Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (72 mg, 0.20 mmol) in methanol (20 mL) was added sodium hydroxide (50 mg, 1.25 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (3N). The product formed a precipitate and was filtered to give 2-(4-fluorophenyl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (41.5 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][C:29]([F:32])([F:31])[CH2:28][N:27]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:32][C:29]1([F:31])[CH2:28][NH:27][C@H:26]([CH2:25][N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])=[N:9]2)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-4,4-difluoropyrrolidine-1-carboxylate (600 mg, 1.11 mmol, 1.00 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) dropwise. The resulting solution was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to give 0.85 g (crude) of 1-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetic acid salt as a brown semi-solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][S:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:11][C:10]=2[C:24]([F:27])([F:26])[F:25])(=[O:8])=[O:7])[CH2:3][CH2:2]1.CI.[CH2:30]([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>ClCCl.O>[CH:1]1([CH2:4][N:5]([CH3:30])[S:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:11][C:10]=2[C:24]([F:26])([F:27])[F:25])(=[O:7])=[O:8])[CH2:3][CH2:2]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(NCC1CC1)c1ccc(Nc2ccc(Cl)cc2Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CI
Product: CN(CC1CC1)S(=O)(=O)c1ccc(Nc2ccc(Cl)cc2Cl)cc1C(F)(F)F
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of N-Cyclopropylmethyl-4-(2,4-dichloro-phenylamino)-2-trifluoromethyl-benzenesulfonamide, (256 mg. 0.58 mmol), methyl iodide (92 mg, 0.65 mmol) and tetrabutylammonium hydrosulfate (38 mg, 0.11 mmol) in 15 ml dichloromethane 3 ml 25% solution of NaOH was added and mixture was stirred for 3 hours. Water was added and mixture was washed twice with 1 N HCl and brine. After drying over sodium sulfate solvent was evaporated and crude solid used in the next stage. Yield 97%.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].O.NN>C(O)COCCO>[CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(CC(=O)O)CC(=O)CCCCCCCCCCC(=O)O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CC(CCCCCCCCCCCCC(=O)O)CC(=O)O
Temperature: 220 °C
Yield: 91.7 %

Procedure:
35 g (0.11 mol) of 3-methyl-5-keto-hexadecanedioic acid (obtained as described under (a) above), 30.8 g (0.55 mol) of potassium hydroxide, 150 ml of diethylene glycol and 20.6 g (0.33 mol) of 80% strength hydrazine hydrate are heated to the reflux temperature for 2 hours. Water and excess hydrazine are then distilled off and the residue is heated for one hour at 220° C. When it has cooled to 15° C., the reaction mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The residue which remains after removing the ethyl acetate from the organic phase is recrystallized from petroleum ether. 30.3 g (91% of theory) of 3-methyl-hexadecanedioic acid are obtained. Melting point: 77°-78° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].[CH3:26][S:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].Cl.N1C=CC=CC=1.C(OCCO)C>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][C:3]([C:24]#[N:25])=[C:2]2[NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=1[S:27][CH3:26]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCOCC1
Reactant: CSc1ccccc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccccc3SC)c(C#N)cnc2cc1OCCCN1CCOCC1

Procedure:
The method of Example 312 was used as well as 0.3 g of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline-3-carbonitrile, 0.14 ml of 2-(methyl mercapto) aniline, 0.1 g of pyridine hydrochloride and 4.0 ml of 2-ethoxy ethanol. This afforded an oil which was purified by silica gel flash chromatography [methylene chloride/methanol (96:4) ] to give 0.16 g of the title compound as an off white solid, mp 179-180 C; mass spectrum (ES, m/e):M+H465.
Reaction SMILES: [OH-:1].[K+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1.O[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(O)C.O>[NH:3]1[C:11]2[C:6](=[C:7]([CH:12]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:1])=[O:17])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1cccc2[nH]ccc12)c1ccccc1O
Reaction time: 23 h

