Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na:1].[N:2]1[C:10]([NH2:11])=[C:9]2[C:5]([N:6](C([C@@H]([C@H](CO)OCP(O)(O)=O)O)=O)[CH:7]=[N:8]2)=[N:4][CH:3]=1.N1C(N)=C2C(N([C:35]([CH2:37][C@H:38]([CH2:51][OH:52])[O:39][CH2:40][P:41]([O:47]C(C)C)([O:43]C(C)C)=[O:42])=[O:36])C=N2)=NC=1>>[Na:1].[N:2]1([C:35]([CH2:37][C@H:38]([CH2:51][OH:52])[O:39][CH2:40][P:41]([OH:43])([OH:47])=[O:42])=[O:36])[C:10]([NH2:11])=[C:9]2[C:5](=[N:6][CH:7]=[N:8]2)[N:4]=[CH:3]1
Reactant: Nc1ncnc2c1ncn2C(=O)[C@H](O)[C@H](CO)OCP(=O)(O)O
Reactant: CC(C)OP(=O)(CO[C@@H](CO)CC(=O)n1cnc2c(N)ncnc21)OC(C)C
Agent: [Na]
Product: Nc1c2ncnc-2ncn1C(=O)C[C@H](CO)OCP(=O)(O)O
Yield: 43 %

Procedure:
This compound was prepared as described for 3a, using 19 (70 mg, 0.23 mmol) as a starting material. Compound 3e (38 mg, 0.11 mmol) was obtained as a colorless solid, in 43% yield, which was characterized as follows:
Reaction SMILES: [SH:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[ClH:21].[CH3:12][C:11]1[C:2]([S:1][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: ClCc1ccccn1
Reactant: Cc1nc2ccccc2nc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc2ccccc2nc1SCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
In a mixture of 70 ml of acetone and 7 ml of water were suspended 1.9 g of 2-mercapto-3-methylquinoxaline and 1.95 g of 2-picolyl chloride hydrochloride. To the suspension was added 4.0 g of potassium carbonate. The resulting mixture was stirred at room temperature for 1 hr., and the solvent was removed under reduced pressure. The residue was extracted with chloroform after addition of chloroform and water. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residue was dissolved in 20 ml of ethanol. To the solution under chilling with ice were successively added 3.2 ml of 5.2N ethanolic hydrochloric acid and ether to precipitate crystals. The crystals were collected by filtration to give 2.25 g of 3-methyl-2-(2-pyridylmethylthio)quinoxaline hydrochloride as a violet crystalline powder.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)=O.[CH3:11][O:12][NH3+:13].[Cl-].[OH-].[Na+]>C(O)C>[CH3:11][O:12][N:13]=[CH:1][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: O=Cc1ncn2ccsc12
Reactant: CO[NH3+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=Cc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 249 mg of 7-formylimidazo[5,1-b]thiazole in 10 ml of ethanol were added 219 mg of o-methylhydroxylamine hydrochloride and 2.67 ml of a 1N sodium hydroxide solution. The reaction mixture was stirred at room temperature for 20 hours, concentrated, then diluted with 50 ml of water, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=1:1) to give 7-methoxyiminomethylimidazo[5,1-b]thiazole (low polar geometrical isomer) in a yield of 164 mg from the low polarity fraction.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[NH:7][CH2:6]1)=[O:4].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CNC(=O)C1
Reactant: BrCCCn1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(=O)N(CCCn2cccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-Oxo-pyrrolidine-3-carboxylic acid methyl ester (1 eq.) in dry DMF is added NaH (1.1 eq.) followed by 1-(3-bromo-propyl)-1H-pyrrole (1 eq.). The reaction mixture is stirred at room temperature overnight. Purification is by normal phase chromatography to yield 5-Oxo-1-(3-pyrrol-1-yl-propyl)-pyrrolidine-3-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH2:15]([N:19]=[C:20]=[O:21])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH2:15]([NH:19][C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:21])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN=C=O
Reactant: NCCCCCCCCCCCCN
Solvent: CCOCC
Product: CCCCNC(=O)NCCCCCCCCCCCCN

Procedure:
22 grams (.110 mole) of 1,12-diaminododecane in 300 cc ether was reacted with 5.0 g (0.0505 mole) Butyl isocyanate, as in Example 2. The precipitate is filtered, washed, and recrystallized from 250 cc alcohol containing 50 cc water. Recovered 7.8 grams. Chilled mother liquor, thereby recovering a second batch of crystals which combined with the first precipitate to give a total of 12.1 grams having a melting point of 97°C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:10]2)=[CH:5][CH:4]=1.O1CCCC1.O.[Li+].[OH-]>CO>[CH3:28][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)=[CH:26][CH:27]=1
Reactant: CN(C)c1ccc(CCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(CCN2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-(4-dimethylaminophenethyl)-3-(4-nitrobenzoyloxy) pyrrolidine (1.00 g, 2.70 mmol) was dissolved in methanol (20 ml), tetrahydrofuran (20 ml) and water (10 ml). 4M-LiOH (3 ml) was added dropwise in the obtained solution, and they were stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was distributed in water and ether. The organic layer was dried and the solvent was evaporated under reduced pressure to obtain (S)-1-(4-dimethylaminophenethyl)-3-hydroxypyrrolidine in the form of a light yellow solid (320 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26]Br)=[CH:19][CH:18]=3)[C:6]=2[CH:29]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])=[CH:19][CH:18]=3)[C:6]=2[CH:29]=1
Reactant: O=C(c1ccc(OCCCBr)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1

