Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#N)[CH:6]=1.C(O)=[O:15]>[Al].[Ni]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[O:15])[CH:6]=1
Reactant: O=CO
Reactant: COC(=O)Cc1cccc(C#N)c1
Agent: [Ni]
Agent: [Al]
Product: COC(=O)Cc1cccc(C=O)c1
Temperature: 25 °C

Procedure:
A mixture of (3-cyano-phenyl)-acetic acid methyl ester (1.56 g, 8.91 mmol), aluminum-nickel alloy (1.63 g) and 75% formic acid (25 mL) was heated at reflux for 1.75 h. The mixture was cooled to room temperature and the solids were removed by filtration through Celite with the aid of boiling EtOH. Water was added and the aqueous solution was washed with CH2Cl2 (3×). Aqueous saturated NaHCO3 was carefully added to the organic solution until the pH was about 8-9. The organic solution was washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (5:1 hexanes:EtOAc) provided the title compound as a clear and colorless oil (870 mg). 1H NMR (400 MHz, CDCl3) δ9.98 (s, 1H), 7.77 (m, 2H), 7.55-7.46 (m, 2H), 3.68 (s, 5H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:14](Cl)(=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:15][C:14]([NH:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a solution of (S)-2-aminobutanoic acid (11.2 g, 109 mmol) in THF (200 mL) and a 2 M aqueous sodium carbonate solution (65.2 ml, 130 mmol) was added dropwise at 0° C. benzyl carbonochloridate (17.06 mL, 119 mmol). After stirring at room temperature for 16 hours, the reaction mixture was extracted with H2O/TBME, the aqueous layer was acidified with HCl (2M in H2O) until pH=2 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give the title compound (22.8 g, 77%) as a colorless oil. The product was used in the next step without further purification. LC-MS: [M−H] 236.2; Rt 0.76 min; (LCMS method 1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A solution of 4-bromo-2-fluorobenzyl bromide (26.8 g, 100 mmol) and sodium cyanide (5.4 g, 110 mmol) in ethanol (40 ml) and water (10 ml) was stirred at 100° C. for 8.5 h. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure, and extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (22.6 g, quant.) as a black oily substance.
Reaction SMILES: C(NCC(C)C)C(C)C.[CH3:10][C:11]([CH3:17])([CH3:16])[CH2:12][CH2:13][CH:14]=[O:15].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>C1(C)C=CC=CC=1>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH:13]([CH:14]=[O:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH3:10]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)CCC=O
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(C=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three necked flask fitted with a Dean-Stark apparatus under argon, a solution of diisobutylamine (4.62 ml from Acros), 4,4-dimethyl pentanal 362 (2.5 g, 0.021 mol.) in toluene (20 ml) is heated at 130° C. for 2 h and water is extracted. The yellow solution is cooled down to room temperature and methyl bromoacetate (3.7 g, 0.024 mol.) is added in one time. The pink solution is stirred at room temperature overnight and 1 h at 90° C. Water (10 ml) is added at this temperature and after 1 h, the solution is cooled down to room temperature. The organic layer is washed with HCl 1N, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to afford an oil which is distilled under reduced pressure (1 mmHg) to afford 5,5-dimethyl-3-formyl-hexanoic acid methyl ester 361 as a liquid (1.1 g, 0.05 mol, Teb (1 mmHg): 69-71° C.). The aldehyde esters are then used in the reductive amination step. Alternatively, alkylation with ethyl bromoacetate can be conducted in the presence of toluene-acetonitrile 1/1 (v/v) as solvent. The final aldehyde can also be distilled under reduced pressure.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[NH2:7]/[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1>O.CO>[NH2:7]/[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2.246 gm (0.0105 mol) of sodium metaperiodate in 10 ml of water was added to a solution of 2.53 gm (0.01 mol) of (E)-2-[(amino)phenylmethylene]-benzo[b]-thiophen-3(2H)-one in 150 ml of methanol, and the mixture was stirred at room temperature for 15 hours. The sodium iodate precipitated thereby was removed by filtration, and the filtrate was diluted with 300 ml of water and extracted exhaustively with dichloromethane. The combined extracts were washed once with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue was recrystallized from ethanol/ethyl acetate using activated charcoal, and yielded 2.28 gm (85% of theory) of pale yellow crystals, m.p. 246°-247° C. (decomposition).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:13][CH2:14][O:15][C:16]([CH:18]([C:22]([CH3:24])=O)[C:19]([CH3:21])=O)=[O:17]>CC(O)=O.O>[CH2:14]([O:15][C:16]([C:18]1[C:19]([CH3:21])=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:22]=1[CH3:24])=[O:17])[CH3:13]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C
Reaction time: 20 h

