Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: ClCCBr
Reactant: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OCCCl)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone (100 mg), 1-bromo-2-chloroethane (127 mg), and potassium carbonate (204 mg) were suspended in N,N-dimethylformamide (3 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (107 mg, yield 30%).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10](Cl)=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:15][NH2:16])=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCc1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OCc1ccc(NN)nc1

Procedure:
7.9 g (39.6 mmol) 5-(tert-butoxymethyl)-2-chloropyridine together with 19.8 g (395.6 mmol) hydrazine hydrate are divided into three portions of equal size and 15 ml ethanol are added to each portion. Each portion is reacted in a single mode microwave (CEM Explorer) at 170° C. for in each case 4 h. Thereafter, the three mixtures are combined and the solvent is removed. The residue is taken up in ethyl acetate and the mixture is washed once with saturated sodium bicarbonate solution. The aqueous phase is extracted once with ethyl acetate. The two ethyl acetate phases are combined and washed once with saturated sodium chloride solution. The mixture is dried over magnesium sulfate and the solvent is removed. The residue obtained is stirred in petroleum ether and the solid is filtered off.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCc3ccccn3)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCc3ccccn3)c3csc(N)n3)[C@H]2SC1
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
To a solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.6 g) in methylene chloride (20 ml) and anisole (3.0 g) was added trifluoroacetic acid (11.2 g) under ice-cooling with stirring, and the stirring was continued at ambient temperature for 1.5 hours. The reaction mixture was added dropwise to diisopropyl ether (300 ml) and the precipitated crystals were collected by filtration, followed by suspending in water (70 ml). After adjusting to pH 7.5 with 1 N aqueous sodium hydroxide, the resultant aqueous solution was washed with ethyl acetate. The aqueous solution was further adjusted to pH 3.4 with 10% hydrochloric acid, followed by collecting the precipitated crystals to obtain 7-[2-(2-aminothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.8 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:27]([CH2:29]O)[CH:28]=1.O>C(#N)C>[Br:20][CH2:29][C:27]1[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=1[S:31]([CH3:34])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)c1ccc(Cl)cc1CO
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1ccc(Cl)cc1CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Step 3) Triphenylphosphine (1.19 g) was suspended in acetonitrile (50 ml), bromine (0.24 ml) was added, and the mixture was stirred at room temperature for 30 min. A solution of [5-chloro-2-(methylsulfonyl)phenyl]methanol obtained in Step 2 (1 g) in acetonitrile (10 ml) was added to the reaction mixture. The mixture was stirred at 70° C. for 3 hr, treated with water, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel chromatography (ethyl acetate:hexane=1:3) to give 2-(bromomethyl)-4-chloro-1-(methylsulfonyl)benzene (0.46 g).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38]>>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(=O)CCl
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCC(=O)N(C)C)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and 2-chloro-N,N-dimethylacetamide (40 mg, 0.332 mmol) using a similar method to that used in Example 11 (6 mg).
Reaction SMILES: [CH2:1]([O:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C1C=CC=CC=1>[C:1]([O:8][CH3:9])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COCc1ccccc1
Solvent: N#Cc1ccccc1
Product: COC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
A mixture of 2 mmole of benzylmethylether, 2 mole % of N-hydroxyphthalimide relative to benzylmethylether, and 5 ml of benzonitrile was stirred for 12 hours at 100° C. under an oxygen atmosphere. The products in the reaction mixture were analyzed by gas chromarography, and, as a result, methyl benzoate (yield 60%) was formed.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[OH:4].[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:12][C:2]([F:1])([F:11])[CH:3]([C:5]1[CH:6]=[CH:7][N:8]=[CH:9][CH:10]=1)[O:4][Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH3:14]
Reactant: CC[Si](Cl)(CC)CC
Reactant: OC(c1ccncc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)OC(c1ccncc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
To 20 ml of pyridine were added 3.4 g of 2,2,2-trifluoro-1-pyridin-4-yl-ethanol and 1.17 g of 4-dimethylaminopyridine, and 3.76 g of triethylsilyl chloride was added at 0° C. After stirring at room temperature for 4 hours, the mixture was poured into an aqueous saturated ammonium chloride solution, followed by extraction with t-butyl methyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5.5 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C:7](=[CH:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21].O=C1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2CO)=C1>>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C:7](=[CH:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21]
Reactant: C[C@]12CC[C@H]3C(=CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2CO
Product: C[C@]12CCC(=O)C[C@@H]1CC=C1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
The title compound is prepared according to the procedure of Example 4 (i) by substituting androst-4,7-diene-3,17-dione for 3-oxo-17β-(hydroxymethyl)-4androstene.
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[C:3]([Cl:7])[C:4](O)=[O:5].O=S(Cl)Cl.C1C=CC=CC=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>C(#N)C>[Cl:7][C:3](=[C:2]([Cl:8])[Cl:1])[C:4]([NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)=[O:5]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(O)C(Cl)=C(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccc(C(=O)O)cc1)C(Cl)=C(Cl)Cl
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Trichloroacrylic acid (500 mg, 2.85 mmol; Alpha Chem. Co.) was added to 7 mL of SOCl2 and the mixture was refluxed for 6 h. After cooling, 5 mL of benzene was added and the solvent was concentrated on the rotary evaporator to 1/3 of its original volume. This step was repeated 4 times, until most of SOCl2 was evaporated. Three mL of acetonitrile were added followed by a suspension of 383 mg (2.80 mmol) of p-amino-benzoic acid in 3 mL of acetonitrile. After 30 min of stirring, TLC showed the disappearance of most starting material and the presence of a product with higher Rf value. The product was purified by preparative silica TLC (EtOAC/Hexane/acetic acid, 2:3:0.05) which gave a pure white powder (89% yield); MS (EI) m/z 293 (M+).
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:24][C:12]2=[N:13][CH:14]=[C:15]([C:18]#[C:19][Si](C)(C)C)[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:18]([C:15]1[C:16](=[O:17])[N:11]2[N:10]=[C:9]([S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[S:24][C:12]2=[N:13][CH:14]=1)#[CH:19]
Reactant: CCCCCCCSc1nn2c(=O)c(C#C[Si](C)(C)C)cnc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc2sc(SCCCCCCC)nn2c1=O
Reaction time: 1 h
Yield: 70 %

