Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[C:10]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][N:9]=2)=[CH:21][CH:20]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: N#Cc1ccnc(Cl)c1
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cc(C#N)ccn2)cc1
Yield: 77.6 %

Procedure:
Using a method similar to Example 381, Part A, using 2-chloroisonicotinonitrile (0.500 g, 3.61 mmol) and [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (Example 377, Part A) (0.856 g, 3.61 mmol) gives the title compound (0.947, 77.6%): MS ES+ 340.2 (M+H)+, base peak MS ES+ 284.0 (M+2H—C(CH3)3))+; TLC [silica gel 60 F254, 40% ethyl acetate in hexanes] Rf=0.30.
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[CH:3][CH:4]1[C:6]([CH3:8])([CH3:7])[C:5]1(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl-].[Na+].CS(C)=O>O>[Cl:1][C:2]([Cl:19])=[CH:3][CH:4]1[C:6]([CH3:8])([CH3:7])[CH:5]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of ethyl 2-(2,2-dichlorovinyl)-3,3-dimethyl-1-ethoxycarbonylcyclopropane carboxylate (5.0 g.), sodium chloride (0.95 g.), and `wet` dimethylsulphoxide (6.0 ml.) was heated at a temperature of 175° to 180° C. under a nitrogen atmosphere for a period of 6 hours, after which it was cooled to the ambient temperature poured into water and extracted with petroleum ether (boiling range 60° to 80° C.). The extracts were dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent to yield a residue comprising about 60% of the cis-isomer and 40% of the trans-isomer of ethyl 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane carboxylate in about 80% yield, identification of which was confirmed by comparison with authentic samples using infra-red spectroscopy and gas-liquid chromatography.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[CH:1]1([C:7]([C:13]2[CH:14]=[CH:15][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
42.6 g (0.291 mol) of cyclohexanecarbonyl chloride and then 30 g (0.277 mol) of anisole are added dropwise at room temperature to a suspension of 44.4 g (0.33 mol) of aluminium chloride in 120 ml of dichloroethane. The reaction mixture is stirred for 1 h and allowed to stand overnight. For working up, the mixture is poured into ice-water and the aqueous phase is extracted with dichloromethane. The organic phase is washed with 1N NaOH and water, dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:13][CH2:14][C:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: O=C1CCc2cccc(O)c2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCc2c(C(=O)CCl)ccc(O)c2N1
Temperature: 0 °C
Yield: 22.4 %

Procedure:
24.3 g of 8-hydroxy-3,4-dihydrocarbostyril (VII) and 68 g of chloroacetyl chloride were added to 130 ml of carbon disulfide, and 200 g of aluminum chloride was added slowly to the mixture while stirring and cooling in ice-water. The mixture was stirred for 6 hours at a temperature of 60° to 70°C and carbon disulfide was distilled off. The resulting residue was poured into 500 ml of ice-water. The precipitated crystals were filtered, washed with water and recrystallized twice from methanol to give 8.0 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril (IV) as light yellow crystals having a melting point of 189° to 191°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Br:10]Br>CN(C=O)C>[Br:10][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[OH:9]
Reactant: COc1ccc(O)cc1
Reactant: BrBr
Solvent: CN(C)C=O
Product: COc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-methoxyphenol (13.00 g, 104.84 mmol) in DMF (50 mL) was added bromine (5.40 mL, 104.84 mmol) at 0° C. The reaction was allowed to warm to room temperature. After stirring for 2 h the reaction was quenched with water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 21.28 g of the crude title compound as a dark oil: 1H NMR (250 MHz, CDCl3) d 7.49 (b, 1H), 6.96 (d, 1H), 6.72-6.62 (m, 2H), 3.71 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>C(O)C>[Cl:25][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixed solution of 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (12.02 g (56.9 mmol)) and toluene (96.0 ml) was added dropwise thionyl chloride (8.11 g (68.2 mmol)), so that the internal temperature did not exceed 25° C., which was stirred for about 90 minutes at room temperature. Ethanol (24.0 ml) was added to this mixed solution to obtain a 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine solution.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C-]#[N:19].[C-]#N.[Na+]>>[C:11]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)([CH3:9])[CH3:10])#[N:19]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: CC(C)(C#N)c1ccc(O)cc1
Temperature: 185 °C

