Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH2:25].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:21][O:22][C:23](=[O:28])[CH:24]([NH:25][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[CH2:26][OH:27]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.29 g (10.93 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.70 g (10.93 mmol) L-serine methyl ester hydrochloride, 1.67 g (10.93 mmol) of hydroxybenzotriazole, hydrate, as well as 1.11 g (10.93 mmol) of triethylamine and 2.26 g (10.93 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethanol and crystallized upon concentration.
Reaction SMILES: [CH2:1]([S:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C.C(N(CC)CC)C.CO>[C:23]([NH:19][C@H:18]([C:20]([OH:22])=[O:21])[CH2:17][S:16][CH2:1][CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCSC[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)=CCCC(C)=CCCC(C)=CCSC[C@H](NC(=O)c1ccccc1)C(=O)O

Procedure:
S-farnesylcysteine was dissolved in dry ethyl acetate/triethylamine in a dry flask under nitrogen. equivalents of benzoylchloride was added in the cold and the suspension was allowed to stir for an hour. The solution was neutralized with dilute HCl. After evaporation, the product was applied to a preparative thin layer chromatography plate and eluted with hexane/ethyl acetate. The pure product was removed from the plate and eluted with methanol. Yields were in the range of 50-75%. The product showed the anticipated nmr and infrared spectra. The parent acid was prepared from the ester by the addition of one equivalent of sodium hydroxide in methanol. The product showed the expected nmr and infrared spectra.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][CH:4]=1)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[NH:20]1[C:1]([C:3]2[CH:19]=[CH:18][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[B:15]([OH:16])[O:14][CH2:13][C:12]=4[CH:17]=3)=[CH:5][CH:4]=2)=[N:2][N:22]=[N:21]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OB1OCc2cc(Oc3ccc(-c4nnn[nH]4)cc3)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 23.5 %

Procedure:
A mixture of 5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole (200 mg, 0.797 mmol), sodium azide (103 mg, 1.59 mmol), and ammonium chloride (85 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL) was stirred at 80° C. for two days. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) followed by trituration with ethyl acetate to give the target compound (55 mg, 23%).
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)[CH2:2]CCC.[F-].O.O.O.[C:22]1([CH3:29])[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.O>CS(C)=O>[CH2:26]([C:27]1[CH2:22][CH:29]=1)[CH2:25][CH2:24][CH2:23][CH2:28][CH3:2]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1ccccc1C
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCC1=CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In situ, 0.586 g (2.0 mmol) of (trans)-1-hexyl-1-(methane sulfonyloxy)-2-(trimethylsilyl)cyclopropane of Preparation Example 9 was dissolved in 2.0 ml of DMSO, 0.94 g of Bu4NF.3H2O was added thereto and the resulting mixture was vigorously stirred at room temperature for one hour. 8.0 ml of xylene and 5.0 ml of water were added to the reaction solution and vigorously stirred for 5 minutes and stood. When the mixture was separated into a xylene layer (upper layer) and an aqueous layer (lower layer), only the xylene layer was collected and the aqueous layer was discarded. 1.0 g of sodium dodecylbenzenesulfonate and 1.0 g of tristyrenylphenykethoxy)12ethanol were added to the xylene layer, stirred for 5 minutes, 2.0 L of water was added thereto and the resulting mixture was slowly stirred such that it was homogeneously mixed. As a result, a 1.0 mM 1-hexylcyclopropene formulation was prepared. This solution was diluted to 1 to 100 times prior to use, as necessary.
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][CH2:13][CH2:14][CH2:15]Br.[OH-].[K+]>CO>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCCCCBr)cc1
Yield: 39.4 %

