Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=C(C#N)[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-:26].[K+].C[C:29]([CH3:31])=[O:30]>>[ClH:1].[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:31]([C:29]([OH:26])=[O:30])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CC(C)=O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Reaction time: 4 h

Procedure:
10-[1-(1-Pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile hydrochloride, L series (5 g) is added to a solution of potassium hydroxide (1.75 g) in glycol (30 cc), and the mixture is stirred for 4 hours under reflux. After cooling, the yellow solution obtained is diluted with acetone (75 cc) and a 3N solution (5 cc) of hydrochloric acid in ethyl ether, filtered and diluted again with acetone (75 cc) and a 3N solution (5 cc) of hydrochloric acid in ethyl ether. After seeding, crystallization is allowed to take place for 15 hours at a temperature in the region of 5° C. The solid obtained is drained, washed with ethyl ether (10 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. 10-[1-(1-Pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride, L series (2.9 g), is thereby obtained in the form of a light yellow solid, m.p. 200° -210° C. (melts forming a paste).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][O:9][C:8]1=[O:12])(=O)C.COCCC1CCOC1=O>[O-2].[Al+3].[O-2].[O-2].[Al+3].CO>[O:4]1[CH2:1][CH2:11][CH:7]([C:8]([O:9][CH3:10])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(=O)OCCC1CCOC1=O
Agent: COCCC1CCOC1=O
Agent: [Al+3]
Agent: [O-2]
Solvent: CO
Product: COC(=O)C1CCOCC1

Procedure:
A solution consisting of 37 wt % of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone, 19 wt % of 3-(2'-methoxyethyl)dihydro-2(3H)furanone, and 44 wt % of methanol, was passed over 140 g of aluminum oxide catalyst (1.5 mm extrudates) in a tubular reactor at a rate of 38 g per hour with the addition of 10 Lh of nitrogen, at a temperature of 250° C. The gaseous effluent was condensed in cold traps and analyzed by gas chromatography. 53 mol % of methyl tetrahydropyran-4-carboxylate was formed, plus 41 mol % of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone and 3 mol % of 5-oxaspiro[2.4 ]heptan-2-one. The conversion of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone was better than 99%.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][NH2:7].[Br:8][C:9]1[C:10](O[C:13](=[O:15])[CH:14]=1)=[O:11]>O>[Br:8][C:9]1[C:10](=[O:11])[NH:6][NH:7][C:13](=[O:15])[CH:14]=1
Reactant: NN
Reactant: O=C1C=C(Br)C(=O)O1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(Br)c(=O)[nH][nH]1
Temperature: 25 °C
Yield: 151 %

Procedure:
This was prepared by a slight variation on the method of Kasnar et al., Nucleosides & Nucleotides, (1994), 13(1-3), 459-79. Hydrazine sulphate salt (51 g) was suspended in water (250 ml), heated to reflux and bromomaleic anhydride (90.38 g) was added dropwise. The mixture was heated at reflux for 4 h then cooled to room temperature. The reaction was repeated with 29 g hydrazine sulphate, 53 g bromomaleic anhydride and 130 ml water. The precipitates were collected by filtration, washed with water and acetone and dried as a combined batch in vacuo to afford 4-bromo-1,2-dihydro-3,6-pyridazinedione as a white solid (113 g).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([F:16])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].[CH3:17][C:18]([CH3:21])([O-:20])[CH3:19].[K+]>CS(C)=O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:18]([O:20][C:13]1[C:12]([F:16])=[CH:11][C:3]([C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5])=[C:2]([F:1])[CH:14]=1)([CH3:21])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Yield: 96.7 %

