Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[C:21]([CH3:36])[CH:20]=2)[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][CH:7]=1)#[N:2].Cl.C(N(CC)CC)C.[N-:46]=[N+:47]=[N-:48].[Na+].Cl>C1(C)C=CC=CC=1.O>[CH3:36][C:21]1[CH:20]=[C:19]([O:18][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([C:5]([NH:4][CH2:3][C:1]3[NH:48][N:47]=[N:46][N:2]=3)=[O:37])=[CH:11][CH:10]=2)[CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:24]=[C:23]([CH3:25])[C:22]=1[C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=1
Reactant: Cc1cc(OC(CC(C)(C)C)c2ccc(C(=O)NCC#N)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(OC(CC(C)(C)C)c2ccc(C(=O)NCc3nnn[nH]3)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
N-Cyanomethyl-4-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-benzamide (160 mg, 0.32 mmol) is dissolved in toluene (20 mL). Triethylamine hydrochloride (132 mg, 0.96 mmol) is added followed by sodium azide (62 mg, 0.96 mmol) and then the reaction is refluxed for 24 h. The mixture is allowed to cool to room temperature, poured into water and adjusted to pH=3 with aqueous HCl. The product is extracted into ethyl acetate, dried, and concentrated to give 145 mg (82%) of the titled compound. MS (ES): 552.2 [M+1]+, 550.2 [M−1]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[C@H:21]12[CH2:29][NH:28][CH2:27][C@@H:26]1[NH:25][CH2:24][CH2:23][O:22]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:28]1[CH2:29][C@H:21]3[C@@H:26]([NH:25][CH2:24][CH2:23][O:22]3)[CH2:27]1)[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)cc2c1=O
Reactant: C1CO[C@H]2CNC[C@@H]2N1
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(N3C[C@@H]4NCCO[C@H]4C3)c(F)cc2c1=O

Procedure:
The title compound is prepared analogously to the procedure of Example 8 by reaction of 6,7-difluoro-1-((1R,2S)-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (1S,6S)-2-oxa-5,8-diazabicyclo[4.3.0] nonane
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][N:14]=2)[CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)=[N:14][CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(-n2ccc(C(=O)OC(C)(C)C)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2ccc(C(=O)O)c2)nc1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 1-(5-acetylpyridin-2-yl)pyrrole-3-carboxylic acid tert-butyl ester (380 mg) in dichloromethane (5 ml) were added trifluoroacetic acid (3 ml) and water (0.3 ml), and stirred at room temperature. After completion of the reaction, the solvent was evaporated in vacuo, to the residue was added water, 1 N aqueous solution of sodium hydroxide was added thereto under ice-cooling to adjust the mixture to pH 10, diethyl ether was added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling, the precipitated solid was collected by filtration, and dried at 60° C. under air blow to give the titled compound (300 mg) as a white solid. MS (ESI) m/z: 231
Reaction SMILES: [CH:1]1([NH:4][CH3:5])[CH2:3][CH2:2]1.FC(F)(F)S([O-])(=O)=O.[N:14]1([S:19](N2C=C[NH+](C)C2)(=[O:21])=[O:20])[CH:18]=[CH:17][N:16]=[CH:15]1>>[CH:1]1([N:4]([CH3:5])[S:19]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)(=[O:21])=[O:20])[CH2:3][CH2:2]1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Reactant: CNC1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(C1CC1)S(=O)(=O)n1ccnc1

Procedure:
Imidazole-1-sulfonic acid cyclopropyl-methyl-amide was prepared in accordance with step A of the general method described in example 76 from cyclopropyl-methylamine and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=202.5 (M+H+).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([N:7]2[C:11](=[O:12])[CH2:10][CH:9]([C:13](OC)=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.B.[Na].CO.Cl>O1CCCC1.O>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH:9]([CH2:13][OH:14])[CH2:10][C:11]2=[O:12])=[CH:5][CH:6]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(C)cc2)C1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N2CC(CO)CC2=O)cc1
Yield: 98.3 %

Procedure:
Methyl 1-(4-tolyl)-5-oxo-3-pyrrolidinecarboxylate (46.00 g) and sodium boron hydride (5.94 g) are suspended in tetrahydrofuran (460 ml) and to the mixture is added dropwise methanol (46.2 ml) over a period of 1 hour under refluxing. The mixture is further heated for 1 hour. After cooling the reaction mixture, conc. hydrochloric acid (13.7 ml) and water (about 5 ml) are added thereto and then the mixture is concentrated under reduced pressure. Methylene chloride (400 ml) is added to the residue and the insoluble material is removed by filtration. The filtrate is washed with water (about 100 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product (39.80 g) as solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]3[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](O)[CH3:32]>C1(C)C=CC=CC=1.O>[C:16]1([C:2]2[CH:15]=[CH:14][C:5]3[S:6][C:7]4[CH:12]=[CH:11][C:10]([C:32]5[CH:31]=[CH:4][CH:3]=[CH:2][CH:15]=5)=[CH:9][C:8]=4[C:4]=3[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc2sc3ccc(Br)cc3c2c1
Reactant: CCO
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3sc4ccc(-c5ccccc5)cc4c3c2)cc1

