Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](F)(=[O:10])=[O:9].CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.C[Si]([C:32]([F:35])([F:34])[F:33])(C)C>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:32]([F:35])([F:34])[F:33])(=[O:10])=[O:9]
Reactant: O=S(=O)(F)c1ccccc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: O
Product: O=S(=O)(c1ccccc1F)C(F)(F)F

Procedure:
The solution of EXAMPLE 12 (44.3 g) in a solution of 450 ml was added to a round bottomed flask fitted with overhead stirrer, nitrogen inlet, cold-water bath and temperature probe. It was cooled down to 12° C. (((CH3)2N)3S)+(F2Si(CH3)3)−, also known as TASF (6.1 g), was added in one portion. Ruppert's reagent (370 g, CH3SiCF3) was charged slowly to the reaction mixture while maintaining the internal temperature less than 23° C. The reaction was completed after addition. Water (220 g) was added to quench the reaction, the layers were separated, and the organic layer was washed twice with 220 g of water. The organic solution was distilled under vacuum with the bath temperature at 50° C. Heptanes (500 g) were added to the residue, and the mixture was distilled down until the solvent was removed. 1H NMR (400 MHz, CDCl3) δ 8.01-8.05 (m, 1H), 7.84-7.87 (m, 1H), 7.44-7.48 (m, 1H), 7.36-7.39 (m 1H).
Reaction SMILES: [Cu][C:2]#[N:3].[NH2:4][C:5]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]>CN1CCCC1=O.C(N)CN>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([C:2]#[N:3])[CH:13]=[CH:14][C:5]=1[NH2:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: COC(=O)c1cc(C#N)ccc1N
Temperature: 180 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
Copper(I) cyanide (available from Alfa Aesar; 10.71 g, 0.12 mol) was added to a stirred solution of methyl 2-amino-5-bromobenzoate (available from Aldrich Chemical Company, Inc.; 25.0 g, 0.11 mol) in N-methyl-2-pyrrolidone (50 mL) and the mixture was stirred at 180° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with aqueous ethylenediamine (water:ethylenediamine=1:1; 250 mL), and filtered through pad of Celite. The filtrate was extracted with EtOAc (3×100 mL), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, evaporated under reduced pressure, and purified by silica gel chromatography (100-200 mesh), using 5-10% ethyl acetate/hexanes as eluent, to give 2-amino-5-cyanobenzoic acid methyl ester (14.0 g, 73%) as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J=1.9 Hz, 1H), 7.57 (dd, J=1.9, 8.8 Hz, 1H), 7.44 (br s, 2H), 6.88 (d, J=8.8 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42][C:43]#[C:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42][C:43]#[C:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C#CCBr)(CC)O[Si](CC)(CC)CC
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 92.6 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol), 15-crown-5(10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (79.0 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1.N>O>[F:32][C:29]1[CH:30]=[C:31]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)[CH:26]=[CH:27][C:28]=1[F:33]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: Fc1ccc(Br)cc1F
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole (yield: 310 mg, 65.7%). mp 187–188° C. 1H NMR (300 MHz, CDCl3) δ 3.09 (s, 3H), 7.18 (d, J=9 Hz, 2H), 7.29 (m, 3H), 7.41 (d, J=9 Hz, 2H), 7.52 (m, 1H), 7.65 (m, 1H), 7.92 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 473 (M+H)+, 490 (M+NH4)+. Anal. calc. for C23H15ClF2N2O3S.0.5 H2O: C, 57.38; H, 3.33; N, 5.82. Found: C, 57.44; H, 3.38; N, 5.52.
