Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)[C:10](=[O:24])[CH:9]([N:25]3[C:29](=[O:30])[C:28]4=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]4[C:26]3=[O:35])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]3[N:20]([C:36]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:21]=[N:22][N:23]=3)[C:10](=[O:24])[CH:9]([N:25]3[C:29](=[O:30])[C:28]4=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]4[C:26]3=[O:35])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nnn[nH]1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 84.2 %

Procedure:
To a solution of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-[(1H-tetrazol-5-yl)methyl]-2 H-1,4-benzodiazepin-2-one (100 g) and trityl chloride (61.96 g) in N,N-dimethylformamide (1.8 l) was added dropwise triethylamine (36.1 ml) under stirring and cooling in an ice-bath. The mixture was stirred for 10 minutes at the same temperature and for 20 hours at ambient temperature. The reaction mixture was poured into water (18 l) under stirring and the resultant precipitate was collected by filtration, washed with water several times and dried in vacuo at 60° C. for 8 hours to give (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-[(1 -trityl-1H-tetrazol-5-yl)-methyl]-2H-1,4-benzodiazepin-2-one (128.2 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Cl[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23](C(C)=C)[C:22]1=[O:33].C(=O)(O)[O-].[Na+].N>O1CCCC1.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:33])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: C=C(C)n1c(=O)n(CCCCCl)c2ccccc21
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1CCCCN1CCC(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
A mixture consisting of 3.0 gm of 4-(3-indolyl)-piperidine, 4.0 gm of 1-(4-chloro-butyl)-3-isopropenylbenzimidazolone, 1.3 gm of sodium bicarbonate, 30 ml of dimethyl-formamide and 30 ml of tetrahydrofuran was refluxed for 16 hours. Thereafter, the reaction mixture was poured into a mixture of ice and ammonia, the aqueous mixture was extracted with ethyl acetate, and the extract solution was washed with water, dried and evaporated to dryness in vacuo. The residue was dissolved in ether, etheric hydrogen chloride was added to the solution, and the precipitate formed thereby was collected by filtration, dried and dissolved in 100 ml of ethanol. The resulting solution was cooled, 16 ml of concentrated sulfuric acid were carefully added while stirring, and the mixture was allowed to stand at 20° C. for two hours, whereupon it was poured into a mixture of ice and ammonia. The precipitate formed thereby was collected by filtration and recrystallized from ethanol, yielding 3.2 gm (55% of theory) of the compound of the formula ##STR13## having a melting point of 196° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37]>C1COCC1.CCOC(C)=O>[OH:37][CH2:36][C:35]([NH:34][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH:15]=1)(=[O:21])=[O:22])([CH3:39])[CH3:38]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: CC(C)(N)CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)CO)c3)c2)n1
Temperature: 25 °C
Yield: 16 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess 2-amino-2-methyl-1-propanol in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.035 g, 16%) as a white solid. MS (ISP) 542.2 [(M+H)+]; mp 92° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:20])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:23](OC)([CH3:25])[CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>C(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]2[O:20][C:23]([CH3:25])([CH3:24])[O:18][C:17]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC(=O)C(Cc2ccc(OCc3ccccc3)cc2)O1
Yield: 87.7 %