Procedure:
2,8-dibromo-dibenzo[b,d]thiophene (14 g), phenylboronic acid (11.0 g) tetrakis(triphenylphosphine)palladium (3.8 g) and potassium carbonate (20 g) were refluxed together in a mixture of toluene (110 mL), ethanol (20 mL) and water (90 mL) overnight. The reaction was quenched with water and the toluene layer was removed and passed through a celite column and the toluene layer was evaporated in a rotary evaporator to yield 6.0 g 2,8-diphenyl-dibenzo[b,d]thiophene.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1.[F:54][C:55]([F:59])([F:58])[CH2:56][NH2:57]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:57][CH2:56][C:55]([F:59])([F:58])[F:54])=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:18])([F:19])[F:20])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: O=C(NCC(F)(F)F)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 98 %

Procedure:
As described for example 92, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, using 2,2,2-trifluoroethylamine instead of cyclopropylamine, to the title compound (115 mg, 98%) which was obtained as a white solid. MS: m/e=464.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5](B(O)O)[C:4]1=[O:30])[CH3:2].Br[C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][C:33]=1[Cl:42].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC.O>[Cl:42][C:33]1[CH:34]=[C:35]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=[CH:37][C:32]=1[C:5]1[C:4](=[O:30])[N:3]([CH2:1][CH3:2])[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: CCn1c(=O)c(B(O)O)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Reactant: CS(=O)(=O)c1ccc(Br)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCn1c(=O)c(-c2ccc(S(C)(=O)=O)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 36.7 %

Procedure:
8-Ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-boronic acid (5, 100 mg, 0.24 mmol), 1-bromo-2-chloro-4-methylsulfonylbenzene (9, 75 mg, 0.28 mmol), sodium carbonate (80 mg, 0.75 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) were mixed under argon in a degassed mixture of dimethoxyethane:water (10:1, 2.5 mL). The resulting suspension was irradiated for 30 min at 120° C. in a microwave reactor. After completion, the reaction mixture was evaporated and the residue was purified by column chromatography using dichloromethane:methanol (100:3) as eluent, The crude product was triturated with isopropyl ether (10 mL) and collected. The title compound (49 mg, 0.088 mmol, 37%) was obtained as a yellow solid. ESMS m/z 553 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J=2.0 Hz, 1H) 7.86 (d, J=8.3 Hz, 1H) 7.69 (dd, J=8.3, 2.0 Hz, 1H) 3.08 (s, 3H).
Reaction SMILES: [NH2-:1].[Na+].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.[C:23]([NH2:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>C1(C)C(C)=CC=CC=1>[NH2:1][C:27]1[CH:28]=[CH:29][C:24]([C:23]([NH2:31])=[O:30])=[CH:25][N:26]=1
Reactant: [NH2-]
Reactant: NC(=O)c1cccnc1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: NC(=O)c1ccc(N)nc1
Temperature: 25 °C
Yield: 17.4 %

