Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=O)[O:6][C:5]2=[O:13].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]C(O)=O)=[CH:17][C:16]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]1)=[O:26].C([O-])(=O)C.[Na+].[Al]>>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[Cl:1])[C:5](=[O:13])[O:6]/[C:7]/2=[CH:21]\[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[C:16]([C:25]([N:27]2[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]2)=[O:26])[CH:17]=1
Reactant: COC1CCN(C(=O)c2cc(CC(=O)O)ccc2F)CC1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: CC(=O)[O-]
Agent: [Al]
Agent: [Na+]
Product: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cc(Cl)c(Cl)cc43)ccc2F)CC1
Temperature: 240 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
A flask charged with 5,6-dichloroisobenzofuran-1,3-dione (370 mg, 1.71 mmol), 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetic acid (43) (496 mg, 1.68 mmol) and Sodium acetate (34 mg, 0.41 mmol) was lowered into a pre-heated aluminium block at 210° C. The resulting mixture was heated further and stirred at 240° C. for 1 hour then cooled. The residue was triturated, with sonication, under ethanol (˜25 mL) and solid collected by suction filtration to afford crude product (128 mg, 16.92%), which was used directly without further purification; m/z (LC-MS, ESI+), RT=2.79 (M+H 450.1 & 452.0).
Reaction SMILES: C1(S([CH2:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[N:13][C:14]([CH:19]3[O:23][CH2:22][CH2:21][O:20]3)=[C:15]([O:17][CH3:18])[CH:16]=2)(=O)=O)C=CC=CC=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].CC(C)([O-])C.[K+]>C(O)C>[CH2:32]([O:31][C:29](=[O:30])[CH:28]=[CH:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[N:13][C:14]([CH:19]2[O:20][CH2:21][CH2:22][O:23]2)=[C:15]([O:17][CH3:18])[CH:16]=1)[CH3:33]
Reactant: COc1cc(CS(=O)(=O)c2ccccc2)c([N+](=O)[O-])nc1C1OCCO1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C=Cc1cc(OC)c(C2OCCO2)nc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.7 %

Procedure:
A mixture of 0.28 g (0.73 mmol) 3-benzenesulfonylmethyl-6-[1,3]dioxolan-2-yl-5-methoxy-2-nitro-pyridine and 0.8 ml (0.73 mmol) of ethyl bromoacetate was dissolved in 10 ml of ethanol. To this solution was added 0.5 ml of potassium t-butoxide (1M in t-butyl alcohol) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was added to 5 ml of water. The suspension was extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated to yield approximately 0.3 g of an oil. Mass spectrum: m/e=325.1 (p+1). This material was used directly in step 6.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][N:25]=[CH:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][N:25]=[CH:24]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2ncncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3ncncc3c2)cc1
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (151 mg, 0.723 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinazoline (100 mg, 0.689 mmol) was added. The resulting mixture was stirred for 4 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale yellow solid (47 mg, 21%), single spot at Rf 0.57 (ethyl acetate). mp 202.1-202.6° C., HPLC purity 96% (tR 2.14 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 9.30 (1H, s), 9.24 (1H, s), 7.99-7.92 (2H, m), 7.77 (2H, d, J=8.4 Hz), 7.68-7.63 (2H, m), 7.23 (1H, d, J=7.7 Hz), 2.57 (2H, t, J=7.6 Hz), 1.57 (2H, sextet, J=7.6 Hz), 0.87 (3H, t, J=7.4 Hz). LCMS: 326.24 (M−). FAB-MS (MH+, C17H17N3O2S): calcd 328.1119, found 328.1118.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:11]=2)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]>CN(C)C=O>[CH2:1]([C:5]1([CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:11]=2)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCCCBr
Reactant: CCCCC1Cc2cc(OCOC)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCC1(CCCC)Cc2cc(OCOC)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of 2-butyl-5-(methoxymethoxy)-1-indanone (1.54 g, 6.2 mmol) in anhydrous N,N-dimethylformamide (DMF, 5 mL) was added to a suspension of sodium hydride (372 mg of a 60% dispersion in mineral oil, 9.3 mmol) in DMF (5 mL). The mixture was diluted with more DMF (2 mL, used to rinse in the indanone solution), placed under a nitrogen atmosphere, and stirred at room temperature for 25 minutes. 5-Bromo-1-pentene (1.47 mL, 12.4 mmol) was then added over 5 minutes, during which time the mixture clarified. After stirring at room temperature for an additional 5 hours, the mixture was quenched with saturated NH4Cl, dried over MgSO4, filtered through a pad of silica, and concentrated under vacuum to afford an oil. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4.0×7.0 cm) silica gel column, eluting with 19:1 hexanes-EtOAc. The product-containing fractions were evaporated under vacuum to afford 2-butyl-5-(methoxymethoxy)-2-(4-pentenyl)-1-indanone as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](N)[CH:3]=1.N([O-])=[O:13].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([OH:13])[CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(O)ncc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
Dissolve 4-methyl-5-nitro-pyridin-2-ylamine (3.0 mmol, 0.5 g) in 0.5 mL of sulfuric acid. Add 7.6 mL of water and cool the solution down to 0° C. Add sodium nitrite (4.5 mmol, 0.3 g) and stir the mixture for two hours, allowing to reach room temperature. Dilute with water and add aq. sodium hydroxide solution 10% until basic pH. Extract in ethyl acetate and wash combined organic layers with saturated aq. sodium chloride solution. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 4-methyl-5-nitro-pyridin-2-ol. MS(ES): m/z=155 [M+H].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[S:12][CH:13]=1.C([Li])CCC.CN(C)[CH:31]=[O:32].O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[S:12][C:13]=1[CH:31]=[O:32]
Reactant: FC(F)(F)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Under a nitrogen atmosphere at −78° C., to a solution (100 mL) of the compound (8.0 g, 23 mmol) obtained in Example 89a in tetrahydrofuran was added n-butyllithium (1.6M hexane solution, 18 mL, 28 mmol), and the mixture was stirred at the same temperature for 1 hr. Anhydrous N,N-dimethylformamide (2.3 mL, 30 mmol) was added to the reaction mixture, and the mixture was stirred at −78° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (5.5 g, 64%) as a pale-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1)([O-])=O.[Cl-].N.C(O)C>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][C:12]([F:13])([F:14])[F:15])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)c(OC(F)(F)F)c1
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(O)c(OC(F)(F)F)c1
Temperature: 50 °C
Yield: 74.6 %

