Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20](OCCN(CC)CC)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.[Cl:33]C1N=C(C=O)C=CC=1.C(CC(N[C@H](C1C=CC=CC=1)CCC)=O)#N>>[C:31](/[C:9](=[CH:8]\[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:33])[N:7]=1)/[C:10]([NH:12][C@H:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Reactant: O=Cc1cccc(Cl)n1
Agent: CCC[C@H](NC(=O)CC#N)c1ccccc1
Product: CCC[C@H](NC(=O)/C(C#N)=C/c1cccc(Cl)n1)c1ccccc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 6-chloropicolinaldehyde was used instead of 6-bromopicolinaldehyde, and (S)-2-cyano-N-(1-phenylbutyl)acetamide was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 8:2 hexanes/ethyl acetate, to give 41 (105 mg, 95%) as a clear oil: MS (ES+) m/z340.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20](OCCCC)=[O:21])[O:17][C:16]2=[O:27])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH3:28]>CO>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20]([NH2:28])=[O:21])[O:17][C:16]2=[O:27])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: N
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The butyl (5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 1, 350 mg, 0.910 mmol) is treated with 7N ammonia in methanol (9.1 mL) under N2, and the mixture is stirred at ambient temperature for 30 mins. The reaction mixture is then concentrated under reduced pressure, and the residue is recrystallized from EtOAc/hexanes to give the title compound, mp 181–183° C.; MS (ESI+) for C14H15N3O4F2 m/z 328 (M+H)+; [α]25D−23 (c 0.94, DMSO).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].O>C1COCC1>[CH2:26]([O:25][C:23]([NH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C=NN)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Nc1ccc(C=NNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.50 g (1.66 mol) of ethyl (3-(4-(aminoiminomethyl)phenyl)ureido)acetate in 20 ml of THF is treated with 2.7 ml of 1N NaOH and cooled to 0° C. 0.29 ml (1.99 mmol) of benzyl chloroformate is added to this mixture and it is stirred at room temperature for 2 h. The pH is kept between 9 and 10 using 1N NaOH. The mixture is then treated with 50 ml of water and extracted with ethyl acetate. After drying (MgSO4), the solvent is removed in vacuo and the residue is stirred with ether.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH3:13]CN=C=NCCCN(C)C.Cl.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:13][O:11][C:10]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:1][CH:2]=1)=[O:12]
Reactant: O=C(O)c1coc2ncccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1coc2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of furo[2,3-b]pyridine-3-carboxylic acid (53 mmol) in 85 mL DCM were added EDC.HCl (58 mmol), DMAP (16 mmol) and 4.3 mL MeOH. The beige suspension was stirred at RT for 2 h. The reaction mixture was diluted with 50 mL DCM and quenched with sat. aq. NaHCO3 solution. The organic phase was washed 3 times with sat. aq. NH4Cl solution and once with brine. The organic layer was dried over MgSO4 and concentrated in vacuo to obtain the desired compound as grey solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CO>C1(C)C=CC=CC=1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:20][C:19]2[CH:21]=[CH:22][C:16]([Br:15])=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: Brc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The method of Taguchi and Westheimer1 was modified as follows: benzophenone (455 g, 2.50 mol) and 4-bromoaniline (473 g, 2.75 mol) were dissolved in toluene (1.2 L) under argon in a 5 L flask containing activated molecular sieves (5 Å, 1.25 kg). The flask was fitted with a reflux condenser, rubber septum, and pressure outlet. The mixture was heated to gentle reflux and shaken occasionally; an intense yellow color soon developed. After 18 h, heating was discontinued and the solution was cooled to rt. The solution was decanted from the molecular sieves, and the sieves were washed with Et2O until the filtrate was colorless. The combined organic solutions were concentrated in vacuo to give an orange oil. MeOH (ca. 80 mL) and a seed crystal of 1 were added. The product was allowed to crystallize at 0° C. and the precipitate was collected by filtration. The mother liquor was further concentrated, and a second crop of crystals was collected from MeOH. Recrystallization of the combined material from MeOH afforded yellow crystals (760 g, 90%). 1: mp 82-83° C.; 1H NMR (300 Mz, CDCl3) δ 7.75 (dd, J=6.9, 1.6 Hz, 2H), 7.52-7.39 (m, 3H), 7.32-7.23 (m, 5H), 7.11 (dd, J=8.5, 2.0 Hz, 2H), 6.61 (dt, J=8.5, 2.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 168.7, 150.4, 139.5, 136.1, 131.6, 131.0, 129.5, 128.8, 128.3, 128.2, 122.8, 116.3, 103.6;IR(CDCl3) 3058, 3024, 1615, 1478 cm−1; Anal. Calcd for C19H14BrN: C, 67.87; H, 4.20. Found: C, 68.08; H, 4.28.