Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14](O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[N:17]1C=CC=C[CH:18]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([C:18]#[N:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: c1ccncc1
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(C#N)c2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxynaphthalene-2-carboxylic acid ethyl ester (2.16 g) and pyridine (1.60 mL) in dichloromethane (100 mL) was added trifluoromethanesulfonic anhydride (2.5 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added water (30 mL), and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N-methylpyrrolidone (33 mL). To the solution were added zinc cyanide (1.41 g) and tetrakis(triphenylphosphine)palladium (0.58 g), and the resulting mixture was stirred at 110° C. for 40 minutes. After the reaction mixture was cooled to room temperature, water (50 ml) and dichloromethane (50 mL) were added to the reaction solution. The insoluble material was removed by filtering through a Celite pad. The aqueous layer was separated, and the organic layer was filtered through an aminopropyl silica gel (eluent: dichloromethane). The organic layer was concentrated under reduced pressure. To the residue was added ethyl acetate (20 mL), and the mixture was washed with water (30 mL, 5 times). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give 4-cyanonaphthalene-2-carboxylic acid ethyl ester (2.25 g). To a mixed solution of this compound (0.45 g) in tetrahydrofuran (10 mL), ethanol (5.0 mL) and water (5.0 mL) was added lithium hydroxide monohydrate (0.25 g), and the mixture was stirred for 1 hour. To the reaction solution was added water (20 mL), and the resulting mixture was washed with diethyl ether. To the aqueous layer was added 1 mol/L hydrochloric acid (3.3 mL), and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure at 50° C. to give the title compound (0.37 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:11]2[C:12]([C@@H:28]([NH:38]C(=O)OC(C)(C)C)[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=3)=[N:13][CH:14]=[C:15]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH:16]=2)[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[NH2:2].[ClH:46].O1CCOCC1>CO>[ClH:46].[NH2:38][C@H:28]([C:12]1[C:11]([C:6]2[CH:7]=[CH:8][C:9]([F:10])=[C:4]([CH:5]=2)[C:1]([NH2:2])=[O:3])=[CH:16][C:15]([N:17]2[C:18](=[O:27])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]2=[O:26])=[CH:14][N:13]=1)[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1-c1ccc(F)c(C(N)=O)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@@H](N)Cc2cc(F)cc(F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-tert-butyl 1-(3-(3-carbamoyl-4-fluorophenyl)-5-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (30G, 29 mg, 0.047 mmol) was dissolved in 0.5 mL of methanol and cooled to 0° C. To it was added 4N HCl/1,4-dioxane (0.05 ml). The reaction mixture was stirred at room temperature for 10 minutes and concentrated to afford the title product. MS (m/z) 516.96 [M+H]+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]1([C:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:15])[CH2:13][CH2:12]1.O>CS(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:14]2([C:11]3([O:10][CH3:9])[CH2:13][CH2:12]3)[CH2:2][O:15]2)=[CH:18][CH:19]=1
Reactant: COC1(C(=O)Cc2ccc(F)cc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC1(C2(Cc3ccc(F)cc3)CO2)CC1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
15 ml of absolute dimethyl sulphoxide are added dropwise at 10° C. under a nitrogen atmosphere to a mixture of 2.2 g (10 mmol) of trimehylsulphoxonium iodide and 0.4 g (13 mmol) of sodium hydride (80% pure). After addition is complete, the mixture is allowed to warm to room temperature in the course of 10 minutes and a solution of 2 g (9.6 mmol) of 4-fluorobenzyl 1-methoxycyclopropyl ketone in 10 ml of absolute dimethyl sulphoxide is then added dropwise with stirring. The reaction mixture is then poured into water. The resulting mixture is extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. 1.5 g (70% of theory) of 2-(4-fluoro-benzyl)-2-(1-methoxy-cyclopropyl)-oxirane are obtained in this manner in the form of an oil. ##STR33##
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]=[C:5]1[CH2:17][CH2:16][C:8]2([S:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[NH:9]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:26](Cl)(=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30].Cl>C(Cl)Cl>[CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]=[C:5]1[CH2:17][CH2:16][C:8]2([S:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[N:9]2[C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:7][CH2:6]1
Reactant: CC(C)CCC(=O)Cl
Reactant: CC(C)CC=C1CCC2(CC1)N[C@@H](C(=O)O)CS2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC=C1CCC2(CC1)SC[C@H](C(=O)O)N2C(=O)CCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 8 ml of methylene chloride are dissolved 0.79 g of (3S)-8-(3-methylbutylidene)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid and 1.20 ml of triethylamine. Into the solution thus obtained are dropwise added a solution of isocaproyl chloride (prepared from 0.48 ml of isocaproic acid, 0.38 ml of oxalyl chloride and 5 ml of methylene chloride) in methylene chloride at 5-10° C., and stirred at ambient temperature for 2 hours. The whole was acidified to pH 2.0 with 2 mol/L HCl and extracted with CHCl3. The combined organic extracts were washed with water and brine, dried on MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography, [eluent; chloroform:methanol=9:1] to obtain 1.10 g of (3S)-8-(3-methylbutylidene)-4-(4-methylpentanoyl)-1-thia-4-azaspiro[4.5]-decane-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]4)[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC1CNCCN1
Solvent: CC#N
Product: C=Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 75.2 %