Procedure:
To a solution of 2,4,5-trifluoro-N-(methylsulfonyl)benzamide (Preparation 16, 1.50 g, 5.92 mmol) in DMSO (10 mL) at room temperature was added potassium t-butoxide (1.46 g, 13.0 mmol). After 18 hours the reaction mixture was diluted with EtOAc (30 mL) and 10% aqueous citric acid solution (15 mL). The pH of the aqueous layer was checked to ensure it was acidic. The organic layer was separated and washed with 10% aqueous citric acid solution (15 mL) and brine (15 mL), dried over magnesium sulphate, filtered and evaporated to yield the title compound as a cream solid (1.76 g, 97%).
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].ON1C(=O)CCC1=O.C(=O)(SC)OC(OC(=O)C(C)C)C.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([O:50]O)=[O:49])[CH:43]=1>C(Cl)Cl.CCOCC>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:41][C:42]1[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=1)[C:48]([OH:50])=[O:49]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: CSC(=O)OC(C)OC(=O)C(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In an alternative synthesis of (10), N-hydroxysuccinimide (558 mg, 4.8 mmol) was added to a solution of compound (6) (500 mg, 2.4 mmol) in CH2Cl2 (10 mL) and the reaction mixture cooled to 0° C. m-Chloroperbenzoic acid (1.62 g, 7.2 mmol, commercial grade: 77% in water) was added over a period of 10 min and the mixture allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ether (50 mL) and washed with water (2×10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (10) together with m-chlorobenzoic acid. The crude product mixture was purified by column chromatography on silica gel, eluting with 4:6 EtOAc: hexane. Residual m-chlorobenzoic acid was removed by repeated crystallizations from a mixture of tert-butyl methyl ether and hexane, resulting in analytically pure product (66 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])[C:5](O)=[O:6].CO.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11]
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
BH3 (1M in THF, 250 mL, 250 mmol) was added dropwise to a cooled sol. of 3,5-dichloro-4-hydroxybenzoic acid (20 g, 96.6 mmol) in THF (200 mL) at 0° C. The resulting mixture was stirred at 0° C. for 15 min., and then at rt for 13 h. The milky mixture was cooled to 0° C., and MeOH (150 mL), then water (100 mL), were added dropwise. The mixture was further stirred at 0° C. for 15 min, and then at rt for 5 h. The mixture was then partially concentrated under reduced pressure. EtOAc (200 mL) and water (50 mL) were added to the residue, and the phases were shaken and separated. The aq. phase was further extracted with EtOAc. The combined org. extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by FC(CH2Cl2/CH3OH, 100:1) led to the title compound as a slightly beige solid (17.86 g, 96%). LC-MS: tR=0.69 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1.C1COCC1.O[Li].O.Cl>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.3 %

Procedure:
To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (8 g, 0.02 mol) in MeOH: THF (300 mL; 1:1) was added LiOH.H2O (5.21 g, 0.124 mol) and the mixture was stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo to obtain the crude compound. The crude material was acidified with HCl (IN), filtered and dried in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (7.0 g, 95%) as a solid.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([SH:7])[CH:2]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[Br:14]Br.S.[Na]>C(O)(=O)C.C(N(CC)CC)C>[Br:14][C:6]1[CH:5]=[CH:4][C:3]([S:7][CH2:11][CH2:10][C:9]([OH:13])=[O:12])=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1cccc(S)c1
Reactant: C=CC(=O)O
Reactant: BrBr
Agent: S
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1cc(SCCC(=O)O)ccc1Br
Temperature: 50 °C

Procedure:
A one-liter, three-necked flask was charged with 50 g (0.4 mol) of m-toluenethiol, 29 g (0.4 mol) of acrylic acid and 1.0 ml of triethylamine, and the mixture was allowed to react at 150° C. for 1 hour. After the reaction mixture was allowed to cool, 200 ml of acetic acid was added to the reaction mixture, and the mixture was heated up to 50° C. to form a complete solution. Then, 21 ml of bromine was gradually added over 30 minutes, and the mixture was further allowed to react at 50° to 60° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into 1.5 liters of a 1% sodium hydrogensulfide aqueous solution, and the formed solid was recovered by filtration and dried to give 110 g of 3-(4-bromo-3-methylphenylthio)-propionic acid as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[O:8]=[C:4]1[CH2:5][CH2:6][CH2:7][C:2]([NH:1][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NC1=CC(=O)CCC1
Product: CCOC(=O)C(=CNC1=CC(=O)CCC1)C(=O)OCC

Procedure:
By the method described in Japanese Patent Application No. 24956/1978, diethyl N-(3-oxo-1-cyclohexen-1-yl)-aminomethylenemalonate was prepared from 3-amino-2-cyclohexenone and diethyl ethoxymethylenemalonate. The product was cyclized under heat to form ethyl 4-hydroxy-5-oxo-5,6,7,8-tetrahydroquinonine-3-carboxylate, followed by hydrolysis. The resulting ethyl 4-hydroxy-5-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate (2.35 g) was suspended in 80 ml of dimethylformamide. The suspension was heated to 60° C., and 1.52 g of potassium carbonate and 1.54 g of ethyl iodide were added, and the mixture was stirred at 70° C. for 30 minutes. Further, 3.46 g of ethyl iodide was added, and the mixture was stirred for 1 hour. The insoluble matter was removed by filtration, and the mother liquor was concentrated to dryness. The product was extracted with chloroform, and the chloroform was distilled off. Methylene chloride was added to the residue, and the insoluble matter was collected by filtration. There was obtained 2.4 g of the captioned product as a light yellow powder. The nuclear magnetic resonance spectrum (DMSO-d6, 60 MC, TMS) had signals at δ1.2-1.5 (6H, m), 1.8-3.3 (6H, m), 4.0-4.5 (4H, m), and 8.4 (1H, s).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].O1CCOCC1.C(O)(=O)C>CCCCCC>[OH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:10]1[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: Nc1ccccc1O
Reactant: COC1CCC(OC)O1
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Oc1ccccc1-n1cccc1

