Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:19][CH3:20])=[C:12]([C:14](=[O:18])[C:15](O)=[O:16])[CH:13]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:19][CH3:20])=[C:12]([C:14](=[O:18])[C:15]([Cl:23])=[O:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a 20 ml volume three-necked flask, 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetic acid (8-c) (1.01 g), toluene (3.5 ml), dimethylformamide (3 drops), and thionyl chloride (624 mg) were added under a nitrogen atmosphere, and stirred at 50° C. for 3 hours. The mixture was concentrated under reduced pressure, and azeotropic-distilled with toluene 3 times to give 937 mg of 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl chloride (6-c).
Reaction SMILES: [C:1]1([C:7]2[CH:18]=[C:10]3[N:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][NH2:35])[CH2:28][CH2:27]1>O1CCCC1.C(Cl)(=O)OCC>[O:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][NH:35][C:15]([C:12]2[CH:13]=[CH:14][N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:18]=[C:10]3[N:11]=2)=[O:17])[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccn2nc(-c3ccccc3)cc2n1
Reactant: NCc1ccccc1N1CCOCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1N1CCOCC1)c1ccn2nc(-c3ccccc3)cc2n1
Temperature: -20 °C
Yield: 68.5 %

Procedure:
To a solution of 2-phenyl- pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid (120 mg), and triethylamine (0.091 ml) in tetrahydrofuran (10 ml), ethyl chlorocarbonate (0.053 ml) was added at −40° C. It was further added with a solution of 2-morpholinobenzylamine (115 mg) in tetrahydrofuran (2 ml), and thereafter heated to −20° C. The reaction solution was distilled under a reduced pressure, and then water was added thereto, extracted with chloroform, and the organic layer was dried with magnesium sulfate. After the reduced-pressure distillation of the solvent, the residue was purified by a silica gel column chromatography, and thereafter recrystallized from acetone-diisopropyl ether to yield N-(2-morpholinophenyl)methyl 2-phenyl-pyrazolo-[1,5-a]-pyrimidine-5-amide (142 mg, 69%). mp: 190-192° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@:4]([CH2:7][CH2:8][C:9]#[N:10])([CH3:6])[NH2:5].C(N(CC)CC)C.C([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32]C(=O)C)[C:26](Cl)=[O:27])(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C@:4]([CH2:7][CH2:8][C:9]#[N:10])([CH3:6])[NH:5][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([OH:32])=[C:23]([OH:22])[CH:24]=1
Reactant: COC(=O)[C@](C)(N)CCC#N
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@](C)(CCC#N)NC(=O)c1ccc(O)c(O)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
1.56 g of 2-(2-cyanoethyl)alanine methyl ester and 1.4 ml of triethylamine were added to a solution of crude 3,4-diacetoxybenzoyl chloride (prepared from 1.96 g of 3,4-diacetoxybenzoic acid and 2.08 g of phosphorus pentachloride) in 30 ml of dichloromethane, at 5° C. The reaction mixture was stirred at 0°-5° C. for one hour and then washed with 30 ml of water. The organic layer was separated off and dried over magnesium sulphate, and the solvent was distilled off. The resulting residue was dissolved in 10 ml of methanol, 8.3 ml of 28% aqueous ammonia solution were added, and the solution was stirred at room temperature for 23 hours. The mixture was then cooled to 5° C., adjusted to pH 2.0 with concentrated hydrochloric acid, diluted with 50 ml of water, and extracted with two 50 ml portions of dichloromethane. The organic extract was dried over magnesium sulphate, the solvent was distilled off, and the resulting residue was purified by silica gel chromatography (eluent: 2:1 mixture of cyclohexane and ethyl acetate), to give 1.60 g of the desired product as a colourless glass.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)=[O:2].[OH-].[Na+].C1(C)C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:24][S:23][C:20]1[N:21]=[CH:22][C:11]2[C:10](=[O:25])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[O:2][CH:39]=[N:38][CH:37]=4)[CH:4]=3)[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]=2[N:19]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C=O)c1)C2=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3cnco3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
(S)-5-(3-Formylphenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (380 mg, 1.07 mmol) obtained in Step 2 was dissolved in methanol (10 mL), and the mixture was stirred at room temperature for 30 minutes after adding sodium hydroxide (120 mg, 2.14 mmol) and p-toluenesulfonylmethylisocyanide (230 mg, 1.18 mmol). After diluting the mixture with ethyl acetate, the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(1,3-oxazol-5-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (300 mg, 71%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.[CH2:11]([O:18][C:19]([NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](O)=[O:30])[CH2:25][CH2:24]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N=C=NCCCN(C)C)C.Cl.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19](=[O:20])[NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](=[O:30])[NH:10][CH2:9][C:4]2[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:25][CH2:24]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3-chloropyrazin-2-yl)methanamine hydrochloride (5 g, 21.38 mmol), (trans)-4-((benzyloxycarbonylamino)methyl)cyclohexanecarboxylic acid (6.23 g, 21.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride (4.51 g, 23.52 mmol), 1-hydroxy-7-azabenzotriazole (1.455 g, 10.69 mmol), and triethyl amine (4.76 ml, 34.2 mmol) in dichloromethane (60 ml) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane with gradient 0.5 to 5% of methanol) to yield benzyl((trans)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl)methylcarbamate (8.79 g).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:37][C:38]([NH2:40])=[S:39].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C>[NH2:40][C:38]1[S:39][CH:2]=[C:3]([CH2:4][C:5]([NH:7][CH:8]2[C:34](=[O:35])[N:10]3[C:11]([C:18]([O:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]23)=[O:6])[N:37]=1
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(/C=C/Cl)CS[C@H]23)cs1
Temperature: 30 °C
Yield: 71.9 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (1.2 g) in a mixture of tetrahydrofuran (15 ml) and ethyl alcohol (15 ml) was added thiourea (0.46 g). The mixture was stirred for an hour at 30° C., poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with 10% aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (0.83 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)#[N:21].NC(N)=O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)=[O:30])[CH:5]=1
Reactant: COC(=O)c1cccc(CNCc2ccccc2)c1
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: NC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(Cc2ccccc2)C(=O)Nc2ccc(C#N)cc2)c1
Yield: 34.4 %