Procedure:
223 mg (1.0 mmol) of 4-nitro-2-trifluoromethoxyphenol, 224 mg (4.0 mmol) of reduced iron powder, and 321 mg (6.0 mmol) of ammonia chloride were successively added to a mixture of 20 mL of ethanol and 6.0 mL of water under argon atmosphere with mechanical stirring. The mixture was slowly heated to 50° C. and allowed to react at this temperature for 1.5 h until the solution turned brown. The reaction was stopped, naturally cooled, filtered under reduced pressure, and the filter cake was washed with 10 mL of ethyl acetate. 20 mL of water and 20 mL of ethyl acetate were added to the filtrate. The organic layer was isolated, and the water layer was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, successively washed with 50 mL of water and 50 mL of saturated saline, dried over anh. MgSO4, filtered and concentrated to obtain 144 mg of a dark red solid. Yield 74.4%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O-:3])=[O:2].C(OC(N1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])=O)C>C(=O)([O-])[O-].[Na+].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([N:13]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:14]([OH:16])=[O:15])([O-:3])=[O:2]
Reactant: N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)[C@H](CSc1ccccc1[N+](=O)[O-])N1C(=O)c2ccccc2C1=O
Yield: 80.8 %

Procedure:
In an aqueous solution (200 ml) of 1.4 g of sodium carbonate is dissolved 2.9 g of S-(o-nitrophenyl)-L-cysteine, and 3.5 g of N-ethoxycarbonylphthalimide is added to the solution under stirring. After the mixture is stirred at room temperature for 5 hours, the insoluble matter is removed by filtration, and the filtrate is made weakly acid with concentrated hydrochloric acid. The crystals which separate out are recovered by filtration, and recrystallized from 30 ml of ethanol to give 3.6 g of 3-(o-nitrophenyl)thio-2(R)-phthalimidopropionic acid as pale yellow needles, melting at 220°-222° C.
Reaction SMILES: C[Si](I)(C)C.[Cl:6][C:7]1[CH:50]=[CH:49][C:10]([CH2:11][CH:12]2[N:17]3[C:18](=[O:44])[CH:19]([NH:33]C(=O)OCC4C=CC=CC=4)[CH2:20][N:21]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])(=[O:24])=[O:23])[CH:16]3[CH2:15][N:14]([CH:45]([CH3:47])[CH3:46])[C:13]2=[O:48])=[CH:9][CH:8]=1.CO>CC#N>[NH2:33][CH:19]1[C:18](=[O:44])[N:17]2[CH:12]([CH2:11][C:10]3[CH:49]=[CH:50][C:7]([Cl:6])=[CH:8][CH:9]=3)[C:13](=[O:48])[N:14]([CH:45]([CH3:46])[CH3:47])[CH2:15][CH:16]2[N:21]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])(=[O:24])=[O:23])[CH2:20]1
Reactant: CC(C)N1CC2N(C(=O)C(NC(=O)OCc3ccccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reaction time: 2 h
Yield: 91.8 %