Procedure:
Following the procedure described in Helvetica Chimica Acta (1952), 35, 478-85, 5.00 g (26.37 mmmol) of 3-nitrophenylhydrazine hydrochloride suspended in 46 ml of 55% aqueous AcOH were dissolved by careful heating and treated (without further heating) with 4.13 ml (26.37 mmol) of ethyl diacetoacetate. The reaction was immediately cooled and kept 20 h at 0° C. The precipitate was diluted with 28 ml of water and after 6 h filtered and washed with 2×5 ml of water to give after drying under reduced pressure 4.66 g (61%) of the title compound as a light yellow solid. MS: 289.9 (MH+).
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1>[CH:18]1([NH:17][C:16]([NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C

Procedure:
The half-ester of the formula (VI) may be converted into an "activated" ester prior to reaction with the 7-(α-aminoarylacetamido)-4-carboxy-Δ3 -cephem derivative using the preferred reagent N-hydroxysuccinimide in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. The "activated" ester product of the formula: ##STR5## is conveniently then reacted with the Δ3 -cephem derivative in the reaction solution in which it has been formed, without isolation. In a typical procedure, a solution of the half-ester, N-hydroxysuccinimide and dehydrating agent in a reaction-inert organic solvent, e.g. tetrahydrofuran, is stirred for several hours at room temperature, after which the solid N,N'-dicyclohexylurea formed in the reaction may be removed, e.g. by filtration. To the solution containing the "activated" ester is then added a solution of the Δ3 -cephem derivative, and reaction generally goes substantially to completion in the presence of a tertiary amine or inorganic base, as hereinbefore examplified and preferably with stirring during a period from 1 to 12 hours at room temperature. The solvent may then be removed, e.g. by evaporation in vacuo, and the residue dissolved in water, the aqueous solution then being acidified, extracted with a water-immiscible organic solvent, e.g. ethyl acetate, and the organic phase subjected to a similar procedure to that described in Method (1) for the isolation and purification of the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
N-t-butyloxycarbonyl-L-alanine (3.8 g, 20 m mole), L-proline benzyl ester hydrochloride (5 g, 20.6 m mole) and 1-hydroxy benzotriazole, which is hereinafter referred to as HOBt (2.7 g, 20 m mole) were suspended in tetrahydrofuran, which is hereinafter referred to as THF (50 ml). N,N'-dimethylaminopropylethylcarbodiimide, which is hereinafter referred to as WSC (3.8 ml) in THF (10 ml) solution was added dropwisely to the above suspended solution while cooling at -15° C. and stirring. The reaction was carried for 3 hours at a temperature of less than 0° C. and thereafter at room temperature overnight. The thus obtained solution was distilled under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order, and dried over anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure leaving a residue. The residue was recrystallized in ether-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.7 g, yield: 89%) having melting point of 71° to 72° C. This product gave one spot by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying with 0.1% ninhydrin and heating).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>CN(C)C=O>[CH2:7]([O:8][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of phenyl-methanol (20.5 g, 190 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride (7.6 g, 190 mmol) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2,5-Dibromopyridine was then added thereto on the ice bath (0° C.), and stirred for 60 minutes at room temperature. The reaction mixture was partitioned into is water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:20 then 1:10) to obtain the title compound (15.1 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][NH:15][C:14](=O)[C:13]=3[CH:12]=[CH:11]2)=[CH:5][CH:4]=1.P(Cl)([Cl:34])(OC1C=CC=CC=1)=O.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:34][C:14]1[C:13]2[CH:12]=[CH:11][N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:18]=2[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1c[nH]c(=O)c2ccn(Cc3ccc(OC)cc3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(Cl)c2ccn(Cc3ccc(OC)cc3)c12