Reaction SMILES: C1(C2(CCC3C=C(C(C)(C)CNC(C4C=CNN=4)=O)C=CC=3)CC(=O)CC(=O)O2)CCCC1.[Cl:34][CH2:35][C:36]#[N:37].[NH2:38][C:39]1[CH:43]=[CH:42][S:41][C:40]=1[C:44]([O:46]C)=O.Cl>O1CCOCC1>[Cl:34][CH2:35][C:36]1[NH:37][C:44](=[O:46])[C:40]2[S:41][CH:42]=[CH:43][C:39]=2[N:38]=1
Reactant: COC(=O)c1sccc1N
Reactant: N#CCCl
Agent: CC(C)(CNC(=O)c1cc[nH]n1)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(CCl)nc2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
This compound was prepared by a modification of a method reported for related fused pyrimidine-4(3H)-ones: (1) Shishoo, C. J.; Devani, M. B.; Pathak, U.S.; Ananthan, S.; Bhadti, V. S.; Ullas, G. V.; Jain, K. S.; Rathod, I. S.; Talati, D. S.; Doshi, N. H. J. Heterocyclic Chem. 1984, 21, 375, and (2) Gerecke, M.; Kyburz, E.; Borer, R.; Gassner, W. Heterocycles 1994, 39, 693). An oven-dried 1-L round bottomed flask was charged with chloroacetonitrile (21.86 g, 0.29 mol, 1.3 equiv), methyl 3-aminothiophene-2-carboxylate (35 g, 0.223 mol), and 4 M HCl in 1,4-dioxane (350 mL). The reaction mixture was stirred at room temperature for 1 d. The mixture was evaporated to dryness. The residue was dissolved in water (600 mL) and treated with aqueous 10% sodium bicarbonate to a pH of 8. The resulting slurry was filtered, and the cake washed with water and dried, affording 38.2 g (85%) of the title product. 1H NMR (DMSO-d6) δ 4.58 (s, 2H), 7.42 (d, J=5.3 Hz, 1H), 8.22 (d, J=5.3 Hz, 1H), 12.84 (br s, 1H). LC-MS (APCI) calcd for C7H5ClN2OS: 200.0; Found (M+H+): 201.0 m/z.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][N:3]=1>I.CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Agent: I
Solvent: CCOC(C)=O
Product: Nc1ccc2[nH]nc(I)c2c1
Temperature: 90 °C

Procedure:
A suspension of 3-iodo-5-nitro-1H-indazole (2.0 g, 6.92 mmol) in stabilized hydroiodic acid (57% wt aqueous solution, 21 mL) was heated at about 90° C. for about 2 hours. The reaction mixture became homogeneous as the reaction progressed. After cooling to ambient temperature, the dark purple mixture was diluted with EtOAc (500 mL) and washed successively with saturated aqueous sodium thiosulfate (200 mL), saturated aqueous NaHCO3 (200 mL) and brine (200 mL). The colorless organic layer was dried over anhydrous magnesium sulfate, and concentrated to dryness to give 3-iodo-1H-indazol-5-ylamine: 1H NMR (DMSO-d6, 400 MHz) 13.03 (s, 1H), 7.26 (d, 1H), 6.85 (m, 1H), 6.44 (d, 1H), 5.03 (s, 2H); LC/MS (30% to 95% acetonitrile/0.01M aqueous ammonium acetate over 4.5 min at 0.8 mL/min; λ=190-700 nm; Genesis C18, 3 μm, 30×4.6 mm column; Electrospray ionization method observing both +ve and −ve ions) Rt 1.25 min.; m/z: 260 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][S:3]1.C1C=CC=CC=1.[Br:14][CH:15]([Br:19])[C:16](Cl)=[O:17]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:7])[N:6]([C:16](=[O:17])[CH:15]([Br:19])[Br:14])[CH2:5][CH2:4][S:3]1
Reactant: CC1(C)NCCS1
Reactant: O=C(Cl)C(Br)Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)SCCN1C(=O)C(Br)Br

Procedure:
To a mixture of 3.5 g. of 2,2-dimethyl thiazolidine, 50 ml. of benzene and 7.1 g. of dibromoacetyl chloride mixed in an ice bath was added 3.1 g. of triethylamine dropwise with stirring and continued cooling. When reaction was complete, the mixture was poured into watwer and the benzene layer separated, dried over magnesium sulfate and the benzene removed under vacuum. Yield was 8.5 g. of a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][C:13](=[O:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].OO.P([O-])([O-])([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][CH:13]([OH:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(=O)CCC2[N+](=O)[O-])cc1OC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=P([O-])([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C2CC(O)CCC2[N+](=O)[O-])cc1OC
Temperature: 78 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere 16.76 g of (3RS,4SR)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanone (compound F2) are dissolved in 300 ml of tetrahydrofurane, the solution is cooled to 78° C., and 75 ml of 1 M solution of potassium tri-sec-butylborohydride in tetrahydrofurane is added dropwise. After stirring for further 1 h, a mixture consisting of 30% hydrogen peroxide solution and phosphate buffer solution is added. Stirring is continued for further 10 min, the reaction mixture is diluted with 400 ml of ethyl acetate and the aqueous layer is extracted with ethyl acetate, the combined organic phases are concentrated to give a foam, which is purified by chromatography on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 1/1 to furnish 10.18 g (60% of theory) of the title compound.
