Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.Cl.N1C=CC=CC=1>O>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:11][C:7]1=2
Reactant: COc1ccc2ccsc2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2ccsc2c1
Temperature: 100 °C
Yield: 98.5 %

Procedure:
6-Methoxybenzo[b]thiophene (6.15 g, 37.45 mmol) and pyridine hydrochloride (18.5 g) were heated together at 210° C. for 1 h. The mixture was cooled to 100° C., diluted with water (125 mL) and extracted with dichloromethane (3×70 mL). The combined extracts were washed with water (125 mL), dried (MgSO4) and evaporated in vacuo to give the title compound (5.54 g, 98%)
Reaction SMILES: Cl[C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1.Cl.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:24]1>>[CH:9]1([NH:8][C:6]([C:5]2[CH:15]=[C:16]([F:17])[C:2]([N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([CH2:29][C:30]([OH:32])=[O:31])[CH2:24]3)=[N:3][C:4]=2[S:18][CH2:19][CH2:20][CH3:21])=[O:7])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C[C@@H]1CCCNC1
Reactant: CCCSc1nc(Cl)c(F)cc1C(=O)NC1CCCCC1
Agent: Cl
Product: CCCSc1nc(N2CCC[C@H](CC(=O)O)C2)c(F)cc1C(=O)NC1CCCCC1

Procedure:
Prepared in a similar manner to that described above from 6-chloro-N-cyclohexyl-5-fluoro-2-(propylthio)nicotinamide using (S)-methyl 2-(piperidin-3-yl)acetate hydrochloride followed by an ester hydrolysis as described above to give the desired compound (190 mg) as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)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>[Cl:17][C:10]1[CH:9]=[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[C:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[F:26])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: OB(O)c1ccccc1F
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Temperature: 100 °C

Procedure:
To a mixture of 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.16 g, 0.41 mmol) and (2-fluorophenyl)boronic acid (0.069 g, 0.49 mmol) in 1,4-dioxane (2 mL) was added 1 N solution of sodium carbonate in water (0.62 mL, 34 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.020 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0-60% EtOAc in Hexane) to give the desired compound as a bis-trifluoroacetate salt (42 mg, 29%). LCMS calculated for C18H15ClFN2O2(M+H)+: m/z=345.1; found: 345.0.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)#[CH:25]>>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([C:24]#[C:25][C:2]2[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Br)nc1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(C#Cc2ccc(C(F)(F)F)cc2)nc1
Yield: 28 %

Procedure:
The title compound was synthesized as described for Example 179 a) in 28% yield, starting from 2-(2-(6-bromopyridin-3-yl)ethylsulfonamido)benzenesulfonamide and 4-ethynyl-alpha,alpha,alpha-trifluorotoluene. Purification by preparative HPLC.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[P:13]12(SP3(SP(SP(S3)(S1)=S)(=S)[S:15]2)=S)=[S:14]>C1(C)C=CC=CC=1>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([P:13](=[S:15])=[S:14])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCCCCOc1ccc(P(=S)=S)cc1
Reaction time: 48 h

Procedure:
n-Pentyloxybenzene (Ia) and P4S10 (in a molar ratio of 10:1) were stirred for six hours at 150° C. under anhydrous conditions. The mixture was cooled, toluene was added, and the reaction flask was left for two days at 5° C. The resulting precipitate was recovered by filtration, washed with anhydrous ether and dried. The yield of product was 46% of theory; after recrystallization from chloroform/petroleum ether it melted at 144°-6° C. Its solubility in tetrahydrofuran was found to be 5 gms/100 ml at room temperature.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[CH2:17][C:16]4[C:12]([CH:13]=[CH:14][N:15]=4)=[CH:11][C:10]=3[O:9][CH2:8]2)[CH2:4][CH2:3]1.C([BH3-])#N.[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.O>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)COC1=C2CC2=NC=CC2=C1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reaction time: 2 h
Yield: 53.4 %

