Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26]C)[C:5]([N:7]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)=[O:6].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[OH:26])[C:5]([N:7]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1ccc(N(C(=O)c2ccc(OC)c(F)c2)c2ccc(F)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)c(F)c1)N(c1ccc(O)cc1)c1ccc(F)cc1
Temperature: 0 °C
Yield: 81.6 %

Procedure:
Compound 3-fluoro-N-(4-fluorophenyl)-4-methoxy-N-(4-methoxyphenyl)benzamide (2a) (138.0 g, 0.374 mol) was dissolved in dry CH2Cl2 (600 mL) at room temperature under an argon. BBr3 (374.75 g, 1.496 mol) was added dropwise with stirring via a syringe at 0° C. in an ice-bath under an argon. The reaction solution was allowed to stir at room temperature overnight. Then, the solution was poured to 1 L of ice water with stifling. The slurry mixture was stirred at room temperature for 2 hours. The white precipitate was filtered, washed with water (2×100 mL) and dried under vacuum. The CH2Cl2 layer was separated, dried over anhydrous MgSO4 (50 g), filtered and concentrated under reduced pressure to dryness. The white precipitate and residue from CH2Cl2 solution were combined and purified by flash column chromatography (silica gel, CH2Cl2/Acetone/MeOH=90/7/3 v/v/v) to give a light tan solid which was recrystallized from hot EtOAc/Hexanes solution twice to afford a white crystalline solid, 104.0 g, 81.6% yield. M.p. 110-112° C. MS (ESI) m/z 364.1 [M+Na]+, 1H NMR (DMSO-d6) δ 10.14 (bs, 1H), 9.71 (bs, 1H), 7.25-7.11 (m, 5H), 7.05-6.99 (m, 3H), 6.78 (t, J=8.6 Hz, 1H), 6.68 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)=[N:10][C:11]([N:12]3[CH2:18][CH:17]4[O:19][CH:14]([CH2:15][CH2:16]4)[CH2:13]3)=[C:6]2[C:5]([CH:31]=[CH2:32])=[N:4]1)[CH3:2].CS(N)(=O)=[O:35].[O-]S([O-])=O.[Na+].[Na+].C(O)(C)(C)C.[OH2:49]>>[OH:49][CH:31]([C:5]1[C:6]2[C:7](=[N:8][C:9]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)=[N:10][C:11]=2[N:12]2[CH2:13][CH:14]3[O:19][CH:17]([CH2:16][CH2:15]3)[CH2:18]2)[N:3]([CH2:1][CH3:2])[N:4]=1)[CH2:32][OH:35]
Reactant: C=Cc1nn(CC)c2nc(-c3ccc(NC(=O)NC)cc3)nc(N3CC4CCC(C3)O4)c12
Reactant: CS(N)(=O)=O
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCn1nc(C(O)CO)c2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)NC)cc3)nc21
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[1-ethyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-3-methylurea (200 mg) (0.46 mmol) in tert-butanol:water (1:1) (8.0 mL) was added AD mix 0 (2.0 g) and methanesulfonamide (400 mg). The mixture was stirred overnight. To the reaction was added 10% Na2SO3 solution and extracted three times with EtOAc. Organics were dried (MgSO4) and filtered off and then concentrated in vacuo. to give a white solid 178 mg. MS m/z=468.2 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:12][CH2:13][C:14](Cl)=[O:15])(=[O:11])[CH3:10].C(N(CC)CC)C.O>C(Cl)Cl>[C:9]([O:12][CH2:13][C:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)=[O:15])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(Br)cn1

Procedure:
In 29 ml of methylene chloride was dissolved 1 g of 2-amino-5-bromopyridine which was then reacted with 0.93 ml of acetoxyacetyl chloride in the presence of 1.61 ml of triethyl amine at room temperature for 1 hour with stirring. Water was added to the reaction mixture before extraction with methylene chloride. The organic layer thus obtained was washed with brine, dehydrated, filtered and concentrated in vacuo. Recrystallization of the concentrate in ethyl ether gave the title compound. 615 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[CH:12][C:11]3[C:6](=[N:7][C:8](O)=[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]=3)[N:5]2[N:21]=1.CN(C=O)C.O=S(Cl)[Cl:29]>C(Cl)(Cl)Cl>[Cl:29][C:8]1[N:7]=[C:6]2[C:11]([CH:12]=[N:13][C:4]3[N:5]2[N:21]=[C:2]([CH3:1])[CH:3]=3)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc2ncc3nc(-c4ccccc4)c(O)nc3n2n1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2ncc3nc(-c4ccccc4)c(Cl)nc3n2n1
Temperature: 70 °C