Procedure:
0.5 ml of a 38% potassium hydroxide solution was added with stirring at 30° C. under an inert atmosphere to a mixture of 0.132 g of indol-4-carboaldehyde, 0.1 ml of 2-hydroxy-acetophenone and 0.189 g of triethylbenzyl ammonium chloride in 2 ml of ethanol and after stirring at 30° for 23 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant and evaporated to dryness. The residue was chromatographed over silica and eluted with methylene chloride to obtain 159 mg of 3-(1H-indol-4-yl)-1-(2-hydroxy-phenyl)-2-propen-1-one melting at ≃164° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][NH:25][C:24]4=[O:29])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:30]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][N:25]([CH3:30])[C:24]4=[O:29])=[CH:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCNC4=O)cc3)CC2)c(C)c1
Reactant: CI
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCN(C)C4=O)cc3)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}tetrahydropyrimidin-2-one (78 mg) described in Example 446 and methyl iodide (14 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (49 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].IC.[C:15](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:2]=1[NH:1][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)ccc1N
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CNc1ccc(Cl)cc1C(=O)OC
Reaction time: 48 h
Yield: 12.7 %

Procedure:
A mixture of methyl 2-amino-5-chlorobenzoate (1.0 g, 5.4 mmol), iodomethane (0.75 ml, 12.0 mmol), potassium carbonate (1.7 g, 12.4 mmol), and acetonitrile (20 ml) was stirred for 48 hours. The mixture was filtered through a pad of celite under suction and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate-hexane (1:19) to provide 5-chloro-2-methylaminobenzoic acid methyl ester (137 mg, 13% yield) followed by 5-chloro-2-dimethylaminobenzoic acid methyl ester (809 mg, 70% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C@@H:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28]([O:32][C:33]([NH:35][C:36]([CH3:42])([CH3:41])[CH2:37][C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:20])[C@H:10]([NH:11][C:38](=[O:39])[CH2:37][C:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])([CH3:42])[CH3:41])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CC(=O)N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
D-Homophenylalanine benzyl ester (725 mg; 3.23 mmol) whose preparation was described in Example 7 Step B, triethylamine (750 ml; 5,38 mmol) and 3-t-butoxycarbonylamino-3-methylbutanoic acid (585 mg; 2.69 mmol) were dissolved in dry methylene chloride (10 ml) and BOP (1.19 g, 2.69 mmol) was added with stirring in small batches to give a slightly cloudy solution. The reaction mixture was stirred at room temperature for 24 h then quenched by adding saturated brine (10 ml). The two phase system was extracted with methylene chloride (2×25 ml) and the combined methylene chloride extracts dried over magnesium sulfate powder, filtered and evaporated on a rotary evaporator under reduced pressure to give a cloudy, colorless oil. This material was taken up in the minimum volume of methylene chloride and chromatographed on silica gel using an eluant composed of ethyl acetate and hexanes in the ratio 1:1 v/v. The product was isolated after evaporation of the volatiles as a clear oil. The yield was 710 mg (88.5%). FAB-MS: -calculated for C27H36N2 O5 468.3; found 469.6 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH3:11])=[N:8][C:7]=2[CH:12]=1.[K].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>CN(C=O)C>[CH3:11][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])=[CH:12][C:7]=2[N:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc2cc(CBr)ccc2o1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc(CN3C(=O)c4ccccc4C3=O)ccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(bromomethyl)-2-methylbenzo[d]oxazole (400 mg; 1.76 mmol) in anh. DMF (2 ml) was treated portionwise with phthalimide potassium salt (327 mg; 1.76 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 18 h. Water was added, and the resulting precipitate was collected by filtration, and washed with water. Drying under HV afforded 2-((2-methylbenzo[d]oxazol-5-yl)methyl)isoindoline-1,3-dione as a brown solid. LC-MS (conditions E): tR=0.66 min.; [M+H]+: 293.15 g/mol.
Reaction SMILES: CC(C)=[O:3].S(=O)(=O)(O)O.[O:10]1[CH2:20][C:11]1([CH3:21])[CH:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH:13]1[OH:19]>>[CH:15]1([CH3:18])[CH2:16][CH2:17][CH:12]([C:11]([OH:3])([CH3:21])[CH2:20][OH:10])[CH:13]([OH:19])[CH2:14]1