Procedure:
Dissolved 3-(benzylamino-methyl)-benzoic acid methyl ester (197 mg, 0.77 mmol) in 5 mL of DMF. To this was added 4-cyanophenyl isocyanate (112 mg, 0.78 mmol). The mixture stirred for 48. LC-MS analysis indicated the desired urea. The mixture was diluted with 100 mL EtOAc, washed with 3×50 mL of H2O and 1×20 mL of brine. The organic phase was dried with MgSO4, filtered and concentrated. The resulting residue was applied to a SiO2 prep plate and eluted with 50% EtOAc/hexanes to give two fractions-one clear band and a tail. LC-MS analysis indicated both band and tail were composed of the product. Both fractions were combined to give 105.7 mg of 3-[1-benzyl-3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid methyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:18]=[CH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C=CC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Reaction time: 1 h
Yield: 1.8 %

Procedure:
To a solution of 2-benzyl-1′-tert-butoxycarbonyl-1′,6′-dihydrospiro[1H-isoindole-1,4′(5′H)-pyridine]-3(2H)-one (11.0 g) in chloroform (20 mL), trifluoroacetic acid (20 mL) was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated. The residue was dissolved in methanol and hydrogenated with 4M hydrogen chloride/ethyl acetate in the presence of 20% palladium carbon at 1 atm of hydrogen for 14 hours. The catalyst was removed by filtration and the filtrate was concentrated. To the residue, aqueous 1N sodium hydroxide (5 mL), di-tert-butyl dicarbonate (655 mg) and dioxane (10 mL) were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subject compound (200 mg).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Li+].[F:10][C:11]([F:16])([F:15])[C@@H:12]1[O:14][CH2:13]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([NH:24][CH2:13][C@@H:12]([OH:14])[C:11]([F:16])([F:15])[F:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: FC(F)(F)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: O[C@H](CNCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of lithium trifluoromethanesulfonate (1.43 g, 9.17 mmol) in CH3CN (30 ml) was added (R)-(+)-3,3,3-trifluoro-1,2-epoxypropane (10.77 g, 96 mmol) slowly at −10° C. After 5 minutes benzylamine (10 ml, 92 mmol) was added slowly. The mixture was allowed to warm as the bath warmed to rt overnight. The mixture was concentrated. The crude product was subjected to silica gel chromatography (330 g, 0-50% EtOAc/hexanes, 10 minute gradient) to afford (R)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol (4-2, 15.9 g, 79%) as a white solid. LRMS m/z (M+H)+ 220.2 calc. 220.1 found.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[S:21](O)=O)=[CH:6][CH:5]=1.[N+](C1C(SC2C=CC=CC=2)=C(S(O)=O)C=C(C=1)C(O)=O)([O-])=O>>[NH2:18][C:17]1[C:9]([O:8][C:7]2[CH:24]=[CH:25][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)=[C:10]([SH:21])[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: COc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(=O)O)cc1
Agent: O=C(O)c1cc([N+](=O)[O-])c(Sc2ccccc2)c(S(=O)O)c1
Agent: [Na]
Product: COc1ccc(Oc2c(N)cc(C(=O)O)cc2S)cc1

