Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[CH:16]=CC(C#C)=CN=1>>[C:11]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1)#[CH:16]
Reactant: CNc1ccc(I)cn1
Reactant: C#Cc1ccc(Cl)nc1
Product: C#Cc1ccc(NC)nc1

Procedure:
(5-Ethynyl-pyridin-2-yl)-methyl-amine was prepared from (5-iodo-pyridin-2-yl)-methyl-amine in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1.S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12]([O:14][CH2:28][CH3:29])=[O:13])[CH:11]=1
Reactant: Cc1cn2cc(C(=O)O)cc(OCc3ccccc3F)c2n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(OCc2ccccc2F)c2nc(C)cn2c1

Procedure:
To 350 mg of 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid were added 18 ml of ethanol and 200 μl of sulfuric acid, followed by heating to reflux overnight. Under reduced pressure, the solvent was removed by filtration to around one third of the amount thereof, and a saturated aqueous sodium hydrogen carbonate solution and chloroform were then added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 330 mg of ethyl 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)CCC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: ClCCl
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(Cc3ccc4ccccc4c3)CC2)cc1
Yield: 35.9 %

Procedure:
A mixture of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine (6.47 g, 0.0214 mol), 2-(bromomethyl)naphthalene (4.74 g, 0.0214 mol), and potassium carbonate (4.84 g, 0.035 mol) was heated 16 h at reflux in 400 mL of 1-butanol containing sodium iodide (0.2 g). The reaction mixture was concentrated to dryness. The residue was partitioned with 5% sodium hydroxide. The chloroform layer was dried (Na2SO4), filtered, and concentrated to give a dark brown oil. The oil was dissolved in methylene chloride and subjected to flash chromatography. Elution was accomplished using methylene chloride, 1% acetone-methylene chloride, 2% acetone-methylene chloride, 5% acetone-methylene chloride, and 10% acetone-methylene chloride. Fractions of similar purity were combined, and solvents were removed to give a viscous gum. This material was dried in vacuo 16 h at 100° C. in the presence of phosphorus pentoxide. This procedure provided 3.40 g (36%) of white glass-like material.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH:11]=[CH2:12])[C:8]2[N:7]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:23]=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:44](Br)(Br)([Br:46])[Br:45]>C(Cl)Cl>[Br:45][C:44]([Br:46])=[CH:23][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([CH:11]=[CH2:12])=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: BrC(Br)(Br)Br
Reactant: C=Cc1cc(C)c(C=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=Cc1cc(C)c(C=C(Br)Br)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-methyl-1-tosyl-7-vinyl-1H-indole-4-carbaldehyde (50 mg, 0.147 mmol) and PPh3 (116 mg, 0.442 mmol) in DCM (1.5 mL) at 0° C., was added CBr4 (73.3 mg, 0.221 mmol) and the reaction was warmed to room temperature. After 10 minutes the reaction mixture was loaded onto silica gel and was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 7.76-7.91 (m, 2H) 7.43-7.61 (m, 3H) 7.17-7.43 (m, 3H) 6.63-6.70 (m, 1H) 5.59 (dd, J=17.18, 1.26 Hz, 1H) 5.27 (dd, J=10.99, 1.14 Hz, 1H) 2.28-2.35 (m, 3H) 2.18-2.28 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:23]=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])C.O>CN(C)C=O>[CH2:15]([CH:14]([CH2:17][CH3:18])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19])[CH3:16]
Reactant: CCC(CC)C(=O)Nc1ccc2ncnc(N)c2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(=O)C(CC)CC)cc12)C(=O)OCC
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 73.7 %

