Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[C:15](=[O:17])[CH3:16].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=2)[CH:11]=[CH:10][C:9]=1[C:15](=[O:17])[CH3:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Potassium carbonate (2.5 eq) was added to a solution of 2′,4′-dihydroxyacetophenone (1 eq) in acetonitrile (400 mL), and the suspension stirred at room temperature. Benzyl bromide (2.5 eq) was added drop wise over 10 minutes and the mixture heated at reflux for 18 hours. The mixture was cooled and evaporated in vacuo to give slurry. The slurry was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was further extracted with dichloromethane and the organic extracts were combined, dried (MgSO4) and evaporated in vacuo. The product was triturated with hexane, filtered and washed with cold hexane and dried in vacuo at 45° C. to give 1-(2,4-Bis-benzyloxy-phenyl)-ethanone as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10][OH:11]>C(OCC)(=O)C.O=[Pt]=O>[CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][OH:11]
Reactant: CC1(C)C2CC=C(CCO)C1C2
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC1(C)[C@H]2CC[C@@H](CCO)[C@@H]1C2
Reaction time: 2.5 h
Yield: 91367.8 %

Procedure:
(−)-Nopol (Aldrich) (66.4 g 0.40 mmol) was dissolved in ethyl acetate (500 mL). PtO2 (2.0 g) was added under N2 atmosphere. The mixture was hydrogenated at 41 psi. Uptake was completed within 2.5 hours. The mixture was filtered, washed with ethyl acetate and concentrated. The residue was distilled at 125-130° C./9.5 mm of Hg. to afford 61.5 g of the title compound.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6](Cl)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>N1C=CC=CC=1.O>[SH:4][C:3]1[N:5]=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:1][N:2]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NNC(N)=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Sc1n[nH]c(-c2cccnc2)n1

Procedure:
To a solution of 19 g (0.200 mol) of thiosemicarbazide in 175 ml of dry pyridine, 29 g (0.200 mol) of nicotinoyl chloride was slowly added at 10° C. After reflux for 40 min. the reaction mixture was concentrated to half the original volume, 500 ml of water was added, and stored in the cold overnight. The precipitate formed was removed by filtration, and the filtrate was evaporated in vacuo. The resulting heavy, yellow oil was dissolved in 300 ml of water, and 64 g (0.600 mol) of sodium carbonate in 400 ml of water was added. After reflux for 4 h the solution was cooled and acidified with conc. hydrochloric acid to pH=4. The formed, colorless precipitate, 65, was isolated by filtration and dried in vacuo. Yield: 35 g (0.297 mol, 98%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)=[O:10]>O1CCCC1>[CH2:20]([N:17]([CH2:18][CH3:19])[C:15]([C:14]1[CH:22]=[CH:23][C:11]([CH:9]([OH:10])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:13]=1)=[O:16])[CH3:21]
Reactant: Br[Mg]c1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Phenylmagnesium bromide (1.0 M solution in tetrahydrofuran, 235 mL, 235 mmol) was slowly added to a flask containing a cold (−78° C.) solution of 4-formyl-N,N-diethylbenzamide (48.18 g, 235 mmol) in 500 mL of dry tetrahydrofuran under nitrogen. The transfer rate was monitored to maintain reaction temperature below −70° C. The reaction was stirred for another 45 minutes at −78° C. and then quenched with 45 mL of saturated aqueous ammonium chloride. After warming to room temperature, the mixture was diluted with 900 mL of diethyl ether and washed with 900 mL of water followed by 230 mL of saturated sodium chloride. The ethereal solution was dried over sodium sulfate and the solvent removed to give crude 4-(N,N-diethylcarbamoyl)benzhydryl alcohol as a light yellow oil. Crude yield was ˜92%.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:33])[NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:36][CH2:37][CH2:38][OH:39]>CCCCCC.C(OCC)(=O)C>[OH:39][CH2:38][CH2:37][NH:36][C:5]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:33]
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Reactant: NCCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)NCCO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 59%. Melting point: 152-155° C. (hexane-ethyl acetate).
Reaction SMILES: Cl[CH:2]1[CH2:8][CH:7]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:5][NH:4][C:3]1=[O:12].[N-:13]=[N+:14]=[N-:15].[Na+].C(Cl)Cl>CS(C)=O.O>[N:13]([CH:2]1[CH2:8][CH:7]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:5][NH:4][C:3]1=[O:12])=[N+:14]=[N-:15]
Reactant: CC(C)C1CCNC(=O)C(Cl)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)C1CCNC(=O)C(N=[N+]=[N-])C1
Temperature: 25 °C