Procedure:
5-Chloro-3-[4-(3-bromopropoxy)benzoyl]-2-phenylbenzofuran (2.0 g., 4.3 mmol.) is refluxed in 100 ml. of ethanol containing 9 ml. of diethylamine for 10 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in ether. The ether solution is washed with aqueous sodium hydroxide and water then concentrated to give the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5[CH:29]=O)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[NH2:32][OH:33]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:26])[CH3:27])=[C:19]5/[CH:29]=[N:32]\[OH:33])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C=O
Reactant: NO
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1/C=N\O
Reaction time: 48 h
Yield: 77.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-1H-indol-5-yl)cyclopropanecarboxamide (100 mg, 0.25 mmol) in dichloromethane (5 mL) was added hydroxylamine hydrochloride (21 mg, 0.30 mmol). After stirring for 48 h, the mixture was evaporated to dryness and purified by column chromatography (0-100% ethyl acetate/hexanes) to yield (Z)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-((hydroxyimino)methyl)-1H-indol-5-yl)cyclopropanecarboxamide (81 mg, 77%). ESI-MS m/z calc. 419.5, found 420.5 (M+1)+; retention time 3.42 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 0.5H), 10.55 (s, 0.5H), 8.56-8.50 (m, 2H), 8.02 (m, 1H), 7.24-7.22 (m, 1H), 7.12-7.10 (m, 1H), 7.03 (m, 1H), 6.96-6.90 (m, 2H), 6.03 (s, 2H), 1.43 (s, 9H), 1.40-1.38 (m, 2H), 1.04-1.01 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:13]([O:11][C:9]1[CH:8]=[CH:7][C:6]([OH:12])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)c1cc(O)ccc1O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(OC(=O)c2ccccc2)ccc1O

Procedure:
Using 6.65 g of 2-tert-butyl-1,4-dihydroxybenzene, 4.6 ml of benzoyl chloride and 200 ml of pyridine, reaction and workup carried out as in Reference Example gave 9.35 g of 4-benzoyloxy-2-tert-butylphenol as white crystals, m.p. 120-121° C. Using. 9.35 g of the white crystals, 1,47 g of sodium hydride, 6.27 g of benzyl bromide and 40 ml of DMF, reaction and workup carried out as in Example 12 gave 6.07 g of yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:18]1([C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([O:39][CH3:40])[C:33](N(OC)C)=[O:34])=[CH:28][CH:27]=3)=[N:23][N:22]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([O:39][CH3:40])[C:33]([C:15]4[O:14][C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[CH:17][CH:16]=4)=[O:34])=[CH:28][CH:27]=3)=[N:23][N:22]=2)[CH2:19][CH2:20]1
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C3CC3)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C5CC5)o4)cc3)o2)cc(OC)c1OC

Procedure:
2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanone was prepared from 2-(3,4,5-trimethoxyphenyl)furan and 2-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.129 g, 42% yield). MS: m/z 491.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[NH2:7][CH2:8][CH2:9][CH2:10][OH:11]>>[OH:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: CC(C)(O)C#N
Reactant: NCCCO
Product: CC(C)(C#N)NCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a neat solution of acetone cyanohydrin (930 mg, 10.9 mmol) at 0° C. was slowly added the 3-amino-1-propanol (861 mg, 11.5 mmol). The resulting solution was stirred at room temperature for 3 hrs and then evaporated under reduce pressure to give the desired compound 3 (1.1 g, 71%) which was directly used for the next step without purification.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH2:15]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33])[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>COCCOC>[CH2:15]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:33])[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)C(C(=O)OCC)C(=O)OCC

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 2-(1-tetradec-4-enylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield diethyl 2-(1-tetradec-4-enylamino)benzoylmalonate.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>>[F:14][C:15]([F:22])([F:21])[C:16]([N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)=[O:17]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CCOC(=O)C(F)(F)F
Product: O=C(N1CCC(O)(c2ccccc2)CC1)C(F)(F)F

