Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([Li])[CH2:9][CH2:10]C.[C:13]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[OH:25])#[N:14]>O1CCCC1.CCCCCC>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:18]=[CH:17][C:16]2[O:25][C:9]([CH3:10])([CH3:8])[N:14]=[C:13]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:15]=2[CH:20]=1
Reactant: [Li]CCCC
Reactant: N#Cc1cc(C(F)(F)F)ccc1O
Reactant: Brc1ccccn1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)N=C(c2ccccn2)c2cc(C(F)(F)F)ccc2O1
Reaction time: 0.5 h

Procedure:
A solution of 2-bromopyridine (0.47 g) in anhydrous tetrahydrofuran (5 ml) was cooled to -78° C. and 1.6M n-butyllithium in hexane (2.1 ml) was added dropwise under an argon atmosphere. The mixture was stirred for 30 minutes. Then, a solution of 2-cyano-4-trifluoromethylphenol (0.19 g) in anhydrous tetrahydrofuran (5 ml) was added to the reaction mixture and the resulting mixture was stirred at -78° C. for an additional 1 hour. The reaction was quenched by adding acetic acid (0.18 g) to the reaction mixture and the solvent was distilled off under reduced pressure. Ammonium acetate (2 g) and 2,2-dimethoxypropane (5 ml) were added to the residue and the mixture was heated under reflux for 3 hours. The solvent was distilled off and the residue was extracted by addition of ethyl acetate and aqueous sodium bicarbonate solution. The ethyl acetate layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by column chromatography on silica gel to obtain 6-trifluoromethyl-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.19 g) (Compound 74).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1(C)[O:23]C(=O)C[C:20](=O)[O:19]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14](=[O:16])[CH2:17][C:18]([O:19][CH3:20])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(Benzyloxycarbonylamino)propanoic acid [N-Cbz-β-alanine] (5.0 g, 22.4 mmoles) is suspended in methylene chloride (100 mL) and 2,2-dimethyl-1,3-dioxane-4,6-dione (3.3 g, 22.9 mmoles), triethylamine (8.5 mL, 61.0 mmoles) and diethyl cyanophosphonate (3.7 mL, 22.8 mmoles) are added. All solids dissolve quickly, and the reaction quickly turns yellow. The solution is stirred for 16 hours at ambient temperature. The reaction mixture is then diluted with methylene chloride (100 mL) and carefully washed three times with aqueous hydrochloric acid (3 M, 50 mL each), three times with water (50 mL each) and once with saturated aqueous sodium chloride (50 mL). The reaction mixture is then dried over anhydrous sodium sulfate, filtered and evaporated to an orange syrup. The syrup is dissolved in anhydrous methanol (200 mL) and heated to reflux for 16 hours. The methanol is evaporated and the crude product purified on silica gel (150 mL bed volume) eluting with methylene chloride (500 mL) then methylene chloride:methanol (99.5:0.5 [v/v], 500 mL then 99:1 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a pale yellow oil. The oil is dried well in vacuo. The yield is 4.5 g (68%).
Reaction SMILES: [OH:1][C:2]([CH:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[NH:29]1[CH2:30][CH2:31][CH:26]([C:2]([C:4]2[S:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]4[N:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=4)[CH:10]=3)=[CH:7][N:8]=2)([OH:1])[CH3:3])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)(c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1)C1CCNCC1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
To a stirred solution of the product of Step 4 (18.2 mg, 0.033 mmol) in dichloromethane (1 mL) was added TFA (1.00 mL, 12.98 mmol) and the mixture was stirred at room temperature. The solvent was removed by evaporation and stripped with ethyl acetate. The residue was concentrated and dried under high-vacuum to afford 1-(piperidin-4-yl)-1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanol (Example 15(2), 12.5 mg, 0.018 mmol) as a TFA salt. APCI: [M+H]+ m/z 450.1. 1H NMR (500 MHz, DMSO-d6): δ 10.34 (1H, s), 8.86 (1H, d, J=4.89 Hz), 8.43 (2H, broad s), 8.14 (1H, s), 8.01 (1H, s), 7.67 (1H, d, J=8.10 Hz), 7.39 (1H, t, 7.88 Hz), 7.34-7.29 (2H, m), 3.18-3.02 (2H, m), 2.61-2.54 (2H, m), 1.92-1.77 (2H, m), 1.51 (3H, s), 1.55-1.41 (1H, m), 1.38-1.22 (1H, m). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Mg]Br>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Reactant: Br[Mg]c1ccccn1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.03 h

Procedure:
LaCl3-2LiCl (0.6 M in THF, 0.78 mL, 0.47 mmol) was added dropwise by syringe to a solution of (4-chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (101.4 mg, 0.226 mmol, Intermediate 41: step d) in dry THF (2 mL). After 2 minutes, the solution was cooled in an ice bath and pyridin-2-ylmagnesium bromide (2.8 mL, 0.7 mmol) was added dropwise via syringe. The reaction was stirred for 3 hours, then quenched with saturated aqueous ammonium chloride and removed from the cold bath. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) followed by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.65-8.61 (m, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.84-7.79 (m, 3H), 7.73-7.67 (m, 2H), 7.51 (s, 1H), 7.49-7.44 (m, 2H), 7.34-7.29 (m, 1H), 7.24-7.19 (m, 1H), 6.34 (s, 1H), 4.36 (s, 2H), 4.07 (s, 3H), 3.43 (s, 3H), 3.01 (s, 3H); MS m/e 549.2 [M+H]+.
