Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[C:4]=2[CH:3]=C1.C[OH:23]>>[CH:3]([C:4]1[C:5]([OH:1])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])=[O:23]
Reactant: CO
Reactant: CS(=O)(=O)NC(=O)CCCCOc1cccc2occc12
Product: CS(=O)(=O)NC(=O)CCCCOc1cccc(O)c1C=O
Temperature: -65 °C

Procedure:
5-(4-Benzofuranyloxy)-N-methylsulphonylpentanamide (0.933 g, 0.003 M) was dissolved in dry methanol (135 ml) and cooled to -65° C. with stirring and exclusion of moisture. Ozonised air was bubbled through the solution at a rate of 20 liters/hr for 45 mins. Nitrogen was then bubbled through the solution (5 mins) to remove excess ozone before the addition of dimethyl sulphide (0.9 ml). The mixture was allowed to warm to room temperature overnight (16 hr). The solvent was removed in vacuo, the residue dissolved in ethyl acetate-ether (1:1), washed with water and extracted with 5% sodium bicarbonate solution. The combined extracts were acidified with concentrated hydrochloric acid the precipitated solid was filtered off, washed wall with water and recrystallised from ethyl acetate-petrol to give 5-(2-formyl-3-hydroxyphenoxy)-N-methylsulphonylpentanamide, m.p. 136°-138° C. (Found: C, 49.54; H, 5.33; N. 4.12, S, 10.14. C13H17NSO6 requires C, 49.51; H, 5.43; N, 4.44; S, 10.17%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[O:8])[NH:6][CH:7]=1.[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:17][N:18](C=O)C>C(=O)([O-])[O-].[Ag+2]>[CH2:16]([O:8][C:5]1[C:4]([OH:9])=[CH:3][C:2]([C:17]#[N:18])=[CH:7][N:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1[nH]cc(Br)cc1O
Reactant: Cc1ccccc1
Reactant: CN(C)C=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Product: N#Cc1cnc(OCc2ccccc2)c(O)c1

Procedure:
For example, 5-bromo3-hydroxy-2 (1H)-pyridinone is protected as the 3-t-butyloxycarbonyl derivative (by treatment with di-t-butyl dicarbonate) and treated with e.g. an appropriately substituted benzyl bromide in the presence of silver carbonate in an inert solvent such as toluene. The resulting 2-benzyloxy substituted derivative is then reacted with cuprous cyanide in an inert solvent such as DMF at elevated temperature to yield 6-benzyloxy-5-hydroxynicotinonitrile. Condensation with a Grignard reagent (e.g. methylmagnesium bromide) yields 6-benzyloxy-5-hydroxy-3-acetylpyridine which is further reacted, with e.g. ethyl bromoacetate, to give the starting material for the Horner-Emmons condensation of process (a).
Reaction SMILES: COCCOC.Br[C:8]1[C:9]([C:14]([O:16][CH3:17])=[O:15])=[N:10][CH:11]=[CH:12][N:13]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:8]1[C:9]([C:14]([O:16][CH3:17])=[O:15])=[N:10][CH:11]=[CH:12][N:13]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B(O)O
Reactant: COC(=O)c1nccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1nccnc1-c1ccccc1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
107 ml of 1,2-dimethoxyethane were aerated with argon, and 597 mg (0.51 mmol) of Pd(PPh3)4 and 2.24 g (10.3 mmol) of methyl 3-brompyrazine-2-carboxylate were added. After 10 min, 3.9 g (15.45 mmol) of 2-(tert-butoxycarbonylaminomethyl)-phenylboronic acid and finally 10.7 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux for 18 h under argon, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 661 mg (19%) of a viscous oil were obtained. MS (ES+): m/z=344 (M+1), 288 (M−55). 1H-NMR (CDCl3): δ=8.78 (1H, d, J=2.4 Hz), 8.67 (1H, d, J=2.4 Hz), 7.54-7.14 (4H, m), 5.11 (1H, br s), 4.22 (2H, d, J=5.9 Hz), 3.79 (3H, s), 1.38 (9H, s).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH:7][C:10](=[O:13])[CH:11]=[CH2:12])[CH3:3]
Reactant: CCOC(=O)[C@H](C)N
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CC(=O)N[C@@H](C)C(=O)OCC
Reaction time: 2 h