Procedure:
2,3-Dihydro-1'-methylspiro[furo[2,3-f]indole-3,4'-piperidine] (D7, 0.056 g, 0.23 mmol) was stirred in acetic acid (5 ml) as sodium cyanoborohydride (0.044 g, 0.70 mmol) was added portionwise over 10 min. The solution was stirred for 2 h, diluted with water (20 ml), basified with saturated K2CO3 solution, and extracted with ethyl acetate. The extract was dried (Na2SO4) and evaporated to give the title compound (0.030 g, 53%) as a white solid.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].[P:22]([O-:34])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[K+].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:21]=[C:4]1[NH:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7](=[O:8])[N:3]1[CH2:2][O:34][P:22](=[O:23])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CCl
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OP(=O)(OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O)OC(C)(C)C
Temperature: 0 °C
Yield: 38.6 %

Procedure:
35.5 Grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione from Step (A), 30.7 g of potassium di(t-butyl) phosphate, 0.6 g of potassium carbonate, and 0.15 g of potassium iodide were slurried into 200 mL acetonitrile. The reaction mixture was heated at reflux for 2.5 hours. The solution was filtered to remove potassium chloride precipitate. The filtrate was cooled to 0° C. and filtered to give 22.3 g of the title compound (38.6% yield); mp 108.5° C. (d). 1H NMR (DMSO-d6): 1.3 ppm (s, 18H), 5.2 (d, 2H), 7.3-7.5 (m, 10H), 9.9 (s, 1H); doublet from long range phosphorus coupling.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CC(C)=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Br
Yield: 95 %

Procedure:
A solution of 4-Bromo-3-nitrophenol (1.0 g, 4.6 mmol) and benzyl bromide (0.82 mL, 7 mmol) in acetonitrile (30 mL) and acetone (15 mL) was treated with K2CO3 (970 mg, 7 mmol). The resulting mixture was heated at reflux under nitrogen for 17 h. The reaction mixture was evaporated in vacuo and the residue was dissolved in 40 mL ethyl acetate. The solution was filtered under vacuum then the filtrate was washed successively with distilled water (30 mL ), 1M HCl solution (30 mL×3), brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed over 100 g of silica gel using 3:1 mixture respectively of hexanes and ethyl acetate to give the benzyl alcohol in 95% yield; 1H NMR(CDCl3) δ5.11(2H, s), 7.02(1 H, dd, J1=2.9, J2=8.9), 7.41(5H, m), 7.46(1 H, d, J=2.9), 7.60(1H, d, J=8.9); 13C NMR(CDCl3) δ71.4, 105.4, 112.4, 121.1, 128.1, 128.9, 129.1, 129.3, 129.5, 135.8, 136.0, 138.2, 158.7; HRMS calcd for C13H10NO3Br: 306.9844; found: 306.9846.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)=O)(C)(C)C.[CH2:17]([N:19]([CH2:38][CH3:39])[C:20]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=O)[C:27]3[C:32]([O:33][C:34]=2[CH:35]=1)=[C:31]([Br:36])[CH:30]=[CH:29][CH:28]=3)=[O:21])[CH3:18].