Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([CH2:12][C:13]#[N:14])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:22][C:23]#[N:24].O>O1CCCC1>[NH2:24][C:23]1[N:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C:12]([C:13]#[N:14])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=1
Reactant: N#CCc1n[nH]c(-c2ccccc2)n1
Reactant: N#CC=C(Br)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccccc2)cc(N)n2nc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.2 %

Procedure:
A solution of 0.18 g (0.001 mol) 5-phenyl-1H-1,2,4-triazole-3-acetonitrile in 7 ml tetrahydrofuran was treated at −70° C. with 1.56 ml (0.0025 mol) butyllithium (1.6 M in hexane). After one hour 0.21 g (0.001 mol) 3-bromo-3-phenyl-2-propenenitrile was added, stirring was continued for one hour, the mixture warmed to room temperature over night and water was added. Extraction with diethylether, chromatography on silicagel with dichloromethane/methanol 99/1 and crystallisation from diethylether gave 3.6 mg 5-amino-2,7-diphenyl-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitril as white cystals. MS m/e (%): 312 (M+H+, 100).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([N:8]1[CH2:34][CH2:33][CH2:32][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([C:19]([C:22]([C:25]([C:28]([F:31])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.CN1CCOCC1.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][CH2:50][C:51](Cl)=[O:52])[CH:44]=1>C(Cl)Cl>[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][CH2:50][C:51]([NH:1][C@H:2]([C:6]([N:8]2[CH2:34][CH2:33][CH2:32][C@H:9]2[C:10]([NH:12][CH:13]([CH:14]([CH3:15])[CH3:16])[C:17](=[O:18])[C:19]([F:21])([F:20])[C:22]([F:23])([F:24])[C:25]([F:26])([F:27])[C:28]([F:31])([F:29])[F:30])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:52])[CH:44]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Reactant: O=C(Cl)CCc1cccnc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CCc1cccnc1)C(C)C)C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Dissolve H-Val-Pro-Val-CF2CF2CF2CF3.hydrochloride (221.0 mg, 0.40 mmol) in methylene chloride (10 mL) and cool to -20° C. while stirring. Add N-methylmorpholine (0.2 mL, 2.0 mmol) and immediately follow with a dropwise addition of 3-(3-pyridyl)propanoyl chloride in methylene chloride (5 mL) at such a rate as to maintain the internal reaction temperature at -10° C. or less. After completion of the addition, allow the reaction mixture to warm to room temperature. After 1.5 hours at room temperature, dilute the reaction mixture with methylene chloride (20 mL) and wash with 1N HCl (2×20 mL), saturated NaHCO3 (2×20 mL) and brine (1×20 mL). Dry (MgSO4) and concentrate in vacuo to give the title product in crude form. Immediately purify the crude product by flash chromatograpy (2×15 cm column eluted with 1:27 MeOH--CH2Cl2) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:11]([S:18][C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: SCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1ncc(SCc2ccccc2)c(Cl)c1=O
Reaction time: 8 h
Yield: 59.4 %

Procedure:
35.8 g (200 millimoles) of 4,5-dichloro-2-methylpyridazin-3(2H)-one are suspended in 300 ml of isopropanol and the suspension is colled to -20° C. A solution of 24.8 g (200 millimoles) of benzyl mercaptan and 20.2 g (200 millimoles) of triethylamine in 200 ml of isopropanol is added dropwise at this temperature, after which stirring is continued for 1 hour at -10° C. and overnight at room temperature. The resulting precipitate is filtered off under suction, washed with isopropanol and water and dried under reduced pressure to give 31.7 g (60%) of a product of melting point 102°-104° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:16]>CN(C)C=O.O>[C:17]1([C:15](=[CH2:14])[CH2:16][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C(CBr)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CN1C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 98.3 %

Procedure:
A mixture of 60 g of potassium phthalimide and 66.4 g of α-bromomethyl styrene (prepared by the method of S. F. Reed, Jr., J. Org. Chem., 30, 3258 (1965)) in 150 ml of dimethylformamide is refluxed for 2 hours, cooled, and diluted with 400 ml of water. The resulting solid is filtered and dried in vacuo to give 83.4 g of N-(2-phenyl-2-propenyl)phthalimide. A small sample that is recrystallized from acetone-hexane has a melting point of 118°-121°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=1.[CH:12](N=C=NC(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:2]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCc1cccnc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 3-(3-pyridinyl)propanoic acid (2.50 g, 16.5 mmol) in CH2Cl2 (110 mL) and MeOH (1 mL) was added DMAP (0.010 g, 0.082 mmol) and diisopropylcarbodiimide (4.17 g, 33.1 mmol). The reaction was stirred for 2 hours at 23° C. then saturated aqueous NaHCO3 (100 mL) was added. The mixture was extracted with CH2Cl2 (100 mL) and the combined extracts were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (elution with 60% EtOAc/hexanes) to provide 2.70 g (99%) of the desired product. MS (DCI/NH3) m/z 166 (M+H)30 .