Procedure:
To 0.5 moles of alanine ethyl ester hydrochloride in 500 ml. of benzene is added 0.5 moles of acryloyl chloride. To this stirred mixture is added portionwise 0.6 moles of anhydrous sodium carbonate. The reaction mixture is then refluxed for 1 hour, stirred an additional 2 hours, filtered, and the filtrate concentrated to give N-acryloylalanine ethyl ester.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[C:6]1([N:12]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:26]>C(Cl)(Cl)Cl.O1CCCC1.C(OC(=O)C)C>[O:14]=[C:13]1[N:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:19]([C:20]2[CH:21]=[CH:22][C:23]([S:2]([NH2:26])(=[O:5])=[O:3])=[CH:24][CH:25]=2)=[CH:18][C:16](=[O:17])[NH:15]1
Reactant: O=S(=O)(O)Cl
Reactant: N
Reactant: O=c1cc(-c2ccccc2)n(-c2ccccc2)c(=O)[nH]1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2cc(=O)[nH]c(=O)n2-c2ccccc2)cc1
Yield: 18.3 %

Procedure:
The chlorosulfonic acid (1.18 g, 10 mmol) was added to a solution of 1,6-diphenyluracil (0.2 g, 0.75 mmol) (synthesized according to the procedure given in Harvey I. Skulnick, Heterocycles, 23, (7), pp1685, 1985) in chloroform (20 ml) and refluxed for 2 hours. The reaction mixture was poured onto ice-water mixture and extracted with ethylacetate. The ethylacetate extract was washed with brine, dried over anhydrous sodium sulphate and concentrated to dryness under reduced pressure. The crude solid thus obtained was taken in tetrahydrofuran (20 ml) and treated with ammonia solution (1 ml) under stirring. The reaction mixture was stirred for 1 hour and concentrated to dryness in vacuum. The product thus obtained was dissolved in ethylacetate, washed with water, brine and dried over anhydrous sodium sulphate. The ethylacetate extract was concentrated to dryness under reduced pressure and purified by column chromatography to yield the title compound (0.1 g, 18.3%). mp: ______.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:28]([C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([F:24])[CH:26]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=Cc1cccc(F)c1
Product: Nc1cc(Br)cc2nc(-c3cccc(F)c3)nn12

Procedure:
The title compound, MS m/e (%): 307 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 3-fluoro-benzaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][N:8](S(C1C=CC(OCC2C=CC=CC=2)=CC=1)(=O)=O)[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([CH:7]1[C:12]([OH:14])([CH3:13])[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CCCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1NCCCC1(C)O
Reaction time: 24 h

Procedure:
To a solution [(4-benzyloxy-benzenesulfonyl)-(4-oxo-pentyl)-amino]-acetic acid tert-butyl ester (compound of formula XVII, 25 g, 56 mmol) in 200 ml of tetrahydrofuran was added potassium tert-butoxide (24 ml of a 1M solution in tetrahydrofuran, 24 mmol). After stirring for about 24 hours at a temperature of about 20° C. to about 25° C., the mixture was diluted with water, acidified with 1M hydrochloric acid and extracted 3 times into ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The stereoisomers were separated by preparative HPLC on a Chiralpak AD column® eluting with 2-propanol-hexane, affording approximately 4 g of each stereoisomer of 1-[4-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid tert-butyl ester (compound of formula XVIII) as a colorless oil.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.[N:5]([CH2:8][C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[C:6]=[S:7].C(O)C>N1C=CC=CC=1>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH2:8][N:5]1[CH:1]=[N:3][N:4]=[C:6]1[SH:7]
Reactant: NNC=O
Reactant: S=C=NCc1ccco1
Solvent: c1ccncc1
Solvent: CCO
Product: Sc1nncn1Cc1ccco1
Yield: 83.7 %

