Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:24].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH:15]1([C:11]2([C:13]([OH:24])=[O:14])[CH2:12][CH:7]3[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[CH2:9][CH:8]3[CH2:10]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=P([O-])(O)O
Reactant: CN(C)C(=O)N1CC2CC(C=O)(C3CCCC3)CC2C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC2CC(C(=O)O)(C3CCCC3)CC2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
5-Cyclopentyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 16b (0.266 g, 0.955 mmol) was dissolved in a solvent mixture of 20 mL of tetrahydrofuran and 10 mL of water. Then sodium dihydrogenphosphate dihydrate (0.448 g, 2.87 mmol), sodium chlorite (0.26 g, 2.87 mmol) and 2-methyl-2-butene (0.24 mL, 2.88 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated to remove tetrahydrofuran and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyclopentyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 16c (0.28 g, yield 99.6%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:10][S:9]2(=[O:24])=[O:23])[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH:17]1([NH:16][C:11]2[O:12][C:13]([CH3:15])([CH3:14])[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[CH:3]=3)[S:9](=[O:24])(=[O:23])[N:10]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OB(O)c1cncnc1
Reactant: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
Under inert gas, 80 mg of [5-(3-bromophenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]cyclohexylamine, 30 mg of pyrimidine-5-boronic acid and 251 mg of cesium carbonate were dissolved in a mixture of 1.2 ml of dioxane and 0.4 ml of water. After purging with argon for 10 minutes, 15 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium were added and the reaction mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the mixture was admixed with 50 ml of ethyl acetate and washed with 15 ml of water and 15 ml of saturated aqueous sodium chloride solution, and the organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and lyophilized. This gave the product (6.4 mg) with a molecular weight of 414.5 g/mol (C21H26N4O3S); MS (ESI): m/e=415 (M+H+).
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:9][C:8]([OH:26])=[C:7]([CH3:27])[C:6]=1[CH3:28])C=C.[CH:29]1[CH:34]=CC=C[CH:30]=1>>[CH3:28][C:6]1[C:7]([CH3:27])=[C:8]([OH:26])[C:9]([CH2:34][CH:29]=[CH2:30])=[C:10]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]=1[OH:4]
Reactant: C=CCOc1c(C(=O)CCCCCCCCCCCCC)cc(O)c(C)c1C
Reactant: c1ccccc1
Product: C=CCc1c(O)c(C)c(C)c(O)c1C(=O)CCCCCCCCCCCCC

Procedure:
90 g of the allyl ether of step 2 were heated to 210° C. under nitrogen atmosphere within 2 h. After cooling the melt was dissolved in 300 ml of benzine (boiling range: 50°-75° C.) and placed in a cool place. The precipitate formed was filtered with suction the next day.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:24])[CH3:25])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(C)C)c1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cccc(CC(C(=O)O)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution-of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(isopropyloxy)benzyl]propanoate (9.8 g, 27.2 mmol) in methanol (50 ml) was added 2N aqueous sodium hydroxide solution (27.2 ml, 54.4 mmol), and the mixture was stirred at room temperature for 3 hrs. The reaction solution was acidified with 6N hydrochloric acid (100 ml). The mixture was extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from hexane to give the objective substance (7.44 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].OO.[OH:28]S(O)(=O)=O>C(Cl)Cl.O>[CH:11]1[C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]([Cl:18])=[C:7]([N:6]2[N:5]=[C:4]([C:19]#[N:20])[C:3]([S+:21]([O-:28])[C:22]([F:25])([F:24])[F:23])=[C:2]2[NH2:1])[C:12]=1[Cl:13]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: ClCCl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Temperature: 13.5 °C
Yield: 74.4 %