Reaction SMILES: CN(C)CCN.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][O:13][N:14]1C(=O)C2=CC=CC=C2C1=O.C(O)(=O)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])=[C:32]([C:44](=O)[CH2:45][CH3:46])[CH:31]=1>CCO>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])=[C:32]([C:44](=[N:14][O:13][CH2:12][C:8]2[S:7][CH:11]=[CH:10][CH:9]=2)[CH2:45][CH3:46])[CH:31]=1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1OCc1cccs1
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(=NOCc1cccs1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.3 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(thiophen-2-ylmethoxy)phthalimide (365 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (1 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (316 mg, 1.0 mmol) in EtOH (2 mL), and the mixture stirred for 15 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-{4-chloro-2-[1-(thiophen-2-ylmethoxyimino)propyl]phenyl}trifluoromethanesulfonamide 207 (364 mg, 85%), as a white solid. M.p. 53-54° C. 1H n.m.r. (400 MHz, CDCl3) δ 11.49, br s,1H; 7.64, d, J=8.8 Hz, 1H; 7.47, d, J=2.4 Hz, 1H; 7.33, m, 2H; 7.16, m, 1H; 7.01, m, 1H; 2.82, q, J=7.6 Hz, 2H; 1.17, t, J=7.6 Hz, 3H. HRMS (M+) 426.0065.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[C:10]([CH2:21][CH:22]2[CH2:24][O:23]2)=[C:9]([O:25]CC2C=CC=CC=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>CO.[Pd]>[C:1]([O:5][C:6]([C:7]1[CH:8]=[C:9]([OH:25])[C:10]2[CH2:21][CH:22]([CH2:24][OH:23])[O:13][C:11]=2[CH:12]=1)=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2CO2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A mixture of 3,5-bis-benzyloxy-4-oxiranylmethyl-benzoic acid tert-butyl ester (200e) (55 g, 0.12 mol), 10% Pd on Carbon (5 g), Et3N (15 g, 0.14 mol), and K2CO3 (20 g, 0.14 mol) in MeOH (250 mL) was stirred under 760 mmHg of H2 at room temperature for 4 hr. TLC (EtOAc/petroleum oil=1/2) showed the reaction was complete. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/petroleum ether=1/3) to give the title compound (18 g, 55% yield) as an off-white solid.
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.[CH2:28]([NH2:33])[CH2:29][CH:30]([CH3:32])[CH3:31].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[CH2:28]([NH:33][C:19]([C:14]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[C:4](=[O:22])[C:3]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]3[C:1]2=[O:27])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:20])[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)CCN
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O

Procedure:
From 3 g (8.4 mmol) of 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), by reaction with isopentylamine in the presence of HOBT and DIC, 3.2 g of 2′-phthalimidomethylbiphenyl-2-carboxylic acid isopentylamide were obtained; m.p. 169° C. The product was dissolved in 100 ml of methanol and treated with 5 ml of hydrazine hydrate. After stirring at 40° C. for 1 h, the cooled reaction mixture was filtered. The filtrate was concentrated and the residue was taken up in methylene chloride. After washing with water, drying and concentrating, 1.8 g of 2′-aminomethylbiphenyl-2-carboxylic acid isopentylamide were obtained.