Procedure:
206 ml (1.44 mmol) of trimethylsilyl iodide (TMSI) are added to a solution of 250 mg (0.36 mmol) of benzyl [6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate in 10 ml of CH3CN at 0° C. The reaction solution is allowed to reach room temperature and is stirred at this temperature for 2 h. 5 ml of MeOH are added to the reaction solution, and then the solution is concentrated in vacuo. The residue is purified on a 5 g SCX cartridge (eluted with MeOH followed by 3N NH3/MeOH). 185 mg of the desired compound are obtained as a white powder. LC/MS 558.07 (calculated, monoisotopic); measured value (M+H)+: 559.10
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:25])C(=O)C1>CC#N>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:25])[NH:10][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCn1c(=O)n(CC)c(=O)c2[nH]cnc21
Solvent: CC#N
Product: CCCCn1c(=O)n(CC)c(=O)c2[nH]c(Cl)nc21
Temperature: 120 °C

Procedure:
3-Butyl-1-ethyl-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.42 mmol) and NCS (56 mg, 0.42 mmol) were suspended in MeCN (5 mL) and heated at 120° C. under microwave irradiation. The reaction mixture was concentrated under reduced pressure and the title compound isolated using HPLC. [HPLC conditions used for the purification: 23 minute run time. Solvents: 0.1% TFA in MeCN and 0.1% TFA in water. MeCN increased from 5% to 95% linearly over 15 minutes. Held at 95% for 2 min. Then decreased to 5% linearly over 1 min., equilibrated at 5% for 5 minutes before next injection.]; 1H NMR (400 MHz; CDCl3) δ: 0.97 (3H, t), 1.31 (3H, t), 1.38-1.45 (2H, m), 1.72-1.80 (2H, m), 4.09-4.20 (4H, m), 13.40 (1H, br.s); m/z 271 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[N:13][OH:14])[NH2:12])=[CH:3]1.[H-].[Na+].[C:17](OC)(=O)[CH:18]=[CH2:19]>C1COCC1>[CH:18]([C:19]1[O:14][N:13]=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[N:12]=1)=[CH2:17]
Reactant: Cn1cc(C(N)=NO)c2ccccc21
Reactant: C=CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1nc(-c2cn(C)c3ccccc23)no1
Reaction time: 0.5 h

Procedure:
1-Methyl-1H-indole-3 carboxamide oxime (C. J. Swain et al, J Med Chem, 1991, 34, 147) (0.500 g, 2.64 mmol) was dissolved in dry THF (20 ml) with stirring, and treated with ground 4A molecular sieves (1.5 g) under nitrogen. After 30 minutes sodium hydride (80% dispersion in mineral oil) (0.087 g, 2.91 mmol) was added. The mixture was then heated to reflux. After 30 minutes the mixture was allowed to cool momentarily and a methyl acrylate (0.475 ml, 5.28 mmol) was added. The mixture was then heated to reflux for a further 3 hours. The reaction mixture was then allowed to cool and was filtered. The filter pad was then washed with THF (2×). The filtrate was then evaporated under reduced pressure. The residue was purified by silica-gel chromatography eluting with pentane EtOAc 3:1 to afford the title compound (D2) as a colourless oil that crystallised on standing rapt 53°-55° C.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26]C(=O)[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].O>>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C@H:9]3[CH2:10][CH2:11][C@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]3)[C:14]=2[C:30]([F:32])([F:33])[F:31])[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(OC4CCC(C5CCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C[C@](N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C4CCCC4)CC3)ccc2c1

Procedure:
The compound was prepared in a manner similar as to that described above (R)-4-[6-(4-Cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (15 mg, 0.000032 mol), (0.14 g, 0.0030 mol), 4.2 M lithium hydroxide, monohydrate in water (0.13 mL, 0.00055 mol) to give 12 mg of the desired product as a white solid (81%). ESI-MS: 419 (M−16)+. 1H NMR (400 MHz, MeOD) δ=8.64-8.50 (m, 1H), 8.17-7.98 (m, 2H), 7.98-7.87 (m, 1H), 7.73-7.62 (m, 1H), 7.50-7.40 (m, 1H), 4.84-4.76 (m, 2H), 3.80-3.58 (m, 2H), 2.12-1.96 (m, 2H), 1.85-1.42 (m, 18H), 1.21-1.05 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1Br.C([Li])CCC.[NH:13]1[C:21](=[O:22])[C:19](=O)[C:17](=[O:18])[NH:16][C:14]1=[O:15]>CCOCC.O1CCCC1>[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Clc1sccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2ccsc2Cl)C(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Following the method of Gronowitz et al. [Chemica Scripta 15, p. 2 (1980)], 2-chloro-3-bromothiophene is reacted with n-butyl lithium in ether at -70° C. After 15 minutes, the organolithium reagent is poured into a solution of alloxan in tetrahydrofuran at -70° C. The reaction mixture is allowed to warm to room temperature for 2 hours, and 5-(2-chloro-3-thienyl)-2,4,6(1H,3H,5H)-pyrimidinetrione isolated according to Example 5.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:20]1[CH:24]=[CH:23][C:22]2[CH:25]([CH2:29][CH2:30]O)[CH2:26][CH2:27][CH2:28][C:21]1=2.C(Cl)(Cl)(Cl)[Cl:33].C(#N)C>>[Cl:33][CH2:30][CH2:29][CH:25]1[C:22]2[CH:23]=[CH:24][S:20][C:21]=2[CH2:28][CH2:27][CH2:26]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCCC1CCCc2sccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: ClCCC1CCCc2sccc21
Reaction time: 3 h
Yield: 56 %