Procedure:
1.5 liter of methylene dichloride & 421.0 gms of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluromethylphenyl)-4-trifluromethylthio pyrazole was charged in a reactor flask with overhead stirring & condenser system. This mass was cooled to 12-15° C. and 68.0 gms of H2O2 (50.0% w/w) & 500.0 gms of H2SO4 (90.0% w/w) were simultaneously added to the mass over a period of 3.0-4.0 hours. The reaction temperature was then raised to 28-30° C. & maintained for about 2.0 hours. The reaction mass obtained thereafter was slowly added into 1700 ml of chilled water at a temperature of about 10-20° C. over a period of 2.0 hours. To this mass, 1500 ml of methylene dichloride was added and the mixture was heated to 60° C. to separate the aqueous and organic layers. The organic phase was washed with water & then with 5% NaHCO3 solution, followed by water wash, till a neutral pH was obtained. The crude yield obtained was 425.0 gms. The obtained crude fipronil was then crystallized from same solvent after partial evaporation to yield crystalline Fipronil (325 gms) with 94.0% purity.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10](Cl)=[O:11])[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:11])[CH2:6]1
Reactant: CN(C)CCN
Reactant: O=C(Cl)N1CCC(Oc2cccc(Cl)c2Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CCNC(=O)N1CCC(Oc2cccc(Cl)c2Cl)C1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution 11.8 g (0.04 mole) of 3-(2,3-dichlorophenoxy)-1-pyrrolidinecarbonyl chloride in 50 ml of chloroform was stirred at 5° C. in an ice bath while the following were added in order: 25 g of ice, 5.52 g of potassium carbonate and 3.87 g (0.044 mole) of N,N-dimethylethylenediamine. The resulting mixture was stirred for 20 hours and worked up by adding additional water followed by separation of the organic phase. The chloroform solution was dried over magnesium sulfate, filtered and concentrated in vacuo to a dark amber oil, 14 g, which solidified on standing. TLC analysis (10% methanol/chloroform) showed 3 spots; therefore, the crude product was chromatographed on 50 g of Fluorisil. Elution with chloroform gave a dark forerun which was discarded, the main portion was collected and rechromatographed through a 50 g Florisil column. The column was washed with 200 ml of methanol and the 2 fractions (chloroform and methanol) were combined before concentrating on a rotary evaporator to give a light amber oil which solidified. Recrystallization from isopropyl ether gave a beige crystalline product; 4.5 g (34%), m.p. 94°-95° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[C:28]([CH3:29])=[CH:27][S:26][C:25]=1[NH2:30]>C(N(CC)CC)C>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[C:28]([CH3:29])=[CH:27][S:26][C:25]=1[NH:30][C:12](=[O:14])[CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: Cc1csc(N)c1-c1nc2ccccc2s1
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)Cc2cccc3cnccc23)c1-c1nc2ccccc2s1

Procedure:
The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid and 3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-amine using Protocol B except that triethylamine was also added. MS (ESI) 416.0 [M+H], Retention time=2.86 min; 1H-NMR (300 MHz, CDCl3) δ 9.40 (s, 1H), 8.57 (d, J=6.04 Hz, 1H), 8.10-8.07 (m, 2H), 8.0 (d, J=6.6 Hz, 1H), 7.90-7.88 (m, 1H), 7.83-7.77 (m, 1H), 7.71-7.68 (m, 1H), 7.55-7.51 (m, 1H), 7.42-7.37 (m, 1H), 6.56 (s, 1H), 4.39 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:18][CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:5])[CH3:4].[C:28]1([CH2:34][CH2:35][CH2:36][CH2:37]I)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[C:3]([O:6][CH2:7][C:8]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])([CH2:18][CH3:19])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:37][CH2:36][CH2:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:15][CH:16]=1)(=[O:5])[CH3:4]
Reactant: CCC(CCc1ccc(O)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Reactant: ICCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CCc1ccc(OCCCCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a suspension of sodium hydride (0.65 g) in dimethylformamide (16 ml) was added a solution of 2-tert-butoxycarbonylamino-2-ethyl-4-(4-hydroxyphenyl)butyl acetate (6.0 g) in dimethylformamide (50 ml) at 0° C. and the mixture was stirred at room temperature for an hour. 4-Phenyl-butyl iodide (90 g) was added to the solution at 0° C. and the mixture was allowed to stand at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1) to give the subject compound (3.6 g). 1H-NMR (270 MHz, CDCl3) δ: 0.89 (3H, t, J=7.3 Hz), 1.45 (9H, s), 1.65-2.01 (8H, m), 2.08 (3H, s), 2.50 (2H, t, J=8.6 Hz), 2.67 (2H, t, J=6.6 Hz), 3.94 (2H, t, J=5.94 Hz), 4.22 (2H, dd, J=16, 11 Hz), 4.42 (1H, br. s), 6.80 (2H, d, J=8.6 Hz) 7.07 (2H, d, J=8.6 Hz), 7.16 (3H, t, J=7.3 Hz), 7.26-7.31 (2H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(Cl)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][C:11](=[O:13])[O:17][C:15](=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Yield: 92 %

