Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:16]1=[O:29])[CH3:14].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].[Cl-].[NH4+]>O1CCCC1>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][C:15]1([CH2:13][CH3:14])[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:16]1=[O:29])[CH3:36]
Reactant: CCC1CCN(Cc2ccc(OC)cc2)C1=O
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC1(CC)CCN(Cc2ccc(OC)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (3.4 mL) in tetrahydrofuran (10 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 15 mL) at −78° C. under nitrogen atmosphere, and the mixture was warmed to 0° C., and stirred for 30 min. The reaction mixture was cooled to −78° C., a solution of 3-ethyl-1-(4-methoxybenzyl)pyrrolidin-2-one (2.8 g) obtained in Step B in tetrahydrofuran (10 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hr. Ethyl bromoacetate (4.0 mL) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.5 g).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C@:3]([C:10]1[S:14][C:13]([S:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[CH:21][C:22](=[O:26])[O:23]3)=[CH:18][CH:17]=2)=[N:12][CH:11]=1)([OH:9])[CH2:4][C:5](OC)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:9][C@@:3]([C:10]1[S:14][C:13]([S:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)=[CH:21][C:22](=[O:26])[O:23]3)=[CH:18][CH:17]=2)=[N:12][CH:11]=1)([C:2]([F:1])([F:35])[F:34])[CH2:4][CH2:5][OH:6]
Reactant: COC(=O)C[C@](O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(Sc3ncc([C@@](O)(CCO)C(F)(F)F)s3)cc2o1
Reaction time: 0.42 h

Procedure:
To methyl(3R)-4,4,4-trifluoro-3-(2-{[4-(4-fluorophenyl)-2-oxo-2H-chromen-7-yl]thio}-1,3-thiazol-5-yl)-3-hydroxybutanoate (0.120 g) in THF at −90° C. was added an ethereal solution of LAH 1.0M (0.29 mL) dropwise. After 25 minutes, the solution was quenched with NH4Cl and brought to rt. After extraction with EtOAc, the solution was dried over MgSO4 and the solvent removed under vacuum. This crude mixture was then treated with NaBH4 in methanol at 0° C. for 15 minute. The mixture was quenched with NH4Cl and extracted with EtOAc. After flash chromatography on silica gel (hexane/EtOAc; 55:45) the title compound was isolated. 1H NMR (400 MHz, acetone-d6): δ 7.90 (s, 1H), 7.68 (m, 2H), 7.62 (s, 1H), 7.56 (dd, 1H), 7.47 (dd, 1H), 7.38 (t, 2H), 6.67 (s, 1H), 6.41 (s, 1H), 4.68 (t, 1H), 3.85 (m, 2H), 2.45 (m, 1H), 2.37 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:14]([OH:21])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16])[CH2:9][CH:10]1[CH2:13][CH2:12][CH2:11]1)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:7][C@@H:8]([CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13]1)[CH:14]([OH:21])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl-(2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-ylcarbamate (51 mg, 0.165 mmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (3.0 mL) was added. After stirring for 1 hour at room temperature, the reaction mixture was evaporated to dryness to give (3S)-3-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxy-butanamide trifluoroacetic acid salt as a white solid. A solution of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxylic acid in dichloromethane/N,N-dimethylformamide (1:1, 6.0 mL) was added to the (3S)-3-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxy-butanamide trifluoroacetic acid salt followed by O (7 azabenzotriazol 1 yl) 1,1,3,3 tetramethyl-uronium hexafluorophosphate (HATU) (75 mg, 0.198 mmol) and diisopropylethylamine (0.1 mL, 0.7 mmol). After 24 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate, and brine. The ethyl acetate layer was dried (magnesium sulfate), filtered and evaporated to dryness under reduced pressure. The crude product was then dissolved in dry dichloromethane (10.0 mL) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane reagent, 112 mg, 0.264 mmol) added. After stirring at room temperature for 2 hours, the reaction mixture was quenched with 0.26M sodium thiosulfate in saturated sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layers were then washed with saturated sodium bicarbonate and brine. Purification by preparative HPLC gave (2S,4R)-1-((S)-(3-tert-butylureido)-3,3-dimethylbutanoyl]-N-((S)-1-cyclobutyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)-quinolin-4-yloxy)pyrrolidine-2-carboxamide in >99% purity by HPLC.
Reaction SMILES: [Na].[CH3:2][OH:3].[N+:4]([O:7][CH2:8][C:9]([CH2:17][O:18][N+:19]([O-:21])=[O:20])([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:10]Br)([O-:6])=[O:5]>O>[N+:4]([O:7][CH2:8][C:9]([CH2:17][O:18][N+:19]([O-:21])=[O:20])([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:10][O:3][CH3:2])([O-:6])=[O:5]
Reactant: O=[N+]([O-])OCC(CBr)(CO[N+](=O)[O-])CO[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Solvent: O
Product: COCC(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Yield: 75 %