Procedure:
Triphenylphosphine (3.94 g, 15 mmol) is added to a solution of 2-(4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)ethanol (2.74 g, 15 mmol) in Cl4C/Acetonitrile 1:1 (20 mL) at room temperature and the mixture is maintained under stirring for 3 hours monitoring the reaction by TLC. The solution is concentrated to half the volume at reduced pressure, CH2Cl2 is added and washed with water. The organic phase is separated and evaporated to dryness. The crude is treated with diethyl ether and the precipitate is filtered. The diethyl ether is evaporated to dryness, and the resulting crude is purified by column chromatography, giving 4-(2-chloroethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene (1.7 g, 8.4 mmol, 56%, oil). 1H NMR (300 MHz, CDCl3): δ 1.54 (m, 1H), 1.79 (m, 1H), 1.92 (m, 3H), 2.20 (m, 1H), 2.77 (m, 2H), 3.00 (m, 1H), 3.64 (m, 2H), 6.86 (d, J=5.2 Hz, 1H), 7.06 (d, J=5.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](\[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:32]([N:35]1[CH:39]=[CH:38][CH:37]=[N:36]1)[C:33]#[CH:34]>O1CCCC1.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)\[C:25]2[CH:26]=[CH:27][C:28]([C:34]#[C:33][CH2:32][N:35]3[CH:39]=[CH:38][CH:37]=[N:36]3)=[CH:29][CH:30]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CCn1cccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#CCn3cccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of methyl (Z)-[2-methyl-4-[3-(4-iodophenyl)-3-(4-methylphenyl]allyloxy]-phenoxy]acetate (310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL) and triethylamine (9 mL) was degassed and 1-propargyl-1H-pyrazole (124 mg, 1.17 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)palladium (54 mg, 0.046 mmol) and copper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture was stirred at ambient temperature for 4 days, subsequently evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water (3×15 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-(3-pyrazol-1-ylpropynyl)phenyl]allyloxy]phenoxy]acetate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35]CC3C=CC=CC=3)=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)C.[Pd]>[CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][OH:35])=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCCOCc3ccccc3)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCCO)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 6.2 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-benzyloxyethoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine in 100 mL of ethanol with 0.5 g of 10% palladium on carbon is hydrogenated at 50 psi for 18 h. The mixture is filtered and the filtrate evaporated to afford 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-hydroxyethoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:18][C:43](=[O:44])[C:42]([S:41][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:46]([OH:47])[CH:17]=2)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OC(=O)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Oc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1)c1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-benzoyloxyacetophenone (1.27 g, 5.31 mmol), lithium bis(trimethyl-silyl)amide (0.977 g, 5.84 mmol), chlorotrimethyl-silane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 205° C.; 1H NMR (400 MHz, DMSO-d6) δ 4.01 (s, 2 H), 6.75 (s, 1 H), 7.21 (m, 1 H), 7.25 (d, 4 H), 7.47 (d, 2 H), 7.63 (t, 2 H), 7.77 (t, 1 H), 7.90 (d, 2 H), 8.16 (d, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5](CO)[CH:6]=[CH:7][CH:8]=1.C=O.[C:14](O)(=[O:16])C.C([BH3-])#N.[Na+]>C(OCC)(=O)C.O>[CH3:11][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:14][OH:16]
Reactant: CN(C)c1cccc(CO)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)c1ccccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round-bottomed flask, (3-(dimethylamino)phenyl)methanol (1 g) and paraformaldehyde (2.5 g) were added to acetic acid (150 mL) to give a suspension. Sodium cyanoborohydride (2.6 g) was added slowly. The mixture was stirred at room temperature overnight. After concentration of the solvent, water and ethyl acetate (1:1, 100 mL) were added. After separation, the aqueous layer was extracted by ethyl acetate (2×20 mL). The combined organic layers were washed with water (3×50 mL), saturated aqueous NaHCO3 (2×30 mL), and dried over Na2SO4. After filtration and concentration, the residue was taken up into CH2Cl2 and the product was purified by flash chromatography (Varian, Superflash SF40-80 g column), eluting with 0-20% methanol/dichloromethane, to provide the title compound.