Procedure:
A mixture of 1-cyclopropyl-8-ethenyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.80 g, 2.9 mmol), 2-methylpiperazine (1.9 g, 19 mmol) and acetonitrile (5 mL) was heated at reflux for 22 hours. The mixture was cooled and concentrated. The residue was dissolved in H2O (50 mL), treated with charcoal and filtered through celite. The pH of the filtrate was adjusted to 7, with HCl (3 N) and after cooling to 0° C. the precipitate was collected and dried to provide 0.81 g (78%) of the desired product; mp 227°-231° dec.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26].[N:27]1([CH2:32][C@H:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][CH2:37][C@@H:33]3[CH2:32][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:14])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(Cl)cccc1Cl
Reactant: C1CN[C@@H](CN2CCCC2)C1
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1OCc1c(Cl)cccc1Cl

Procedure:
{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone was prepared from 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.S(Cl)([Cl:14])=O.O1CCOCC1>CN(C)C=O>[Cl:14][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1](=[O:10])(=[O:11])[N:2]=1
Reactant: O=S1(=O)N=Cc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S1(=O)N=C(Cl)c2ccccc21
Reaction time: 8 h

Procedure:
100 g (545 mM) of benzisothiazole-1,1-dioxide 100 ml. of thionyl chloride, 4 ml. of dimethylformamide (catalyst) and 400 ml. of dioxane are refluxed overnight. Thionyl chloride (50 ml.) and dimethylformamide (1 ml.) are added to the reaction mixture which is again refluxed overnight. The reaction mixture is evaporated to dryness and the residue recrystallized from toluene to obtain 73.4 g of 3-chloro-1,2-benzisothiazole-1,1-dioxide, m.p. 140°-145°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:42][CH2:43][Cl:44])(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(#N)C>C(OC(C)C)(C)C>[Cl-:44].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][N+:30]1[N:31]=[CH:32][N:33]([CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(C[n+]1cn(COC(=O)C(C)(C)C)cn1)c1ccc(F)cc1F
Product: [Cl-]
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 48.8 %

Procedure:
A mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone(0.5 g), chloromethyl pivalate (15.7 g) and acetonitrile (2.4 g) was stirred for 6.5 hours at 100° C. After having been cooled, the mixture was diluted with diisopropyl ether (10 ml), and the resulting powder was collected by filtration. The powder was subjected to silica gel column chromatography (eluent: ethyl acetate→acetone→acetone/ethanol=10/1→acetone/ethanol=5/1) to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(2,2-dimethylpropanoyloxy)methyl]-1H-1,2,4-triazolium chloride(Compound 2, 0.32 g) as a white powder. The above Compound 2 (0.4 g) was crystallized from ethyl acetate (20 ml) to give white crystals (0.3 g) of Compound 2.
Reaction SMILES: COC1C=[C:5]([CH2:9][CH:10]([CH2:21][CH3:22])[CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=1.[C:23](Cl)(=[O:27])[C:24](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[CH2:34](Cl)Cl>CN(C=O)C>[CH2:21]([CH:10]1[CH2:9][C:5]2[C:6](=[CH:7][CH:8]=[C:23]([O:27][CH3:34])[CH:24]=2)[C:12](=[O:14])[CH:11]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:22]
Reactant: CCC(Cc1cccc(OC)c1)C(C(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC1Cc2cc(OC)ccc2C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 3-{[3-(methyloxy)phenyl]methyl}-2-phenylpentanoic acid (54) (0.98 g, 3.28 mmol) in CH2Cl2 (20 mL) at room temperature was added oxalyl chloride (0.88 mL, 9.85 mmol) followed by one drop of DMF. The mixture was stirred at room temperature overnight. CH2Cl2 and excess of oxalyl chloride were removed under vacuum. The residue was dissolved in CH2Cl2 (30 mL), cooled in an ice bath, AlCl3 (0.67 g, 4.93 mmol) was added. The resulting brown solution was stirred at 0° C. for 5 h. Poured into 1 N HCl (35 mL) with ice, and the mixture was extracted with CH2Cl2. The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (6.5:1) to give 0.84 g (91%) of the title compound (55) as a greenish-yellow oil. 1HNMR indicated it was a mixture of two diastereomers with a ratio of 2:1.
Reaction SMILES: C[NH:2]CCOCCNC.[CH3:10][N:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[NH:13].NC(N)=[NH2+].NC(N)=N.[C:26](=[O:28])=[O:27]>>[C:26](=[O:28])([O-:27])[NH2:2].[CH3:10][N:11]([CH3:17])[C:12](=[NH:13])[N:14]([CH3:16])[CH3:15]
Reactant: O=C=O
Reactant: CNCCOCCNC
Agent: CN(C)C(=N)N(C)C
Agent: N=C(N)N
Agent: NC(N)=[NH2+]
Product: NC(=O)[O-]

