was taken up in EtOAc and water, the aqueous layer extracted with EtOAc, dried over Na2SO4 and concentrated to give the product as a white solid (170 mg, 76%).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl.[CH3:33][C:34]1[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=1)[CH2:37][C:38]1([C:44]([O:46][CH3:47])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:41]3[CH2:42][CH2:43][C:38]([CH2:37][C:36]4[CH:48]=[CH:49][CH:50]=[C:34]([CH3:33])[CH:35]=4)([C:44]([O:46][CH3:47])=[O:45])[CH2:39][CH2:40]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Reactant: COC(=O)C1(Cc2cccc(C)c2)CCNCC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(Cc2cccc(C)c2)CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a cold (−78° C.) solution of 3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl alcohol (184 mg, 0.81 mmol) and dilsopropylethylarnine (155 μL, 0.89 mmol) in dichloromethane (3.8 mL), trifluoromethanesulfonic anhydride (143 μL, 0.85 mmol) was added. The resulting mixture was stirred at −78° C. for 20 min., and was treated with a solution of methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt (276 mg, 0.97 mmol; Example 61, Step B) and diisopropylethylamine (186 μL, 1.07 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at −78° C. for one h., and at room temp. for two h. The resultant solution was concentrated under vacuum, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[S:5](Cl)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.Cl>ClCCl>[CH3:12][C:11]1[CH:13]=[CH:14][C:8]([S:5]([NH:4][CH2:1][CH:2]=[CH2:3])(=[O:7])=[O:6])=[CH:9][CH:10]=1
Reactant: C=CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Allylamine (10.6 mL, 0.14 mol) is added over a period of 4 minutes to a solution of tosyl chloride (25.1 g, 0.13 mol) in dichloromethane (250 mL) cooled in an ice bath. Triethylamine (24 mL, 0.18 mol) is added and then the solution is stirred at ambient temperature for 1.25 hours. Aqueous 3N HCl solution (60 mL) is added and the phases are then separated. The organic phase is washed with another amount of aqueous 3N HCl solution (60 mL) and then with 5% aqueous sodium bicarbonate solution (60 mL). The organic phase is dried over Na2SO4, filtered and concentrated to obtain the expected compound in the form of a solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].[CH3:14][O:15][CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].CC([O-])=O.[Na+]>Cl.O.CCO>[F:1][C:2]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:3]=1[NH:4][N:10]=[C:18]([C:17](=[O:23])[CH2:16][O:15][CH3:14])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=N[O-]
Reactant: COCC(=O)CC(=O)OC
Reactant: Nc1cc(I)ccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCC(=O)C(=NNc1cc(I)ccc1F)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
To a suspension of 2-fluoro-5-iodoaniline (9.83 g, 41.5 mmol) in 6 M HCl aqueous solution (83.0 mL) was added a solution of NaNO2 (3.43 g, 49.8 mmol) in water (8.3 mL) at 0° C. To a suspension of methyl 4-methoxy-3-oxobutanoate (5.37 mL, 41.5 mmol) and NaOAc (124 g) in EtOH (70 mL) was added the above solution at 0° C. The mixture was stirred at 0° C. for 10 min. The precipitates were collected by filtration, washed with water, dissolved in EtOAc, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound (14.2 g, 87% yield) as a red solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.31 (3H, s), 3.83 (3H, s), 4.64 (2H, s), 7.03-7.41 (1H, m), 7.43-7.66 (1H, m), 7.85-8.07 (1H, m), 12.20 (1H, brs).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(O)(=O)C.C(O)(C)C>[C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([OH:10])[C:9]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:18][CH:17]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(C(O)(c2ccccc2)C(O)(c2ccccc2)c2ccc(OC(C)=O)cc2)cc1
Yield: 99.1 %

Procedure:
0.04 g of acetic acid was added to 35.98 g of isopropyl alcohol, and 4.02 g of 4-acetoxybenzophenone was dissolved therein. To this solution, ultraviolet rays were irradiated by a high pressure mercury lamp (UVL-100HA, manufactured by Riko Kagaku Sangyo K.K.) to carry out the reaction for 6 hours. After the reaction, the solvent was distilled off to obtain 4.00 g of 1,2-bis(p-acetoxyphenyl)-1,2-diphenyl-1,2-ethanediol (compound (C5)).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2C)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccccc1C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 3) 80.0 mg (0.190 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.89(2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.46 (2H, s), 7.29-7.14 (4H, m), 6.59 (1H, s), 5.90 (1H, t, Hz), 2.39 (2H, m), 2.60 (3H, s), 1.39 (3H, s), 1.29 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2ccc(CC(Cl)=NO)cc2)o1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)o1
Temperature: 45 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
To a mixture of (4-(5-methyl-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (11 mg, 0.043 mmol) described in Manufacturing Example 46-1-6 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2-ylamine (4.0 mg, 0.034 mmol) described in Manufacturing Example 1-2-3 and triethylamine (9.4 μL, 0.068 mmol) at room temperature, which was stirred for 3 hours at 45° C. The reaction mixture was cooled to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:3) to obtain the title compound (5.1 mg, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:56]1[CH:57]=[C:58]([S:62]([NH2:65])(=[O:64])=[O:63])[CH:59]=[CH:60][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH:11][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([S:62](=[O:64])(=[O:63])[NH2:65])[CH:57]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)sc1N
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C)sc1Nc1cccc(S(N)(=O)=O)c1
Yield: 23.7 %

Procedure:
A microwave vial was charged with 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.300 g, 1.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.28 g, 0.48 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.17 g, 0.16 mmol). Degassed dioxane (15.00 ml) was added, followed by 3-bromobenzenesulfonamide (0.38 g, 1.61 mmol) and cesium carbonate (0.93 g, 2.87 mmol) The vial was then irradiated in a microwave oven at 150° C. for 15 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography (heptane ethyl acetate) to yield 2-methyl-5-(3-sulfamoyl-phenylamino)-thiazole-4-carboxylic acid ethyl ester (0.13 g, 24%) as an off-white solid, MS (ISP): m/e=342.1 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:8][C:9]([CH3:19])([CH3:18])[C@@H:10]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[C:12]=[O:13]>O1CCCC1>[CH3:8][C:9]([CH3:19])([CH3:18])[C@@H:10]([C:14]([O:16][CH3:17])=[O:15])[NH:11][C:12]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])=[O:13]
Reactant: C=CCCCNC
Reactant: COC(=O)[C@@H](N=C=O)C(C)(C)C
Solvent: C1CCOC1
Product: C=CCCCN(C)C(=O)N[C@H](C(=O)OC)C(C)(C)C
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of N-methylpent-4-en-1-amine (2.0 g, 20.2 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature under nitrogen. To this was added methyl 3-methyl-N-(oxomethylene)-L-valinate (3.5 g, 20.2 mmol) and the resulting solution stirred 2 h. Contents of the reaction flask were evaporated and subjected to flash column chromatography eluting with hexane/ethyl acetate 60/40 to give methyl 3-Methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valinate as an orange oil, 3.02 g (55% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH2:32])[C:26]=1[OH:33].C(N(CC)CC)C.[O-:41][C:42]#[N:43].[K+].Cl>CO>[OH:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][C:42]([NH2:43])=[O:41])[C:26]=1[OH:33]
Reactant: N#C[O-]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(-c4nnn[nH]4)cc(-c4cccc(CN)c4O)c3O)nc2c1
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(N)c1ccc2[nH]c(-c3cc(-c4nnn[nH]4)cc(-c4cccc(CNC(N)=O)c4O)c3O)nc2c1
Temperature: 50 °C
Reaction time: 72 h
Yield: 8.3 %

Procedure:
2-(2,2′-Dihydroxy-5-(1H-tetrazol-5-yl)-3′-aminomethylbiphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.2 g 0.2 mmol), prepared as in Example 7, was dissolved in methanol (10 mL). The solution was treated with triethylamine (0.2 mL, 1.5 mmol) and then potassium cyanate (0.09 g, 1.1 mmol aqueous solution, 0.5 mL) was added in 3 portions over 1 hour. 1N hydrochloric acid (5 mL) was added and the mixture was stirred at 50° C. over 3 days. Drying afforded crude product, which was subjected to purification by reverse phase HPLC to give 2-(2,2′-dihydroxy-5-(1H-tetrazol-5-yl)-3′-ureidomethyl-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.008 g) as a brown solid. LCMS calcd. 484.47, obsrvd. (M+H) 485.1, (M−H) 483.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]1[C:18]2[N:17]([C@H](C3C=CC(Cl)=CC=3)C)[C:16]3[C:11](=[CH:12][C:13]([F:32])=[CH:14][C:15]=3[S:28]([CH3:31])(=[O:30])=[O:29])[C:10]=2[CH2:9][CH2:8][CH2:7]1)C.C1COCC1.CO.[Li+].[OH-]>CC(O)=O>[CH3:1][O:3][C:4](=[O:33])[CH2:5][C@@H:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([F:32])=[CH:14][C:15]=3[S:28]([CH3:31])(=[O:30])=[O:29])[C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C[C@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C[C@H]1CCCc2c1[nH]c1c(S(C)(=O)=O)cc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of Step 5 in a 2:1 mixture of THF and methanol (0.1M) was added 1N aqueous LiOH (3 eq). The mixture was stirred at room temperature for 2 hr, AcOH was added and the solvent was removed by evaporation. The residue was taken up in EtOAc/H2O and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was swished in 30% EtOAc in hexane, and the product was suspended in diethyl ether and sonicated for 45 min, filtered, and dried under high vacuum at 50° C. for 24 hr to give the title compound as a white solid. MS (−APCI) m/z 462.1 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])#[N:22]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cccc(C#N)c2)c(=O)[nH]c1=O
Yield: 53.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (207 mg, yield: 53.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.[Cl:14][C: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>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[Cl:14])[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Product: Clc1ccc2nc(CN3CCN(c4ccccc4Cl)CC3)cn2c1

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4. Step 1; 0.289 g) and 1-(2-chlorophenyl)piperazine monohydrochloride (Aldrich; 0.381 g) give, after crystallization from ethyl acetate/hexane, 0.2423 g of the title compound; mp 123-123.5° C.; MS m/z 360; IR (mineral oil) 1325, 1475, 1039, 2818, 2810 cm-1 ; 1H NMR (CDCl3) δ2.77, 3.12, 3.79, 6.96, 7.04, 7.12, 7.21, 7.34. 7.52. 8.14.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C@H:11]([C@@H:27]([OH:29])[CH3:28])[C:12]([NH:14][NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[O:17])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CN(C=O)C.N1C=CN=C1.[C:41]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])([CH3:43])[CH3:42]>CCOC(C)=O.O>[Si:45]([O:29][C@@H:27]([CH3:28])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:30])[C:12]([NH:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:17])=[O:13])([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc3[nH]ccc3c2)[C@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc3[nH]ccc3c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 186 %

Procedure:
A 500 mL round bottomed flask was charged with N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-1H-indole-5-carbohydrazide (1.94 g, 4.56 mmol) and DMF (200 mL). Imidazole (1.55 g, 22.78 mmol) and tert-butyldimethyl silyl chloride (2.06 g, 13.68 mmol) were then added to the mixture which was stirred at room temperature for 18 h. Water (80 mL) was added to the mixture followed by EtOAc (150 mL). The phases were partitioned and the organic phase washed with water (70 mL) (×4), brine (50 mL), dried (Na2SO4) and concentrated to furnish a white solid. Purification by flash column chromatography [EtOAc-hexanes (1:2) as eluent] afforded the title compound as a colorless oil (4.58 g, 35% yield). 1H NMR (500 MHz, acetone d6, δ in ppm) δ 10.51 (br s, 1H), 9.5 (br s, 1H), 8.22 (br s, 1H), 7.70 (d, J=8.41 Hz, 1H), 7.55-7.47 (m, 2H), 7.44-7.42 (m, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.58-6.56 (m, 1H), 5.51 (d, J=7 Hz), 4.63-4.55 (m, 1H), 4.23-4.19 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.23 Hz, 3H), 0.95 (s, 9H), 0.17 (s, 3H) and 0.13 (s, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][CH2:24][CH2:25]O)(=[O:16])=[O:15])=[C:9]([CH3:27])[CH:8]=1.O>CN(C=O)C>[Br:2][CH2:25][CH2:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[S:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([O:6][CH3:5])=[CH:8][C:9]=1[CH3:27])(=[O:16])=[O:15]
Reactant: BrP(Br)Br
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCO)c(C)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCBr)c(C)c1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
PBr3 (2.64 mmol, 1.5 eq) was added to a solution of 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propan-1-ol (1.76 mmol, 1 eq) in DMF (6 ml) at 0° C. and the mixture was stirred for 30 min. Water (20 ml) was subsequently added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and sat. sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel). Yield: 25%
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].[Cl:29][C:30]([Cl:34])([Cl:33])[CH2:31]O.N1C=CC=CC=1>ClCCl>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:31][C:30]([Cl:34])([Cl:33])[Cl:29])=[O:27]
Reactant: O=C(O)CCCCCCCCCO
Reactant: OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCCCCCCCO)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution of N,N′-dicyclohexylcarbodiimide (DCC, 2.41 g; 14.1 mmol) in dry dichloromethane (15 mL) was added drop-wise to a stirred solution of 10-hydroxydecanoic acid (1.88 g; 10.0 mmol), 2,2,2-trichloroethanol (6.13 g; 41.0 mmol), and pyridine (4.1 mL) in dry dichloromethane (35 mL) cooled to 0° C. (bath temperature) under argon. After stirring one hour at 0° C., the mixture was stirred at ambient temperature overnight. The reaction mixture was vacuum filtered and acetic acid (3 mL) was added to the filtrate. After standing 30 min, the mixture was refiltered and the filtrate was diluted with diethyl ether (150 mL). The solution was washed with 1 M HCl (3×25 mL), water (3×25 mL), saturated NaHCO3 solution (2×25 mL), and saturated NaCl solution (1×25 mL). After drying (MgSO4), filtration, and evaporation, the residue was purified by flash chromatography on a 170×25 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1), collecting 12×25 mL fractions. Fractions 3-5 were evaporated and the residue was vacuum dried at 50° C. and 0.05 mm Hg on a Kugelrohr apparatus to remove excess 2,2,2-trichloroethanol. 2.1 g (66%) product was obtained (colorless oil).
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[NH:14])[NH:12][OH:13])=[CH:7][CH:6]=1)C.[CH2:16]([N:18]([CH2:29][CH3:30])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22](O)=O)[CH3:17].[OH-].[Na+]>C1COCC1>[CH2:29]([N:18]([CH2:16][CH3:17])[C:19]1[CH:20]=[C:21]([C:22]2[O:13][N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:15])=[CH:10][CH:9]=3)[N:14]=2)[CH:25]=[C:26]([CH3:28])[N:27]=1)[CH3:30]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: CCOC(=O)c1ccc(C(=N)NO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)c1cc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc(C)n1

Procedure:
The title compound is prepared in analogy to Example 8 starting from 4-(N-hydroxycarbamimidoyl)-benzoic acid ethyl ester and 2-diethylamino-6-methyl-isonicotinic acid except that in the final step, the ethyl ester is cleaved under basic conditions (3 N aq. NaOH in THF); LC-MS: tR=0.77 min; [M+1]+=353.09; 1H NMR (D6-DMSO): δ 1.16 (t, J=6.8 Hz, 6H), 2.43 (s, 3H), 3.58 (q, J=6.5 Hz, 4H), 7.00 (s, 1H), 7.07 (s, 1H), 8.00 (d, J=8.0 Hz, 2H), 8.04 (d, J=8.0 Hz, 2H).