Reactant: CC1CCC(C2(C)CO2)C(O)C1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Product: CC1CCC(C(C)(O)CO)C(O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a solution of acetone (116 g; 2 mol) and a 3% aqueous solution of sulfuric acid (35 g) was added 8,9-epoxy-p-menthan-3-ol (17 g; 0.1 mol), and the mixture was stirred at room temperature for 16 hours. Then, the acetone was distilled and recovered, and the concentrated solution was mixed with water (40 ml) and heated to within 80° C. of the distilling temperature to completely recover the acetone. The remaining aqueous solution was cooled, neutralized with a 10% aqueous solution of sodium carbonate, and saturated with sodium chloride. The reaction product was extracted with THF, dried over anhydrous magnesium sulfate, and concentrated to give a crude product (19 g). The crude product was purified by column chromatography on silica gel. That is, the crude product was eluted with 50% ethyl acetate-n-hexane, then eluted with ethyl acetate only, and the eluate was concentrated to give a highly pure title compound (4) (7 g; a mixture of diastereomers). This was a mixture of solid and liquid, and the mixing ratio of diastereomers was calculated as 7:3 by measuring with NMR. Analytical results on the title compound are given below. Optical rotation [α]D25=+15.6 (c=1, EtOH)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:15](O)(=O)[CH3:16].[CH3:19]O>>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:15]([CH3:16])[CH3:19])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(=O)O
Product: CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.0 g Piperidin-4-yl-carbamic acid tert-butyl ester in 15 ml methanol 7.34 ml acetone, 3.14 g Na(CN)BH3 and 0.3 ml acetic acid were added. After stirring for 16 h at RT the solvent was removed under reduced and the residue was partitioned between 30 ml of water and 30 ml ethylacetate. The organic layer was washed with saturated Na2CO3 solution, water and then dried over Na2SO4. The solvent was removed under reduced pressure and yields a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:21])[CH2:18][C:19]#[N:20])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)[CH3:2].Cl.[C:23]([Cl:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:19]([CH2:18][C@H:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)[CH2:12][CH2:13]1)[CH3:21])#[N:20].[CH2:23]([Cl:31])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCOc1ccc(NC2CCN([C@H](C)CC#N)CC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1ccc(N(C(=O)c2cccnc2)C2CCN([C@H](C)CC#N)CC2)cc1
Product: ClCc1cccnc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A solution of the above nitrile (0.18 g, 0.63 mmol) and nicotinoyl chloride hydrochloride (0.45 g, 2.5 mmol) in THF (6 mL) was then treated with DIPEA (0.55 mL, 3.2 mmol) and stirred at 80° C. for 16 h. The reaction was cooled to room temperature, concentrated under reduced pressure, diluted with CH2Cl2 (10 mL) and washed with brine solution (2×10 mL). The combined organic extracts were then dried (Na2SO4), filtered and concentrated and the crude material purified by flash column chromatography on silica gel (25:1:0.1 CH2Cl2/MeOH/NH4OH) to afford N-[(R)-1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-N-(4-ethoxy-phenyl)-nicotinamide impure with nicotinyl chloride (88%).
Reaction SMILES: [Na].[CH3:2][CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1)[CH2:4][CH3:5].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:2][CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][O:14][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:9][CH:8]=1)[CH2:4][CH3:5]
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Reactant: Clc1ccccn1
Agent: [Na]
Product: CCC(C)Oc1ccc(OCCOc2ccccn2)cc1

Procedure:
In the same manner, the sodium salt of 2-[4-(1-methylpropoxy)phenoxy]ethanol and 2-chloropyridine are reacted together to give 2-{2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine, MS m/e 288} (M+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:11]([NH:16][NH2:17])(=[O:15])[CH2:12][CH2:13][CH3:14].C([OH:20])C>>[OH2:3].[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:17][NH+:16]([O-:20])[C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH3:2])=[CH:5][CH:6]=1
Reactant: CCCC(=O)NN
Reactant: CCO
Reactant: CC(=O)c1cc[n+]([O-])cc1
Product: CCCC(=O)[NH+]([O-])N=C(C)c1ccncc1
Product: O
Yield: 84 %