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19].Cl>>[CH3:21][O:20][C:18]([NH:1][C@@H:2]([CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)[C:3]([OH:5])=[O:4])=[O:19]
Reactant: COC(=O)Cl
Reactant: N[C@H](C(=O)O)C1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of (S)-amino-(tetrahydro-pyran-4-yl)-acetic acid (1 g, 6.28 mmol) in saturated aqueous sodium bicarbonate solution (12.32 mL, 125.6 mmol) was stirred until all solids were dissolved. Methyl chloroformate (0.97 mL, 12.56 mmol) was added dropwise, the reaction mixture was stirred for 1 h, and 1N HCl was added to adjust pH to 1. The reaction mixture was extracted with ethyl acetate (3×15 mL) and the combined organic extracts were dried over sodium sulfate, filtered, concentrated and dried overnight under vacuum to give the title intermediate (1.36 g, 99% yield) as a white, sticky solid. (m/z): [M+H]+ calcd for C9H15NO5 218.10 found 218.3.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.CC1C=CC(S([CH2:21][N+:22]#[C-:23])(=O)=O)=CC=1.[C:24]([O:35][CH3:36])(=[O:34])/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1COCC1>[CH3:36][O:35][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][C:28]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:21][NH:22][CH:23]=1
Reactant: COC(=O)/C=C/CCCC(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCc1c[nH]cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
To a 1 M solution of LiN(TMS)2 in THF (5.9 mL, 5.9 mmol) cooled at −78° C. under argon was added a solution of TOSMIC (1.15 g, 5.9 mmol) in THF (15 mL) dropwise. After 40 min at −78° C. a solution of dimethyl (2E)-hept-2-enedioate (1.1 g, 5.9 mmol) in THF (15 mL) at −78° C. was added slowly. The solution was stirred for 10 min, then the cold bath was removed and the reaction was allowed to warm at room temperature. THF was evaporated and the residue partioned between H2O (200 mL) and DCM (200 mL). Aqueous layer was extracted with DCM and the combined organic layers anidrified on Na2SO4, filtered and concentrated to give a residue which was chromatographed on silica gel (eluant: AcOEt/hexane 3/7) to afford 633 mg (yield: 40%) of the title compound as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH2:22].CO>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:22]([CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: NCc1ccccn1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccccn1
Temperature: 150 °C
Yield: 49.8 %

Procedure:
Into a microwave vial was combined 5-nitro-isochromen-1-one (1 g, 0.005 mol), 2-pyridinemethanamine (1 g, 0.009 mol), and methanol (20 mL, 0.5 mol). The mixture was heated at 150° C. for 2 hours. The mixture was cooled to room temperature. The usual work up of the reaction mixture gave a crude product which was then purified using a flash chromatography over silica gel to give the pure product as a yellow solid (0.7 g). MS m/z=282.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[CH3:10].OS(O)(=O)=O.[N+]([C:19]1[CH:20]=C(S(O)(=O)=O)C=C[CH:24]=1)([O-])=O>OCC(CO)O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][C:4]=1[CH3:10])[N:7]=[CH:20][CH:19]=[CH:24]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Reactant: COc1ccc(N)cc1C
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: COc1cc2cccnc2cc1C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To 4-methoxy-3-methylaniline (6.7 g) was added concentrated H2SO4 (12.4 mL), followed by glycerin (21.1 g), m-nitrobenzenesulfonic acid (6.53 g), H3BO3 (3.4 g) and FeSO4.7H2O (3.2 g). The mixture was stirred at 140° C. for 1 h. The reaction was cooled to 25° C., quenched with ice-water and neutralized with 30% KOH. The mixture was extracted with DCM (2×), and the combined extracts dried with Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc) to give 6-methoxy-7-methylquinoline LCMS-ESI+ (m/z): 174.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([F:12])[CH:4]=1.CCN(C(C)C)C(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:12][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=1)[CH2:2][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1