Procedure:
A process wherein a solventless mixture of Bisphenol A and cyanide ion in the form of sodium cyanide is heated in a closed vessel to about 185° C. and maintained at that temperature for about 20 hours to produce 4-(1-cyano-1-methylethyl)phenol with a conversion of about 100 percent and a selectivity of about 80 percent based on Bisphenol A.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: Cc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: BrCc1ccc2nccnc2c1
Temperature: 85 °C

Procedure:
In a 100 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolved together with N-bromosuccinimide (2.32, 13.0 mmol) and benzoyl peroxide (0.15 g, 0.62 mml) in 31 g of chlorobenzene. The mixture was heated up to 85° C. to give a pale yellow solution that slowly turned red. The solution was maintained at 85° C. for two hours to give a red solution of 6-bromomethyl-quinoxaline. The solution was then cooled down to room temperature with the formation of a precipitate mainly composed of succinimide. The solution was then mixed with an equal volume (˜31 ml) of pentane to ease the precipitation of succinimides (NHS as well as any unreacted NBS). After filtration, the orange solid obtained (1.4 g) was extracted few times with pentane (4 times, 50 ml each) to recover any remaining 6-bromomethyl-quinoxaline. The extracts were combined with the yellow solution of bromomethyl-quinoxaline and vacuum dried to give a yellow solid (1.92 g) that was suspended in an alkaline solution prepared by dissolving 2.0 g of sodium hydroxide pellets in 30 g of water. The catalyst (5% Pd/C) was added to the alkaline mixture (0.2 g) and the suspension was heated up to 85-95° C. and sparged with air for 48 hours. The black suspension was filtered to give an amber solution that was neutralized with dilute sulfuric acid to give a yellow powder (1.28 g, 85% yield) that precipitated from solution (6-quinoxaline-carboxylic acid).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.[CH2:18](O)[CH3:19]>>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1ccc(O)cc1

Procedure:
Sulfuric acid (230 g) was dropped under stirring for 10 minutes to an ethanol solution (1500 mL) of 3-(4-hydroxyphenyl)propionic acid (1150 g), and refluxed successively for 5 hours. The reaction mixture was concentrated and the obtained concentrated solution was poured into water (1,000 mL) and stirred with addition of ethyl acetate. After separation of the solution, an ethyl acetate layer was neutralized with an aqueous solution of a saturated sodium carbonate, washed with a small amount of water and then dried over anhydrous magnesium sulfate. Ethyl acetate and unreactcd ingredients were distilled off from the ethyl acetate layer to obtain concentrates (1,400 g). The concentrates were purified by distillation under a reduced pressure to obtain ethyl 3-(4-hydroxyphenyl)propionate (1,144 g). The boiling point was 160° C./4.0 hPa.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][C:7](=[O:31])[C:6]=2[CH:32]=1.O.[BH4-].[Na+].Cl>C(O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][CH:7]([OH:31])[C:6]=2[CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (2 gm.) was suspended in n-propanol (80 ml) & water (12 ml) and then added sodium borohydride (0.253 gm.) at 35° C. and the reaction mixture was stirred for 1 hr. To the reaction mixture was added hydrochloric acid (12 ml). Than the reaction mixture was stirred for 1 hour. The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (1.65 gm).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)C>ClCCl>[CH2:16]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCBr
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOc1ccccc1O
Yield: 28.8 %

Procedure:
Catechol (35.0 g, 0.32 mol), potassium carbonate (109.0 g, 0.79 mol) and 1-bromohexane (52.5 g, 0.32 mol) were added to ethanol (300 ml) and heated under reflux for 48 h. After cooling, dichloromethane (300 ml) was added and the solid residues removed by filtration. The solvents were then removed in vacuo and the crude product was purified by column chromatography on silica gel to give title compound (17.9 g, 29%) as a colourless liquid. Found: C, 73.90; H, 9.20. C12H18O2 requires C, 74.19; H, 9.34. δH (CHCl3) 6.95-6.83 (m, 4H, ArH), 5.66 (s, 1H, OH), 4.04 (t, J 7, 2H, ArOCH2), 1.89-1.79 (m, 2H, ArOCH2CH), 1.55-1.35 (m, 6H, CH2), 0.95 (t, J 7, 3H, CH2CH3). MS (FAB), 194 (M+, 100%), 110 (45%), 95 (7%), 83 (12%), 69 (9%), 55 (18%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CS(C)=O>[C:10]1([S:16]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C
Yield: 378.7 %

