Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CN2C(=O)C3NC(N)=NC=3N(CC3CC3)C2=O)CC1.[CH:21]1([CH2:24][N:25]2[C:34](=[O:35])[C:33]3[NH:32][CH:31]=[N:30][C:29]=3[N:28]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:26]2=[O:27])[CH2:23][CH2:22]1.[N+:40]([O-])([OH:42])=[O:41]>>[CH:21]1([CH2:24][N:25]2[C:34](=[O:35])[C:33]3[NH:32][C:31]([N+:40]([O-:42])=[O:41])=[N:30][C:29]=3[N:28]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:26]2=[O:27])[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])O
Reactant: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Agent: Nc1nc2c([nH]1)c(=O)n(CC1CC1)c(=O)n2CC1CC1
Product: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1

Procedure:
A process for making 1,3-dicyclopropylmethyl-8-amino xanthine which process comprises reacting 1,3-dicyclopropylmethyl xanthine with nitric acid to yield 1,3-dicyclopropylmethyl-8-nitro xanthine and thereafter reducing the nitro group to an amino group to yield 1,3-dicyclopropylmethyl-8-amino xanthine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:23].CN(C)C1C=CC=CC=1>C1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[N:6]=[C:5]2[Cl:23]
Reactant: COc1ccccc1-c1nc2ccc(Br)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1

Procedure:
6-Bromo-2-(2-methoxyphenyl)quinazolin-4(3H)-one (674 mg, 2.0 mmol), POCl3 (624 mg, 4 mmol), and N,N-dimethylaniline (740 mg, 6.1 mmol) were dissolved in benzene (12 mL) and refluxed for 3 h. The reaction mixture was diluted with EtOAc, and the organic phase was washed with aqueous saturated NaHCO3 (1×) and H2O (2×), dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-5% EtOAc in CH2Cl2/hexanes (1:1) gave 6-bromo-4-chloro-2-(2-methoxyphenyl)quinazoline. LC/MS: m/z 348.9 (M+H)+ at 3.66 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH2:13][C@@H:14]([C:22]([OH:24])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH3:2][CH:1]([CH3:3])[C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([NH:13][C@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:24])=[O:23])=[O:11])[CH2:6][CH2:5]1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: O
Product: CC(C)[C@H]1CC[C@H](C(=O)N[C@H](Cc2ccccc2)C(=O)O)CC1

Procedure:
EP1334963A discloses a method for producing nateglinide crystals from a reaction mixture containing nateglinide. The nateglinide is obtained by reacting trans-4-isopropylcyclohexane carboxylic acid chloride with D-phenylalanine in a mixed solvent of a ketone and water in the presence of an alkali, followed by neutralisation with an acid. Specific adjustment of the temperature of the mixture and the concentration of ketone solvent results in precipitation of nateglinide crystals. The ketone solvent(s) in the reaction is usually essential to proceed the reaction. However, a large quantity of acetone in the reaction causes high proportion of by-product.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C>[CH2:1]([OH:13])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCC#CCCO
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCO
Yield: 91.5 %

Procedure:
To a solution of 3.20 g (17.5 mmoles) of 3-dodecyn-1-ol in 35 ml. of ethyl acetate was added 0.300 g of Lindlar catalyst (Lindlar, Helvetica Chimica Acta 35, 450 (1952)). The hydrogenation was carried out at atmospheric pressure with stirring. When the theoretical quantity of hydrogen had been taken up, the hydrogenation was stopped and the reaction mixture was filtered through Celite. After removal of the solvent, in vacuo, the residue was evaporatively distilled under reduced pressure to afford 2.95 g (91.6%) of (Z)-3-dodecen-1-ol as an oil.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15]>O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(F)c1F