Reaction SMILES: I[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28][CH2:29][CH3:30])=[CH2:27])CCC>C1(C)C=CC=CC=1>[CH2:29]([O:28][C:26]([C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1)=[CH2:27])[CH3:30]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)ncnc32)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
[10 g, 25 mmol] of 4-Iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine was dissolved/suspended in 200 mL of dry toluene along with [2.0 g, 2.85 mmol] of palladium (II) bis-triphenylphosphine dichloride. The mixture was purged with nitrogen gas for ˜5 minutes before mixture was heated to 90° C. in an oil bath under an atmosphere of nitrogen gas. Added slowly dropwise over 2 hours, was [12.66 mL, 13.54 g, 37.5 mmol] of tri-n-butyl(1-ethoxyvinyl) tin in 100 mL of dry toluene. After completing the addition, the mixture was heated for an additional 6 hours under nitrogen. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure until the remaining volume was ⅕ the original. Added to this slurry was 160 mL of petroleum ether and the mixture was stirred for 1 hour, the solid being isolated via suction filtration and washed with petroleum ether. The damp solid was slurried in acetonitrile, stirred for one hour and the solid re-isolated via suction filtration and airdried. The resulting pale yellow solid, 7.2 g representing an 82% yield was utilized without further treatment.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:16]([O:18]C)=O.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27](O)[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:49](C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@H:27]([O:1][C:2]1[CH:6]=[C:5]([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:16]([NH2:49])=[O:18])[CH3:28]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: C[C@H](O)c1ccccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(-n2cnc3ccncc32)sc1C(N)=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under a nitrogen atmosphere 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 57.2 mg of (1S)-1-(2-chlorophenyl)ethanol and 95.7 mg triphenylphosphine are dissolved in 1 ml anhydrous THF. To this mixture a solution of 80.9 mg diisopropyl azodicarboxylate in 0.5 ml anhydrous THF is added dropwise and the mixture is stirred for 14 h at room temperature. The solvent is evaporated under vacuum. After extraction with ethyl acetate and a saturated solution of sodium chloride, the organic phase is dried over MgSO4. The solvent is removed under vacuum and the remaining residue is dissolved in 2 ml dichloromethane and filtered through a short plug of silica gel (eluent: ethyl acetate). After evaporation of the solvent, the remaining residue and 20 ml of a saturated solution of ammonia in methanol are stirred in a microwave vial at 125° C. for 8 h in the microwave cavity. Subsequently the solvent is removed under vacuum. The remaining residue is dissolved in 2 ml dichloromethane and is purified by flash chromatography (eluent: ethyl acetate, followed by ethyl acetate/methanol 95/5 (v/v)) to yield the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(OP(Cl)(=O)OCC)C.[NH2:18][C:19]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([OH:27])=[C:21]([CH2:28][CH3:29])[CH:20]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:18][C:19]1[CH:20]=[C:21]([CH2:28][CH3:29])[C:22]([OH:27])=[C:23]([CH2:25][CH3:26])[CH:24]=1)=[O:8]
Reactant: O=C(O)c1cccs1
Reactant: CCc1cc(N)cc(CC)c1O
Agent: CCOP(=O)(Cl)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)c2cccs2)cc(CC)c1O
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
Under ice-cooling, 128 mg of 2-thienylcarboxylic acid is dissolved in 3 ml of acetonitrile, and to the resultant solution are added 303 mg of triethylamine, then 207 mg of diethylphosphorochloridate. After the mixture is stirred for 30 minutes, 201 mg of 4-amino-2,6-diethylphenol is added and the reaction mixture is stirred at room temperature. After completion of the reaction, ice chips are added, and then an aqueous 5 % sodium hydrogen carbonate is added. The crystals precipitated are collected by filtration, washed with isopropyl ether and the residue is recrystallized from ethyl acetate to give 150 mg of 4-(2-thienylcarbonyl)amino-2,6-diethylphenol as white crystals.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl>C1COCC1.O.CO>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1noc(N)c1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Br