Procedure:
As shown in the following Scheme, hydroquinone (1) (4.5 g (grams)) and 1,6-dibromo hexane (2) (10 g (grams)) were dissolved in methanol (100 ml (milliliters)) at a room temperature. Potassium hydroxide (2.3 g (grams)) was added to the resulting mixture solution, and then fluxed at 60° C. (Celsius) overnight. Next day, the temperature of the reaction mixture is lowered to a room temperature, and methanol was evaporated from the reaction mixture. Then, the reaction mixture was extracted three times with water (100 ml (milliliters)) and ethyl acetate (100 ml (milliliters)). Water was removed over magnesium sulfate, and the solvents were evaporated, and the resulting reaction mixture was purified using a column chromatography (developer solution: ethylacetate/hexane=1/5 volume ratio) to obtain 4.4 g (grams) of 4-(6-bromohexyloxy)phenol (3).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[C:20]([N:22]=[C:23](SC)[S:24][CH3:25])#[N:21]>CO>[C:20]([N:22]=[C:23]([S:24][CH3:25])[NH:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])#[N:21]
Reactant: CSC(=NC#N)SC
Reactant: CC(N)C(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CSC(=NC#N)NC(C)C(=O)c1ccccc1
Yield: 80.2 %

Procedure:
Triethylamine (1 ml) was added to a solution of 2-aminopropiophenone hydrochloride (0.93 g) and dimethyl cyanodithioimidocarbonate (0.73 g) in methanol (3 ml), and the mixture was refluxed for 15 minutes and evaporated under reduced pressure. The residue was dissolved in chloroform and the solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate and diluted with diisopropyl ether. The resultant precipitates were collected by filtration, washed with diisopropyl ether and dried to give 2-(3-cyano-2-methyl-1-isothioureido)propiophenone (0.99 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (41 mg) and morpholine (53 mg) were suspended in N,N-dimethylformamide (4 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then 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 methanol-chloroform to give the title compound (34 mg, yield 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.O[C:21]1[CH:22]=[C:23]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:24]=CC=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[O:9][C:10]3[CH:21]=[CH:22][C:23]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][C:12]=3[O:11]2)=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)c(O)c1
Reactant: COC(OC)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc2c(c1)OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)O2
Temperature: 60 °C
Yield: 37.7 %

Procedure:
A mixture of di(4-chlorophenyl)dimethoxymethane (26 g) (see Preparation 13) and methyl (3,4-dihydroxyphenyl)acetate (16 g) (see Preparation 12) in toluene (200 ml) was heated under reflux in a Dean-Stark apparatus for one hour. The reaction was cooled to 60° C. and p-toluenesulphonic acid was added (50 mg). After heating under reflux for 16 hours the solution was cooled, washed with aqueous sodium bicarbonate (100 ml, dried (MgSO4) and evaporated to a brown gum. Flash chromatography (silica, eluant=4:1 hexane/ethyl acetate) gave the title compound as a pale yellow gum (13.7 g). LRMS m/z=415(m)+.
Reaction SMILES: Br[C:2]1[CH:22]=[N:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7]3[N:16]=[CH:15][C:14](C)=[C:13](C)[C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:19]([N:6]1[C:5]2[N:21]=[CH:22][C:2]([C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][C:4]=2[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][CH:15]=[N:16][C:7]1=2)[CH3:20]
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2c1ncc(C)c2C
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2cccnc21
Yield: 120.9 %

Procedure:
To a solution of 8-bromo-5,11-dihydro-3,4-dimethyl-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.05 g, 0.14 mmol), phenylacetylene (0.03 g, 0.28 mmol), and triethylamine (3.5 mL) in 1.5 mL of acetonitrile was added tetrakis(triphenylphosphine)palladium(0) (10 mg) and copper(I) iodide (5 mg). The resultant mixture was heated at reflux for 2 hours. The solvent was removed at reduced pressure, and the residue was purified by preparative thin layer chromatography, eluting with ethyl acetate/hexanes. The product was recrystallized from ethyl acetate/petroleum ether to provide 60 mg of the title compound, m.p. 228°-229° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][C:11]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:10][C:9]3=[O:21])[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC1(c2ccccc2)CCN(c2ccnc(Cl)n2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)CCN(c2ccnc(-c3cccc(F)c3)n2)C(=O)O1
Yield: 16.7 %