Procedure:
Decarboxylation of 3,4,5,6-tetrafluorophthalic acid was carried out by following the procedure of Example 1, except that 238 g of 3,4,5,6-tetrafluorophthalic acid and 480 g of water were used. The reaction product was separated by following the procedure of Example 1 [pH 1.33 at 30° C. at the time of charging]. This example was found to have produced 2,3,4,5-tetrafluorobenzoic acid in a yield of 87.5 mole %.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35](Cl)=[O:36]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35]([C:25]3[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:27][O:28][C:24]=3[CH3:23])=[O:36])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 489.1 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[C:8]([CH2:13]O)[CH:9]=[CH:10][C:11]=1[CH3:12]>CCOCC>[Cl:3][CH2:13][C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:6]([F:5])[CH:7]=1
Reactant: Cc1ccc(CO)cc1F
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(CCl)cc1F
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.892 g, 7.5 mmol) was added to a solution of the product of STEP 1 (1.0 g, 6.4 mmol) in 10 ml ether dropwise at 0° C. After 30 min, the reaction was quenched with crushed ice carefully, and diluted with H2O. The product was extracted with ether. The organic layer was washed with saturated NaHCO3 solution, brine, dried with Na2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/9) to give a colorless liquid in 10.5 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][Si:14]([C:17]#[C:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(2-iodophenyl)acetate (I9) (4.65 g, 16.8 mmol), PdCl2(PPh3)2 (295 mg, 421 μmol) and Cu(I)I (80.0 mg, 421 μmol) were placed into an oven dried reaction flask under nitrogen. (Trimethylsilyl)acetylene (2.80 mL, 20.2 mmol), dry degassed THF (20 mL) and triethylamine (20 mL) were added and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure to give a black residue which was adsorbed onto silica then chromatographed on silica gel (0-5% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I10) (4.63 g, 99%) as a light brown liquid; 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J=7.5, 0.8 Hz, 1H), 7.32-7.14 (m, 3H), 3.84 (s, 2H), 3.71 (s, 3H), 0.26 (s, 9H). LCMS Method C: rt 6.64 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:5][OH:6]
Reactant: Nc1cc(C(=O)O)ccc1F
Solvent: C1CCOC1
Product: Nc1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
3-Amino-4-fluorobenzoic acid (15 g, 97 mmol) in tetrahydrofuran at 0° C. was treated with 1.0 M borane-tetrahydrofuran complex (50 mL), stirred overnight at room temperature, treated with an additional 130 mL of 1.0 M borane-tetrahydrofuran complex, stirred 10 hours, quenched by the addition of methanol, stirred 3 hours at room temperature, concentrated and partitioned between aqueous sodium bicarbonate/methylene chloride. The methylene chloride layer was separated, dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Sc3ccccc3)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
In a 50 mL round bottom flask under N2, was dissolved 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in 50 mL of dichloromethane then cooled to −78° C. Solid m-CPBA (77%) (1.25 g, 7.23 mmol) was added portionwise to the reaction, and the mixture was warmed slowly over 3 h to rt. After 3 h, the reaction mixture was diluted with dichloromethane and then neutralized with aqueous NaHCO3 (sat). The aqueous phase was extracted three times with dichloromethane, and then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO. DCM:MeOH 100:0 to 90:10) to afford 7-methoxy-4-(phenylsulfinyl)quinoline (1.37 g, 93.7% yield) as an off-white foam. MS (ESI pos. ion) m/z: 284 (MH+). Calc'd exact mass for C16H13NO2S: 283.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][OH:5].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[N+](C1C=CC=CC=1C=O)([O-])=O.Cl>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH:4]=[O:5]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: CC(C)[O-]
Agent: Cl
Agent: O=Cc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
(2E)-3,7-Dimethyl-2,6-octadien-1-ol (310 mg, 2.0 mmol) was dissolved in benzene (1 mL), added with aluminum isopropoxide (40 mg, 0.1 eq, 0.20 mmol) and 2-nitrobenzaldehyde (390 mg, 1.3 eq, 2.6 mmol) and stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was added with ethyl acetate and made acidic with addition of 2 N hydrochloric acid, and then the organic layer was separated. Subsequently, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain 280 mg (yield: 93%, E:Z=87:13) of the title compound as yellow oil.
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(C)=O.Cl.O>[CH:1](=[C:8]1[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(=Cc2ccccc2)CC1
Reaction time: 4 h
Yield: 96.2 %