Procedure:
A mixture of 4-amino-6-(2-ethylbutyramido)quinazoline (0.9 g) and diethyl ethoxymethylenepropanedioate (0.95 g) in N,N-dimethylformamide (4 ml) was stirred at 100° C. for 2 hours and 40 minutes. Water was added to the reaction mixture. The resulting crystals were collected, washed with water and dried. The crude crystals were chromatographed on silica gel with 20% ethyl acetate-chloroform and recrystallized from a mixture of ethyl acetate, chloroform and hexane to give crystaline diethyl [[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (1.1 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: Clc1cnccn1
Reactant: CN1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cnccn1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
(S)-(-)-1-Methyl-2-pyrrolidinemethanol (Aldrich Chemical Co., 0.5 g, 4.34 mmol) was dissolved in anhydrous THF and brought to 0° C. NaH ((80% dispersion in mineral oil), 131 g, 4.56 mmol) was added and the reaction mixture was allowed to warm to room temperature with stirring. After 30 minutes 2-chloropyrazine (0.497 g, 4.34 mmol) was added via syringe. The mixture was stirred for 48 hours. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and a brine solution. The organic layer was then dried over MgSO4. The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3) to give 0.81 g (97% yield) of the title compound as an oil. TLC Rf =0.3 (10% MeOH/CHCl3). MS (DCI/NH3) m/e 194 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.24 (d, J=1.5 Hz, 1H, 8.11 (d, J=3 Hz, 1H), 8.07 (dd, J=3, 1.5 Hz, 1H), 4.36 (dd, J=9, 6 Hz, 1H), 4.28 (dd, J=9, 6 Hz, 1H), 3.16-3.08 (m, 1H, 2.7-2.58 (m, 1H, 2.47 (s, 3H), 2.34-2.24 (m, 1H, 2.08-1.93 (m, 1H, 1.91-1.67 (m, 3H).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:23][OH:24])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[C:25]1([CH2:31]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[O:3]1[C:7]2([CH2:8][CH2:9][CH:10]([C:13]3[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:23][O:24][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12]2)[O:6][CH2:5][CH2:4]1
Reactant: OCc1cccc(C(F)(F)F)c1C1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cccc(COCc2ccccc2)c1C1CCC2(CC1)OCCO2

Procedure:
A suspension of 3.3 grams (0.084 mole) of sodium hydride (60% in mineral oil) in 20 mL of toluene is stirred, and a solution of 24.3 grams (0.080 mole) of [(1,4-dioxaspiro[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methanol in 65 mL of toluene is added dropwise. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about one hour. After this time a solution of 13.7 grams (0.080 mole) of phenylmethyl bromide in 45 mL of toluene is added dropwise. Upon completion of addition, the reaction mixture is heated to reflux where it is stirred for about 4 hours. The reaction mixture is then cooled and shaken with water. The organic layer is separated and dried with magnesium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure, yielding phenylmethyl [(1,4-dioxaspiro[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.C[Mg]Br.[CH2:18]=[O:19].Cl>O1CCCC1.C(OCC)C.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:18]=[O:19])[C:5]([OH:8])=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: C=O
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=Cc1cc(Cl)cc(C2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To 100.4 mmol of 4-chloro-2-cyclohexyl phenol in 40 ml of tetrahydrofuran was added dropwise a 3-molar methylmagnesium bromide solution (36.8 ml; 110.4 mmol) in diethyl ether. After two hours of stirring at room temperature, gas evolution ceased. About 90% of the solvent were removed in vacuo and toluene (250 ml), triethylamine (20 ml), and paraformaldehyde (7.53 g; 251 mmol) were added. The mixture was heated to 88° C. and held at this temperature for two hours. After cooling down to room temperature, the yellow solution was introduced into cold hydrochloric acid (1M, 250 ml). The organic phase was separated and dried over sodium sulphate. After removal of the solvent in vacuo, 5-chloro-3-cyclohexyl salicylaldehyde was recrystallized from ethanol at −20° C. Yield: 59%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>COCCOC>[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCCn1ccnc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 28.2 g (0.2 mol) of 1-fluoro-4-nitrobenzene, 31.3 g (0.25 mol) of 3-imidazol-1-ylpropylamine and 34.8 ml of triethylamine in 30 ml of 1,2-dimethoxyethane was heated for half an hour with stirring. The mixture was poured into 1.5 liters of ice-cold water and the crystalline precipitate was filtered off, reimpasted in water and then in isopropyl alcohol and dried under vacuum at 40° C. over phosphorus pentoxide. Yellow crystals (36.6 g) which, after purification by recrystallization from refluxing 96° ethanol, melted at 124° C., were obtained, the elemental analysis of which, calculated for C12H14N4O2, was:
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH2:21][C:22]1[CH:27]([C:28]([OH:30])=[O:29])[N:26]2[C:31](=[O:43])[CH:32]([NH:33][C:34](=[O:42])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:25]2[S:24][CH:23]=1>O1CCOCC1>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:21][C:22]2[CH:27]([C:28]([OH:30])=[O:29])[N:26]3[C:31](=[O:43])[CH:32]([NH:33][C:34](=[O:42])[CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C@H:25]3[S:24][CH:23]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)=CS[C@H]12
Reactant: COc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COc1ccc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)cc1
Reaction time: 1 h