Procedure:
To a solution of 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.33 mmol) and 3-fluorophenylboronic acid (80 mg, 0.53 mmol), K2CO3 (1 mL, 2 M) in 1,4-dioxane (3 ml) at 0° C. under N2 was slowly added Pd(Ph3)2Cl2 (20 mg, 20%). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 3-(2-(3-fluorophenyl)pyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (20 mg, yield 17%). 1H NMR (CDCl3, 400 MHZ): δ=1.71 (s, 3H), 2.37 (m, 1H), 2.6 (m, 1H), 3.54 (m, 1H), 4.34 (m, 1H), 7.08 (m, 1H), 7.25 (m, 1H), 7.34 (m, 5H), 7.96 (m, 1H), 8.09 (m, 1H), 8.16 (m, 1H), 8.6 (m, 1H). LC-MS Method 3, tR=1.46 min, m/z=364.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7](O)[C@H:5]([OH:6])[C@@H:3]1O.[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH:17]1[O:19][C@H:7]([CH2:5][O:6][C:11](=[O:12])[CH3:9])[C@@H:9]([O:10][C:2](=[O:1])[CH3:3])[C@H:11]([O:12][C:5](=[O:6])[CH3:7])[C@@H:18]1[O:10][C:2](=[O:1])[CH3:3])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 96.7 %

Procedure:
Analogously to what is described in the literature [M. L. Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.), Academic Press, New York, Vol. II, 53, pp. 211-215, (1963)], the reaction of 150 g (832.5 mmol) of α,β-D-mannopyranose with a mixture that consists of 1500 ml of absolute pyridine and 1500 ml of acetic acid anhydride yields, after working-up, 315 g (96.7%) of the above-mentioned title compound as a crude product in the form of a viscous and colorless oil. By 1H-NMR spectroscopic study of the thus obtained title compound, it was possible to determine the a to β ratio of both anomers at 4:1. Separation of the α,β-anomers of the above-mentioned title compound can be eliminated to carry out the reaction steps below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.C([CH2:15][S:16]([CH2:19][S:20]([CH2:23][C:24](O)=O)(=[O:22])=[O:21])(=[O:18])=[O:17])(O)=O>C(O)(=O)C>[OH:11][C:10]1[CH:9]=[CH:8][C:5](/[CH:24]=[CH:23]/[S:20]([CH2:19][S:16](/[CH:15]=[CH:6]/[C:5]2[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:17])=[O:18])(=[O:21])=[O:22])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: COc1cc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Yield: 60 %

Procedure:
A solution of 3-methoxy-4-hydroxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 60% yield. m.p. 125-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.Cl.[NH2:21][OH:22].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([C:8](=[N:21][OH:22])[NH2:9])[CH:7]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1Nc1ncc(C#N)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)[C@@H]1CCC[C@@H]1Nc1ncc(C(N)=NO)cc1Cl
Yield: 100 %

Procedure:
A solution of cis-methyl 2-(3-chloro-5-cyanopyridin-2-ylamino)cyclopentanecarboxylate (0.154 g; 0.55 mmol), hydroxylamine hydrochloride (0.057 g; 0.82 mmol) and DIEA (0.143 mL; 0.82 mmol) in EtOH (2 mL) was stirred at ambient temperature for 42 hours. The solvent was evaporated in vacuo and the residue dissolved in DCM/water. The mixture was passed through a hydrophobic frit and the solvent evaporated in vacuo to afford the title product (0.172 g; quantitative). 1H NMR (CDCl3, 400 MHz) δ 8.25 (1H, d, J=2 Hz), 7.74 (1H, d, J=2 Hz), 5.74 (1H, d, J=8.4 Hz), 4.77-4.70 (3H, m), 3.61 (3H, s), 3.19-3.14 (1H, m), 2.14-1.70 (6H, m).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[C:21]([CH2:29][NH:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:21]([CH2:29][NH:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][N:34]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: O=C(CNCCC1CCCCN1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(CNCCC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21)c1ccccc1