Procedure:
0.025 mol of sodium and 0.12 mol of absolute methanol are used to prepare the methylate solution. 0.02 mol of 3-nitryloxy-2,2-bis(nitryloxymethyl)propyl bromide is added and the mixture is refluxed for 5 hours, with stirring and with the exclusion of moisture. After cooling, the reaction mixture is added to 5 times the amount of water and the ether (Me-PETriN ether) is separated off, washed again with water, dried and purified by column chromatography. Yield: 75%. Elemental analysis: (C: conforms, H: conforms, N: conforms).
Reaction SMILES: [CH3:1][C:2](O)([CH3:5])[CH:3]=[CH2:4].[C:7]([OH:10])(=[O:9])[CH3:8].B(O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:7]([O:10][CH2:4][CH:3]=[C:2]([CH3:5])[CH3:1])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: C=CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: OB(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)OCC=C(C)C
Reaction time: 4 h

Procedure:
A mixture of 3-methyl-3-hydroxybut-1-ene (32 g.), acetic acid (150 ml.) and boric acid (30 g.) was stirred at 105° for 4 hours. The cooled reaction mixture was diluted with water, neutralised with solid sodium carbonate and extracted with ether (3 × 50 ml.) The combined ethereal extracts were brine washed, dried and the solvent removed giving a pale yellow oil (30 g.) Distillation gave 3,3-dimethylallyl acetate as a colourless oil (22 g.) b.p. 44°-45°/14 mm Hg.
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]([F:31])([F:30])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=O.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[S:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[S:22]([N:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]([C:7]([F:31])([F:30])[F:6])=[CH2:2])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: [Li]CCCC
Reactant: O=C(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)cc1)C(F)(F)F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
n-BuLi (0.59 mL, 2.5 M solution in toluene, 1.5 mmol) was added to a stirring mixture of methyltriphenylphosphonium bromide (0.53 g, 1.5 mmol) and THF (3.1 mL) at room temperature under a nitrogen atmosphere. After 30 min, a mixture of 2,2,2-trifluoro-1-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)ethanone (0.50 g, 1.2 mmol) and THF (3.1 mL) was added. After an additional 1 h, saturated aqueous ammonium chloride (25 mL) was added, the mixture was partitioned between EtOAc (50 mL) and saturated aqueous ammonium chloride (25 mL). The layers were separated, the organic material was washed sequentially with saturated aqueous ammonium chloride (25 mL) and brine (25 mL), and dried (Na2SO4) purified via column chromatography (10 g of silica, 20% EtOAc in hexanes) to provide 1-(2-thiophenylsulfonyl)-4-(4-(1-(trifluoromethyl)ethenyl)phenyl)piperazine (0.23 g) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][CH2:18][C:19]([OH:21])=O)[S:16][CH2:15][CH2:14][CH2:13][S:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(O)=O.[CH2:33]([NH2:45])[CH2:34][C:35]1[CH:44]=[CH:43][C:40]([O:41][CH3:42])=[C:37]([O:38][CH3:39])[CH:36]=1>O1CCCC1>[CH3:39][O:38][C:37]1[CH:36]=[C:35]([CH:44]=[CH:43][C:40]=1[O:41][CH3:42])[CH2:34][CH2:33][NH:45][C:19](=[O:21])[CH2:18][CH2:17][C:11]1([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[S:12][CH2:13][CH2:14][CH2:15][S:16]1
Reactant: COc1ccc(C2(CCC(=O)O)SCCCS2)cc1OC
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C(O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CCNC(=O)CCC2(c3ccc(OC)c(OC)c3)SCCCS2)cc1OC
Reaction time: 3 h

Procedure:
13.2 g of 2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionic acid, 4 g of triethylamine and 180 ml of tetrahydrofuran are cooled to 0° C and treated dropwise within 10 minutes with 5.44 g of chloroformic acid is isobutyl ester in 80 ml of tertrahydrofuran. The mixture is then held at room temperature for 3 hours and treated at 0° C with 7.25 g of homoveratrylamine in 40 ml of tetrahydrofuran. The suspension is left to stand at 3° C for 48 hours, then evaporated, treated with water and extracted with ether/methylene chloride (3:1). The ethereal extracts are washed with water, sodium bicarbonate solution, 1-N tartaric acid and water. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized from methylene chloride/ether at 0° C. There is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionamide of melting point 135°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.O>C1(C)C=CC=CC=1.CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Ti]
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=N[C@@H](C)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 90.9 %