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[CH2:38]([N:19]([CH2:17][CH3:18])[C:20]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[C:11]3[CH2:12][CH:13]4[NH:8][CH:9]([CH2:15][CH2:14]4)[CH2:10]3)[C:27]3[C:32]([O:33][C:34]=2[CH:35]=1)=[C:31]([Br:36])[CH:30]=[CH:29][CH:28]=3)=[O:21])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: CCN(CC)C(=O)c1ccc2c(=O)c3cccc(Br)c3oc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(Br)cccc1C2=C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A suspension of zinc powder (5.59 g, 85.5 mmol) in tetrahydrofuran (THF, 100 mL) at 0° C., was treated with titanium(IV)chloride (4.69 mL, 42.8 mmol) by dropwise addition. The resultant mixture was heated at reflux for 2 h. The resultant solution was cooled to 0° C. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.4 g, 10.7 mmol) and 5-bromo-9-oxo-9H-xanthene-3-carboxylic acid diethylamide (4.0 g, 10.7 mmol) were added and the solution was heated at reflux for 4 h. Potassium sodium tartrate tetrahydrate (30 g, 106 mmol) was added to the reaction mixture and allowed to stir at ambient temperature overnight. The inorganic solids were removed by filtration and washed successively with THF, EtOAc and dichloromethane. The solvent was evaporated in vacuo. Purification by flash chromatography using a gradient 1% to 10% methanol (with ammonia, 2 N) in dichloromethane as the eluent gave Compound 7j (3.65 g). Crude product was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%), to give the trifluoroacetic acid salt of compound 7j. MS: m/z 467.0 (MH+). 1H NMR (DMSO-d6): δ 1.0-1.2 (br m, 6 H), 1.32 (d, 2 H, J=7.9 Hz), 1.75-1.85 (br m, 2 H), 2.85-3.10 (m, 4 H), 3.15-3.50 (br m, 4 H), 4.01 br s, 2 H), 7.15-7.26 (m, 3 H), 7.42 (d, 1 H, J=6.7 Hz), 7.49 (d, 1 H, J=7.9 Hz), 7.66 (d, 1 H, J=7.9 Hz), 8.81 (br s, 1 H) and 9.12 br d, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]1[CH2:25]O.C(S(Cl)(=O)=O)C.[CH:34]1([CH2:37][NH2:38])[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]1[CH2:25][NH:38][CH2:37][CH:34]1[CH2:36][CH2:35]1
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: NCC1CC1
Agent: CCS(=O)(=O)Cl
Product: CN(C)Cc1nnc(CNCC2CC2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 47, 2',5-dichloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with ethanesulfonyl chloride followed by (cyclopropylmethyl)amine, to give 2',5-dichloro-2-[3-[[(cyclopropylmethyl)amino]methyl]-5-[(dimethylamino)-methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](I)[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[Cu][C:28]#[N:29]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:28]#[N:29])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (600 mg, 1.2 mmol) in tetrahydrofuran (15 mL) was added copper(I) iodide (137 mg, 0.72 mmol), tetrakis(triphenyphosphine)palladium(0) (416 mg, 0.36 mmol) and copper(I) cyanide (860 mg, 9.6 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 397 mg of the title compound as a crude yellow solid.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].OC([N:11]1[C:20]2[C:15](=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH2:12]1)CO.[C:24](OCC)(=[O:26])C>O1CCCC1.O>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][C:12]([CH:24]=[O:26])=[N:11]2)([O-:23])=[O:22]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cccc2c1C=CCN2C(O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c([N+](=O)[O-])cccc2n1
Reaction time: 20 h