Procedure:
3-Chloro-5-isopropyl-azepan-2-one (3.4 g, 18 mmol) and sodium azide (3.51 g, 53.9 mmol) were reacted in dry dimethyl sulfoxide (50 ml) overnight at 80° C. under an argon atmosphere. The reaction mixture was allowed to cool to r.t. diluted with water (200 ml) and extrated with CH2Cl2 (4×). The combined organic fractions were washed with water (3×), brine and dried (MgSO4) filtered and evaporated under reduced pressure. The crude yellow oil was purified over silica gel (ethyl acetate/n-heptane 1:2): yellow oil 2.6 g (70%); MS: m/e=197.4 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: ClCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.0 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.262 g), stirred for 15 minutes and treated with chloromethoxybenzene (1.1 g). The mixture was heated at 60° C. for 1.5 hours and worked up as in Example 20. The material was crystallized from diethyl ether-hexane to provide 1 g of alpha-oxo-4-[[(phenoxy)methyl]oxy]benzeneacetic acid methyl ester, mp 52°-54° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>>[C:10]([N:9]=[C:12]([NH2:13])[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)#[N:11]
Reactant: N#C[N-]C#N
Reactant: Nc1cccc(F)c1
Agent: [Na+]
Product: N#CN=C(N)Nc1cccc(F)c1

Procedure:
A solution of 3-fluoroaniline and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(=O)(O)[O-].[Na+]>CCOCC>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[NH:2][C:12](=[O:14])[CH3:13]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49435.4 %

Procedure:
A mixture of 2-aminoindan hydrochloride (13.3 g, 78 mmol), acetic anhydride (6 g, 0.157 mmol) and saturated sodium bicarbonate (100 mL) in ether (100 mL) was stirred at room temperature for 1 h. The organic phase was separated, and the aqueous layer back washed with ether. The combined organic layer was washed with saturated chloride solution, dried over magnesium sulfate, filtered and evaporated to give the acetamide (13.6 g) in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1>O.O1CCOCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:15]2[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:19])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Br)ccc1C=C1C(=O)OC(C)(C)OC1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 4-bromo-2-methylbenzaldehyde (1.99 g, 10.00 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (2.16 g, 15.0 mmol) in water (20 mL) and 1-4-dioxane (2 mL) was heated at about 75° C. for about 2 h. Additional 2,2-dimethyl-1,3-dioxane-4,6-dione (0.72 g, 5.0 mmol) was added and heating at about 75° C. was continued for about 2 h. The reaction was cooled to rt and solids were filtered off and rinsed with water (25 mL). The resulting solid was air dried on the funnel and then triturated with Et2O (about 20 mL) and filtered. The product was dried overnight in the vacuum oven at about 50° C. to yield 5-(4-bromo-2-methylbenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.75 g, 8.46 mmol, 85%) as a pale yellow solid: LC-MS (Table 1, Method g) Rt=2.43 min, m/z 341/343 (M−H+NH3)−; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.51-7.42 (m, 2H), 2.33 (s, 3H), 1.77 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:48][C:49]12[CH2:56][CH:53]([NH:54][CH2:55]1)[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]2>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:54]2[CH2:55][C:49]3([CH3:48])[CH2:56][CH:53]2[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]3)=[O:15])=[CH:16][CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a mixture of 4-tert-butoxycarbonylamino-benzoic acid (50 g, 0.21 mol) and HOBT (31.33 g, 0.231 mol) in dry THF (0.5 L) was added EDAC (44.44 g, 0.231 mol). The resulting mixture was stirred for 10 min followed by addition of a mixture of DIPEA (40.4 ml, 0.231 mol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (39.4 ml, 0.231 mol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. To the residue was added water (600 ml) and the resulting mixture was extracted with EtOAc (3×500 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:2) as eluent. Pure fractions were collected and evaporated to dryness. To the solid residue was added diethyl ether (100 ml) and the precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50° C. affording 60.5 g (77%) of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester as a solid.
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[C:8](=[S:9])[NH:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:5]1)([CH3:3])[CH3:2].C([Li])(CC)C.[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C1CCCCC1>[Cl:23][C:12]1[CH:11]=[C:10]([C:6]2[NH:7][C:8](=[S:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:17])[N:5]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccc(C2=NC(C)(C(C)C)C(=S)N2)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc(C2=NC(C)(C(C)C)C(=S)N2)cc1Cl
Temperature: 25 °C