Reactant: O=[N+]([O-])c1cc(F)cc(CBr)c1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A −20° C. solution of 1-(bromomethyl)-3-fluoro-5-nitrobenzene (0.95 g, 4.06 mmol) and DIEA (1.418 ml, 8.12 mmol) in THF (20 mL) was treated drop-wise with a solution of 1-methylpiperazine (0.488 g, 4.87 mmol) in THF (10 mL) and stirred at RT overnight as the cooling bath expired. The solid was removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-(3-fluoro-5-nitrobenzyl)-4-methylpiperazine (820 mg, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.97 (dt, J=8.6, 2.3 Hz, 1H), 7.64 (dd, J=9.2, 2.2 Hz, 1H), 3.60 (s, 2H), 2.41 (s, 8H), 2.21 (s, 3H); MS (ESI) m/z: 254.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][C:10]([CH3:15])=[CH:11][C:12](O)=[O:13].O>C(Cl)Cl>[CH3:9][C:10]1([CH3:15])[CH2:11][C:12](=[O:13])[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2]1
Reactant: Oc1cccc(O)c1
Reactant: CC(C)=CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(=O)c2ccc(O)cc2O1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
In a flask were placed 55.1 grams (0.5 mole) of resorcinol and 55.1 grams (0.5 mole) 3,3-dimethylacrylic acid. Then, 150 grams of polyphosphoric acid was added, and a steam bath applied to the flask. A red liquid began to form; the temperature of the reaction mixture quickly rose to 120° C. The flask was stirred for 45 minutes at 110° C., then allowed to cool. The contents were poured into a mixture of 500 milliliters water and 400 milliliters methylene chloride then stirred and filtered. The precipitate was washed several times with portions of methylene chloride, water and toluene. There was obtained 65.8 grams, (68% of theoretical yield) 2,2-dimethyl-7-hydroxy-4-chromanone, m.p. 170°-174° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:37]I>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH3:37])[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: CI
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 68.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271F, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (370 mg, 0.75 mmol) and methyl iodide (106 mg, 0.75 mmol) were converted to the title compound (260 mg, 68%). 1H NMR (CDCl3) δ 8.70 (d, J=1.2 Hz, 1H), 8.24 (dd, J=8.0, 1.6 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.43 (s, 1H), 7.37-7.33 (m, 3H), 7.28-7.27 (m, 2H), 5.17 (s, 2H), 3.98 (s, 3H), 3.92 (br s, 2H), 3.45 (br s, 2H), 3.24 (s, 3H), 1.68-1.52 (m, 4H), 1.37-1.24 (m, 4H), 0.94-0.90 (m, 6H); MS(ESI+) m/z 507.0 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH:16]=[C:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])=[CH:24][CH:25]=1)[C:3]1[N:4]=[CH:5][CH:6]=[CH:7][N:8]=1
Reactant: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1ncccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CN(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
5-(4-[2-(N-Methyl-N-(2-pyrimidinyl)amino) ethoxy]benzylidene)-2,4-thiazolidinedione (2.4 g) in dry 1,4-dioxan (150 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (3 g) until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (mp 150°-51° C.) was obtained after crystallisation from methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:22]([O-:25])(=[S:24])[CH3:23].[K+]>CN(C)C=O>[C:22]([S:24][CH:14]1[CH2:13][CH2:12][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:16][CH2:15]1)(=[O:25])[CH3:23]
Reactant: CCOC(=O)c1csc(N2CCC(OS(C)(=O)=O)CC2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CCC(SC(C)=O)CC2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-4-methanesulfonyloxypiperidine (76 mg, 0.23 mmol) (obtained as described in Reference Example 13(3)) in dimethylformamide (4.0 ml) was added potassium thioacetate (145 mg, 1.3 mmol) at room temperature, and the reaction mixture was then stirred in an oil bath (80° C.) for 8 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 4-acetylthio-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)piperidine (67 mg, yield 94%) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:7]=1.C([O-])=O.[NH4+]>C(O)C.O.[Fe]>[NH2:16][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2cncc(Br)c2)c1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(/C=C/c2cncc(Br)c2)c1