Procedure:
A 40 mL scintillation vial containing Compound (10-4) (220 mg, 0.8 mmol, 1 eq.), CHCl3 (12 mL), DMF (12 mg, 0.16 mmol, 2 eq.), and SOCl2 (0.56 g, 3.2 mmol, 4 eq.) was heated at 70° C. under nitrogen for 1.5 hours. Then the mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in CHCl3 (20 mL) and washed with saturated NaHCO3 (5 mL). The water solution was extracted with CHCl3 (2×5 mL). The combined organic phases were dried over MgSO4. After filtration and concentration, the residue was purified by silica gel chromatography using EtOAc and heptane as the mobile phases to furnish Compound (10-5) as a yellowish solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([CH3:17])=[CH:9][N:8]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.C(#N)C>[Cl:3][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([CH3:17])=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cnc(CO)c(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cnc(CCl)c(C)c1[N+](=O)[O-]
Temperature: 12.5 °C

Procedure:
8.0 ml (0.11 mole) of thionyl chloride in 20.0 ml of methylenechloride was added to a solution of 20.0 gms 2-hydroxymethyl-3,5dimethyl-4-nitropyridine, of formula-II obtained in step-(a), at temperature of 10-15° C. over a period of 1 hr. The reaction is maintained at 10-15° C. for further 30 min. Aqueous 10% solution of sodium carbonate was slowly added to the reaction mixture at 10-15° C. and pH adjusted to 8.0 to 8.5. The organic base (compound) is over anhydrous sodium sulfate and solvent was removed under vacuum to obtain crude product. (purity 85%) Pure compound is isolated by re-crystallization from acetonitrile.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:40](Cl)(=[O:44])[O:41][CH2:42][CH3:43]>CO.ClCCl>[OH:26][CH2:25][CH2:24][N:23]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[C:16]2[CH2:22][N:21]([C:40]([O:41][CH2:42][CH3:43])=[O:44])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1
Reactant: CCOC(=O)Cl
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in MeOH (0.5 mL) and dichloromethane (5 mL). Triethylamine (0.033 mL, 0.23 mmol) was added followed by ethyl carbonochloridate (0.022 mL, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under reduced pressure. The crude was dissolved in dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding ethyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (28.0 mg, 24%).
Reaction SMILES: [CH2:1](Br)[C:2]#[C:3][CH3:4].[CH2:6]([O:8][C:9]([CH2:11][NH:12][C:13](=[N:21][C:22]#[N:23])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:6]([O:8][C:9]([CH2:11][N:12]([CH2:1][C:2]#[C:3][CH3:4])[C:13](=[N:21][C:22]#[N:23])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)CNC(=NC#N)Oc1ccccc1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCN(CC(=O)OCC)C(=NC#N)Oc1ccccc1

Procedure:
11 ml of but-2-ynylbromide are added to a mixture of 30.2 g 1-ethoxycarbonylmethyl-3-cyano-2-phenyl-isourea and 20.0 g potassium carbonate in 200 ml acetone. After 1 d (day) stirring at ambient temperature a further 6.5 g potassium carbonate and 3.5 ml of but-2-ynylbromide are added. After another 20 h at ambient temperature the solvent is removed and ethyl acetate is added. The organic phase is washed with water, dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:15]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:27][C:28]1[CH:29]=[C:30]([N:35]=[C:36]=[O:37])[CH:31]=[CH:32][C:33]=1[F:34]>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([NH:35][C:36]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][C@@H:16]3[CH2:17][CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)[CH2:15]3)[CH2:22][CH2:23]2)=[O:37])[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: CS(=O)(=O)c1ccc(CCCN2CCC[C@@H](CN3CCNCC3)C2)cc1
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(CCCN2CCC[C@@H](CN3CCN(C(=O)Nc4ccc(F)c(Cl)c4)CC3)C2)cc1
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 1-[((3R)-1-{3-[4-(methylsulfonyl)phenyl]propyl}piperidin-3-yl)methyl]piperazine (215 mg, 0.57 mmol) in toluene (15 ml) was added 3-chloro-4-fluorophenyl isocyanate (107 mg, 0.62 mmol) and the solution stirred for 18 hours. A further portion of 3-chloro-4-fluorophenyl isocyanate (54.0 mg, 0.31 mmol) was added and stirred for 30 minutes. The reaction was evaporated to an oil and flash column chromatography (silica, CH2Cl2 to 10% MeOH/CH2Cl2) gave N-(3-chloro-4-fluorophenyl)-4-[((3R)-1-{3-[4-(methylsulfonyl)phenyl]propyl}piperidin-3-yl)methyl]piperazine-1-carboxamide as a white foam (155 mg, 50%).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[CH:12][CH2:13][OH:14])[C:9]3[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:21])[CH3:20].[Br:22]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>ClCCl>[Br:22][CH:12]([C:10]1([O:21][CH2:19][CH3:20])[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[CH2:7][O:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2)[CH2:13][OH:14]
Reactant: OCC=C1c2ccccc2COc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC1(C(Br)CO)c2ccccc2COc2ccccc21
Temperature: 25 °C
Yield: 86.4 %