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g, 7.34 mmol), 2,2-dimethoxypropane (18.63 g, 179 mmol) and pyridinium p-toluene sulfonate (0.92 g, 3.66 mmol) in CHCl3 (80 mL) was heated to reflux for 40 minutes under N2. The reaction was cooled and worked up extractively with CH2Cl2 and water. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 10:1 hexanes:acetone to afford 2.01 g (88%) 5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one. Rf=0.53 (1:1 hexanes:acetone). 1H NMR (500 MHz, CDCl3) δ 7.43-7.35 (m, 4H), 7.34-7.29 (m, 1H), 7.16 (d, 2H, J=8.80 Hz), 6.91 (d, 2H, J=8.80 Hz), 5.04 (s, 2H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.13 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 2.99 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 1.50 (s, 3H), 1.36 (s, 3H); MS (ES+) Calc'd for C19H20O4 (M+NH4) 330. Found m/z 330 (100%).
Reaction SMILES: [C:1]([Si:5]([Cl:8])(Cl)[Cl:6])([CH3:4])([CH3:3])[CH3:2].[Li][N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]1>C(OCC)C>[C:1]([Si:5]([N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]1)([Cl:8])[Cl:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]N1CCC(C)CC1
Reactant: CC(C)(C)[Si](Cl)(Cl)Cl
Solvent: CCOCC
Product: CC1CCN([Si](Cl)(Cl)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
Under argon, a reaction vessel fitted with a stirrer was charged with 100 ml diethylether and 11.7 g. t-butyltrichlorosilane (0.0615 mol) and stirring was commenced. To this vessel was added dropwise 6.34 g 1-lithio-4-methylpiperidine in diethylether solution from (b) above via a cannula over a 30 min. period and stirring was continued for about 16 hours. The vessel was fitted with a condenser and the reaction mixture was refluxed for 1 hr. and cooled to room temperature. The solution was filtered through a medium porosity frit and the LiCl precipitate was washed three times with 20 ml portions of diethylether. The diethylether was removed from the filtrate in vacuo to provide a clear yellow oil. The crude product was distilled under vacuum (60°-68° C., @ 0.7 torr) to give a clear to slightly cloudy oil of 6.45 g of t-butyl(4methylpiperidyl)dichlorosilane.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH2:17]([N:24]([CH:29]([CH3:31])[CH3:30])[C:25](=[O:28])[CH:26]=[CH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:27][CH2:26][C:25]([N:24]([CH:29]([CH3:30])[CH3:31])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:28])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)N(Cc1ccccc1)C(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)N(Cc1ccccc1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 5 mmole), N-benzyl-N-isopropyl-2-propenamide (1.0 g, 5 mmole) (prepared from acryloyl chloride and benzylisopropylamine), and triethylamine (0.05 ml) in methanol was stirred for 60 hours at room temperature. The reaction mixture was concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[Se](=O)=[O:16].O1CCOCC1.O>O>[N+:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH:1]=[O:16])[CH:11]=[CH:10]2)([O-:14])=[O:13]
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 90 °C

Procedure:
2-Methyl-6-nitroquinoline (0.4 ml, 0.5M solution in dioxane) was treated with selenium dioxide 90.2 ml, 0.9M solution in 9/1 dioxane/water) and heated to 90° C. overnight. The mixture was cooled to room temperature and diluted with water (1 ml). The mixture was then extracted with ethyl acetate (3×2 ml). The organic extract was then dried in vacuo to give 6-nitro-2-quinolinecarboxaldehyde which was carried forward without further purification. Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 6-nitro-2-quinolinecarboxaldehyde prepared above in dry dimethylformamide (0.2 ml) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h, the mixture was treated with water (0.2 ml) and loaded onto an IBSIL-C87 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 282 as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH3:8]CN(CC)CC.[CH:15]([C:17]1([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=O.C([BH3-])#N.[Na+]>CO>[CH2:23]([O:22][C:21]([NH:20][C:17]1([CH2:15][NH:6][CH2:5][C:4]([O:3][CH2:2][CH3:8])=[O:7])[CH2:19][CH2:18]1)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCN(CC)CC
Reactant: O=CC1(NC(=O)OCc2ccccc2)CC1
Reactant: COC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CNCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of glycine methyl ester hydrochloride (16.24 g, 116.31 mmol) and Et3N (16.21 mL, 116.31 mmol) in MeOH were added a solution of benzyl 1-formylcyclopropylcarbamate (5.10 g, 23.26 mmol) in MeOH (100 mL) and sodium cyanoborohydride (1.83 g, 29.08 mmol). The reaction was stirred at room temperature overnight, and the solvent was removed in vacuo. The resulting residue was suspended in Et2O and washed with aqueous 5% NaOH solution. The aqueous layer was extracted once with Et2O and once with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford the product.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.Cl>>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: COC(=O)CCCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(O)CCCCCOc1ccc([N+](=O)[O-])cc1
Yield: 80.2 %