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A mixture of 3-bromo-5-[(E)-2-(3-nitrophenyl)vinyl]pyridine (5.55 g), iron powder (3.05 g) and ammonium formate (5.73 g) in ethanol (90 ml) and water (30 ml) was stirred at 90pbC. for 30 minutes. The mixture was filtered while hot. The filtrate was added to sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated to give 3-[(E)-2-(3-aminophenyl)vinyl]-5-bromopyridine (3.57 g).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:27]1[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:35])=[O:3])=[CH:14][CH:13]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.74 (2H, m), 8.39 (2H, d), 8.26 (1H, m), 8.16 (2H, m), 7.64 (2H, d), 7.55 (2H, d), 4.18 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s)
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(O)=[O:2].S(=O)(=O)(O)O.[CH2:41]([OH:43])[CH3:42]>>[CH2:41]([O:43][C:4](=[C:1]=[O:2])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:42]
Reactant: CCO
Reactant: COc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=C=O)CCCCCCn1c(-c2ccc(OC)cc2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
1-(7-Carboxyheptyl)-2-(4-methoxyphenyl)-4,5-diphenyl-imidazole (0.4 g) was reacted with ethanol and concentrated sulphuric acid in a method similar to Example 18 to give, after work-up and column chromatography on silica gel eluted with a dichloromethane:ethanol gradient, 1-(7-ethoxy-carbonylheptyl)-2-(4-methoxyphenyl)-4,5-diphenylimidazole (0.21 g, 50%) as an oil. Found: C, 77.39; H, 7.55; N, 5.96%; C32H36N2O3 requires: C, 77.39; H, 7.31; N, 5.64%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=2[NH:12][C:11](=[S:31])[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(F)c(F)cc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Fc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-1,3-dihydro-7,8-difluoro-2H-1,4-benzodiazepin-2-thione (IImm) was prepared by reacting 0.003 moles of 5-(2-chlorophenyl)-1,3-dihydro-7,8-difluoro-2H-1,4-benzodiazepin-2-one (Imm) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=2)[N:22]=[C:21]1[CH3:32].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40]>O1CCCC1>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=2)[N:22]=[C:21]1[CH:32]=[C:39]([OH:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: CCOC(=O)c1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=c1c2cc(F)ccc2nc(C=C(O)c2ccccn2)n1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of diisopropylamine (0.061 mL, 0.47 mmol) in tetrahydrofuran (2.7 mL) was chilled to -78° C. and butyllithium (0.134 mL, 0.34 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 20 min and then a solution 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.10 g, 0.35 mmol) in tetrahydrofuran (0.7 mL) was added dropwise. The solution became intense red and was stirred 30 min. In a separate vessel a solution of ethyl picolinate (0.491 mL, 3.6 mmol) in tetrahydrofuran (2 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold ethyl picolinate solution via canula over a two minute period. The resulting mixture was stirred 30 minutes at -78° C. and then was allowed to warm to ambient temperature. The reaction was quenched with water. The mixture was repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was triturated with ether/hexane and the yellow solid which formed was collected and dried to yield 0.054 g (40%) of 3-(2-chloro-phenyl)-6-fluoro-2-(2-hydroxy-2-pyridin-2-yl-vinyl)-3H-quinazolin-4-one which had: mp>250° C. 1H NMR (DMSOd) δ8.45 (d, J=5 Hz, 1 H), 7.97 (d, J=7 Hz, 1 H), 7.90 (dt, J=1, 8 Hz, 1 H), 7.88-7.58 (m, 7 H), 7.35 (sym m, 1 H), 5.80 (s, 1 H). Analysis calculated for C21H13ClFN3O2 : C, 64.05; H, 3.33; N, 10.67. Found: C, 64.16; H, 3.71; N, 10.72.