Procedure:
A mixture of 50.7 g (1.3 moles) of sodamide preformed in situ as in Example 1, 400 cc of xylene containing 0.1 cc of oleic acid and 73.3 g (0.6 mole) of nicotinamide was placed in an autoclave such as the one described in Example 2. The autoclave was closed and purged of air with ammonia. It was pressurized to 60 psig with ammonia and 200 psig with nitrogen. The pressure relief valve was set at 360 psig. The autoclave was heated to 122°-145° C. and maintained within this temperature range for 3 hours during which time hydrogen was evolved. The reaction mixture was cooled to room temperature and carefully hydrolyzed with 150 cc of water. Maximum temperature during hydrolysis was 18° C. The hydrolyzed mixture was filtered. The filter cake was washed with water and dried to give 14.3 g of 6-aminonicotinamide, m.p. 240°-247° C. The aqueous phase of the filtrate was separated and adjusted to pH 6.0 with concentrated hydrochloric acid. A precipitate formed which was filtered, washed with water and dried to give 5.4 g of 6-aminonicotinic acid, m.p. 314° C. with decomposition. The yield of 6-aminonicotinamide was 17.4% and the yield of 6-aminonicotinic acid was 6.5%. Both structures were confirmed by IR and NMR spectra. This result significantly differed from prior art references which report the classic Chichibabin amination product of nicotinamide to be exclusively 2-aminonicotinamide. Caldwell, Tyson and Lauer, J. Am. Chem. Soc., 66, 1479 (1944). Uses for the 6-aminonicotinic acid product of applicants' reaction were the same as stated in Example 4, whereas the recovered 6-aminonicotinamide was found effective as a rodenticide as reported in Johnson, Can. Pat. No. 1,089,763, for its inhibitory effect against Lactobacillus arabinosus as reported in Kitamura, et al., Yakugaku Zasshi, 95, 547 (1975).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>C(N(CC)CC)C>[CH2:11]([N:13]([CH2:14][CH3:15])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCNCC
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
4-Iodobenzoyl chloride (10.0 g) was added portionwise to diethylamine (2.92 g) in triethylamine (40 ml) at 20°. The resulting slurry was stirred at room temperature for 1 h, diluted with ER (150 ml), filtered and evaporated to give the title compound as an orange solid (10.2 g) m.p. 68°-70°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:20]N1C(=O)CCC1=O>ClCCl.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[S:12][C:13]([I:20])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: NC(=O)c1ccsc1NC(=O)OCc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(I)sc1NC(=O)OCc1ccccc1

Procedure:
To a solution of benzyl[3-(aminocarbonyl)-2-thienyl]carbamate (4.39 g, 15.88 mmol) in dichloromethane (440 mL) was added N-iodosuccinimide (3.57 g, 15.88 mmol). An additional amount of N-iodosuccinimide (1.07 g) was added in 3 portions over the next 60 min to drive the reaction to completion. The dark reaction mixture was diluted with ethyl acetate (700 mL), hexanes (100 mL), aqueous sodium thiosulfate (1 M, 150 mL), and aqueous sodium hydroxide (1 M, 300 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[C:11]([CH3:17])[CH:10]=2)[S:5][C:6]=1[Cl:7].CO[CH:20](OC)[N:21]([CH3:24])[CH2:22][CH3:23].C1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([N:13]=[CH:20][N:21]([CH2:22][CH3:23])[CH3:24])=[C:11]([CH3:17])[CH:10]=2)[S:5][C:6]=1[Cl:7]
Reactant: CCN(C)C(OC)OC
Reactant: Cc1cc(Oc2nc(Cl)c(Cl)s2)c(C)cc1N
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(Cl)c(Cl)s2)cc1C
Temperature: 105 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
To a mixture of 2.0 g (6.9 mmol) of 4-[(4,5-dichloro-1,3-thiazol-2-yl)oxy]-2,5-dimethylaniline in 2.5 ml toluene a solution of 9.7 mmol of N-(dimethoxymethyl)-N-methylethanamine (60% in methanol) was added. The reaction mixture was stirred for 16 hrs at 105° C. The reaction mixture was concentrated in vacuo. Column chromatographie (gradient: cyclohexane->ethyl acetate) yielded 2.4 g (6.7 mmol) 97% of N′-{4-[(4,5-dichloro-1,3-thiazol-2-yl)oxy]-2,5-dimethylphenyl}-N-ethyl-N-methylimidoformamide; log P (pH 2.3)=2.04
Reaction SMILES: [C:1]1([C:7]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:8][CH2:9][C@@H:10]2[O:16][C@H:15]([CH2:17][O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:13]([OH:14])[C@@H:11]2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.CO>CN(C)C=O>[C:53]1([CH2:52][O:14][C@H:13]2[C@H:11]([O:12][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C@@H:10]([CH2:9][O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:16][C@H:15]2[CH2:17][O:18][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: BrCc1ccccc1
Reactant: O[C@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(CO[C@H]2[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 165.7 %

Procedure:
A solution of 800 mg of 2,5-anhydro-1,6-bis-O-(triphenylmethyl)-D-glucitol in 16 ml of dry dimethylformamide was treated with 240 mg of freshly washed sodium hydride. The mixture was stirred 1.5 hours, then 1.30 g of benzyl bromide was added and stirring continued for 2.5 days. Methanol was added, the solvents removed in vacuo and the residue taken up in chloroform/water. The organic layer was washed with water and brine, then dried and evaporated, giving a yellow oil which was flash chromatographed, eluting with hexane:ethyl acetate (12:1), giving 847 mg of the desired compound.
Reaction SMILES: O=C1C[C:6](=O)[CH2:5][CH:4]([C:9]([OH:11])=O)[CH2:3]1.S(N=[N+]=[N-])(N=[N+]=[N-])(=O)=O.C1(C)C=CC(S(N=[N+]=[N-])(=O)=[O:28])=CC=1.C(N(CC)CC)C.[CH2:41]([OH:43])C>C(#N)C.C1C=CC=CC=1>[CH2:41]([C:4]([CH2:3][OH:28])([CH2:9][OH:11])[CH2:5][CH3:6])[OH:43]
Reactant: O=C1CC(=O)CC(C(=O)O)C1
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-]
Solvent: CC#N
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(CO)(CO)CO