Procedure:
A mechanically stirred solution of 20.0 g of 4-isopropyl-4-methyl-2-p-tolyl-2-imidazolin-5-thione in 200 mL of dry tetrahydrofuran is treated dropwise with 160 mL of a 1.2M solution of sec-butyl lithium (0.191 mol) in cyclohexane over a 40 minute period at -72° to -65° C. After stirring the resulting solution at -40° to -35° for one and one-half hours, a solution of 21.4 g (0.090 mol) of hexachloroethane in 125 mL of dry tetrahydrofuran is added dropwise. Addition temperature is allowed to reach -20° C. After warming to room temperature over a 16 hour period, the reaction is treated with 200 mL of ice water plus 200 mL of a saturated sodium chloride solution. The mixture is carefully acidified to pH 3 with concentrated sulfuric acid. The phases are separated and the aqueous phase is extracted with 200 mL ether. The organic phases are combined, dried over magnesium sulfate and concentrated to an oily residue. The residue is purified by chromatography on silica gel to give pure 2-(2-chloro-p-tolyl)-4-isopropyl-4-methyl-2-imidazolin-5-thione.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:2]2([CH3:1])[CH2:7][CH2:6][C:5]3[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=3[O:3]2)[CH2:18][CH2:19]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN1CCNCC1)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN1CCN(C(=O)c3ccccc3)CC1)O2
Reaction time: 1 h

Procedure:
To stirred solution of 3,4-dihydro-2,5,7,8-tetramethyl-2-(1-piperazinylmethyl)-2H-1-benzopyran-6-ol (EXAMPLE 126, 0.3 g, 1.0 mmol), triethylamine (0.11 g, 1.1 mmol) and methylene chloride (3 ml) is added dropwise over 1-2 min a solution of benzoyl chloride (0.16 g, 1.1 mmol) in methylene chloride (2 ml). The mixture is stirred at 20°-25° for 1 hr and diluted with methylene chloride (20 ml), washed with water (20 ml), dried over sodium sulfate and the solvent removed at reduced pressure to leave a residue. The residue is flashed chromatographed on silica gel (25 g) eluting with ethyl acetate/hexane (1/1) to give the product as an oil that is crystallized from ether to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[C:11]#[N:12].[Cl-].[Cl:14][C:15](Cl)=[N+:16]([CH3:18])[CH3:17]>ClCCl>[C:7]([C:4]1[C:3]([C:11]#[N:12])=[C:2]([N:1]=[C:15]([Cl:14])[N:16]([CH3:18])[CH3:17])[S:6][N:5]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: C[N+](C)=C(Cl)Cl
Reactant: CC(C)(C)c1nsc(N)c1C#N
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)C(Cl)=Nc1snc(C(C)(C)C)c1C#N
Yield: 67.7 %

Procedure:
In the manner of Example VI, 9.1 g of 5-amino-3-tert-butyl- 4-cyanoisothiazole and 9.8 g of N-(dichloromethylene)-N,N-dimethylammonium chloride were allowed to react in 50 ml of dichloromethane. The volatile materials were evaporated under reduced pressure. The residue was recrystallized from hexane to give 9.2 g of N'-(3-tert-butyl-4 -cyano-5-isothiazolyl)-N,N-dimethylchloroformamidine, mp 94°-100°. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: N[C:2]1[C:3]([I:13])=[C:4]([C:8]([I:12])=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].S(=O)(=O)(O)O.[OH-].[Na+].[C-:25]#[N:26].[K+]>[Cu]Cl.O>[C:25]([C:2]1[C:3]([I:13])=[C:4]([C:8]([I:12])=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6])#[N:26]
Reactant: [C-]#N
Reactant: Nc1c(I)cc(I)c(C(=O)O)c1I
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1c(I)cc(I)c(C(=O)O)c1I
Temperature: 30 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
20.6 g. of 3-amino-2,4,6-triiodobenzoic acid is suspended in 220 ml. of water. After the dropwise addition of 24 ml. of a 30% aqueous sodium nitrite solution at 0° C., the pH value is brought down to 2 by adding dilute sulfuric acid. The batch is then stirred for one hour in an ice bath. By the gradual, dropwise addition of dilute sodium hydroxide solution, the batch is raised to pH 4.5, and the solution is allowed to stand under ice cooling. In the meantime, a solution of 20 g. of copper(I) chloride and 34 g. of potassium cyanide in 160 ml. of water has been prepared, warmed to 30° C., and the diazotization solution is added thereto all at once, under the occurrence of strong frothing. The mixture is stirred for another 15 minutes at 30° C. and then the copper salts are separated by acidifying the reaction solution to pH 3 with concentrated hydrochloric acid. The filtrate is brought to pH 0.5- 1 by the further addition of concentrated hydrochloric acid, and the precipitate, after several hours of agitation in an ice bath, is vacuum-filtered and washed with water. The compound, moist from vacuum-filtering, is suspended in 50 ml. of water, dissolved by adding dilute sodium hydroxide solution, and the solution is treated by stirring with activated carbon and filtered to a clear state. By adding drops of concentrated hydrochloric acid, the solution is brought to pH 0.5-1 and then stirred for several hours in an ice bath; the precipitate is vacuum-filtered. After washing with acetone-containing water and drying at 50° C., 16 g. (76% of theory) of 3-cyano-2,4,6-triiodobenzoic acid is obtained as a white powder, m.p. 238°-240° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.Cl[C:35]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:40]=1>>[CH2:35]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:32][CH3:33])(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])=[CH:24][CH:25]=1)[CH3:40]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1