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0-5° C. After stirring at 0-5° C. for 10 min., the reaction was warmed to room temperature for 10 min. to complete the reaction. The reaction mixture was re-cooled to 0° C. and 4-tert-butylbenzenesulfonyl chloride (512 mg, 2.2 mmol) was added slowly. Stirring was continued for 20 min. at 0-5° C. Excess sodium hydride was decomposed by addition of methanol (0.4 ml) followed by water (0.5 ml). The mixture was acidified with hydrochloric acid and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give a crude product, which was purified by recrystallization from ethyl acetate/hexanes to give a white solid in 21% yield, m.p. 170° C. (dec.).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:9]1[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]2[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:2]=[CH:3][CH:4]=2)=[N:8]1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2F)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccccc2F)nc1-c1ccnn1-c1ccccc1
Yield: 31 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(2-fluorophenyl)pyridazin-4(1H)-one (crude 776 mg, 2.70 mmol) in 20 mL of methanol was added phenylhydrazine (438 mg, 4.10 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(2-fluorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (278 mg, 31% for two steps) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]=2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33]Cl)[CH3:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]=2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:30][CH2:29][N:31]([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:15][CH:14]=2)=[CH:25][CH:26]=1
Reactant: O=C(c1ccc(O)cc1)c1c(Cc2ccc(Cl)cc2)oc2ccccc12
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc(C(=O)c2c(Cc3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
A solution of 2-(4-chlorobenzyl)-3-(4-hydroxybenzoyl)benzofuran (2.0 g., 5.5 mmol) of 50 ml. of toluene is added to a slurry of 0.5 g. of a 57% sodium hydride dispersion (0.01 mol.) in 5 ml. of toluene. The reaction mixture is refluxed for 10 minutes, then 0.82 g. (5.5 mmol.) of 2-diethylaminoethyl chloride is added and the mixture is heated at 90° for 4 hours. The mixture is filtered and the filtrate concentrated under reduced pressure to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:15].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1>C1COCC1.CCCCCC>[C:16]12([C:14](=[O:15])/[CH:13]=[CH:32]/[C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(/C=C/c1cccnc1)C12CC3CC(CC(C3)C1)C2
Yield: 69.9 %

Procedure:
To a stirred solution of diisopropylamine (1.54 ml, 11 mmol) in THF (40 ml) at 0° C. was added butyllithium (1.6M; 6.25 ml, 10.0 mmol) in hexane, followed after 5 minutes by 1-adamantyl methyl ketone (1.96 g, 11.0 mmol). After stirring for 30 minutes at 0° C. the resulting solution of the lithium enolate of 1-adamantyl methyl ketone was then added to a stirred solution of 3-pyridinecarboxaldehyde (0.94 ml, 10.0 mmol) in THF (12 ml) at room temperature. After 3 hours the mixture was partitioned between diethyl ether and water, and the ether layers were concentrated. Chromatography, on elution with petrol-ether-triethylamine, 100:50:1 afforded the product as a solid (1.87 g, 70%), which crystallised from hexane, m.p. 98°-101° C.; IR νmax 1679 cm-1 ; 1H-NMR (CDCl3) δ1.65-1.84 (12H, m, adamantyl CH2), 2.10 (3H, s, adamantyl CH), 7.27 (1H, d, J 15.8 Hz, COCHCH), 7.38 (1H, m, Py 5-H), 7.68 (1H, d, J 15.8 Hz, COCHCH), 7.93 (1H, m, Py 4-H), 8.55 (1H, m, Py 6-H), 8.81 (1H, m, Py 2-H); MS m/z 267 (M+).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:19]=1[N:18]=[C:9]([C:10]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:11])[CH:8]=[C:7]2[O:20][CH3:21].COC1C2C(=C([N+]([O-])=O)C=CC=2)N=C(C([NH:29]C2NN=NN=2)=O)C=1>>[NH2:29][C:4]1[CH:5]=[C:6]2[C:19](=[CH:2][CH:3]=1)[N:18]=[C:9]([C:10]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:11])[CH:8]=[C:7]2[O:20][CH3:21]
Reactant: COc1cc(C(=O)Nc2nnn[nH]2)nc2c(N)cccc12
Reactant: COc1cc(C(=O)Nc2nnn[nH]2)nc2c([N+](=O)[O-])cccc12
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccc(N)cc12

Procedure:
8-Amino-4-methoxy-N(1H-tetrazol- 5-yl)quinaldamide, m.p. 276° (d), was prepared by the hydrogenation of 4-methoxy-8-nitro-N(1H-tetrazol- 5-yl)quinaldamide.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[S:32]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)([O:35][CH3:36])(=[O:34])=[O:33]>>[S:32]([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)([O-:35])(=[O:34])=[O:33].[CH3:36][P+:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:30])[F:31])=[CH:8][CH:7]=1)([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: FC(F)(F)c1ccc(P(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)cc1
Product: C[P+](c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 73.4 %

Procedure:
A mixture of 5.25 g (11.3 mmol) of tris (4-trifluoromethylphenyl)phosphine and 2.43 g (13.0 mmol) of methyl tosylate were allowed to react for 2 hr at 135° C. A total of 5.41 g (8.29 mmol, 73.4%) of product was obtained, which was further purified by recrystallization from toluene-ethanol.