Procedure:
In 100 ml of tetrahydrofurane, 5.4 g of the thus obtained 2-heptylthio-6-trimethylsilylethynyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, and the solution was cooled to -65° C. in an acetone-dry ice bath. To the cooled solution, a solution of 0.93 g of tetrabutylammonium fluoride in 200 ml of tetrahydrofurane was added dropwise. The solution was stirred at -70°~-65° C. for 1 hour. After the solution was brought to room temperature, the solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent and thus 3.0 g of 6-ethynyl-2-heptylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 140°~142° C. Yield 70%.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[Cl:42]C(N(C)C)=C(C)C>ClCCl>[Cl:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1
Reactant: CC(C)=C(Cl)N(C)C
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21

Procedure:
The stirred solution of 0.980 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 20 ml of dichloromethane is admixed with 2.12 ml of 1-chloro-N,N,2-trimethylpropenylamine (chlorenamine) in portions over 24 hours. The reaction mixture is poured onto water (100 ml) and extracted with tert-butyl methyl ether (100 ml). The organic phase is washed with brine (50 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.39 (2:1 EtOAc-heptane); Rt=5.57
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:18])[CH3:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:18])[CH3:17])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CC(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 36.2 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide (96 mg, 0.317 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (81 mg, 0.397 mmol), 4 N HCl in dioxane (100 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 7 hours. Evaporated off solvent and purified with normal phase chromatography eluting with 97/3/1 CH2Cl2/MeOH/NH4OH to yield an off-white solid, N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-acetamide (54 mg, 36%). mp 227° C.; LCMS: m/z=471.38 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.71 (dd, 1H, J=8.6, 2.3 Hz), 7.32 (m, 1H), 6.91 (d, 1H, J=8.6 Hz), 6.81 (m, 1H), 6.13 (m, 1H), 3.79 (m, 2H), 3.20 (s, 1H), 2.35 (m, 2H), 2.25 (m, 1H), 2.11 (m, 2H), 2.04 (m, 1H), 1.81 (m, 8H), 1.36 (m, 8H).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[Br:24])[C:2]([CH3:4])=[O:3].C1(N)CCCCC1>C(O)C>[C:2]([NH:1][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([OH:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[Br:24])(=[O:3])[CH3:4]
Reactant: CC(=O)Nc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1Br
Solvent: CCO
Solvent: NC1CCCCC1
Product: CC(=O)Nc1ccc(-c2ccc(C(O)CCC(=O)O)cc2)cc1Br
Yield: 53 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-acetamino-3'-bromo-4-biphenylyl)-4-oxo-butyric acid. Yield: 53% of theory, m.p. 125°-126° C. Melting point of the cyclohexylamine salt: 165°-167° C. (from ethanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17](=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12](/[CH:19]=[CH:18]/[C:17](=[O:20])[CH3:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)nc1
Reactant: C=CC(C)=O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)/C=C/c1ccc(OCc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 38.2 %

Procedure:
To a solution of 2-(benzyloxy)-5-bromopyridine (600 mg) in DMF (12 mL) were added 3-buten-2-one (400 mg), tris(dibenzylidene acetone) dipalladium(0) (74 mg), triethylamine (460 mg), and tris(o-tolyl)phosphine (70 mg) at room temperature under nitrogen flow, and the mixture was stirred at 100° C. for 24 hours. The reaction liquid was allowed to cool, and insolubles were filtered through Celite. Water was added to the filtrate, followed by three times extractions with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1-3/2) to obtain (3E)-4-[6-(benzyloxy)pyridin-3-yl]but-3-en-2-one (220 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:4].[H-].[Na+].[CH:18](OC)=[O:19]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:18][OH:19])=[O:4]
Reactant: COC=O
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=CO)c1c(C(=O)OC)ccn1C
Reaction time: 8 h