Procedure:
Dissolved 2-[6,11-dihydro-dibenz[b,e]oxepin-11-ylidene]-ethanol (10.90 g, 0.0457 mol) in 175 mL of dichloromethane. Added ethanol (21.07 g, 26.8 mL, 0.457 mol), and cooled to 0° C. under a nitrogen atmosphere. Added N-bromosuccinimide (8.96 g, 0.0503 mol) portionwise. Warmed slowly to room temperature over 60 mins. Added 200 mL of saturated NaHCO3, and separated layers. Extracted aqueous solution with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 1:4 ethyl acetate:hexane. Combined appropriate fractions, and evaporated to give 14.35 g (86% yield) of 2-bromo-2-[6,11-dihydro-11-ethoxy-dibenz[b,e]oxepin-11-yl]-ethanol as a light yellow oil. ##STR43##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[C:14]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Reaction time: 3 h

Procedure:
Piperazine (5.0 g, 58.04 mmol) was dissolved in CHCl3 (100 ml) and Et3N (9 ml, 64.6 mmol) was added. This solution was heated to reflux and a solution of triphenylmethyl chloride (16.36 g, 58.68 mmol) in CHCl3 (100 ml) was added dropwise, via the reflux condenser, over a period of 4 hours. The reflux was then continued for 3 hours more and then was cooled and allowed to stand at room temperature overnight. A solid precipitated and was filtered off. The filtrate was evaporated to dryness to an oil which was partitioned between 10% aqueous Na2CO3 (150 ml) and CHCl3 (150 ml). The aqueous layer was washed with two additional portions of CHCl3 (2×150 ml) and the pooled organic layers were dried (MgSO4), filtered and evaporated to dryness to give a straw-colored syrup. This was purified on a silica gel 60 column (800 g) wet packed in CHCl3 and then developed with CHCl3 :MeOH (9:1) and then CHCl3 :MeOH (4:1). Fractions containing the required product were pooled and evaporated to dryness to give the title compound. Mass spec showed M+ at m/e 328. NMR (CDCl3, δ from TMS): 3.04 (br) piperazine methylenes; 7.06-7.58 (m) aromatics.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[H][H].[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][C:30](Cl)=[O:31])[CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][C:30](=[O:31])[CH2:29][CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)CC1CCOCC1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: [H][H]
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1CCOCC1)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (715 mg, 3.0 mmol) in DMF (20 mL) was added sodium hydride (purity of about 60%, 120 mg, 3.0 mmol, 1.0 eq.). The mixture was stirred until no more hydrogen was generated, to obtain a solution. Then, tetrahydro-2H-pyran-4-ylacetyl chloride (1.2 eq.) was added thereto, and the mixture was stirred at a room temperature for 1 hour. To the mixture was added a saturated sodium hydrogencarbonate aqueous solution, and the resulting precipitate was separated by filtration, washed with water, and dried to give 1-phenyl-4-(tetrahydro-2H-pyran-4-ylacetoxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (738 mg, yield 67%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:18]1[CH:23]=CC=C[CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][C:18]([CH3:23])([CH3:19])[O:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)CCc1ccc(O)c(O)c1
Reactant: c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCNC(=O)CCc1ccc2c(c1)OC(C)(C)O2
Temperature: 0 °C
Reaction time: 11 h