Procedure:
A procedure similar to Examples 1 and 2 was carried out using a ˜1:˜2.1 mixture of 1,5-bis(methylamino)-3-oxapentane (BMAOP) with pKa ˜9.87 and 1,1,3,3-tetramethylguanidine (˜1:1.05 mixture on the basis of amine sites) for ˜2 hours. Only one product, a mixed dicarbamate (monocarbamate at each amine site), appeared to form. The 1H NMR spectrum after carboxylation showed movement of the guanidinium protons (in relatively fast equilibrium with any remaining guanidine protons) downfield to ˜9.92 ppm, plus movement of the amine —NCH2— backbone resonance from ˜2.6 to ˜3.2-3.4 ppm. That most of BMAOP molecules reacted was confirmed by the absence of free peaks. Based on integration of the product peak at ˜161.6 ppm compared to the sharp C—O peak of DMAOP at ˜69.89 ppm, ˜99.7 mol % of BMAOP molecules were calculated to have reacted with CO2 to form a mixed carbamate with tetramethylguanidine. The difunctional BMAOP molecules appeared to react with two pairs of tetramethylguanidine and CO2 to form two mixed carbamate moieties per molecule at room temperature (˜199.4 mol % of CO2 per DMAOP molecule).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:17][C@H:18]1[CH2:22][C@@H:21]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][C:26]([N:47]2[CH2:51][CH2:50][C@@H:49]([NH:52][C:53]([NH:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:54])[CH2:48]2)=[N:27][C:28]=3[NH:32][CH2:33][CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:20]([OH:62])[C@@H:19]1[OH:63])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:17][C@H:18]1[CH2:22][C@@H:21]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][C:26]([N:47]2[CH2:51][CH2:50][C@@H:49]([NH:52][C:53]([NH:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:54])[CH2:48]2)=[N:27][C:28]=3[NH:32][CH2:33][CH:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:20]([OH:62])[C@@H:19]1[OH:63]
Reactant: O=C(Nc1cccnc1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)OCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
To a solution of ((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-carbamic acid benzyl ester trifluoroacetate (step 1) (35 mg, 46 μmol) in ethanol (1 ml) under an inert atmosphere of argon is added 10% palladium on carbon (10 mg). The reaction mixture is purged with argon and placed under a positive atmosphere of hydrogen overnight after which time, the mixture is filtered through celite and the catalyst washed with ethanol. The organic portions are combined and concentrated in vacuo to yield the title compound. MS (ES+) m/e 635 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](=[O:16])[N:14]=[N:15][C:11]3=[CH:10][C:9](=[O:17])[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.I([O-])(=O)(=O)=[O:26].[Na+]>CO>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](=[O:16])[N:14]=[N:15][C:11]3=[CH:10][C:9](=[O:17])[N:8]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:7]=2[CH:24]=1)=[O:26]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1
Agent: [Na+]
Solvent: CO
Product: CS(=O)c1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1