Procedure:
2-Methoxycarbonylmethyl-1-methyl-1H-pyrrole-3-carboxylic acid methyl ester (5.7 g) in dry tetrahydrofuran (100 ml) was stirred at room temperature under argon. Sodium hydride (60% dispersion in mineral oil, 7.13 g) was added portionwise followed by methyl formate (2.5 ml) and the mixture was left to stir overnight. The reaction was cooled in ice and quenched by the addition of the minimum amount of methanol. The solution was again cooled and acidified to pH1 with aqueous 5N hydrochloric acid. The reaction was diluted with ethyl acetate and water, the aqueous separated and extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried (MgSO4) and filtered. The solvent was evaporated to yield an oil consisting of two layers. The top layer was discarded and the lower layer solidified on standing to give the crude title compound as a brown solid (8.62 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][CH2:13][C:14]2[S:18][CH:17]=[N:16][C:15]=2[C:19]([O:21]C)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C>C1COCC1.O.CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[O:21]=[C:19]1[C:15]2[N:16]=[CH:17][S:18][C:14]=2[CH2:13][N:12]1[CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1
Reactant: COC(=O)c1ncsc1CNC1CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(N2Cc3scnc3C2=O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.9 %

Procedure:
A mixture of compound 3c (320 mg, 0.98 mmol) and LiOH.H2O (123 mg, 2.93 mmol) in THF (8 mL) and H2O (4 mL) was stirred at room temperature for 20 h. The pH of the reaction mixture was adjusted to 5 with aq. 10% HCl. Concentration gave the crude compound 3d. A mixture of compound 3d (0.98 mmol), HOBt (132 mg, 0.98 mmol), Et3N (0.41 mL, 2.93 mmol), EDCI (318 mg, 1.66 mmol), and DMAP (25 mg, 0.21 mmol) in DMF (4 mL) was heated at 65° C. for 5 h. The reaction mixture was cooled to room temperature and diluted with CH2Cl2. The solution was washed with H2O, dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 3e (185 mg).
Reaction SMILES: [CH3:1][C:2]([C:11]([O:13][CH3:14])=[O:12])([CH3:10])[NH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].C([O-])(O)=O.[Na+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[CH3:10][C:2]([C:11]([O:13][CH3:14])=[O:12])([CH3:1])[N:3]([CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:27]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CCNC(C)(C)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1ccccc1)C(C)(C)C(=O)OC
Reaction time: 8 h
Yield: 20.8 %

Procedure:
To a mixture of methyl 2-methyl-N-[3-(methyloxy)-3-oxopropyl]alaninate (11.71 g, 57.62 mmol) in 1:1 DCM-water (300 mL) was added NaHCO3 (9.68 g, 115.2 mmol) followed by benzoyl chloride (7.02 mL, 60.48 mmol). The mixture was vigorously stirred overnight, and the phases were then separated. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (35% EtOAc in hexanes) to give methyl 2-methyl-N-[3-(methyloxy)-3-oxopropyl]-N-(phenylcarbonyl)alaninate (3.6787 g, 21% yield) as a colorless oil. LCMS: (M+H)+: 308.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]1([CH3:29])[CH:15]([CH2:16][CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1>O.C(O)C>[N:1]([CH2:17][CH2:16][CH:15]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][C:6]1([CH3:5])[CH3:29])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3OC2(C)C)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)Oc2ccccc2CC1CCN=[N+]=[N-]

Procedure:
A solution of 3.9 g (60 mmol) of sodium azide in 10 ml of water is added to a solution of 14.4 g (40 mmol) of 2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman (prepared as described in Example 38) in 200 ml of ethanol. The mixture is boiled under reflux for 18 hours. After cooling, the ethanol is evaporated off in vacuo, water is added to the residue and extraction is carried out with dichloromethane. The dichloromethane phase is washed with water, dried over sodium sulfate and concentrated by evaporation, yielding 8.7 g (94% of the theoretical yield) of 3-(2-azidoethyl)-2,2-dimethyl-chroman in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCSCCCC(F)(F)C(F)(F)F)[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=2)[C:3]1=[O:41].CS(OCCCCC[CH2:53][CH2:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][CH2:60][C:61]([F:67])([F:66])[C:62]([F:65])([F:64])[F:63])(=O)=O>>[CH3:42][C:2]1([CH3:1])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:53][CH2:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][CH2:60][C:61]([F:67])([F:66])[C:62]([F:63])([F:65])[F:64])[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([C:37]([F:38])([F:40])[F:39])[CH:29]=2)[C:3]1=[O:41]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Yield: 13 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 1, 10-[(4,4,5,5,5-pentafluoropentypthio]decyl methanesulphonate (prepared according to an experimental protocol similar to that described in WO 2005077968) replacing 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate. The expected compound is obtained in the form of a pale yellow oil with a yield of 13% (125 mg).