Procedure:
A solution of formic acid hydrazide (439 mg, 7.809 mmol) in pyridine (20 ml) was added to a solution of 2-isothiocyanatomethyl-furan (1 g, 7.185 mmol) in pyridine (20 ml). Reaction took place at room temperature overnight, and ethanol (20 ml) was added directly to the reaction and placed in 80C bath overnight. Solvent was evaporated and the title compound (1.09 g, 83%) was obtained from purification by SPE chromatography on silica gel with 500 ml 20%, 250 ml 25%, 250 ml 30%, 250 ml 35%, 250 ml 40%, and 250 ml 50% ethyl acetate in hexanes. 1H NMR (CD3OD), δ (ppm): 14.0 (bs, 1H), 8.19 (s, 1H), 7.52 (q, 1H), 6.52 (m, 1H), 6.42 (m, 1H), 4.90 (s, 2H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.[Br:23][C@@H:24]([CH2:28][OH:29])[C:25]([OH:27])=O.[Cl-].[CH3:31][O:32][C:33]1[CH:46]=[CH:45][C:36]([CH2:37][NH2+:38][CH2:39][S:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:35][CH:34]=1>O1CCCC1>[CH3:31][O:32][C:33]1[CH:46]=[CH:45][C:36]([CH2:37][N:38]([CH2:39][S:40][C:41]([CH3:42])([CH3:44])[CH3:43])[C:25](=[O:27])[C@@H:24]([Br:23])[CH2:28][OH:29])=[CH:35][CH:34]=1
Reactant: COc1ccc(C[NH2+]CSC(C)(C)C)cc1
Reactant: O=C(O)[C@@H](Br)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN(CSC(C)(C)C)C(=O)[C@@H](Br)CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.13 g (20 mmol) of dicyclohexyl carbodiimide and 2.79 ml (20 mmol) of triethylamine are added at room temperature while stirring to a mixture of 3.38 g (20 mmol) of 2-(S)-bromo-3-hydroxypropionic acid and 5.151 g (20 mmol) of p-methoxybenzyl-tert.-butylthiomethylammonium chloride (Example 24) in 100 ml of tetrahydrofuran. The mixture is stirred for two hours at room temperature and the dicyclohexylurea that has precipitated is filtered off with suction. The filtrate is concentrated by evaporation under reduced pressure and the residue is chromatographed over 500 g of silica gel using toluene/ethyl acetate (9:1). The title compound is obtained in the form of a colourless, viscous oil.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[CH3:20])(O)[CH2:5]1)[CH2:2][CH3:3].[OH-].[Na+]>Cl>[CH3:20][N:15]1[C:16]2[C:12](=[C:11]([C:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CCCN1CCCC(O)(c2cccc3c2ccn3C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCN1CCC=C(c2cccc3c2ccn3C)C1
Yield: 81 %

Procedure:
A solution of 8.2 g of 1-propyl-3-(1-methyl-1H-indol-4-yl)-3-piperidinol in 250 ml of 1 N hydrochloric acid was refluxed for 4 hours and while cooling in an ice bath, sodium hydroxide solution was added thereto until the pH was alkaline. The mixture was extracted with methylene chloride and the organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-triethylamine mixture to obtain 6.2 g of 1-methyl-4-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole with an Rf=0.2.
Reaction SMILES: [CH2:1]([C:8]1([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[CH2:1]([C:8]1([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCN1CCC(O)(Cc2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(NCCCN1CCC(O)(Cc2ccccc2)CC1)c1ccc(O)cc1
Reaction time: 4 h
Yield: 88.2 %

Procedure:
Palladium on carbon (10%, 50 mg) was added to a solution of N-[3-(4-benzyl-4-hydroxy-piperidin-1-yl)-propyl]-4-benzyloxy-benzamide (185 mg, 0.40 mmol) in acetic acid (5 ml). The hydrogenation was complete after 4 h. The catalyst was removed by filtration through celite and the solvent was evaporated. Sodium bicarbonate (10% aq. solution, 2 ml) was added, and the aqeous layer extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered and evaporated to give N-[3-(4-benzyl-4-hydroxy-piperidin-1-yl)-propyl]-4-hydroxy-benzamide (130 mg, 87%) as a white solid. MS: me/e=369 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:23])[CH:13]([OH:22])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:38])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:23])[CH:13]([O:22][C:30]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:38])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCC(O)C(=O)c1ccc(F)c2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(F)c2ccccc12
Yield: 100.5 %