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[C:21]3[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O.C(Cl)Cl>[C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:30])=[CH:15][C:14]=3[C:21]3[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COc1ncccc1-c1cc(C#N)ccc1OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile (1.15 g, 3.07 mmol) in dimethylsulfoxide (25 mL) and methylene chloride (25 mL) was added potassium carbonate (0.85 g, 6.15 mmol) followed by addition of 35% hydrogen peroxide aqueous solution (5.30 mL, 61.60 mmol) dropwise. The mixture was stirred at ambient temperature for 4 h, the volatiles were removed by evaporation in vacuo. The residue was diluted with water (100 mL). The precipitate was collected by filtration and washed with water to give the title compound as a colorless solid (0.97 g, 80%): 1H NMR (300 MHz, CDCl3) δ 8.18-8.15 (m, 1H), 7.84-7.79 (m, 1H), 7.71-7.69 (m, 1H), 7.54-7.50 (m, 1H), 6.95-6.91 (m, 2H), 5.85 (br s, 2H), 3.87 (s, 3H), 3.49 (s, 2H), 1.89 (br s, 3H), 1.68-1.37 (m, 12H); MS (ES+) m/z: 393.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([CH2:21][OH:22])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][CH3:27].Cl>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([CH2:21][O:22][CH2:24][CH2:25][O:26][CH3:27])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(CO)nn1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: COCCBr
Agent: Cl
Solvent: CN(C)C=O
Product: COCCOCc1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 80 °C

Procedure:
To a solution of 500 mg of 2-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-hydroxymethyl-2H-pyrazole-3-carboxylic acid in 5 ml DMF 480 mg Cs2CO3 and 204 mg 1-Bromo-2-methoxy-ethane were added and the mixture was heated to 80° C. for 5 h. Then the mixture was acidified to pH 4 with aqueous HCl and filtered through a chem elut® cartridge by elution with ethyl acetate. After concentration the crude product was directly subjected to the next reaction step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-morpholino-2-phenylquinoxaline-6-carboxylate (136.4 mg, 0.39 mmol, 1.00 equiv) in methanol (12 mL), a solution of sodium hydroxide (78.2 mg, 1.96 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was sent for prep-HPLC. This resulted in 56 mg (41%) of 3-morpholino-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(OCC)(=O)[CH2:18][C:19]([O-:21])=[O:20].[Na]>>[N+:14]([C:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH2:18][C:19]([OH:21])=[O:20])([O-:16])=[O:15]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [Na]
Product: O=C(O)Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
2,4,6-Trinitrophenylacetic acid (mp 159°-160° C.) is prepared from 1-chloro-2,4,6-trinitrobenzene and ethyl malonate in the presence of metallio sodium in accordance with a procedure by M. Kimura in J. Pharm. Soc. Jpn., 73, 1216 (1953).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:5](OCC)=[O:6].[NH:17]([C:19]1[N:24]=[CH:23][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][CH:20]=1)[NH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:6]=[C:5]1[N:17]([C:19]2[N:24]=[CH:23][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][CH:20]=2)[NH:18][CH:3]=[C:4]1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NN)nc1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 0 °C

Procedure:
2.2 g (10.0 mmol) of the compound from Example 2A are initially charged in 50 ml of ethanol. 2.1 g (10.0 mmol) of the compound from Example 15A and 380 mg (2.0 mmol) of p-toluenesulfonic acid are added, and the mixture is stirred under reflux for 16 h. The mixture is then cooled to 0° C., and the solid formed is filtered off and washed once with a little ethanol (batch 1). The mother liquor is concentrated and the residue is triturated with a little ethanol. The solid obtained is filtered off and washed once with ethanol (batch 2). The two solids batches are combined and dried under high vacuum. The solid is then stirred in tert-butyl methyl ether for 30 min, filtered off again and dried under high vacuum.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][CH:9]([C:14](=O)[CH3:15])[C:10](OC)=[O:11])=[CH:6][CH:5]=1)#[N:2].[NH2:19][C:20]([NH2:22])=[NH:21].C(O)(=O)C>CCO>[NH2:22][C:20]1[N:21]=[C:10]([OH:11])[C:9]([CH2:8][C:7]2[CH:17]=[CH:18][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=2)=[C:14]([CH3:15])[N:19]=1
Reactant: N=C(N)N
Reactant: COC(=O)C(Cc1ccc(CC#N)cc1)C(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1

Procedure:
A mixture of the crude product from step (i) and guanidine (16 g) in EtOH (350 ml) was heated under reflux for 5 h. The mixture was cooled, neutralised with acetic acid, and the solid filtered and dried, 22.1 g.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.I[CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:9]([N:6]1[CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:7]1)[CH3:10]
Reactant: CCI
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCNC(=O)C1