Procedure:
A mixture of 4-fluorobenzaldehyde (6 g, 48 mmol), sodium benzenesulfinate (7.5 g, 4.6 mmol), and dimethylsulfoxide (30 mL) was heated at 100° C. for 20 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated to give a white solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was purified using flash chromatography (Analogix SuperFlash™ column, 15%-40% ethyl acetate in hexanes) to give 4.29 g (41%) of 4-(benzenesulfonyl)-benzaldehyde as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[C@@H:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2.Br>C(O)(=O)C>[C:27]1([C@H:8]2[CH2:7][CH2:6][C:5]3[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11][C:10]=3[C@H:9]2[C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 100 °C

Procedure:
A mixture of cis-1-[2-[4-(6-methoxy-2-phenyl-1,2,3,4 tetrahydronaphthalen-1-yl)phenoxy] ethyl}pyrrolidine (12 g, 28 mmol), acetic acid (75 mL), and 48% HBr (75 mL) was heated at 100° C. for 15 h. The solution was cooled and the resulting white precipitate was collected by filtration. The hydrobromide salt (9.6 g, 69%) was dissolved in CHCl3/MeOH and was stirred with saturated NaHCO3 (aq). The layers were separated and the aqueous layer was further extracted with CHCl3/MeOH. The combined organic layers were dried (MgSO4), filtered, and concentrated to yield product as an off-white foam.
Reaction SMILES: C([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:6]=2[CH:5]=1)(O)=O.N1C2C(=CC=CC=2)C=CC=1>C(OC(C)C)(C)C.[Cu]>[Cl:13][C:12]1[C:6]2[CH:5]=[CH:4][S:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Agent: [Cu]
Solvent: CC(C)OC(C)C
Solvent: c1ccc2ncccc2c1
Product: Clc1cccc2sccc12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 2-carboxy-4-chlorobenzo[b]thiophene (7.24 g), quinoline (36 ml), and copper powder (1.45 g) was stirred at 145 to 155° C. for 1 hour. After the mixture was allowed to cool to room temperature, the mixture was diluted with diisopropyl ether (145 ml), and insoluble materials were removed by filtration. The filtrate was washed with dilute hydrochloric acid (40 ml of 35% concentrated hydrochloric acid+200 ml of cold water) and with water, then dried over magnesium sulfate, and concentrated. A trace amount of precipitates was further removed from the concentrate by filtration to obtain 4-chlorobenzo[b]thiophene.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH:6]1[CH:7]=[C:8]2[CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=3[C:13](=[O:14])[C:9]2=[C:10]([OH:12])[CH:11]=1>C1C=CC=CC=1.N1C=CC=CC=1>[OH:21][C:20]1[C:15]2[C:13](=[O:14])[C:9]3[C:8](=[CH:7][CH:6]=[CH:11][C:10]=3[OH:12])[CH:22]([C:1](=[O:4])[CH2:2][CH3:3])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Reactant: CCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21

Procedure:
24.9 g (0,269 moles) propionyl chloride is added, while stirring, to a mixture containing 50.9 g (0,225 moles) anthralin in 1575 ml of benzene and 27.5 ml of pyridine. The reaction mixture is cooked using a return condenser for 20 hours while stirring. The solution is filtered and the filtrate is evaporated dry under a lowered pressure. The residue is crystallized out from acetic acid. Yield 27.6 g (43.5% of the theoretical). M.p.=149°-154° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]O.C(O)(=O)CC>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Solvent: O
Solvent: CCC(=O)O
Product: CC(C)=CCCC(C)=CC=O
Temperature: 130 °C

Procedure:
A mixture of 100 parts of 3,3-dimethylacrolein, 200 parts of prenol and 150 parts of propionic acid is heated for three hours at 130°C, the water formed being distilled out azeotropically. The reaction product is worked up. 24 parts of citral is obtained. This is equivalent to a yield of 51°% of theory at a conversion of 26% (based on 3,3-dimethylacrolein).
Reaction SMILES: N#N.[F:3][C:4]1[C:9]([C:10]2[CH2:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH:15]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.[ClH:23].CC(O)C>[Pd].CCO>[ClH:23].[ClH:23].[F:3][C:4]1[C:9]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1C=C(c2cccnc2F)CCC1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CCO
Solvent: CC(C)O
Product: Fc1ncccc1C1CCCNC1
Reaction time: 0.08 h