Procedure:
Ethyl 1-{[4-(methyloxy)phenyl]methyl}-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (2.90 g) and phenyl dichlorophosphate (18 ml) were heated at 180° C. under argon for 30 minutes. The reaction mixture was allowed to cool, poured onto iced water, and neutralised to pH7 using solid sodium bicarbonate. To the reaction mixture was added ethyl acetate and the insoluble material was filtered off. The aqueous was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a clear oil (2.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:12]Cl>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:12]
Reactant: ClI
Reactant: COC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
Methyl 4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of acetic acid, and the stirred mixture was warmed to 65° C. A solution of ICl (37.8 g, 0.233 mol) in 50 mL of AcOH was added dropwise over 40 min. The mixture was stirred at 65° C. for 5 h and then stirred an additional 16 h at room temperature. The precipitated product was isolated via filtration, washed with water and dried under vacuum to give 27.5 g (99% pure by LCMS and HNMR)) of desired product. The mother liquors were evaporated and the resulting residue was washed with water and dried under vacuum to give another 31 g (95% pure by LCMS and NMR) of desired product. The combined yield of methyl 4-hydroxy-3-iodobenzoate was 58.5 g (90.3% yield).
Reaction SMILES: C(OC(=O)C(CS(N1CCN(C2C=CC(Br)=CC=2)CC1)(=O)=O)C(C)C)(C)(C)C.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:37][CH:36]=2)[CH:30]=1.[CH3:47][O:48][C:49]([C:51]1([CH2:57][S:58](Cl)(=[O:60])=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[O:50]>>[CH3:47][O:48][C:49]([C:51]1([CH2:57][S:58]([N:44]2[CH2:45][CH2:46][N:41]([C:38]3[CH:37]=[CH:36][C:35]([C:31]4[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=4)=[CH:40][CH:39]=3)[CH2:42][CH2:43]2)(=[O:60])=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[O:50]
Reactant: c1cncc(-c2ccc(N3CCNCC3)cc2)c1
Reactant: COC(=O)C1(CS(=O)(=O)Cl)CCOCC1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Product: COC(=O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Yield: 55 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)piperazine-1-sulfonylmethyl]-3-methyl-butyric acid ter-butyl ester, from 1-(4-pyridin-3-yl-phenyl)piperazine (0.18 g) and 4-chlorosulfonylmethyl tetrahydropyran-4-carboxylic acid methyl ester (0.23 g), to yield the title compound as a white solid (0.19 g, 55%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](OC)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:10](=[O:17])[CH2:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Yield: 89.2 %

Procedure:
A mixture containing 6.0 g (0.05 mol) of acetophenone, 40.8 g (0.30 mol) of methyl benzoate, and 3.73 g (0.06 mol) of 90% CaO is heated with stirring at 195°-200° C. for three and one-half hours while under nitrogen. The methanol (3.6 mL) that is distilled during the reaction is collected in a Dean Stark collector. The mixture is cooled, and 100 mL of toluene is added. The resulting mixture is cooled in cold water and acidified with 6N HCl. Stirring is continued until all of the solid is dissolved (ca 30 minutes). The toluene layer is separated and washed with aqueous Na2CO3 and water. Evaporation of the toluene solution gave 10 g of 1,3-diphenyl-1,3-propanedione as an oil representing an 89% yield based on acetophenone.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>C1COCC1>[Si:15]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
p-OSi-St chain transfer agent was synthesized in two steps. In a 500 ml flask equipped with a magnetic stirring bar, 70.4 g of imidazole was mixed with 52.4 g (0.42 mol) of 4-hydroxybenzaldehyde and 77.4 g of t-butyldimethylsilyl chloride in THF solution. The mixture was stirred at ambient temperature for 4 hours before being poured into cold water. The organic layer was separated and extracted with ether, then dried with magnesium sulfate. After evaporating the solvent, 94 g of 4-(t-butyldimethylsilyloxy)benzaldehyde (90% yield), a deep yellow color liquid, was obtained. The second reaction step was performed under a nitrogen atmosphere. In a 500 ml flask equipped with a magnetic stirring bar, 123.6 g of methyltriphenylphosphonium bromide suspended in THF was treated with 149.6 ml of n-butyllithium (2.5M in hexane). After 1 hour, 80.0 g of 4-(t-butyldimethylsilyloxy)benzaldehyde was introduced dropwise into the red solution. The mixture was stirred overnight at room temperature and then poured into cold water. The organic layer was separated by ether extraction and dried with magnesium sulfate. Further purification was performed by distillation under vacuum (10 Torr) at elevated temperature (80° C.). 65 g of p-OSi-St was obtained with a yield of more than 90%. Its structure was confirmed by 1H NMR spectrum.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:24][NH:25][O:26][CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][O:26][N:25]([CH3:24])[C:6]([C:3]1([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]1)=[O:7]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (150 mg, 0.974 mmol), 1-hydroxybenzotrizole monohydrate (224 mg, 1.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (280 mg, 1.46 mmol) and N,O-dimethylhydroxylamine hydrochloride (142 mg, 1.46 mmol) in DMF (5 mL) was added DIPEA (0.50 mL, 2.92 mmol) and the mixture was stirred at room temperature for overnight. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc. The collected organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to provide compound A103-1 (164 mg, 85%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8]CC1C=CC=CC=1.C(O)C>[Pd].OCC(CO)O>[CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[OH:8]
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: OCC(O)CO
Solvent: CCO
Product: Cc1[nH]ccc(=O)c1O
Reaction time: 24 h
Yield: 71 %