Procedure:
3.22 g of 8-(methylthio)-6-phenyl-1H-s-triazolo [4,3-a] [1,5]benzodiazepine-1,5 -dione and 2.14 g of sodium metaperiodate in 500 ml methanol is stirred at +5° C. for 24 hours. The reaction is evaporated; the residue dissolved in methylene chloride, washed with water, dried and concentrated. The concentrate is chromotographed on twenty silica gel (1000μ plates, 20× 20 cm) using acetone-methanol (9:1) as eluting solvent. the band containing the product is removed, stirred with acetone-methanol (4:1) and the silica gel filtered off. The filtrate is evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[C:16]2/[C:17](=O)[N:18]([CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][CH2:21]/2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[C:16]2/[C:17]3[N:18]([CH:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[N:36]=3)[CH2:19][CH2:20][CH2:21]/2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(/C=C2\CCCN(CC(=O)c3ccncc3)C2=O)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C2\CCCn3cc(-c4ccncc4)nc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-1-(2-oxo-2-pyridin-4-ylethyl)piperidin-2-one (150 mg) and ammonium acetate (555 mg) in acetic acid (2 mL) was stirred at 120° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-2-propanol) to obtain 121.5 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([OH:15])=O)=[CH:5]2.[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].C(N=C=NCCCN(C)C)C>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:6]2[NH:7][C:8]3[C:4](=[CH:3][C:2]([F:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:5]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: COc1cc2[nH]c(C(=O)O)cc2cc1F
Agent: CCN=C=NCCCN(C)C
Product: COc1cc2[nH]c(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)cc2cc1F

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-fluoro-6-methoxyindole-2-carboxylic acid (PREPARATION 92, 0.30 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.32 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.33 g), the title compound is obtained, mp 193°-194°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:36][N+:37]#[C-:38])(=O)=O)=CC=1>CO>[O:2]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:13])[N:11]=3)[CH:8]=2)=[CH:38][N:37]=[CH:36]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cnco3)ccc2n1
Yield: 34.9 %

Procedure:
To a suspension of 200 mg of 6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 8) in 10 mL of methanol are added 104 mg of potassium carbonate and 147 mg of para-toluenesulfonylmethylisonitrile (TOSMIC). The reaction mixture is refluxed for 2 hours and then evaporated to dryness under reduced pressure, taken up in 300 mL of dichloromethane and washed with water. The organic phase is dried and concentrated to dryness on silica and then chromatographed on a silica cartridge, eluting with a gradient of from 0 to 20% of methanol in dichloromethane. The fractions containing the expected product are concentrated to dryness and the solid obtained is triturated with a small amount of dichloromethane, filtered off and dried to give 80 mg of 6-(oxazol-5-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)[C:4]#[N:5].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[Cl:12][C:11]1[C:6]([CH:3]([C:4]#[N:5])[NH:2][C:24](=[O:26])[CH3:25])=[N:7][CH:8]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:10]=1
Reactant: N#CC(N)c1ncc(C(F)(F)F)cc1Cl
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C#N)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h

Procedure:
0.67 g of amino[3-chloro-5-(trifluoromethyl)-2-pyridinyl]acetonitrile hydrochloride (0.00245 mol) are dissolved in 15 mL of dichloromethane, 0.68 mL of triethylamine are added. After 10 min. at room temperature, 0.18 mL of acetyl chloride (0.00245 mol) are added, the reaction mixture is stirred overnight. The reaction is quenched with 20 mL of water.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]3[NH:15][CH2:16][CH2:17][CH:11]23)=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.[CH:20](O)=O.Cl>O1CCOCC1>[CH3:20][N:15]1[CH2:16][CH2:17][CH:11]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:14][CH2:13][CH:12]12
Reactant: O=CO
Reactant: O=[N+]([O-])c1ccc(N2CCC3NCCC32)cc1
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC2C1CCN2c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 1-(4-nitrophenyl)octahydropyrrolo[3,2-b]pyrrole (0.7 g), formaldehyde (37%; 0.27 ml), formic acid (0.28 ml) and dioxane (1 ml) was heated to reflux for two hours. The cooled reaction mixture was mixed with hydrochloric acid (2M; 1.7 ml) and concentrated. The residue was taken up in water, and potassium hydroxide was added until the reaction was strongly alkaline. The resulting precipitate was filtered off with suction. The product with the molecular weight of 247.30 (C13H17N3O2); MS (ESI): 248 (M+H+) was obtained in this way.