Procedure:
A mixture of 6-(4-nitrophenoxy)-hexanoic acid methyl ester (125 g) and concentrated hydrochloride acid (1.2 L) was refluxed for 16 hours. The reaction mixture cooled was to room temperature, filtered, dried and recrystallised from a mixture of ethyl acetate and hexane (1:6) to obtain pure 6-(4-nitrophenoxy)-hexanoic acid (95 g) as a white powder with a melting point of 104-107° C. The product was characterized by 1H NMR (CDCl3) δ 1.60 (m, 2H, CH2), 1.76 (m, 2H, CH2), 1.90 (m, 2H, CH2), 2.42 (t, 2H, CH2), 4.04 (t, 2H2, OCH2), 6.96 (d, 2H, Ar), 8.20 (d, 2H, Ar).
Reaction SMILES: Br[CH:2]([CH2:10]Br)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[SH:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.C(Cl)(Cl)Cl>C1C=CC=CC=1>[S:12]1[CH2:13][CH2:14][NH:15][CH:2]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:10]1
Reactant: CC(C)(C)OC(=O)C(Br)CBr
Reactant: NCCS
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CSCCN1

Procedure:
Preferably, t-butyl 2,3-dibromopropionate prepared according to J. Perkin Trans I, p. 1321 (1973) is treated with 2-mercaptoethylamine and triethylamine in a suitable solvent, such as a mixture of chloroform and benzene, to provide t-butyl tetrahydro-2H-1,4-thiazine-3-carboxylate, which upon reaction with a compound of the formula V under suitable conditions, such as in the presence of triethylamine in dichloromethane solution at 25° C., provides compounds of the formula II-c. Oxidation of this material with a suitable oxidizer, such as sodium perborate or m-chloroperbenzoic acid, provides the corresponding sulfoxide, preferably as a single diastereomer.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]1)=[O:6])[CH3:3].[N+:15]([C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[O:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25])([O-:17])=[O:16].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)CC)C>CN(C)C=O.O>[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:24]([C:23]2[C:22]([O:21][C:20]3[CH:31]=[CH:32][CH:33]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[N:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1CCC(CN)CC1
Reactant: O=C(O)c1cccnc1Oc1cccc([N+](=O)[O-])c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(CNC(=O)c2cccnc2Oc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-Aminomethyl-cyclohexanecarboxylic acid ethyl ester hydrochloride (0.500 grams, 2.26 mmole), 2-(3-Nitro-phenoxy)-nicotinic acid (0.588 grams, 2.26 mmole), 1-hydroxybenzotriazole hydrate (0.366 grams, 2.71 mmole) and 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.564 grams, 2.93 mmole) in dimethylformamide (50 ml) was was added triethyl amine (0.456 grams, 4.52 mmole) and stirred over the weekend at room temperature. The mixture was diluted with water (150 ml) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give an oil which was purified by chromatography on silica eluting with 40% ethyl acetate/hexane to give an oil. (1.05 g). MS (m/e) 428 (M++1); 1H NMR (CDCl3) d 1.01 (2H, m), 1.2 (3H, t), 1.4 (2H, q), 1.6 (1H, m), 1.90 (2H, d, J=12.5 Hz), 2.0 (1H, d, J=12.5 Hz), 2.2 (1H, m), 3.4 (2H, m), 4.10 (2H, q), 7.20-8.7 (7H, m).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]3[CH:12]=[CH:13][C:14]([O:16]C)=[CH:15][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](I)(C)C>C(Cl)(Cl)Cl.CO.[Cl-].[Na+].O>[C:1]1([C:7]2[O:11][C:10]3[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2oc(-c3ccccc3)cc2c1
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Oc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 50 °C
Yield: 87.5 %