Procedure:
8 g of tetrabutyl ortho-titanate are added to a solution of 116 g (0.72 mol) of (S)-1-(4-chlorophenyl)-ethylamine (65% ee) and 114.5 g (0.727 mol) of 4-chloroacetophenone in 500 ml of toluene at room temperature with stirring, and the mixture is then refluxed for 6 hours at the water separator. The reaction mixture is filtered, and the filtrate is evaporated under reduced pressure to give 191.3 g (91% of theory) of (S)-[1-(4-chlorophenyl)-ethyl]-[1-(4-chlorophenyl)-ethylidene]-amine.
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt]=O.C(O)(=O)C>[C:1]([CH:5]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ncc2ccccc2c1-c1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(C)C1NCc2ccccc2C1c1ccccc1

Procedure:
A mixture of 28.5 g. (0.11 mole) of 3-tert. butyl-4-phenyl isoquinoline, 2.85 g. platinum oxide and 300 ml. of acetic acid is hydrogenated at room temperature and 50 psi until two equivalents of hydrogen are absorbed. The catalyst is filtered off and the acetic acid is evaporated in vacuo. The residue is dissolved in ether, washed with 50% sodium hydroxide, water and saturated sodium fluoride solution, dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from petroleum ether to give 3-tert.butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; m.p. 79°-81° C.
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[CH3:24][OH:25]>>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[O:25][CH3:24]
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (200 mg, 0.5 mmol) in methanol (20 mL) was added NaH (Aldrich, 60%, 0.6 g, 15 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated under reflux for 1.5 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 25% ethyl acetate in hexanes) to give 6-fluoro-5-methoxy-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 73.2 mg, 51.9%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=O>O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 21 %

Procedure:
4-[4-(4-Chloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (59 mg, 21%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-4′-chloroacetophenone (available from Alfa Aesar) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.12 (br s, 1H), 8.57 (s, 1H), 8.33 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.09-8.16 (m, 3H), 7.41-7.79 (m, 6H).
Reaction SMILES: C1([N:7]2[CH:11]=[NH+:10][N:9](C3C=CC=CC=3)[N:8]2C2C=CC=CC=2)C=CC=CC=1.[Cl-].[C:25]1([N:31]2[N:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:34]=[C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[NH2+:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH:8]=[N:7][CH:11]=[N:10][NH2:9].[C:36]1([N:35]2[N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:32]=[C:33]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH2+:34]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C1=[NH+]N(c2ccccc2)N(c2ccccc2)N1c1ccccc1
Agent: [Cl-]
Agent: c1ccc(C2=NN(c3ccccc3)N(c3ccccc3)[NH2+]2)cc1
Product: N=NC=NN
Reaction time: 0.06 h

Procedure:
The present process is conducted on finfish fillets which are believed to be fresh and/or which have been kept on ice. A predetermined weight of a fish fillet, such as 25 gms, is kneaded with a predetermined volume of a liquid growth medium, such as 25 ml, (1:1 ratio) for 2 to 5 minutes at room temperature, e.g., 23° to 25° C., shaking vigorously, and then a predetermined volume of the liquid filtrate, such as 5 ml, is mixed with a small amount, such as 1 ml, of the colorless triphenyl tetrazolium dye salt indicator reagent and allowed to incubate for 10 to 20 minutes at room temperature, e.g., 15°-25° C., shaking vigorously every 5 minutes. The following reaction takes place with the use of 2,3,5-triphenyl tetrazolium chloride as the indicator reagent: ##STR1## This reduction reaction is enabled by the functioning electron transport system of the viable bacterial flora on the fish and proceeds in proportion to the quantity of the enabling bacteria present. The greater the concentration of the red-colored 2,3,5-triphenyl tetrazolium formazan formed in the bacterial cells, the greater the intensity of the color of the formazan solution extracted from the sample.
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:11]=1)=[O:6]>CC(O)=O>[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([C:12](=[O:15])[CH3:13])=[CH:10][CH:11]=1)=[O:6]
Reactant: COC(=O)c1ccc(C(=O)CBr)o1
Agent: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(C)=O)o1

Procedure:
Bromination of 5-acetyl-furan-2-carboxylic acid methyl ester (0.27 g, 1.61 mmol) with Br2 (0.082 mL) in AcOH (6 mL) at room temperature gave 5-(2-bromo-acetyl)-furan-2-carboxylic acid methyl ester; MS: 246.1 (M+H+).
Reaction SMILES: C1([C@@H]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]2[C:23]([O:25][CH3:26])=[O:24])C)C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:9][C@H:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][C@@H:11]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N[C@@H](C)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of 260A (1.10 g, 3.03 mmol) in MeOH (31 mL) at room temperature was treated with ammonium formate (1.51 g, 24.3 mmol) and 10% Pd/C (110 mg). The reaction mixture was heated to reflux for 14 hours then cooled to room temperature. The solid material was removed by filtration and washed with MeOH. The filtrate was concentrated in vacuo to give 0.75 g (yield: 96%) of Compound 260B as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]([NH:18]C(C)(C)C)=O)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]#[N:18])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncccc1CCc1cccc(Cl)c1
Yield: 95.1 %