Procedure:
A mixture of 2,5-dimethoxytetrahydrofuran (39.6 g), o-aminophenol (36 g), dioxane (300 ml), and glacial acetic acid (180 ml) are heated under reflux for 4 hr. The solvents are removed and the residue distributed between ethyl acetate and 5% NaHCO3. The organic phase is washed with water, dried (MgSO4), filtered, and evaporated. The dark oily residue is subjected to chromatography on 2 kg of silica and eluted with chloroform to afford an oil. After being covered with hexane and stored for several days, the oil solidifies giving the title compound, m.p. 52° - 54° C. (Reported m.p. by Artico, et al., cited above, 45° - 47° C).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)Cl)c1C
Yield: 91.6 %

Procedure:
2,3-dimethylbenzoic acid (35.0 g, 233 mmol) was heated to reflux temperature, in dry benzene (80 ml) containing thionyl chloride (45.0 g, 378 mmol) for five hours. The mixture was cooled, filtered and evaporated under reduced pressure to give 2,3-dimethylbenzoyl chloride (36.0 g, 92%) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1>P(O)(O)O.C1(C)C=CC=CC=1>[CH3:2][C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:6]=1[OH:15])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COc1ccc(CO)cc1
Agent: OP(O)O
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 2,4-di-t-butylphenol (41.2 g), phosphorous acid (2 drops) and toluene (5 ml) was heated to 180°-200° in a three-necked flask fitted with a Dean-Stark trap containing toluene. 4-Methoxybenzyl alcohol (27.6 g) was melted and added in a slow stream to the mixture during 45 min. Heating was continued for a further 15 min by which time the theoretical amount of water (3.6 ml) had distilled. The reaction mixture was then distilled under pressure to give a pale yellow oil which rapidly crystallized. Recrystalization from methanol yielded colorless needless, m.p. and mixed m.p. with authentic material, 84°-85°; yield 59.3 g (91%). Found: C,80.9;H,9.26; calc for C,22H30O2 :C,81.0;H,9.21); 1Hmmr spectrum: δ1.30,9H,S; δ1.38,9H,S; δ3.79,3H,S; δ3.83,2H,S; δ4.61,H,S; δ6.84,2H,D(J=8 Hz); δ7.03, 1H,D(J=2 Hz); δ7.14,2H,D(J=8 Hz); δ7.23,1H,D(J=2 Hz).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](N)[C:4]=2[CH2:3][O:2]1.[N+]([O-])([O-])=O.[Na+].[S:16](=[O:18])=[O:17].[ClH:19]>C(O)(=O)C.O.O.O.[Cu](Cl)Cl>[CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:16]([Cl:19])(=[O:18])=[O:17])[C:4]=2[CH2:3][O:2]1
Reactant: Nc1cccc2c1COC2
Reactant: O=S=O
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(Cl)c1cccc2c1COC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 22.1 g of the crude hydrochloride salt prepared in Example 2 in a mixture of 30 ml of concentrated hydrochloric acid and 30 ml acetic acid was cooled to 0°-5°. A solution of 6.2 g of sodium nitrate in 15 ml water was added dropwise at 0°-5°. The thick suspension was diluted with 19 ml of concentrated hydrochloric acid to facilitate stirring and 1.0 g of sodium nitrate was added; stirring was continued for 1 hour. The suspension of the diazonium salt was added portionwise at 0°-5° to a stirred mixture of 80 ml of acetic acid, 25 ml of sulfur dioxide and 1.6 g of copper (II) chloride dihydrate. The resulting pale green suspension was allowed to warm to ambient temperature and stirred for 4.5 hours. The yellow-green solution was poured into 1000 ml of cold water and the aqueous mixture extracted three times with 1-chlorobutane. The combined organic solution was washed three times with water and saturated sodium bicarbonate solution, then dried over magnesium sulfate, and filtered. Evaporation of the solvent in vacuo gave 9.8 g of 1,3-dihydrobenzo[c]furan-4-sulfonyl chloride as a yellow oil which crystallized on cooling and scratching, m.p. 40°-43°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(C=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(CNCc1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
To a solution of 4-fluorobenzylamine (2.00 mL, 17.6 mmol) and dimethoxyacetaldehyde (60% solution in water, 3.00 mL, 19.9 mmol) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (5.90 g, 26.4 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours, followed by the addition of saturated sodium bicarbonate (50 mL) and extraction with ethyl acetate (3×100 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography to afford N-(4-fluorobenzyl)-2,2-dimethoxyethanamine (2.70 g, 71%): 1H NMR (300 MHz, CDCl3) δ 7.24-7.19 (m, 2H), 6.97-6.89 (m, 2H), 4.43-4.39 (m, 1H), 3.70 (s, 2H), 3.30 (s, 6H), 2.67 (dd, J=5.4, 1.5 Hz, 2H); MS (ES+) m/z 214.3 (M+1).
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.[C:18](=[O:21])([O-])[O-].[K+].[K+]>CCOCC>[CH2:3]([N:10]([CH2:1][O:21][CH3:18])[CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CNCc1ccccc1
Reactant: C=O
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: COCN(Cc1ccccc1)C[Si](C)(C)C
Temperature: 0 °C