Procedure:
A solution of 2-phenyl-5-methoxybenzo[b]furan (K K Thomas and M M Bokadia, J Indian Chem. Soc. 1966, 43, 713) (0.5 g, 2.23 mmol) in absolute chloroform (4 ml) was treated with trimethylsilyl iodide (0.44 ml, 3.09 mmol) and warmed at 50° C. for 48 h. A further quantity (0.22 ml) of trimethylsilyl iodide was added during this period. The reaction mixture was diluted with methanol (20 ml), treated with brine (40 ml) and extracted into diethyl ether (2×40 ml). The combined extracts were washed with aqueous sodium metabisulphite, followed by brine (40 ml) and dried over sodium sulphate. After concentration in vacuo the residue was distilled to give the title compound as a colourless solid (0.41 g, 88%) b.p. 250° C., 0.1 mm Hg (Kugelrohr).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[Br-].[O:7]1[CH2:11][CH2:10][O:9]C1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[N:50]=[C:51]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:52][C:53]=1[CH3:54])C=O>CCCCCC>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:3]=[CH:2][CH:1]2[O:9][CH2:10][CH2:11][O:7]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[N:50]=[C:51]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[O:52][C:53]=1[CH3:54]
Reactant: [Li]CCCC
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C=CC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of n-butyl lithium in hexane (1.6 M, 15.6 ml) was added dropwise, at -15° C., to a mixture of (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (10.74 g) and tetrahydrofuran (110 ml). The mixture was stirred for 1 hour at the same temperature, to which was added 3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (6.74 g). After being stirred for 4 hours at 50° C., the reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed successively with 0.1 N HCl, water and a saturated saline solution, and dried (MgSO4), followed by distilling off the solvent. The residual oily product was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:2, v/v), was obtained 2-[2-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]vinyl]-1,3-dioxolane (4.84 g) as an oily product. This oily product (4.84 g) was dissolved in tetrahydrofuran (90 ml). To the solution was added palladium-carbon (5%, 50% wet, 1.8 g), which was subjected to catalytic hydrogenation at room temperature under 1 atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated. The resulting oily product was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:3, v/v), was obtained 2-[2-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-1,3-dioxolane (3.03 g, 37%), which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.90-91° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9].[Br:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[Br-:10].[CH2:15]([O:14][C:12]([CH2:11][N+:6]1[C:5]([CH3:9])=[C:4]([CH2:3][CH2:2][OH:1])[S:8][CH:7]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: Cc1ncsc1CCO
Solvent: CCO
Product: CCOC(=O)C[n+]1csc(CCO)c1C
Product: [Br-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
A solution of 5-(2-hydroxyethyl)-4-methylthiazole (306 g) and ethyl bromoacetate (356.2 g) in ethanol (1 L) was heated to reflux. After two hours, the ethanol was removed by distillation and the residue treated with isopropanol (1.5 L). The resulting solution was cooled to about 0° C., causing crystallization of compound 1. After three hours, the crystalline material was separated from the mother liquor. Additional crystals were obtained by prolonged cooling of the mother liquor at 0° C. Combination of the crystalline material gave 474.3 g of compound 1. Melting point 96°-98° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH:11][C:12]([CH2:14][O:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:17]1)=[O:13].[C:49](Cl)(=[O:51])[CH3:50]>ClCCl.C(N(CC)CC)C>[C:49]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH:11][C:12]([CH2:14][O:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:17]1)=[O:13])(=[O:51])[CH3:50]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)NCc2ccccc2CCN)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)NCc2ccccc2CCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 0.49 g of tert-butyl 3-({[2-(2-aminoethyl)phenyl]methylcarbamoyl}methoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 10 ml of dichloromethane and 0.22 ml of triethylamine is admixed at 0° C. with 0.15 ml of acetyl chloride and stirred at room temperature over 17 hours. The reaction mixture is diluted with dichloromethane, washed with 1N HCl (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.09 (EtOAc); Rt=5.10.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](N)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]([Si](C)(C)C)([F:17])([F:16])[F:15].O.[F-].C([N+:28]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34]CC)CCCC)CCC>C1COCC1.C([O-])(O)=O.[Na+]>[F:15][C:14]([F:17])([F:16])[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:28]2[CH2:33][CH2:34][CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([OH:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(c1ccc(S(=O)(=O)N2CCCCCC2)cc1)C(F)(F)F
Reaction time: 0.08 h

Procedure:
The 4-acetylbenzenesulfonamide prepared above (247 mg, 0.879 mmol, 1.0 equiv) was dissolved in 10 mL THF followed by the addition on 3.52 mL of a 0.5M solution of CF3TMS in THF. After 5 min, 229 mg of tetrabutylammonium fluoride hydrate (0.879 mmol, 1.0 equiv) was added to the stirring solution. After stirring 21 h the reaction mixture was diluted with sat. NaHCO3, extracted (2×EtOAc), dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 2% MeOH/CH2Cl2) gave the product as a white solid. 1H NMR (DMSO, 400 MHz) δ 7.80 (s, 4H), 6.84 (s, 1H), 3.21 (t, J=5.8 Hz, 4H), 1.71 (s, 3H), 1.63 (m, 4H), 1.50 (m, 4H).