Procedure:
A mixture of 5.48 gm (0.04 mole) of 4-acetylpyridine 1-oxide, 4.09 gm (0.04 mole) of butyric acid hydrazide and 100 ml of absolute ethanol is refluxed 6 hours. The reactions mixture is evaporated in vacuo to give a solid. The crude product is crystallized from ethyl acetate/ethanol to yield 7.41 gm (84%) of the title compound; mp 209.7°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1F)[CH:7]=[O:8])[CH3:2].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1[N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(C=O)cc(OCC)c1-n1cncn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of 3,5-diethoxy-4-fluoro-benzaldehyde (5.00 g, 23.56 mmol, 1.0 equiv; intermediate 21) in DMSO (50 mL) was added 1H-[1,2,4]triazole (3.26 g, 47.12 mmol, 2.0 equiv) and K2CO3 (6.51 g, 47.12 mmol, 2.0 equiv) and the reaction mixture stirred at 110° C. for 1 h. The solution was poured on crashed ice, the reaction mixture extracted with ethyl acetate (2×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was evaporated under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (1:1→0:1) providing 5.28 g (86%) of the title compound. MS (ESI): 261.9 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:7][N:6]=[C:5]([CH2:8][C:9]([OH:11])=O)[CH:4]=1.[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[C:3]([CH3:2])[NH:7][N:6]=2)[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: Cc1cc(CC(=O)O)n[nH]1
Agent: Cl
Product: Cc1cc(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)n[nH]1
Yield: 45 %

Procedure:
Proceeding as in Example 1, but substituting 2-(5-methyl-1H-pyrazol-3-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 177, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(5-methyl-1H-pyrazol-3-yl)acetyl)pyrrolidine-2-carboxamide (42 mg, 45%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 12.25 (s, 1H), 9.92 (s, 1H), 7.63-7.54 (m, 2H), 7.33-7.26 (m, 2H), 7.25-7.15 (m, 6H), 7.05-6.93 (m, 4H), 5.87 (s, 1H), 4.52-4.45 (m, 1H), 3.77-3.45 (m, 2H), 3.34-3.27 (m, 2H), 2.24-1.85 (m, 6H). MS (EI) for C30H29FN4O3. found 513.0 (MH+).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12](O)[CH2:13][CH2:14][OH:15].C(OC)(OC)OC.C(N(CC)CC)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:2]1([CH2:9][CH2:10][CH3:11])[O:15][CH2:14][CH2:13][CH2:12][O:1]1)[CH3:8]
Reactant: OCCCO
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC1(CC(=O)OCC)OCCCO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.5 %

Procedure:
A mixture of ethyl 3-oxohexanoate (5 g, 31.6 mmol), 1,3-propanediol (3.61 g, 47.4 mmol), trimethyl orthoformate (5.78 ml, 34.8 mmol), and p-toluenesulfonic acid monohydrate (272 mg, 1.58 mmol) was stirred at room temperature for 22 hours. After completion of the reaction, triethylamine (881 μl, 6.32 mmol) was added to the reaction mixture which was then concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (5.5 g, yield: 80.5%) as a light yellow oil.
Reaction SMILES: Cl[CH:2](Cl)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][S:12]([NH2:15])(=[O:14])=[O:13].[C:16](=[O:19])([O-])O.[Na+]>C(#N)C>[CH3:11][S:12]([N:15]=[C:2]([O:19][C:16]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:14])=[O:13]
Reactant: ClC(Cl)Oc1ccccc1
Reactant: CS(N)(=O)=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of dichlorophenoxymethane (1 g) in acetonitrile (10 mL) was added methanesulfonamide (0.39 g) under ice-cooling, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resuling mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1-(N-methanesulfonylimino)-1,1-diphenoxymethane (0.95 g). To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (50 mg) in tetrahydrofuran (1 mL) was added 1-(N-methanesulfonylimino)-1,1-diphenoxymethane (26 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2-aminoethanol (49 mg), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.008 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added acetic acid (0.01 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (38 mg).