Procedure:
3-(3,4-Dichlorophenyl)glutaric acid (100 g) was treated with acetyl chloride (300 mL) and the resulting mixture heated at reflux for 5 hours. The cooled reaction mixture was then azeotroped with toluene and concentrated under reduced pressure. The residue was slurried with diethyl ether (250 mL) and filtered to afford the title compound (86 g).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[CH2:14][CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[O-:34][N+:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[N:13]3[CH2:14][CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:12]3=[N:11][C:4]=2[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Product: CC(C)(C)OC(=O)N1CCCn2c(nc3c[n+]([O-])c4ccccc4c32)C1

Procedure:
The general method described in Part E of Example 4 was used to treat tert-butyl 11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (30.0 g, 88.6 mmol) with mCPBA (23.8 g of 77% pure material, 138 mmol) to provide tert-butyl 5-oxido-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate. The product was not dried over magnesium sulfate but was dried under high vacuum overnight.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>C(O)C>[C:13]([C:15](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])[C:16]([NH2:18])=[O:17])#[N:14]
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: N#CCC(N)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc(F)cc1[N+](=O)[O-])C(N)=O
Temperature: 25 °C
Reaction time: 28 h

Procedure:
A mixture of 4-fluoro-2-nitrobenzaldehyde (8.70 g., 51.5 millimoles), 2-cyanoacetamide (4.7 g., 54.4 millimoles), piperidine (0.032 g., 0.37 millimole) and ethanol (80 ml.) is stirred at room temperature for 28 hours. The solid which formed is separated by filtration, washed with ethanol (45 ml.) and dried. Yield = 10 g. (83.5%) of the title acrylamide as light tan crystals M.P. 278°-279° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:9][C:4]1[C:3]2[NH:10][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:1][C:2]=2[CH:7]=[C:6]([OH:8])[CH:5]=1
Reactant: Nc1cc(O)cc(Cl)c1NC(=O)C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Oc1cc(Cl)c2[nH]c(C3CCOCC3)nc2c1
Reaction time: 8 h

Procedure:
0.50 g (1.85 mmol) N-(2-amino-6-chloro-4-hydroxyphenyl)tetrahydro-2H-pyran-4-carboxamide were placed in 20 mL methanol, a spatula tip of p-toluenesulphonic acid monohydrate was added and the mixture was boiled overnight. The reaction mixture was evaporated down i.vac. and purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:13](SCC)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Br.[OH2:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:13]([OH:27])[N:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCSc1nc(Nc2ccc(OC)c(Cl)c2)cc(-c2ccccc2)n1
Reactant: O
Agent: Br
Product: Oc1nc(Nc2ccc(O)c(Cl)c2)cc(-c2ccccc2)n1
Temperature: 30 °C

Procedure:
A mixture of compound (3-chloro-4-methoxyphenyl)-(2-ethylsulfanyl-6-phenylpyrimidin-4-yl)amine and 47% hydrobromic acid solution in water (10 mL) was stirred at refluxing temperature for 12 hours. The reaction mixture was cooled to temperature in the range of 20-40° C. and excess of acid was removed under vacuum. The mixture was then neutralized with ammonia solution. The solid thus obtained was filtered off and dried under vacuum to afford the title compound as a pale brown color solid.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]([C:22]1[CH:23]=[C:24]([CH2:33][CH2:34][C:35](O)=[O:36])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])([CH3:20])[CH3:19]>C1(C)C(C)=CC=CC=1>[C:29]([C:26]1[CH:25]=[C:24]([CH2:33][CH2:34][C:35]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)=[O:36])[CH:23]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[C:27]=1[OH:28])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc(N2CCN(C(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1

Procedure:
A mixture of 23.4 g. (0.1 mole) ethyl 4-(piperazin-1-yl)-benzoate (base), 600 ml. xylene and 27.8 g. (0.1 mole) 3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionic acid is boiled under a water separator for 28 hours, then evaporated to dryness in a vacuum and the residue is taken up with diethyl ether. For the removal of unreacted ethyl 4-(piperazin-1-yl)-benzoate, the ether solution is extracted with 1N hydrochloric acid, washed with water and aqueous sodium bicarbonate solution, dried with anhydrous sodium sulphate and mixed with hydrogen chloride-containing diethyl ether, whereby the hydrochloride precipitates out. This is washed with diethyl ether and recrystallised from ethanol to give 32.0 g. (60% of theory) of the desired product as colourless crystals; m.p. 196°-198° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cnc1Oc1cccc(F)c1