Procedure:
A solution of 0.044 g of anisole and 0.0172 g of p-toluenesulphonic acid in 2 ml of anhydrous dioxane is mixed with 0.035 g of 3-hydroxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the resulting solution is left to stand for one hour at room temperature. The solvent is removed under reduced pressure and the residue is triturated with diethyl ether to remove the excess of p-toluenesulphonic acid and is worked up in accordance with the process described in example 6. 3-(4-Methoxy-benzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid containing a small amount of the corresponding 2-methoxybenzyl compound is thus obtained; in a thin layer chromatogram, this acid does not differ from the product of the process of example 1.
Reaction SMILES: C([N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:16]=1)[C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=O)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>>[N:21]1([C:17]2[CH:16]=[C:15]([NH:4][C:5]3[CH:10]=[CH:9][C:8]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[CH:7][C:6]=3[N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CC(=O)N(c1cccc(-n2ccnc2)c1)c1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccco1
Product: O=[N+]([O-])c1cc(-c2ccco2)ccc1Nc1cccc(-n2ccnc2)c1
Yield: 77 %

Procedure:
N-(3-(1-Imidazolyl)phenyl)-4-(2-furanyl)-2-nitroaniline (7o) was prepared analogously from 6c (Example 8) and 2-furanylboronic acid. Yield: 77%. Mp 147-149° C.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.[H-].[Na+].[CH2:24](I)[CH:25]([CH3:27])[CH3:26].O>CN(C)C=O>[CH2:24]([O:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]2[N:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:3]=[C:2]([CH3:1])[C:14]=12)[CH:25]([CH3:27])[CH3:26]
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(OCC(C)C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To an ice-cold solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (1.93 g, 7.0 mmol) in N,N-dimethylformamide (30 mL), sodium hydride (oiliness, content 60%, 0.42 g, 10.5 mmol) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, isobutyl iodide (2.0 mL, 17.4 mmol) was added to the mixture, and the mixture was stirred at room temperature for 16 hours, and heated under reflux at 70° C. for 8 hours. The reaction solution was allowed to cool and iced water was added to the mixture, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate:chloroform=3:1:1) to give the title compound (0.54 g, 23% yield).
Reaction SMILES: [C:1]([C:3](=[C:15]([NH:27][C@H:28]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]([CH2:35][C:36](=[O:42])[N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:29]1=[O:43])[NH:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([CH3:25])=[CH:22][C:21]=2[CH:26]=1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)=[O:5])#[N:2].[CH3:44][N:45](C(F)=[N+](C)C)[CH3:46].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CNC.C1COCC1>C(#N)C.CO>[C:1]([C:3](=[C:15]([NH:27][C@H:28]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]([CH2:35][C:36](=[O:42])[N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:29]1=[O:43])[NH:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([CH3:25])=[CH:22][C:21]=2[CH:26]=1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([N:45]([CH3:46])[CH3:44])=[O:11])=[CH:8][CH:7]=1)=[O:5])#[N:2]
Reactant: Cc1cc2cc(NC(N[C@H]3CCCCN(CC(=O)N4CCCC4)C3=O)=C(C#N)C(=O)c3ccc(C(=O)O)cc3)ccc2o1
Reactant: CN(C)C(F)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc2cc(NC(N[C@H]3CCCCN(CC(=O)N4CCCC4)C3=O)=C(C#N)C(=O)c3ccc(C(=O)N(C)C)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The compound of Example 2 (59 mg, 0.10 mmol) was dissolved in 1 mL of acetonitrile. To the solution was added TFFH (26.4 mg, 0.10 mmol) and triethylamine (0.016 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 30 min and then 2 M dimethyl amine in THF (0.060 mL, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for an additional 2 h. The reaction mixture was loaded onto a SCX cartridge (prewashed with methanol and then acetonitrile). The column was eluted with acetonitrile, 1/1 acetonitrile/methanol and methanol to provide the title compound (44 mg, 72%) as a white solid: MS (ESI, pos. ion spectrum) m/z 611 (M+H); HPLC (method B) tR 3.7 min, purity 100%.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=O)=[CH:10][CH:9]=1)[CH2:4][OH:5].Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:5][CH2:4][CH:3]([NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:15]/[C:16](=[N:35]\[OH:36])/[C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=2)=[CH:10][CH:9]=1)[CH2:2][OH:1]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(CO)CO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(CO)CO)cc1