Procedure:
A mixture of 9.5 g (0.033 mol) of 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 9.8 g (0.04 mol) of 2-[2-[(benzoyl)methylamino]ethyl]-piperidine, 4.2 g (0.04 mol) of sodium carbonate and 300 ml of acetonitrile is refluxed for 10 hours. Then the reaction mixture is filtered and the filtrate is evaporated to dryness in vacuo. The crude product obtained is purified by chromatography on silica gel (Baker, 30-60 μm) with a mixture of methylene chloride/methanol/cyclohexane/ammonia/ethyl acetate=68:15:15:2:500 as eluant.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:14])=[N:5][C:6](Cl)=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[N:2].N[CH:16]([CH2:19]C)[CH2:17][OH:18].[CH:21]([NH:24]C(C)C)(C)C.ClCl>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:7]=[C:6]([NH:24][CH2:21][CH:17]([OH:18])[CH2:16][CH3:19])[N:5]=1
Reactant: CC(C)NC(C)C
Reactant: N#Cc1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: CCC(N)CO
Agent: ClCl
Product: CCC(O)CNc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Yield: 55 %

Procedure:
Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) was added by pipette at a dropwise rate over 3 minutes to 2-aminobutanol (1.5 g, 6 mmol). Di-isopropylamine (0.9 g, 7 mmol) was added after 10 minutes and the resultant mixture was heated in a sealed tube at 70° C. for 30 minutes to selectively displace the chlorine at position 6 before quenching in ice-cold water and extracted with dichloromethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with diethylether and the resultant solid was used in the next step without further purification. 2-Chloro-6-(2-hydroxybutylamino)-4-(trifluoromethyl)pyridine-3-carbonitrile was isolated in 55% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10](C(OCC)=O)[C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.8 %

Procedure:
To a stirred solution of tert-butyl ethyl (5-nitropyridin-2-yl)malonate (6.93 g, 22.3 mmol, step 1 of Example 1) in dichloromethane (75 mL) was added trifluoroacetic acid (7.64 g, 67.0 mmol) at room temperature, and the mixture was stirred at room temperature for 20 h. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (5:1 to 4:1) to give 3.27 g (70%) of the title compound as an orange oil.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8](Br)=[N:7][N:6]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[C:5]1=[O:22])[CH:2]=[CH2:3].[Na].[CH3:24][OH:25]>>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([O:25][CH3:24])=[N:7][N:6]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[C:5]1=[O:22])[CH:2]=[CH2:3]
Reactant: CO
Reactant: C=CCn1c(=O)c(Br)nn(-c2cccc(NC(C)=O)c2)c1=O
Agent: [Na]
Product: C=CCn1c(=O)c(OC)nn(-c2cccc(NC(C)=O)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
According to Scheme 3 Step 3: To a solution of compound 6(B) (800 mg, 2.19 mmol) in MeOH (10 mL) was added. a solution of sodium methoxyde 2M in methanol (1.1 mL, 2.19 mol). After 1 h of stirring at room temperature, the mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 10 g SiO2) using CH2Cl2/MeOH 98/2 as eluant to afford N-(3-(4-allyl-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 6(C) (600 mg, 86%) as a white solid.
Reaction SMILES: [OH2:1].[OH:2][CH2:3][CH:4]([CH2:6][OH:7])O>>[CH:3]([CH:4]=[CH2:6])=[O:2].[C:6]([OH:7])(=[O:1])[CH:4]=[CH2:3]
Reactant: O
Reactant: OCC(O)CO
Product: C=CC(=O)O
Product: C=CC=O

Procedure:
The stream (6) has a high water content due to the composition of the stream (5) entering the reactor (glycerol charge) and to the reaction itself (dehydration). Stage b) in the process according to the invention consists in separating this stream (6) into a phase (9) enriched in acrolein and a phase (10) rich in water and depleted in acrolein. This stage b), such as the partial separation of the water described, for example, in Patent Application WO 08/087315 on behalf of the Applicant Company or such as the separation described in Application WO 2006/136336, has the aim of removing most of the water present and the heavy byproducts before sending the stream comprising the acrolein to a purification stage, in a process for the manufacture of acrolein, or to the stage for the oxidation of acrolein to give acrylic acid, in a two-stage process for the manufacture of acrylic acid from glycerol. This partial separation of the water thus makes it possible to avoid damage to the catalyst of the 2nd stage of the oxidation of acrolein to give acrylic acid and to avoid, during the subsequent stages, the removal of large amounts of water, which could well be expensive and result in losses of acrylic acid. In addition, it makes it possible to remove a portion of the “heavy” impurities formed during the dehydration of the glycerol.