Procedure:
To a stirred solution of methyl 2,5-dichloronicotinate (J. Med. Chem. 1993, 36, 2676, 353 mg, 1.71 mmol) and 3-fluorophenol (291 mg, 2.6 mmol) in toluene (5 mL) was added potassium carbonate (360 mg, 2.6 mmol) in one portion. The resulting mixture was heated at reflux temperature for 16 h with azeotroping using a Dean Stark apparatus. The mixture was poured into water (50 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL). The organic extracts were washed with water (50 mL) and brine (50 mL), dried (sodium sulfate), and concentrated under reduced pressure to give crude methyl 5-chloro-2-(3-fluorophenoxy)nicotinate. To a stirred solution of the crude ester in methanol (10 mL) was added 2 N sodium hydroxide aqueous solution (2 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between ether (30 mL) and water (30 mL). The organic phase was separated and the aqueous phase was acidified with 2 N hydrochloric acid (10 mL). The acidic mixture was extracted with dichloromethane (50 mL×3). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated to afford 448 mg (93%) of the title compound as off white solids: 1H-NMR (CDCl3) δ 8.44 (1H, d, J=2.6 Hz), 8.26 (1H, d, J=2.6 Hz), 7.46–7.36 (1H, m), 7.07–6.89 (3H, m); MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:19]=[O:20].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[CH:4][C:3]=2[CH:19]=[O:20])=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1ccc(Oc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2C=O)cc1
Temperature: 160 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A mixture of 4-fluoro-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde (750 mg, 2.639 mmol), 4-(tert-butyl)phenol (436 mg, 2.903 mmol), potassium carbonate (547 mg, 3.958 mmol) and dimethylacetamide (4 ml) was stirred at 160° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=15:1) to give the title compound (598 mg, 54.7%) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([I:10])[N:7]=[CH:6]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CS(C)=O.O>[I:10][C:8]1[N:7]=[CH:6][N:5]([CH2:4][CH2:3][CH2:2][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]=1
Reactant: C1CCNC1
Reactant: ClCCCn1cnc(I)c1
Solvent: CS(C)=O
Solvent: O
Product: Ic1cn(CCCN2CCCC2)cn1
Yield: 78.2 %

Procedure:
A solution of the chloride 292 (1.2 g, 4.44 mmol) and pyrrolidine (1.1 mL, 13.3 mmol) in dry DMSO (2 mL) was heated at 60° C. under nitrogen for 3 h. The reaction mixture was cooled, diluted with water and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane, 5:95 to 20:80) to afford 293 (1.06 g, 3.47 mmol, 78% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, J=1.2 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 2.45-2.33 (m, 4H), 2.29 (t, J=7.2 Hz, 2H), 1.84 (q, J=7.2 Hz, 2H), 1.72-1.62 (m, 4H). MS (m/z): 305.9 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH3:19])=[O:17].Cl>O>[CH3:19][O:18][C:16]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:17]
Reactant: COC(=O)Cl
Reactant: OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Yield: 94.2 %

Procedure:
4-Hydroxymethylpiperidine (1.0 g, 8.6 mmol) was dissolved in water (15 mL) and cooled to 0° C. To this solution was added dropwise a solution of potassium carbonate (4.8 g, 34.7 mmol) in water (10 mL), followed by methyl chloroformate (2.68 mL, 34.7 mmol). The mixture was stirred vigorously and allowed to warm to room temperature over 2 h. After stirring overnight (16 h), the reaction mixture was acidified with 6M aqueous hydrochloric acid and extracted with dichloromethane (3×60 mL). The extracts were combined, dried over sodium sulfate and filtered. The filtrate was evaporated to yield the title intermediate (1.4 g, 8.1 mmol, 93%) as a colorless oil. (m/z): C8H15NO3 calcd. 173.11; found 156.2 [M-H2O+H]+. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 0.98 (m, 2H), 1.52 (m, 1H), 1.63 (br d, 2H), 2.72 (br m, 2H), 3.23 (d, 2H), 3.56 (s, 3H), 3.95 (br d, 2H), 4.48 (br s, 1H).