Procedure:
2.99 g (14.0 mmol) of sodium periodate is added to a solution that consists of 1.64 g (7.0 mmol) of 1-(1,2-dihydroxyethyl)-5-nitroquinoline in 42 ml of tetrahydrofuran and 7.0 ml of water. After 20 hours at room temperature, ethyl acetate is added, and the organic phase is washed with saturated sodium chloride solution. After the organic phase is dried on sodium sulfate, after the solvent is removed, and after purification on silica gel with hexane-ethyl acetate (0-100%), 1.40 g (99% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=1)=[O:4].[CH3:23]I.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:23])[C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=1)=[O:4]
Reactant: CNC(=O)C1=CC2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1=CC2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 97.1 %

Procedure:
To a mixture of 0.64 g of N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carboxamide, 1.05 g of methyl iodide and 40 ml of dried N,N-dimethylformamide was added 0.13 g of sodium hydride (60%) with stirring under ice-cooling and the mixture was stirred at room temperature for 17 hours. Ice water was added therein and the resultant mixture was extracted with ether. An organic layer was washed with water and dried. The solvent was distilled to obtain 0.65 g of N,N-dimethyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carboxamide. Subsequently, 0.63 g of a Lawesson's reagent and 30 ml of benzene were added therein, and the mixture was refluxed with heating for 1.5 hours. After the reaction solution was vacuum-condensed, the residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.43 g of N,N-dimethyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide. Subsequently, 1.80 g of methyl iodide, 0.28 g of cyanamide and 20 ml of tetrahydrofuran were added therein. 0.29 g of sodium hydride (60%) was added therein with stirring under ice-cooling and the mixture was stirred at room temperature for 17 hours. Ice water was added therein and the resultant mixture was extracted with methylene chloride. After an organic layer was washed with water and dried, the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.28 g of N-cyano-N',N'-dimethyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydro-pyran]-4-amidine with a melting point of 202°-203° C.
Reaction SMILES: [I-].[Cl:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O=[C:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1.[Cl-].[NH4+]>C(OCC)C>[Cl:2][CH:3]=[C:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC(=CCl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Chloromethyltriphenylphosphonium iodide (270 mg, 0.62 mmol) was added to a solution of potassium tert-butoxide (67 mg, 0.59 mmol) in anhydrous diethyl ether (5 ml) under nitrogen and the resulting bright yellow mixture stirred for 30 minutes at ambient temperature. The reaction was then cooled to 0° C. and a solution of 1-tert-butyl 2-methyl (2S)-4-oxo-1,2-pyrrolidinedicarboxylate (100 mg, 0.41 mmol in 2 ml anhydrous diethyl-ether) was added dropwise. The reaction was then warmed to room temperature and stirred for 30 minutes before adding saturated aqueous ammonium chloride solution (0.5 ml). The organic layer was removed in vacuo, and the aqueous washed with diethyl ether (3×5 ml). The combined organic layers were dried with brine and magnesium sulfate before filtering and removal of solvent. The desired product was isolated by silica gel chromatography, eluting with 15% ethyl acetate in hexanes to give 105 mg (93% yield) as a off-white wax.
Reaction SMILES: Cl[Si](C)(C)C.[F:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[NH2:12].C(N(C(C)C)C(C)C)C.[C:29](Cl)(=[O:36])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[F:6][C:7]1[CH:8]=[C:9]([CH2:10][CH:11]([NH:12][C:29](=[O:36])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH3:35])[C:13]([OH:15])=[O:14])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: NC(Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCCC/C=C/C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC/C=C/C(=O)NC(Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6.3 ml (49.7 mmol) of chlorotrimethylsilane are added to a solution of 5.0 g (24.9 mmol) of 3,5-difluoro-DL-phenylalanine in dichloromethane (150 ml) and the reaction mixture is heated to reflux for 1 h. After cooling to 0° C., 9.7 ml (55.9 mmol) of ethyldiisopropylamine are added slowly and then, dropwise, 3.64 g (24.9 mmol) of trans-2-heptenoyl chloride. The reaction mixture is stirred overnight with slow warming to RT and remains standing at RT for 2 days. For working up, it is evaporated to dryness in vacuo, the residue is taken up using diethyl ether and extracted with 2.5 pc. aqueous sodium hydrogencarbonate solution (250 ml). The aqueous phase is extracted twice with ether, and the combined organic phases are extracted a further three times with sodium hydrogencarbonate solution. The combined aqueous phases are brought to pH=2 using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate, filtered, and the solvent is concentrated in vacuo. The residue is washed by stirring with diethyl ether and filtered. The filter residue is isolated, the filtrate is concentrated and again treated with diethyl ether. After repetition twice, a total of 6.12 g (79% of th.) of product are obtained as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[Si:23]([O:30][CH2:31][CH:32]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:33]OS(C)(=O)=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O.O>[Si:23]([O:30][CH2:31][CH:32]([CH2:39][O:40][Si:41]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:42])[CH3:43])[CH2:33][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)c(C=O)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 1 h
Yield: 329.3 %

Procedure:
Ex-13D: To a solution of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13C, 0.10 g, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C. Methanesulfonic acid 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propyl ester (Ex-13A, 0.24 g, 1.3 mmol) was then added dropwise in three equal portions with stirring at 1 h intervals. After the last addition, the reaction was stirred for an additional 1 h at 80° C. and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic phase was sequentially washed with a saturated ammonium chloride solution (15 mL), water (15 mL), and brine (15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:6) gave 0.78 g (90%) of 2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde as a pale green solid, mp 91–92° C. 1H-NMR (300 MHz, CDCl3) δ 10.34 (s, 1H), 8.13 (s, 1H), 7.41 (dd, 1H, J=3.6, 1.2 Hz), 7.28 (dd, 1H, J=5.1, 1.2 Hz), 7.05 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.22 (d, 2H, J=5.7 Hz), 3.96 (s, 3H), 3.80 (d, 4H, J=5.7 Hz), 2.33 (pentet, 1H, J=5.7 Hz), 0.88 (s, 18H), 0.012 (s, 12H). HRMS (EI) Calcd. for C28H46O5SSi2: 550.2604 (M+); Found: 550.2593.