Reaction SMILES: [C:1]1([CH:11]([CH2:16][C:17](O)=[O:18])[CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(Cl)(=O)C>[C:1]1([CH:11]2[CH2:16][C:17](=[O:18])[O:14][C:13](=[O:15])[CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(CC(=O)O)c1cccc2ccccc12
Solvent: CC(=O)Cl
Product: O=C1CC(c2cccc3ccccc23)CC(=O)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of commercial 1-naphthaldehyde (25 g) and ethyl acetoacetate (40.5 ml) in ethanol (30 ml) piperidine (3 ml) was added with stirring at rt. The orange coloured solution was kept at rt for a week. The viscous orange oil (the bis-adduct of acetoacetate to the aldehyde) was not further purified but used directly for the next step. The oil was added in portions to 40% NaOH (500 g) with stirring and rinsed with ethanol. The resulting orange slurry was stirred at reflux for 2 h. After cooling to rt the mixture was filtered and washed with water to give an orange coloured, partly resinous solid (sodium salt of 3-(1-naphthyl)glutaric acid). The salt was slurried in conc. HCl/water 1:1 (300 ml) and kept at rt for 3 d. The remaining solid was isolated by suction filtration and washed with water. The still wet filter cake was taken up in acetone (200 ml) and the organic layer was dried by addition of sodium sulfate. After filtration the solvent was removed by distillation and the residue (32.1 g amorphous orange solid) was triturated with ethyl acetate (40 ml) to leave a light yellowish powder (11.6 g) which was identified by NMR as the desired 3-(1-naphthyl)glutaric acid. The suspension of 3-(1-naphthyl)glutaric acid in acetyl chloride (16 ml) was heated to reflux with stirring for 1.5 h. After cooling to rt precipitation of the product is completed by addition of petrol ether (100 ml). The precipitate is isolated by suction filtration, washed with petrol ether, and dried in vacuo to provide 3-(1-naphthyl)glutaric anhydride (10.54 g) as light beige solid.