Procedure:
1.5 g of N-butyl-3-(3,4- dihydroxyphenyl)propionamide was dissolved in a mixed solvent consisting of 30 ml of benzene and 10 ml of tetrahydrofuran and 4 ml of acetonedimethylacetal was added to the solution. Then a small amount of p-toluenesulfonic acid was added to the solution and the solution was stirred for 11 hours under reflux. With a further addition of 2 ml of acetonedimethyl acetal, stirring was continued under reflux for 6 hours. After cooling, the solution was poured over ice water containing sodium hydrogen carbonate and was mixed thoroughly. The solution was extracted with ethyl acetate, washed with water and then dried with sodium sulfate anhydride. After removing the solvent by evaporation under reduced pressure, the resulting residue was purified by chromatography on silica gel column using a mixed solvent (chloroform:methanol=100:l) and thus 0.84 g of oily N-butyl-3-(2,2-dimethyl-1,3-benzodioxol-5-yl)propionamide was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccc(F)c(Cl)c2)n1
Temperature: 80 °C

Procedure:
To a solution of 6-bromopicolinaldehyde (1.07 g, 5.74 mmol) in dioxane (30 mL) at ambient temperature was added 3-chloro-4-fluorophenylboronic acid (1.00 g, 5.74 mmol), 2M cesium carbonate (8.60 mL, 17.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.234 g, 0.287 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. After cooling to ambient temperature the mixture was concentrated and the residue was partitioned between water and CH2Cl2. The organic extract was concentrated and purified by chromatography (10% ethyl acetate:hexanes) to provide the title compound. MS (DCI+) m/z 236 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:26][O:27][NH2:28].N1C=CC=CC=1.O>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:28][O:27][CH3:26])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CON
Reactant: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
To a solution of 200 mg of the N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide prepared in Step 1 in Synthetic Example 15 and 133 mg of methoxyamine hydrochloride in 2.7 ml of ethanol, 168 mg of pyridine was added, and the mixture was stirred at 80° C. for 6 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (10 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 191 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[CH:11]1([C:14]([CH3:16])=[O:15])[CH2:13][CH2:12]1.C[O-].[Na+].C1C=CC=CC=1>O>[CH:11]1([C:14](=[O:15])[CH2:16][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:13][CH2:12]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)c1cnccn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1cnccn1

Procedure:
A stirred mixture of 14.0 g. of methyl pyrazinoate, 16.8 g. of cyclopropylmethyl ketone, 6.0 g. of sodium methoxide and 200 ml. of benzene is heated under reflux for 5 hours. A 400 ml. volume of water is added to the mixture. The benzene phase is separated and the aqueous solution is made weakly acidic with dilute hydrochloric acid. A yellow solid precipitates, which is collected and recrystallized from hexane to give white crystals, m.p. 111°-112°C.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.CO.[CH2:13](Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:13][O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[CH:3][CH:4]=[N:5][CH:6]=1
Reactant: O=C(O)c1cnccc1Br
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnccc1Br
Temperature: 0 °C
Yield: 45.6 %

Procedure:
To a solution of 4-bromonicotinic acid (16.8 g, 83.2 mmol, 1.0 eq.) in DCM (250 mL) at 0° C. was added DMAP (1.0 g, 8.2 mmol, 0.1 eq.). MeOH (2.7 g, 83.7 mmol, 1.0 eq.) was added dropwise with stirring at 0° C. EDC (16.8 g, 87.6 mmol, 1.1 eq.) was then added. The resulting solution was stirred for 3 hours at 0° C. The reaction was then quenched with water (100 mL). The resulting solution was extracted with DCM. The organic layer was washed with saturated aqueous NaCl (3×100 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to yield 4-bromonicotinic acid methyl ester (8.2 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH:19]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[OH-].O1CCC[CH2:38]1.[C:42]([O:46]C)(=[O:45])[CH:43]=[CH2:44]>CO>[C:42]([OH:46])(=[O:45])[CH2:43][CH3:44].[CH3:38][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:35]=[CH:34][C:5]=2[N:6]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:12][CH2:11]2)[C:7]1=[O:9]
Reactant: C1CCOC1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: C=CC(=O)OC
Agent: [OH-]
Solvent: CO
Product: CCC(=O)O
Product: Cn1c(=O)n(C2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
To a stirred mixture of 8.8 parts of 5-chloro-1-{1-[4,4-bis(p-fluorophenyl)butyl]-4-piperidyl}-2-benzimidazolinone, 1 part of N,N,N-trimethylbenzenemethanaminimum hydroxide solution 40% in methanol and 135 parts of tetrahydrofuran is added dropwise a solution of 8.6 parts of methyl 2-propenoate in 45 parts of tetrahydrofuran at 45° C. Upon completion, stirring is continued overnight at 50° C. The reaction mixture is evaporated. Water is added to the residue and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, yielding methyl 6-chloro-3-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-2-oxo-2H-benzimidazole 1-propanoate; mp. 186.2° C.