Procedure:
The starting material is prepared as follows: The mixture of 25 g of 4-hydroxy-4-phenylpiperidine and 50 ml of ethyl trifluoroacetate is refluxed overnight and evaporated. The residue is taken up in benzene, the solution washed with 1N hydrochloric acid, dried and evaporated. The residue is recrystallized from ethyl acetate-petroleum ether, to yield the 1-trifluoroacetyl-4-hydroxy-4-phenylpiperidine melting at 123°-125°.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([Mg]Cl)[CH2:12][CH3:13]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][CH3:13]
Reactant: CCC[Mg]Cl
Reactant: BrC1=Cc2ccccc2C1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Product: CCCC1=Cc2ccccc2C1
Yield: 99.8 %

Procedure:
To an oven-dried 250 mL round bottom flask containing a magnetic stir bar and equipped with a reflux condenser and vacuum adapter was added 2-bromoindene (15.0 g, 76.9 mmol) and Ni(dppp)Cl2 (0.42 g, 0.77 mmol) (dppp=1,3-bis(diphenyl-phosphino)propane). The flask was stoppered and evacuated. Deoxygenated anhydrous diethyl ether (150 mL) was added via cannula under argon at -78° C. The reaction was stirred under argon without exterior cooling as 42 mL of a 2.0 M propylmagnesium chloride in ether solution was added via syringe (84 mmol propylmagnesium chloride). The reaction was placed in a dry ice/acetone bath when a vigorous reflux was achieved. The dry ice/acetone bath was removed after 2 minutes, and the reaction was stirred at room temperature under argon for 90 minutes. The reaction was carefully poured into water and 10 weight percent aqueous HCl was added until the mixture was acidic. The mixture was extracted with ether (3×200 mL), and the combined organic layers were washed with water (1×250 mL), with aqueous sodium bicarbonate (1×250 mL), and with aqueous saturated sodium chloride solution (1×250 mL). Drying over anhydrous sodium sulfate followed by filtration and solvent removal yielded 12.14 g (99.7 percent) of the desired product.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([F:17])[C:4]([CH2:8][N:9]2[N:13]=[N:12][C:11]([C:14](N)=[O:15])=[CH:10]2)=[C:5]([F:7])[CH:6]=1.N(CC1C(F)=CC=CC=1F)=[N+]=[N-].[C:30](OC)(=[O:33])C#C>>[F:17][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([F:7])[C:4]=1[CH2:8][N:9]1[CH:10]=[C:11]([C:14]([O:33][CH3:30])=[O:15])[N:12]=[N:13]1
Reactant: C#CC(=O)OC
Reactant: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Agent: [N-]=[N+]=NCc1c(F)cccc1F
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
WO 2010/043849 describes the process for the preparation of Rufinamide as shown in scheme III below, which comprises the reaction of 2-(azidomethyl)-1, 3-difluorobenzene with methyl propiolate to obtain methyl 1-(2,6-difluorobenzyl)-1H-1,2,3,-triazole-4-carboxylate and which is reacted with ammonia to yield Rufinamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:10]=[C:9]2[CH3:19])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[Cl-].[CH:26]1([Zn+])[CH2:28][CH2:27]1>C1COCC1>[CH:26]1([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:10]=[C:9]3[CH3:19])=[CH:4][N:3]=2)[CH2:28][CH2:27]1
Reactant: Cc1nc(C#C[Si](C)(C)C)cn1-c1ccc(Cl)nc1
Reactant: [Zn+]C1CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C#C[Si](C)(C)C)cn1-c1ccc(C2CC2)nc1

Procedure:
2-Chloro-5-(2-methyl-4-trimethylsilanylethynyl-imidazol-1-yl)-pyridine (425 mg, 1.47 mmol) were dissolved in 0.4M cyclopropylzinc chloride in THF (7.33 mL, 0.4M in THF) and tetrakis(triphenylphosphin)palladium (34 mg, 0.03 mmol) were added. The reaction mixture was refluxed for 16 hrs and poured into 50 mL sat. sodium bicarbonate solution. The mixture and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->1:1 gradient) and the desired product was obtained as a light yellow solid (395 mg, 91%), MS: m/e=296.2 (M+H+).
Reaction SMILES: C=C1OCOC1=O.C1CC=CC=1.[OH:13][C:14]1([C:21]([OH:23])=[O:22])[CH2:19][CH:18]2[CH2:20][C:15]1=[CH:16][CH2:17]2>>[OH:13][C:14]1([C:21]([OH:23])=[O:22])[CH2:19][CH:18]2[CH2:20][CH:15]1[CH2:16][CH2:17]2
Reactant: O=C(O)C1(O)CC2CC=C1C2
Agent: C1=CCC=C1
Agent: C=C1OCOC1=O
Product: O=C(O)C1(O)CC2CCC1C2