Procedure:
4.2 g (14.5 mmol) of 2-methyl-3-benzyloxypyridine-4(1H)-one of glycerol is put into the mixture of 54 mL ethanol—6 mL H2O, and 0.11 g of Pd/C at 10% is added. The reaction medium is subjected to catalytic hydrogenolysis under agitation at room temperature for 24 hours. At the end of this hydrogenolysis, the reaction medium is filtered. The filtered Pd/C is washed with EtOH; then the filtrate is evaporated under reduced pressure. The solid residue is re-crystallized in a MeOH-ethyl acetate mixture to obtain 2.05 g (10.3 mmol) of 2-methyl-3-hydroxypyridine-4(1H)-one of glycerol, which is pure at chromatographic and NMR analyses. Yield: 71%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: Cl
Product: COC(=O)c1ccc(Cl)nc1Cl
Reaction time: 48 h

Procedure:
19.1 g (0.1 mole) of 2,6-dichloronicotinic acid [Guthzeit and Laska, J. pr. Ch. 58 [2], 425 (1898)] are suspended in 250 ml of methanol and, while stirring and cooling with ice, hydrogen chloride gas is introduced until the mixture is saturated. The reaction mixture is allowed to stand for 48 hours at room temperature and subsequently heated for 3 hours to reflux temperature. It is then evaporated to dryness in a high vacuum at 40° C and the residue is dried in a high vacuum at 40° C. The brown crystalline product is recrystallised from ether-pentane to yield methyl 2,6-dichloronicotinate with a melting point of 53°-54° C.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.Br[C:10]([CH3:15])([CH3:14])[C:11](Br)=[O:12].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:14][CH:10]1[CH2:15][C:4]2[C:5](=[CH:6][C:1]([CH3:8])=[CH:2][C:3]=2[CH3:7])[C:11]1=[O:12]
Reactant: Cc1cccc(C)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
m-Xylene (34.1 g, 0.32 moles) and 2-bromoisobutyryl bromide (73.9 g, 0.32 moles) were stirred in methylene chloride (500 mL) at 0° C. as AlCl3 (108.98 g, 0.82 moles) was added slowly as a solid under a nitrogen flow over a 20 minute period of time. The reaction was then allowed to stir at 0° C. for 1 hour and then for 16 hours at 20° C. After the reaction period the mixture was poured on crushed ice and then filtered through diatomaceous earth (Celite™ brand). The mixture was then extracted with 1 M HCl (2×100 mL), 1 M NaHCO3 (1×100 mL), and H2O (1×100 mL) and the organic layer dried over MgSO4. Filtration followed by removal of the volatiles resulted in the isolation of a yellow oil. Vacuum distillation resulted in the isolation of the desired product as a pale yellow oil (50.4 g, 89.9 percent yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17]>>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][OH:18])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: C#CCCCO
Product: OCCCC#Cc1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedures described in example 1F], 1-iodo-3-trifluoromethoxy-benzene and pent-4-yn-1-ol gave the title compound as a red liquid.