Procedure:
The compounds useful as solubilization inhibition agents according to this invention can be easily prepared, for example, by esterifying 3,5-dioxocyclohexane carboxylic acid with the alkanol according to known esterification procedures and converting the resulting 3,5-dioxocyclohexane carboxylic acid ester to the corresponding 4-diazo-3,5-dioxocyclohexane carboxylic acid ester by reacting the ester with any suitable sulfonylazide, such as p-toluenesulfonyl azide (TSA) or naphthylenesulfonyl azide (NSA), in the presence of a catalyst such as dry triethylamine and any suitable solvent such as ethanol, benzene or acetonitrile any the like. Generally after reacting for a period of about 3 to about 15 hours the reaction mixture is filtered to remove the precipitated sulfonamide and the filtrate is evaporated to dryness. The product may then be partially purified by partitioning between methylene chloride and dilute alkali hydroxide. The residues may be purified either by recrystallization, if the product is a solid, or by chromatography, such as flash chromatography on silica gel if the product is an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C(C1C=CC=CC=1)CCC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCc1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 832 mg (5.52 mmol) of 2-cyclopropyl-6-methylphenol were added normal butylbenzene (2.76 g) and 333 mg (5.65 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 308 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 61%) and 2.9 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][C:10]#[CH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:9][C:10]#[CH:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCC(O)c1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reaction time: 0.08 h
Yield: 31.7 %

Procedure:
A solution containing 19 g (84.5 mmol) of the semi-purified reaction product of Example 1 dissolved in 50 ml of DMF was cooled to 0° C. (ice bath) and 12.9 g (190 mmol) of imidazole was added in one portion. The reaction mixture was stirred 10 minutes until all the imidazole dissolved and then was added in one portion 14.3 g (95 mmol) of t-butyldimethylchlorosilane. After stirring for 5 minutes, the ice bath was removed and the reaction mixture was stirred for an additional 2 hr. at R.T. The reaction was then poured into 500 ml of ether and washed 3× with 50 cc of H2O and 1× with 100 ml of brine. The organic layer was then separated, dried (MgSO4), and removal of all solvent yielded 29.32 g of crude product. Separation by reverse phase HPLC (gradient elution with acetonitrile-water) yielded 9.1 g of the titled product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2].Br[CH2:17][C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:17][C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC1=Nc2ccccc2NC(=O)C1
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Temperature: -17 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(A) (5.0 g, 24.5 mmol) in DMF (100 mL) was added potassium bistrimethyl silyl amide (49 mL of 0.5 M solution in toluene, 24.5 mmol) at 0° C. The reaction mixture was stirred for 20 minutes and was cooled to −17° C. A solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1 (A) (6.9 g, 27 mmol) in DMF (50 mL) was added dropwise so the internal temperature remained below −15° C. The reaction mixture was stirred at −16° C. for 1 hour, was warmed to room temperature and was diluted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and was concentrated. The resulting pale brown solid was triturated with ether to obtain 3.2 g of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide as a white powder. The filtrate was concentrated and the residue was triturated with ether/hexanes. The solid was collected by filtration to give a second crop of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (3.4 g). MS 380.2 (M+1).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[CH2:21]1[CH2:26][O:25][CH:24]=[CH:23][CH2:22]1>>[O:25]1[CH2:26][CH2:21][CH2:22][CH2:23][CH:24]1[O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: C1=COCCC1
Product: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=O

Procedure:
The THP ether 60, which was prepared from estrone 1 (6.3 g, 23.3 mmol) and DHP (3.0 g, 33 mmol) using the same procedure as described for compound 35, was obtained as a white solid (7.5 g, 91%): 1 H NMR (300 MHz, CDCl3) δ0.91 (s, 3, CH3), 2.89 (m, 2), 3.60 (m. 1), 3.92 (m, 1), 5.40 (m, 1), 6.81 (d, J=2.5 Hz, 1, ArH), 6.86 (dd, J=2.5, 8.5 Hz, 1, ArH), 7.20 (d, J=8.5 Hz, 1, ArH).