Procedure:
An optically active 5-methylenedioxolan-4-one derivative is subjected to Diels-Alder reaction with cyclopentadiene, and the resulting Diels-Alder reaction product is hydrolyzed to convert it into an optically active 2-hydroxynorbornene-2-carboxylic acid, which is then subjected to catalytic hydrogenation to form an optically active 2-hydroxynorbornane-2-carboxylic acid. The hydroxycarboxylic acid is subjected to oxidative decarboxylation to obtain an optically active 2-norbornanone.
Reaction SMILES: [CH2:1]([C:8]1[O:14][CH:13]2[CH:10]([C:11](=[O:35])[N:12]2[CH:15]([C:32]([CH3:34])=[CH2:33])[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:36].ClCl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(Cl)(Cl)(Cl)Cl.CC(C)=O>[CH2:1]([C:8]1[O:14][CH:13]2[CH:10]([C:11](=[O:35])[N:12]2[CH:15]([C:32]([CH2:34][Cl:36])=[CH2:33])[C:16]([O:18][CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)OC21
Agent: ClCl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: C=C(CCl)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)OC21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(Step 1) To a solution of diphenylmethyl 2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo[3.2.0]hept-2-en-6-yl)-3-methyl-3-butenoate (4.6 g) in ethyl acetate (70 ml) are added 2.74 M-solution of hydrochloric acid in ethyl acetate (3.8 ml) and 1.47 M-solution of chlorine in carbon tetrachloride (12 ml), and the mixture is stirred at room temperature for 15 minutes. Then, aqueous 5% sodium thiosulfate (80 ml), sodium hydrogen-carbonate (3.4 g) and acetone (240 g) are added to the reaction mixture, and the combined solution is kept at room temperature for 2.5 hours. The product is isolated by extracting with ethyl acetate, drying over sodium sulfate, and evaporating to yield diphenylmethyl 2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo[3.2.0]hept-2-en-6-yl)-3-chloromethyl-3-butenoate (3.33 g), mp. 82°-83° C.
Reaction SMILES: Cl[C:2]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[Cl:11])=[O:3].[CH3:12][C:13]([C:25]([N-:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[NH2:14].C(N(CC)CC)C>C1COCC1>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C:13]([NH:14][C:2](=[O:3])[O:4][C@@H:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]2[Cl:11])([CH3:12])[C:25](=[O:26])[NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:17]1
Reactant: O=C(Cl)O[C@@H]1CCCC[C@H]1Cl
Reactant: CC(N)(Cc1c[nH]c2ccccc12)C(=O)[N-]CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)O[C@@H]1CCCC[C@H]1Cl)C(=O)NCCc1ccccc1
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of trans(±)-2-chlorocyclohexyl chloroformate (0.16 g, 0.75 mmol) in anhydrous THF (5 mL) at room temperature was added dropwise a solution of α-methyl-DL- tryptophylphenethylamide (0.23 g, 0.7 mmol) in THF (5 mL), followed by a solution of triethylamine (0.07 g, 0.7 mmol) in THF (5 mL). The reaction was complete after 30 minutes by thin layer chromatographic analysis. The solvent was removed in vacuo and the residue taken up in ethyl acetate (30 mL) and washed successively with 1M aqueous citric acid (2×20 mL), saturated NaHCO3 solution (2×20 mL), 1M NaOH solution (20 mL) and water (4×20 mL). The organic phase was dried over MgSO4 and filtered. Removal of the solvent by vacuum distillation gave the title compound (0.273 g, 81%), a white solid crystallized from ether-hexane, mp 69°-78° C. (ether-hexane); IR (film) 1709 and 1656 cm-1 ; NMR (CDCl3) δ1.2-1.4 (3H, m), 1.54 (3H, s), 1.6-1.8 (3H, m), 2.03-2.23 (2H, m), 2.63-2.69 (2H, m), 3.2-3.5 (4H, m), 3.72-3.79 (1H, m), 4.67-4.73 (1H, m), 5.23 (1H, br.s), 6.1-6.2 (1H, m), 7.0-7.6 (10H, m), 8.08 (1H, br.s); Anal. (C27H32N3O3Cl), C, H, Cl, N.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[O:9]1[CH2:10][CH2:11][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]1=2
Reactant: COC(=O)C1=Cc2ccccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1=Cc2ccccc2OCC1
Reaction time: 2 h
Yield: 109.5 %

Procedure:
2,3-Dihydro-benzo[b]oxepine-4-carboxylic acid methyl ester (2.4 mmol) was dissolved in methanol. 5 ml of 2 mol/l sodiumhydroxide was added and the solution was stirred for two hours. The solvent was removed in vacuo. 2 mol/l hydrochloric acid were added and the solvent again removed in vacuo. The residue was extracted by diethylether. Evaporation of the solvent yielded 0.5 g of 2,3-Dihydro-benzo[b]oxepine-4-carboxylic acid. LC-MS: 1.8 min, 191.2 (MH+)