Procedure:
Under vigorous stirring, at rt, 8-benzylidene-1,4-dioxaspiro-[4.5]-decane (1.8 g, 7.81 mmol) was dissolved in a acetone/HCl (10% v/v) mixture (70 mL:35 mL) and left to stir 4 h. The crude mixture was diluted in water and extracted with AcOEt (3×40 mL). The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford pure title compound (1.4 g, 96%) as colorless oil. 1H NMR (CDCl3): δ 2.44 (t, J=7.0 Hz, 2H), 2.53 (t, J=6.8 Hz, 2H), 2.65-2.72 (m, 2H), 2.74-2.80 (m, 2H), 6.49 (s, 1H), 7.21-7.27 (m, 3H), 7.32-7.39 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24]>CN(C)C=O>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([N:9]([CH2:25][C:23]([Cl:22])=[CH2:24])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CNc1cccc(C(F)(F)F)c1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cl)CN(C#N)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
N-(3-(trifluoromethyl)phenyl)cyanamide (18.6 g) was dissolved in N,N-dimethylformamide (DMF) (93.0 g), to which powdered potassium carbonate (20.7 g) and potassium iodide (1.7 g) were added at room temperature with stirring. Further, 2,3-dichloro-1-propene (13.3 g) was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 1 hour. After cooling to room temperature, waster was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 25.8 g of N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide as an oil (99% yield in appearance). The percentage areas of gas chromatography and liquid chromatography were 98% and 99%, respectively.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:22]([O-])([OH:24])=[O:23].O>C(O)(=O)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCOC)c(OCCOC)c1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of ethyl 3,4-bis(2-methoxyethoxy)benzoate (23.23 g, 77.87 mmol) in acetic acid (80 mL) was added dropwise to concentrated nitric acid (21 mL) cooled with an ice bath at such a rate as to keep the internal temperature below 5° C. After 30 min, the solution was allowed to warm to room temperature and stirred for 48 h. The solution was poured onto iced water (400 mL) and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed cautiously with saturated aqueous sodium bicarbonate (3×200 mL) and brine (2×100 mL). The organic phase was dried (Na2SO4) and concentrated to give the title compound as a solid (24.82 g, 93%).
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10](=O)[CH3:11])([O-])=O.O.[N+](C(OC1C=CC=CC=1)C(=O)C)([O-])=O>CO>[CH3:11][CH:10]1[NH:3][C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[O:8][CH2:9]1
Reactant: [H][H]
Reactant: CC(=O)COc1ccccc1[N+](=O)[O-]
Agent: CC(=O)C(Oc1ccccc1)[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: CC1COc2ccccc2N1
Temperature: 40 °C

Procedure:
Reaction conditions: 150 bar of hydrogen, reaction temperature 80° C. with a residence time of about 60-90 minutes. The space velocity was about 2 g of o-nitrophenoxyacetone per g of catalyst used and hour. The catalyst used was a sponge metal catalyst from H. C. Starck, Amperkat Ni—Mo 3706 (exchange of the water under which the catalyst is stored for methanol). The yield was 90%; 42 g of nitrophenoxyacetone were converted per gram of theoretically dry catalyst. Thereafter, the hydrogenation had to be stopped owing to the massive formation of secondary components (in particular of the 3MBM dimer). Good mixing was ensured by stirring. In order to prevent precipitation of the reactant solution, it was heated to 40° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:9][CH2:10][CH2:11][CH2:12][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Oc1ccc(OCCCBr)cc1

Procedure:
A mixture of 88.0 g. (0.80 m.) of hydroquinone, 161.6 g. (0.80 m.) of 1,3-dibromopropane and 55.2 g. (0.40 m.) of potassium carbonate in 2 liters of 2-butanone was heated at reflux for 24 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The solid and liquid phases of the residue were separated, and the liquid fraction was chromatographed on silica gel using chloroform-acetonitrile (95:5) as the eluant. There was thus obtained 37.2 g. of 4-(3-bromopropyloxy)phenol as a light brown oil which was used directly in the next reaction.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Temperature: 30 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.), conc. hydrochloric acid (1.84 g.), methanol (36 ml.) and tetrahydrofuran (30 ml.) was stirred at 30° C. for 2 hours. The resultant solution was concentrated in vacuo. Water (60 ml.) was added to the residue and the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.86 g.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][NH:43]6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:48][O:49][C:50]([NH:52][C@@H:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[O:63][CH3:64])[C:54](O)=[O:55])=[O:51].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:47])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:54](=[O:55])[CH:53]([NH:52][C:50]([O:49][CH3:48])=[O:51])[C:57]6[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=6[O:63][CH3:64])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)c1ccccc1OC
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1OC
Temperature: 0 °C
Yield: 46.9 %