Reaction SMILES: [C:1]1([C:7]([O:9][C@@H:10]2[CH2:20][O:19][C@@H:12]3[C@@H:13]([OH:18])[C@@H:14]([O:17][C@H:11]23)[O:15][CH3:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]I>CN(C=O)C.C(OCC)(=O)C.[Ag-]=O>[CH3:21][O:18][C@@H:13]1[C@H:12]2[O:19][CH2:20][C@@H:10]([O:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[C@H:11]2[O:17][C@H:14]1[O:15][CH3:16]
Reactant: CI
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1O
Agent: O=[Ag-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1OC
Temperature: 60 °C
Yield: 76 %

Procedure:
A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-D-glucofuranoside (1.03 g, 3.7 mmol), silver (I) oxide (0.85 g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 60° C. for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (10 g) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-D-glucofuranoside as a colorless oil, 0.82 g, 76% yield. 1H NMR (400 MHz; CDCl3): 8.11-8.09 (d, 2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09 (tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4.08-4.03 (tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+].[I:16]I.S(=O)(=O)(O)[O-].[Na+]>CN(C)C=O>[I:16][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Reactant: II
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a solution of methyl 1H-indazole-6-carboxylate (865 mg, 4.91 mmol) in N,N-dimethylformamide (12 mL) was added potassium hydroxide (840 mg, 3.05 mmol) followed by iodine (1.54 g, 5.9 mmol). The mixture was stirred at room temperature for 3 hours. Sodium bisulfate (30 mL of 5% aqueous) was added and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (5-65% ethyl acetate/heptanes) to afford methyl 3-iodo-1H-indazole-6-carboxylate as a colorless solid (1.16 g, 78%). 1H NMR (400 MHz, DMSO-d6, δ): 13.84 (s, 1H), 8.13 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1([NH:29]C(OCC2C=CC=CC=2)=O)[CH2:23][N:22]([S:24]([O-:27])(=[O:26])=[O:25])[C:21]1=[O:28]>CO.[Pd]>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[NH2:29][C:20]1([O:19][CH3:18])[CH2:23][N:22]([S:24]([O-:27])(=[O:25])=[O:26])[C:21]1=[O:28]
Reactant: COC1(NC(=O)OCc2ccccc2)CN(S(=O)(=O)[O-])C1=O
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: COC1(N)CN(S(=O)(=O)[O-])C1=O
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
(±)-3-Methoxy-3-[[(phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (143 mg, see Example 49) is dissolved in 15 ml of dry methanol. Na2B4O7.10H2O (12 mg, 0.1 equiv.) is added, followed by 10% palladium on carbon (72 mg). The mixture is hydrogenated at one atmosphere pressure for 15 minutes. The catalyst is removed by filtration and the filtrate evaporated in vacuo, yielding 114 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([F:38])[C:31]=1[CH2:39][CH:40]([NH2:42])[CH3:41]>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:42][CH:40]([CH3:41])[CH2:39][C:31]4[C:32]([F:38])=[C:33]([F:37])[CH:34]=[C:35]([F:36])[C:30]=4[F:29])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Solvent: CCCCO
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Yield: 42.8 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.54 g, 1.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.34 g, 1.62 mmol), Hunig,s base (0.87 g, 6.75 mmol), and 12 mL of anhydrous 1-butanol was heated at reflux for 13-14 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.33 g of the designed compound as yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.33 (s, 1H, NH), 11.29 (br s, 1H, NH), 11.00 (d, J=5.7 Hz, 1H, NH), 7.97 (s, ArH), 7.73-7.70 (m, 1H, ArH), 7.40 (d, J=7.6 Hz, 1H, ArH), 6.21 (d, J=7.6 Hz, 1H, ArH), 4.32-4.28 (m, 1H, CH), 3.65 (t, J=6.3 Hz, 2H, CH2), 3.08 (d, J=5.1 Hz, 2H, CH2), 2.72 (s, 3H, CH3), 2.19 (S, 6H, 2×CH3); 1.36 (d, J=6.3 Hz, 3H, CH3), 1.11 (t, J=6.3 Hz, 2H, CH2); Mass (ESI, negative) m/z 568.8 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C1COCCN1
Product: N#Cc1ccnc(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A mixture of 2-chloro-4-cyanopyridine (2.5 g, 18 mmol) and morpholine (6.29 g, 72 mmol) was heated at 110°-120° C. for 4 hours. The reaction mixture was cooled, poured into ice-water (15 ml) and stirred for 30 minutes. A yellow solid was obtained, which was collected by filtration, washed with water and dried in vacuo at 70° C. in the presence of P2O5 to afford 1.8 g (53%) of 2-(4-morpholinyl)-4-cyanopyridine, m.p. 135°-136.5° C.