Procedure:
In analogy to example 151, step 3, N-(1,3-dihydroxypropan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=464.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:34].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:34])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])=[CH:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CC(=O)N4CCOCC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(CC(=O)N4CCOCC4)cc3)cc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
To a solution of 6-chloro-5-{4-[2-(morpholin-4-yl)-2-oxoethyl]phenyl}-1H-indole-3-carbaldehyde (249 mg, 0.650 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (880 mg, 13.1 mmol) and sodium phosphate monobasic dihydrate (2030 mg, 13.01 mmol) in water (3 mL) via addition funnel. The icebath was removed and the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with aqueous sodium sulfite, concentrated in vacuo and extracted with ethyl acetate (4×25 mL). The combined organic phases were washed with brine (20 mL), dried and concentrated in vacuo. The crude product was purified by prep-HPLC (Column: Phenomenex Synergi C18 150*30 mm*4 μm; Mobile phase: from 38% MeCN in water (0.225% FA) to 58% MeCN in water (0.225% FA); Wavelength: 220 nm) to afford the title compound (65 mg, 28% yield) as a white solid. MS (ES+) 399.0 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[N+]([O-])(O)=O.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH2:36])=[NH:35])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>CC#N>[NH2:12][C:10]1[S:11][C:7]([C:5]2[CH:4]=[CH:3][N:36]=[C:34]([NH:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:25])=[O:26])[CH:28]=3)[N:35]=2)=[C:8]([CH3:17])[N:9]=1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Reactant: CS(=O)(=O)c1cccc(NC(=N)N)c1
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: Cc1nc(N)sc1-c1ccnc(Nc2cccc(S(C)(=O)=O)c2)n1

Procedure:
By condensation of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine and N-(3-methanesulfonyl-phenyl)-guanidine nitrate. Yellow solid. Anal. RP-HPLC: tR=13.1 min (0-60% MeCN, purity >97%). 1H-NMR (DMSO-d6) δ: 2.55 (s, 3H, CH3), 3.19 (s, 3H, CH3), 6.97 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.47 (m, 1H, Ph-H), 7.54 (t, 1H, J=7.5 Hz, Ph-H), 8.08 (m, 1H, Ph-H), 8.34 (brs, 1H, Ph-H), 8.40 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.86 (sbr, 2H, NH2). MS (ESI+) m/z 362.38 [M+H]+ (C15H15N5O2S2 requires 361.44).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[NH:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:17][N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26](Cl)Cl.[Si](C=[N+]=[N-])(C)(C)C>CO>[CH3:26][N:19]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:17][N:16]=[C:15]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCCCCc1ccccc1)c1nnc(-c2ccccn2)[nH]1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: Cn1c(C(=O)CCCCCCc2ccccc2)nnc1-c1ccccn1
Yield: 23 %

Procedure:
A sample of 14b (3.0 mg, 0.009 mmol) was dissolved in a mixture of MeOH (0.1 mL): CH2Cl2 (0.1 mL). TMSCHN2 (7 μL, 0.013 mmol) was added dropwise causing gas to evolve, and after 0.5 h the reaction mixture was quenched with the dropwise addition of AcOH (50 μL). All volatiles were removed under reduced pressure to afford a residue that was purified by preparative thin layer chromatography (SiO2, 50% EtOAc-hexanes). The title compound (0.735 mg, 23%) was isolated along with the two other regioisomers (16; 1.01 mg, 32%; 17; 0.496 mg, 16%) as a colorless solid: 1H NMR (CDCl3, 500 MHz) δ 8.71 (dd, 1H, J=0.9, 4.9 Hz), 8.33 (d, 1H, J=8.0 Hz), 7.88 (dt, 1H, J=1.8, 7.8 Hz), 7.41 (ddd, 1H, J=1.1, 4.9, 7.6 Hz), 7.28 (m, 2H), 7.16 (m, 3H), 4.37 (s, 3H), 3.28 (t, 2H, J=7.4 Hz), 2.61 (t, 2H, J=7.7 Hz), 1.78 (m, 2H), 1.64 (m, 2H), 1.42 (m, 4H); HRMS-ESI-TOF m/z 349.2020 ([M+H]+, C21H24N4O requires 349.2023). Tetrazoles (15a-15e, 19a, 19b):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:9]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:10]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[N:9]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2Cl)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2Cl)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 72.9 %

Procedure:
To a solution of methyl 2-(2-(2-chlorophenyl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (27 mg; 0.066 mmol) in methanol (660 μL) was added a 10 N sodium hydroxide solution (66 μL; 0.66 mmol) and the mixture was heated at 100° C. for 18 h. The volatiles were removed under reduced pressure and the mixture was acidified by adding 6N hydrochloric acid. The suspension was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure to give 19 mg (72%) of the title compound as a white solid. ESI/APCI(+): 395 (M+H).