Procedure:
By replacing mono sodium salt of 4-(p-methoxyphenoxy)-5-nitro-3-sulfinobenzoic acid (12 g) for the mono sodium salt of 5-nitro-4-phenylthio-3-sulfinobenzoic acid (11 g) in Example 11B, 5-amino-4-(p-methoxyphenoxy)-3-mercaptobenzoic acid is obtained with a melting point of 182°-184° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:28].S(Cl)([Cl:32])(=O)=O.O>C(Cl)Cl>[Cl:32][C:4]1[CH:5]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([F:25])([F:26])[F:27])[CH:9]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:28]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)cc(Cl)c1O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a stirred solution of 2-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol (0.332 g, 0.8. mmol) in CH2Cl2 (10 ml) was added sulfuryl chloride (0.113 g, 0.84 mmol) at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, and the whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with CH2Cl2-hexane to give the subtitle compound (0.318 g, 88.6% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[BH4-].[Na+]>CCO>[CH2:9]([NH:1][CH2:2][CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCc1c[nH]cn1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: c1ccc(CNCCc2cnc[nH]2)cc1

Procedure:
Compound XIIIA is prepared by treatment of a mixture of compound XIIA, histamine, and benzaldehyde in a solvent such as MeOH or EtOH, with a reducing agent such as NaBH4 to provide N-benzyl-2-(1H-imidazol-5-yl)ethanamine (compound not shown). To this compound in water at 0° C., is added KOH followed by acetaldehyde. After approximately six hours at 80° C. followed by treatment with acid, compound XIIIA, PG=Bn, is isolated. Trifluoromethyl derivative XIVA is also prepared from compound XIIA. To a solution of compound XIIA in a solvent such as water at a temperature of about 0° C., is added a base such as KOH along with trifluoroacetaldehyde. After heating at a temperature of approximately 80° C. for approximately 6 hours and acidification, compound XIVA is isolated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.F[C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH3:26])=[N:20]2.CS(C)=O>O>[CH3:26][C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][C:23]([F:25])=[CH:24][C:15]=2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:20]=1
Reactant: Cc1ccc2c(F)cc(F)cc2n1
Reactant: C1CNCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(N3CCNCC3)cc(F)cc2n1
Temperature: 120 °C
Yield: 20.7 %

Procedure:
A stirred mixture of piperazine (20 g), potassium carbonate (32 g), 5,7-difluoro-2-methylquinoline hydrochloride (WO2002034754, 20 g) and dimethylsulfoxide (390 mL) was heated to 120° C. for 15 hours. The mixture was cooled to room temperature, diluted with water (600 mL) and extracted with 6×500 mL portions of a mixture of DCM-ether (15:85). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried (sodium sulfate) and the solvent was partially evaporated under vacuum. The precipitate formed during the evaporation was filtered-off, washed with ether (50 mL) and dried under vacuum to give the title compound (4.7 g, 21%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[O:11][CH3:12].C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:25](Cl)(=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[CH3:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[C:4]([O:11][CH3:12])[CH:5]=1)=[O:34]
Reactant: COc1cc(CN)ccc1O
Reactant: CCCCCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCC(=O)NCc1ccc(O)c(OC)c1
Reaction time: 0.5 h