Procedure:
4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=485.2 (M−H), was prepared in analogy to example 30, steps 1 to 6. Step 5 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride, yielding 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([I:11])=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:19])C(=O)C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:19][C:10]1[N:9]=[C:8]([I:11])[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: Clc1nccn2c(I)ncc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nccn2c(I)nc(Br)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 8-chloro-3-iodo-imidazo[1,5-a]pyrazine (730.0 mg, 2.61 mmol) in DMF (8.00 mL) was added NBS (557.9 mg, 3.13 mol) in 3 portions at 0° C. The resulting mixture was allowed to warm up to rt. and stirred at rt. for 2 hours. To the mixture was added 30 mL saturated NaHCO3 aq. solution, extracted with DCM (20 mL×3). Organic phase was combined and dried (Na2SO4) and evaporated to give crude material which was used in next step without further purification. 1H NMR (400 MHz, MeOD) δ 7.48 (d, J=5.1 Hz, 1H) 8.02 (d, J=5.1 Hz, 1H). MS (ES: m/z: 357.68, 359.67, 361.68 [MH+]. HPLC: tR=3.22 min (OpenLynx: polar—5 min).
Reaction SMILES: BrCC1(CO)COC1.[N:9]([CH2:12][C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1)=[N+:10]=[N-:11].[N-]=[N+]=[N-].[Na+].ClCC1(CO[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)COC1.ClCC1(C)COC1>CC(C)=O.O>[N:9]([CH2:12][C:13]1([CH2:17][O:18][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:16][O:15][CH2:14]1)=[N+:10]=[N-:11]
Reactant: ClCC1(COc2ccccc2)COC1
Reactant: [N-]=[N+]=NCC1(CO)COC1
Agent: CC1(CCl)COC1
Agent: OCC1(CBr)COC1
Agent: [N-]=[N+]=[N-]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCC1(COc2ccccc2)COC1
Yield: 87 %

Procedure:
As such, it has been discovered that monofunctional azidooxetane compounds, i.e., 3-azidomethyl-3-R1 -oxetanes, can also be prepared by combining a neat halooxetane with an aqueous metallic azide solution and a phase transfer catalyst (PTC). For example, using the process of the present invention, 3-chloromethyl-3-methyloxetane gives the corresponding 3-azidomethyl-3-methyloxetane (AMMO) in 97% yield. Moreover, 3-bromomethyl-3-hydroxymethyloxetane was previously converted to the corresponding 3-azidomethyl-3-hydroxymethyloxetane in acetone. Using the process of the present invention, however, 3-bromomethyl-3-hydroxymethyloxetane is converted to the corresponding 3-azidomethyl-3-hydroxymethyloxetane, without the use of an organic solvent, using an aqueous sodium azide solution and a phase transfer catalyst. The process of the present invention gives the same result with a faster rate of reaction and without the use of an organic solvent. In addition, 3-chloromethyl-3-methyloxetane 3-chloromethyl-3-phenoxymethyloxetane reacts with an aqueous solution of sodium azide in water with a PTC to give 3-azidomethyl-3-phenoxymethyloxetane in 87% yield.