Procedure:
To a mixture of ethyl 6-(4-fluoro-1-naphthyl)-5-hydroxy-6-oxohexanoate (19.0 g), pyridine (5.50 g) and tetrahydrofuran (100 ml) was added dropwise phenyl chlorocarbonate (10.8 g) with stirring under ice-cooling. After 16 hours of stirring at room temperature, the reaction mixture was concentrated, diluted with ethyl acetate (400 ml) and washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluoro-1-naphthyl)-6-oxo-5-phenoxycarbonyloxyhexanoate as a yellow oil (26.3 g, 96%).
Reaction SMILES: [OH-:1].[OH-].[Mg+2:3].[S:4](=[O:6])=[O:5]>>[S:4](=[O:1])([OH:6])[O-:5].[Mg+2:3].[S:4](=[O:1])([OH:6])[O-:5]
Reactant: O=S=O
Reactant: [OH-]
Agent: [Mg+2]
Product: O=S([O-])O

Procedure:
Referring to FIG. 1, wood chips are heated with a magnesium bisulphite cooking acid (C/A) in digesters 10 and the pulp and spent sulphite liquor are discharged into washers 12. The liquor is passed through a filter and the filtrate having 13-15% solids is fed to a weak liquor storage tank 16. Some of the weak liquor is recycled to the washers. The weak liquor is concentrated in an evaporator 18 and transferred to a heavy liquor storage tank 20 at a concentration between 55-57% solids as required for operation of the recovery system. The heavy liquor is fired in a recovery boiler 22 and the combustion products of the sulphur and magnesium in the liquor are discharged from the boiler in a gas stream as sulphur dioxide and solid particles of magnesium oxide ash. The major portion of the magnesium oxide is removed from the gas stream in a precipitator 24 and washed in a washer 26. The magnesium oxide from the washer is fed to slakers 28 to produce magnesium hydroxide which is stored in a slurry tank 30. This magnesium hydroxide slurry together with some makeup is fed to a scrubber 32. The sulphur dioxide from the precipitator 24 is forced to flow upwardly through the scrubber 32 by an induced draft fan 34, countercurrent to the magnesium hydroxide flow, so as to recover the sulphur dioxide by reaction with the magnesium hydroxide to produce magnesium bisulphite acid. This acid is fed to a conventional clarifier 36 and then to a fortification tower 38 where it is fortified with makeup sulphur dioxide coming from a sulphur burner 40 through coolers 42. Some SO2 makeup is also fed to the scrubber through the fortification tower. The finished cooking acid is fed through filters 44 and stored in a cooking acid storage tank 46 for reuse in the digesters 10.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=O)[CH:2]=1.[NH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][O:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:26][O:25][CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[N:18]=[C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COC[C@@H]1CCCN1N
Reactant: O=C1CCCCC1c1cnc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC[C@@H]1CCCN1N=C1CCCCC1c1cnc2ccccc2c1

Procedure:
A mixture of (±)-2-(3-quinolinyl)cyclohexanone (0.5 g, 2.2 mmol), (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (`SAMP`)(0.28 g, 2.2 mmol) and p-toluenesulphonic acid (10 mg) was refluxed in toluene (15 ml) for 2.5 hours. The toluene was removed in vacuo (40° C./14 mmHg,) to give a crude oil which was partitioned between water (20 ml) and ethyl acetate (25 ml). The aqueous layer was extracted with ethyl acetate (2×25 ml) and the combined organic extracts were dried over sodium sulphate then concentrated in vacuo to give (2S)-(+)-2-(methoxymethyl) -1-[2-(3-quinolinyl)cyclohexylideneamino]pyrrolidine and (2S)-(-)-2-(methoxymethyl)-1-[2-(3-quinolinyl)cyclohexylideneamino]pyrrolidine as a 50:50 mixture of diastereoisomers (0.69 g, 2 mmol).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH:6]([CH2:10][OH:11])[C:7]([O-:9])=[O:8].[Li+].[C:13](OCC)(=[O:15])[CH3:14]>>[C:1]([O:5][CH:6]([CH2:10][O:11][C:13](=[O:15])[CH3:14])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C([O-])C(O)CO
Reactant: CCOC(C)=O
Reactant: CC(=O)Cl
Agent: [Li+]
Product: CC(=O)OCC(OC(C)=O)C(=O)O
Reaction time: 24 h