Procedure:
58.5 parts of 4-hydroxy-3-methoxybenzylamine hydrochloride, 200 parts of benzene and 200 parts of water were charged into a reaction vessel equipped with a three-one motor the rotational frequency of which is variable and an outlet having a stopper at the bottom portion and stirred. 58 parts of potassium carbonate was added to the mixture and further 54 parts of pelargonoyl chloride was added dropwise to the resultant mixture at room temperature. In this state, the mixture was stirred for 3 hours until the end of the reaction. After the stirring was stopped and the mixture was allowed to stand for 30 minutes, the water layer in the lower layer was discharged from the bottom portion. The residue was distilled under a reduced pressure to remove the solvent almost completely, thereby obtaining crude nonylic acid vanillylamide. As a result of quantitative analysis of a slight amount of product by high pressure liquid chromatography (hereinunder referred to as "HPLC"), the purity of nonylic acid vanillylamide was determined to be 91.7%. The irritant nature thereof to skin, especially, to mucosae was strong.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29]/[CH:30]=[C:31]1/[C:32]2[CH:45]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:43]=[CH:42][C:33]=2[O:34][CH2:35][C:36]2[N:41]=[CH:40][CH:39]=[CH:38][C:37]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:14]2[CH2:18][CH2:17][N:16]([CH2:28][CH2:29][CH:30]=[C:31]3[C:37]4[CH:38]=[CH:39][CH:40]=[N:41][C:36]=4[CH2:35][O:34][C:33]4[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]3=4)[CH2:15]2)[CH2:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCNC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCNC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-N-ethyl-acetamide (0.09 g, 0.31 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.07 g, 0.51 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.095 g, 0.25 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([CH:18]=[O:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[C:14]1[CH:13]=[C:12]([F:11])[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=1
Reactant: COc1ccc(F)c(Br)c1
Reactant: O=Cc1cc(F)cc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)c(-c2cc(F)cc(C=O)c2)c1
Temperature: 90 °C
Yield: 28.6 %

Procedure:
To a RBF was added 2-bromo-1-fluoro-4-methoxybenzene (1.850 mL, 9.02 mmol, Oakwood), 3-fluoro-5-formylphenylboronic acid (1667 mg, 9.93 mmol, Combi-blocks), tetrakis(triphenylphosphine)palladium (521 mg, 0.451 mmol) and potassium carbonate (3741 mg, 27.1 mmol). A condenser and septum was attached and 1,4-dioxane (24.100 mL) and water (6.03 mL) were added. The mixture was heated at 90° C. for 2 h, at which time the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with brine (20 mL) and dried over MgSO4. The solution was filtered and concentrated. The residue was absorbed onto a plug of silica gel and purified by chromatography through a 50 g silica column, eluting with a gradient of 0% to 30% EtOAc in Heptane, to provide 2′,5-difluoro-5′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (640 mg, 2.58 mmol, 28.6% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.01-10.14 (m, 1H), 8.01 (q, J=1.56 Hz, 1H), 7.82 (tdd, J=1.41, 2.59, 9.76 Hz, 1H), 7.67-7.78 (m, 1H), 7.32 (dd, J=9.65, 10.42 Hz, 1H), 7.18 (dd, J=3.23, 6.46 Hz, 1H), 7.05 (td, J=3.57, 9.00 Hz, 1H) 3.83 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[Cl:20].O>C1COCC1>[Cl:20][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:10]=1[NH:9][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(Cl)CCCCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)CCCCCl)c(Cl)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 696 μl (0.84 g, 5.39 mmol) 5-chloro-pentanoylchloride in 10 ml THF is slowly added dropwise to 1.00 g (5.39 mmol) methyl 4-amino-3-chloro-benzoate in 20 ml THF with 1 ml TEA with stirring in the ice bath. After stirring for 16 hours at ambient temperature, for 3 hours at 50° C. and for 3 hours at reflux temperature the mixture is poured into water and extracted with ethyl acetate. After the organic phases have been dried over sodium sulphate the mixture is evaporated down i. vac. and the residue remaining is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 85:15).