Procedure:
A solution of 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide (175 g; 0.55 mol) in 525 mL (5.6 mol) of phosphorous oxychloride was heated at reflux for 3 h. Excess phosphorus oxychloride (-300 mL) was removed by distillation and the remaining solution was carefully poured into ice-water. The pH of the solution was adjusted to 8 with 50% aqueous sodium hydroxide while the temperature was maintained at 25°-30° C. The mixture was stirred for 2h during which time the pH was maintained at 8. The product was collected by filtration, washed with water and dried in a vacuum oven at 50° C. to give 127 g (95%) of crystalline 3-[2-(3chlorophenyl)ethyl]-2-pyridinecarbonitrile: m.p. 72°-73° C.; NMR (200 MHz, CDCl3)δ2.9-3.1 (m,2H), 3.1-3.2 (m,2H), 7.0-7.1 (m,1H), 7.1- 7.3 (m,3H), 7.42 (dd,1H,J=7.3, 5 Hz); 7.56 (dd,1H,J=7.3, 1.2 Hz), 8.48 (dd,J=5, 1.2 Hz); mass spectrum, m/e (rel intensity) 242 M+ (18). Anal. Calcd for C14H11N2Cl: C,69.28; H,4.59; N,11.54; Cl 14.61. Found: C,69.37; H,4.48; N,ll.39; Cl,14.48.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH2:24][CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH2:24][CH3:25])[N:9]=3)[CH:5]=2)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Product: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-ethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.89) (0.30 g, 0.739 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.209 g, 0.813 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 25%) and additional off-white solid (0.20 g, 50%). MS (ISP) 539.3 [(M+H)+]; mp 169° C.
Reaction SMILES: C(C1C=CC(N(C)C)=CC=1Br)C1C=CC(N(C)C)=CC=1Br.[C:22](=[O:24])=O.[Li]C(CC)C.[Si](Cl)(Cl)(C)C.Cl.[CH3:36][N:37]([CH3:57])[C:38]1[CH:39]=[CH:40][C:41]2C[C:45]3[CH:47]=[CH:48][C:49]([N:51]([CH3:53])[CH3:52])=[CH:50][C:44]=3[Si:43]([CH3:55])([CH3:54])[C:42]=2[CH:56]=1.O=O.[O-][Mn](=O)(=O)=O.[K+]>C1COCC1.CC(C)=O>[CH3:36][N:37]([CH3:57])[C:38]1[CH:39]=[CH:40][C:41]2[C:22](=[O:24])[C:45]3[CH:47]=[CH:48][C:49]([N:51]([CH3:52])[CH3:53])=[CH:50][C:44]=3[Si:43]([CH3:54])([CH3:55])[C:42]=2[CH:56]=1
Reactant: CN(C)c1ccc2c(c1)[Si](C)(C)c1cc(N(C)C)ccc1C2
Reactant: O=C=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: CN(C)c1ccc(Cc2ccc(N(C)C)cc2Br)c(Br)c1
Agent: C[Si](C)(Cl)Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1ccc2c(c1)[Si](C)(C)c1cc(N(C)C)ccc1C2=O
Reaction time: 2 h

Procedure:
4,4′-Methylenebis(3-bromo-N,N-dimethylaniline 1 (2.00 g, 4.85 mmol, 1 eq.) was dissolved in dry THF (200 ml) and stirred at −78° C. on the CO2(s)/acetone bath. sec-BuLi (1.4 mol/l solution in n-hexane, 10 ml, 14.0 mmol, 3 eq.) was slowly added for 30 minutes to the solution and stirred for further 2 hr at the same temperature. SiMe2Cl2 (1 ml, 8.22 mmol, 1.8 eq.) was added to the reaction mixture and stirred at room temperature for 2 hr. 1N HCl aqueous solution was added carefully to neutralize the solution, and THF was evaporated. The resulting aqueous solution was extracted with EtOAc, and the organic phase was washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, filtered and evaporated to obtain the crude including N3,N3,N7,N7,5,5-hexamethyl-5,10-dihydrodibenzo[b,e]siline-3,7-diamine 2, which was used for the next reaction immediately due to its high sensitivity toward oxygen. The resulting crude including 2 was dissolved in acetone (30 ml) and stirred at −15° C. on the crashed ice/NaCl(s) bath. KMnO4 powder was added portionwise (300 mg×6) for 30 minutes, and stirring was continued for further 2 hr at the same temperature. The purple suspension was filtered through a Celite pad, and the yellow filterate was evaporated. The resulting residue was purified by silica gel column chromatography (nhexane/CH2Cl2=20/80) to obtain 3,7-Bis(dimethylamino)-5,5-dimethyldibenzo[b,e]silin-10(5H)-one as a yellow solid. (689 mg, 41%)