Procedure:
To a solution of {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester (0.04 g, 0.05 mmol) and (S)-Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid (0.02 g, 0.08 mmol, 1.5 equiv.) in CH2Cl2 (0.5 mL) was added K3PO4 (0.03 g, 0.15 mmol, 3 equiv.). The slurry was cooled to 0° C. and COMU (0.03 g, 0.06 mmol, 1.25 equiv.) and the reaction was stirred at 0° C. for 1 hour. The slurry was diluted with CH2Cl2 and filtered. The filtrate was concentrated and the crude product was purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide {1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.02 g, 50%) as a white powder. LCMS-ESI+: calc'd for C48H52N8O7: 852.4 (M+). Found: 853.6 (M+H+). 1H-NMR: 400 MHz, (acetone-d6) δ: (Mixture of rotomers) 10.96-11.01 (m, 2H), 8.29 (s, 1H), 8.07 (s, 1H), 7.73-7.89 (m, 7H), 7.35-7.48 (m, 4H), 7.33 (t, 1H), 7.05 (d, 1H), 6.96 (t, 1H), 6.36 (d, 1H), 5.91 (d, 1H), 5.21-5.26 (m, 3H), 4.29 (t, 1H), 3.90 (s, 3H), 3.78-3.93 (m, 2H), 3.60 (s, 3H), 3.58 (s, 3H), 3.30 (q, 2H), 2.59-2.65 (m, 2H), 2.36 (m, 1H), 1.90-2.21 (m, 6H), 0.85-0.93 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7]OC(=O)[O:4]1.[F:9][C:10]([F:18])([F:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12].C(=O)=O>O>[F:9][C:10]([F:18])([F:17])[C:11]1([C:13]([F:16])([F:15])[F:14])[O:4][CH:3]([CH2:2][OH:1])[CH2:7][O:12]1
Reactant: O=C1OCC(CO)O1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: O=C=O
Solvent: O
Product: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 118 °C
Reaction time: 40 h

Procedure:
118 Grams glycerol carbonate (1 mole) is placed in a 500 ml three neck flask, fitted with a thermometer, magnetic stirrer, gas-inlet tube, and a condenser cooled with a dry ice-isopropyl alcohol bath. Hexafluoroacetone gas is added to the vigorously stirred glycerol carbonate at 27° to 60° C. until 142 grams (0.85 moles) has been absorbed. The dry ice condenser is now replaced by a water condenser which is connected to a dry ice trap so that hexafluoroacetone which escapes during reaction may be condensed. The temperature is raised slowly to about 118° C. at which point CO2 evolution begins. The temperature is allowed to rise to 148° C. during a 40 hour reaction period. The resulting product is mixed with water (50 ml) and the organic layer separated and diluted with chloroform. The chloroform solution is washed several times with water and 5% NaHCO3 solution. Vacuum stripping gives crude 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane. This is distilled at 78° - 80° C./25 mm Hg and the yield of pure product is 92%, based on utilized hexafluoroacetone. The twice distilled product has a refractive index of 1.35046 (20° C.) and upon analysis contained 47.19% fluorine, 30.02% carbon, and 2.22% hydrogen.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:15]#[N:16])[CH2:6]C(C#N)C(OCC)=O)[CH3:2]>[OH-].[Na+].O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:15]#[N:16])=[CH2:6])[CH3:2]
Reactant: CCOC(=O)C(C#N)CC(C#N)C(=O)OCC
Agent: *CO*
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C#N)C(=O)OCC
Yield: 114.4 %

Procedure:
In a 400 liter capacity stirrer-equipped vessel, 130 kg of distillation residue from the production of 2-cyanoacrylate, containing 75.1% by weight of 2,4-dicyanoglutaric acid diethyl ester (410 moles), were mixed with 21.3 kg of water and the resulting mixture reacted with 8.83 kg of 92% polyoxymethylene (271 moles) in the presence of 804.6 g of 32% NaOH solution which was required to adjust the pH into the range of from 4 to 6. The reaction was carried out and the reaction product worked up in the same way as described in EXAMPLE 1. 58.7 kg of pure 2-cyanoacrylic acid ethyl ester were obtained, corresponding to a yield of 60.1% by weight, based on 100% 2,4-dicyanoglutarate.