Reaction SMILES: CO.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N:23]1[N+:27]([O-])=[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]2=[N:24]1.S(=O)(=O)(O)O>O>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N:23]1[N:27]=[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]2=[N:24]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 92.8 %

Procedure:
To the wet product 12 g thus obtained, were added methanol 60 ml, water 30 ml, 97% sodium hydroxide 13.0 g and 9-fluorene 0.5 g, and glucose 5.5 g was further added to the mixture over one hour while stirring at 50° to 55° C. The mixture was reacted while stirring at 75° C. (boiling point) for 5 hours. As this result, the N-oxide disappeared, thus Process (c) being completed. The reaction liquor was neutralized with 62% sulfuric acid 19.8 g to pH 8 to precipitate a crystal. The precipitated crystal was separated by filtration, and the separated crystal was fully washed with water and further with methanol. The washed crystal was then dried, thus obtaining 9.4 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole having a melting point of 128° to 130° C. at the yield of 92.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.O=S(Cl)Cl.[CH2:15](O)[CH3:16]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:15][CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: Nc1ccc(C(=O)O)nc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(N)cn1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 5-aminopicolinic acid (13.5 g, 97.7 mmol) in anhydrous ethanol (200 mL) was added SOCl2 (60.0 mL, 504 mmol) dropwise at 0° C. under N2 atmosphere. The resulting mixture was heated at reflux and stirred overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in a saturated aqueous NaHCO3 solution so that that pH of the solution was approximately pH 9-10. The reaction mixture was extracted with EtOAc (8×250 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to afford the title compound as a brown solid (14.3 g, 88%)
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][O:14][C:15](=[O:25])[CH2:16][N:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.BrCCC=C.CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1.CCCCCC.O>[CH3:13][O:14][C:15](=[O:25])[CH:16]([CH2:11][CH2:10][CH:9]=[CH2:8])[N:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CN=Cc1ccccc1
Reactant: [Li]CCCC
Agent: C=CCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(N=Cc1ccccc1)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve diisopropylamine (15.4 mL, 110 mmol) in tetrahydrofuran (250 mL), place under a nitrogen atmosphere and cool to -78° C. Add n-butyllithium (39 mL of a 2.7M solution in hexane, 105 mmol). Stir for 30 minutes and add, by dropwise addition, a solution of N-(phenylmethylene)glycine methyl ester (17.7 g, 100 mmol) in tetrahydrofuran (25 mL). Stir for 15 minutes and add 4-bromobutene (13. 5 g, 100 mmol) and allow to warm slowly to room temperature. Add hexamethylphosphoramide (20 mL, 100 mmol) and stir under a nitrogen atmosphere for 3 hours. Pour into water, extract into ethyl ether and wash with brine several times. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as an amber oil (25 g).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[CH:9]([OH:11])[CH3:10])=[CH:5][CH:6]=1
Reactant: CC(=O)/C=C/c1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)/C=C/c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
22.2 Gm (0.1 mol) of (E)-4-(4-biphenylyl)-3-butene-2-one, dissolved in 1 liter of 95% ethanol, were added in small amounts within 10 minutes to a solution of 1.9 gm (0.05 mol) of sodium borohydride in 300 ml of 95% ethanol. Subsequently, the mixture was stirred for 1 hour at room temperature. The excess reducing agent was removed by careful addition of 3 gm of glacial acetic acid. The solvent was subsequently distilled off in water aspirator vacuum. 500 Ml of water were added to the residue, and the reaction mixture was exhaustively extracted with ether. The combined ether extracts were washed with water, dried over sodium sulfate and evaporated. The residue was recrystallized from ethyl acetate/petroleum ether (ratio of volume: 1:9) in the presence of charcoal. 16.1 Gm (72% of theory) of colorless crystals, m. p. 138°-139°C, were obtained; the compounds was completely identical with that prepared in Example 25 according to thin-layer chromatogram, melting point, mixed melting point and spectra.