Procedure:
To a N2 purged RBF containing tert-butyl 5-(2-fluoropyridin-3-yl)-3,4-dihydropyridine-1(2H)-carboxylate (673 mg, 2.418 mmol) was added 10% Pd/C (50 mg, 0.470 mmol) and EtOH (15 mL). After stirring for 5 minutes, 5N HCl in iPrOH (4.0 mL, 20.00 mmol) was added and the flask capped with a balloon of H2. After 16 hours, LC-MS shows ˜30% conversion. The balloon was refilled. After a further 5 days, LC-MS shows complete consumption of starting material. The reaction was filtered through a celite cartridge and the cartridge rinsed with DCM:10% EtOH (50 mL). The filtrate was concentrated in vacuo to give 2-fluoro-3-(piperidin-3-yl)pyridine dihydrochloride as a yellow foam. The material was carried forward without further purification.
Reaction SMILES: [Cl:1][C:2]([Cl:24])([Cl:23])[CH2:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)CCl>[Cl:24][C:2]([Cl:1])([Cl:23])[CH2:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:34](=[O:35])[CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:37])([F:25])[F:38])=[CH:32][CH:31]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CSc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1ccc(C(F)(F)F)cc1)OCc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
2-(4-Hydroxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (70 mg, 0.173 mmol) was added to a stirred mixture of (4-trifluoromethyl-phenyl) acetic acid (39 mg, 0.190 mmol), EDC×HCl (50 mg, 0.259 mmol), DMAP (2.1 mg, 0.017 mmol) and DCM (3 mL). The reaction mixture was stirred at rt overnight, according to LC-MS analysis the reaction was uncomplete. Additional EDC×HCl (50 mg, 0.259 mmol), DMAP (2.1 mg, 0.017 mmol) and 2-(4-hydroxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (70 mg, 0.173 mmol) were added and the mixture was stirred for 3 h. More DCM was added and the mixture was washed with 0.25M HCl, the organic portion was dried through a phase separator and concentrated to give the titled compound (112 mg, 100%); Mass spectrum: M−H+590.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
4-Bromo-3-fluorobenzoic acid, as described above, (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].N.[H][H]>[Ni].C(O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:8](=[O:9])[NH:20][CH2:19]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Combine 3-cyano-3-phenylpentanedioic acid diethyl ester (243 g, 0.84 mol) and ethanol (2.5 L), concentrated aqueous ammonia (325 mL), and Raney nickel (250 g, prewashed three times with water) in a two gallon autoclave. Charge with 200 psi of hydrogen. Heat to 50° C. After 24 hours, vent the reactor and purge with nitrogen. Filter the reaction mixture through a celite pad and rinse the solids with ethanol (1 L). Evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]1[O:17][N:16]=[CH:15][C:14]=1[C:18](Cl)=[O:19]>C([O-])(O)=O.[Na+].CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH3:12][C:13]1[O:17][N:16]=[CH:15][C:14]=1[C:18]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:9][CH:8]=1)=[O:19]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1oncc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
4-Trifluoromethylaniline (5.75 g, 35.7 mm) was dissolved in a mixture of NaHCO3 (3.16 g, 37.6 mm), N,N-dimethylacetamide (0.7 ml, 7.5 mm) and toluene (70 ml). The mixture was warmed to 40° C. and 5-methylisoxazole-4-carboxylic acid chloride (5 g, 34.4 mm) was added dropwise over 20 min. The mixture was stirred at this temperature for another 3 h. and then it was heated to reflux temperature. The hot mixture was washed with water (3×10 ml). The organic phase was allowed to cool to ambient temperature, which induced leflunomide to precipitate as a white powder. The powder was isolated by filtration and then dried at 60° C. to give leflunomide (8.0 g, 86%) in 99.5% purity.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(#N)C>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1oncc1C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
A solution of 0.05 mol of 5-methylisoxazole-4-carbonyl chloride (7.3 g) in 20 ml of acetonitrile is added dropwise at room temperature to a solution of 0.1 mol of 4-trifluoromethylaniline (16.1 g) in 150 ml of acetonitrile. After stirring for 20 minutes, the precipitated 4-trifluoromethylaniline hydrochloride is filtered off with suction and washed twice with 20 ml of acetonitrile each time and the combined filtrates are concentrated under reduced pressure. 12.8 g of white crystalline 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)-anilide (compound 1) are thus obtained.