Procedure:
Acetyl chloride (500 ml) was added dropwise without stirring to the gummy like mass of lithium 2,3-dihyroxypropanoate (13) (171 g, 1.51 mole). The gummy like mass dissolved slowly and the mixture was left for 24 h at ambient temperature. Then the mixture was stirred and heated to reflux for 6 h. After cooling the mixture was diluted with ethyl acetate (700 ml) and filtered through a tight glass filter (por. G4). The filtrate was evaporated to a oil, which was dissolved in ethyl acetate (750 ml) and washed with water (2×70 ml, pH=2). After drying over magnesium sulfate and treatment with activated charcoal (1.5 g) the mixture was filtered. The filtrate was evaporated to a light orange coloured oil. Yield (crude) 218 g (75%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:4])=[O:3].CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(N(C)S(C)(=O)=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of methyl 3-[(methylsulfonyl)amino]-5-nitrobenzoate obtained in Reference Example 88.22 g (30 mmol), methyl iodide 2.0 mL (32 mmol), potassium carbonate 10.4 g (75 mmol) and acetone (250 mL) was stirred at room temperature for 16 hours. The mixture was filtered to remove the precipitates and the solvent was evaporated. To the residue was added water (150 mL) and the mixture was extracted twice with ethyl acetate (100 mL). After drying of the mixture on magnesium sulfate, the solvent was evaporated to give 8.55 g (29.7 mmol) of the title compound (yield: 99%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH2:33]O)[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]>>[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH2:33][N:8]3[C:6]4=[N:7][C:2]([F:1])=[CH:3][CH:4]=[C:5]4[N:10]=[C:9]3[CH2:11][CH2:12][CH3:13])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]
Reactant: C/C(C#N)=C1/c2ccc(CO)cc2COc2cc(F)ccc21
Reactant: CCCc1nc2ccc(F)nc2[nH]1
Product: CCCc1nc2ccc(F)nc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 42.3 %

Procedure:
[step 3] Using 5-fluoro-2-propyl-3H-imidazo[4,5-b]pyridine (47 mg, 0.262 mmol) obtained in step 2 and (E)-2-[3-fluoro-8-(hydroxymethyl)dibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (70 mg, 0.238 mmol) obtained in Reference Example 1, step 5, and in the same manner as in Reference Example 3E, the title compound (46 mg, 42%) was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].O[CH2:10][C@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1>>[C:1]([O:4][CH2:5][C:6]([O:8][CH2:10][C@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:36])([F:35])[F:37])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)O
Reactant: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Product: CC(=O)OCC(=O)OC[C@@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1

Procedure:
The title compound was synthesized by a condensation method similar to that of Step A of Example 3-1 using acetoxyacetic acid instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14.
Reaction SMILES: C1(P([C:25]2[CH:30]=[CH:29]C=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)CCO.C(O)C=C.N.[CH2:41]([NH:44][CH2:45][CH:46]=[CH2:47])[CH:42]=[CH2:43]>Cl[Pd]Cl.O>[CH2:41]([NH2:44])[CH:42]=[CH2:43].[CH2:41]([N:44]([CH2:29][CH:30]=[CH2:25])[CH2:45][CH:46]=[CH2:47])[CH:42]=[CH2:43]
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: C=CCNCC=C
Agent: Cl[Pd]Cl
Agent: N
Solvent: OCCCO
Solvent: C=CCO
Solvent: O
Product: C=CCN
Product: C=CCN(CC=C)CC=C
Reaction time: 2 h

Procedure:
To 1.8 mg (0.01 millimole) of PdCl2 was added 8.5 mg (0.02 millimole) of 1,4-bis(diphenylphosphino)butane, and 5.0 g of 1,3-propane-diol, 3.6 mg of water and 9.1 mg (0.01 millimole) of tetramethyl hydroxide were added and reaction between 8.4 g (145 millimoles) of allyl alcohol and 4.6 g (271 millimoles) of ammonia was carried out at 110° C. with stirring for 2 hours. As the products, there were obtained 0.20 g (3.5 millimoles) of monoallylamine, 0.78 (8.0 millimoles) of diallylamine and 0.92 g (6.7 millimoles) of triallylamine. The conversion based on allyl alcohol was 29.8%, and the selectivity was 91.7%.