Procedure:
Into a round bottom 3-neck flask equipped with a nitrogen flow and a magnetic stirrer was added formaldehyde (74.000 mmol, 7.4000×10−2 mol) (as a 37% aqueous solution). The flask was cooled to 0° C. and N-benzyl-N-(trimethylsilyl)methylamine (10.000 g, 5.1716790×10−2 mol) was added dropwise with stirring. After stirring for 10 minutes at 0° C., methanol (6.000 mL, 0.14811874 mol) was added in one portion. Potassium carbonate (4.000 g, 2.8942408×10−2 mol) was added to the mixture to absorb the aqueous phase. The mixture was stirred for one hour, then the nonaqueous phase decanted, and then potassium carbonate (2.000 g, 1.4471204×10−2 mol) was added. The mixture was stirred at 25° C. for 12 hours. Ether is added to the mixture and the solution was dried over potassium carbonate, filterd and concentrated under reduced pressure. The residue is distilled at reduced pressure to give the product as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:28][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 73.1 %

Procedure:
In 100.4 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 22.7 g (0.1 mole) of L-phenylalanine methyl ester sulfate was added with stirring at 5°-10° C. Successively 17.6 g (0.21 mole) of sodium acetate was added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. Thereafter 87.1 g of water was added to the reaction mixture to adjust the concentration of organic carboxylic acid to 53.5% by weight. After cooling to 0°-5° C., precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 31.2 g (73.1% yield on L-phenylalanine methyl ester sulfate).
Reaction SMILES: Br.F[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([CH3:37])[CH:31]=1.CC1CCCO1>CN1C(=O)CCC1.O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:3]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=2[C:5]([NH:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[O:6])=[C:32]([CH3:37])[CH:31]=1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Reactant: Cc1cc(F)ccc1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a 50 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer was added 1-methyl-2-pyrrolidinone (NMP) (3.75 liters). The solution was stirred, 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide hydrobromide salt (1500.2 g, 3.94 moles, 1.0 eq) was added and chased with NMP (1 liter), and the jacket temperature was adjusted to 35° C. Potassium carbonate (1631.9 g, 11.8 moles, 3.0 eq, 325 mesh) was then added portionwise over 10 minutes, during which time the reaction temperature increased to 40° C. The resulting suspension was treated with a solution of 4-fluoro-2-methylphenol (5, 546.1 g, 4.33 moles, 1.1 eq, AK Scientific) in NMP (2.25 liters) with stirring, and the addition funnel was then rinsed with NMP (0.75 liters) to give an orange suspension. The jacket temperature was raised to 61° C. over 30 minutes and the suspension was stirred overnight under nitrogen, at which time the reaction was judged to be complete by HPLC analysis. To the reaction mixture was added 2-methyltetrahydrofuran (15 liters) and water (15 liters) and the mixture stirred until all solids dissolved. Stirring was stopped, the orange aqueous layer drained off, and the organic layer washed with water (7.5 liters) while stirring and a jacket temperature of ˜52° C.). The aqueous wash procedure was repeated 4 times (3×7.5 liter water washes, then 1×4.5 liter water wash). The resulting organic slurry was stirred at a jacket temperature of 50.8° C., and isopropyl acetate (6 liters, Sigma Aldrich) was added. The jacket temperature was ramped down to 20° C. over 30 minutes, and the slurry was stirred overnight before collecting the precipitated solid by filtration. The collected solid was returned to the reactor, slurried in isopropyl acetate with stirring for about 2 hours, then filtered, rinsed with isopropyl acetate (1.5 liters) and dried in vacuo at 65° C. to give 1253.1 g (78%) of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a) as an off-white solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1>CCOCC>[C:5]([NH:8][CH:9]1[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]1)(=[O:7])[CH3:6]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)NC1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (70 g, 0.686 mol) was added dropwis to an ice cooled solution of 4-Amino-2,2,6,6-Tetramethyl-piperidin (34.6 g. 0.221 mol) in ether (100 ml). After the addition was complete (about 1 h), the reaction mixture was stirred for 30 minutes at room temperature. The precipitated white product, 4-acetylamino-2,2,6,6-Tetramethyl-piperidin (55.6 g, 98%) was filtered off and washed with ether and air dried. m.p. 175° C. subl.