Temperature: 55 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
A mixture of 2-oxopiperazine (1.07 g), iodoethane (1.72 g) and potassium carbonate (2.76 g) in acetonitrile (50 mL) was stirred at 55° C. for 3 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with DCM and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-40% to give 4-ethylpiperazin-2-one (0.991 g) as a colourless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH2:19])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1.[C:24]1([C:30]2[S:31][CH:32]=[C:33]([C:35](O)=[O:36])[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH:19][C:35]([C:33]4[N:34]=[C:30]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[S:31][CH:32]=4)=[O:36])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Solvent: O
Product: O=C(Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1)c1csc(-c2ccccc2)n1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(morpholinomethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 2-phenylthiazole-4-carboxylic acid. The product was isolated by precipitation by the addition of water, triturated with hot methanol, dissolved in CH2Cl2, washed with dilute NaHCO3, concentrated and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C27H23N5O2S2: 513.13. Found (M+H)+ m/z=514.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].O.[CH:26]([CH:28]=O)=O.O>C(O)CCC>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[NH:10][C:11](=[O:14])[C:12]2[C:7](=[N:6][CH:26]=[CH:28][N:13]=2)[N:8]=1)[CH2:23][CH3:24]
Reactant: O=CC=O
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCO
Product: CCCOc1ccccc1-c1nc2nccnc2c(=O)[nH]1
Yield: 97.5 %

Procedure:
A stirred mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.25 g), glyoxal hydrate (0.4 g), water (62.5 ml) and n-butanol (1 ml) was heated under reflux for one hour to afford a crude product (0.97 g) which was collected and washed with water. The crude product together with another sample (0.12 g) similarly prepared was eluted from a silica column with chloroform. The combined fractions containing product were evaporated under reduced pressure to afford a solid (0.96 g) which was recrystallized from ethanol-water to afford the title compound, 0.8 g, m.p. 177.5-178.5° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4].[SH:10][CH2:11][C:12](O)=[O:13]>C(#N)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>[C:1]([O:6][CH2:7][CH:8]1[S:10][CH2:11][C:12](=[O:13])[O:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC=O
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CCCC(=O)OCC1OC(=O)CS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A solution of 24 (3.90 g, 0.030 mol), mercaptoacetic acid (3.32 g, 0.036 mol) and p-TsOH.H2O (0.28 g, 1.5 mmol) in acetonitrile (600 ml) was heated at reflux for 3.5 hours. During the period of reflux, four portions of 25 ml each were drained from a Dean-Stark trap (to remove the water-acetonitrile azeotrope). Analysis of the reaction solution by TLC (6:1 hexane:AcOEt) revealed one major new component and no unreacted aldehyde (visualized by PMA and 2,4-DNP stains). The reaction solution was allowed to stir at room temperature for 16 hours, and then evaporated to dryness. The residue was partitioned between concentrated NaHCO3 (50 ml) and AcOEt (75 ml); the aqueous portion was extracted with additional AcOEt (2×75 ml). The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude material (6 g) was purified by flash chromatography (125 grams silica gel with 20% ethyl acetate in hexane). Compound 25 (3.27 g, 16 mmol, 53%) was obtained as an oil: TLC (3:1 hexane:AcOEt)—one spot with Rf=0.41; 1H-nmr (CDCl3)—compatible with structure; mass spectrum (FAB)—m/z=205.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])=[CH:8][CH:9]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[C@@H](O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CNC[C@@H](C)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A solution of (R)-(−)-1-amino-2-propanol (9.00 g, 0.12 mol) in tetrahydrofuran (40 ml) and acetic acid (5 ml) was added dropwise to a solution of p-anisaldehyde (5.45 g, 0.04 mol) in tetrahydrofuran (40 ml), and once addition was complete, the solution was stirred at room temperature for 2 hours. The solution was cooled in an ice-bath, and sodium triacetoxyborohydride (9.50 g, 0.0.045 mol) was added portionwise, and then the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (150 ml) and sodium hydroxide solution (150 ml, 0.5N). The layers were separated and the aqueous phase was saturated with sodium chloride, then extracted with further dichloromethane (3×30 ml). The combined organic solutions were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (gradient elution 98:2:0.2 to 97:3:0.3 dichloromethane:methanol:0.88 NH3) to afford an orange oil (4.9 g). 1H-NMR (CDCl3, 400 MHz) δ: 1.12 (d, 3H), 2.39 (dd, 1H), 2.70 (dd, 1H), 3.62-3.79 (m, 6H), 6.82 (d, 2H), 7.19 (d, 2H). LRMS: m/z (ES+) 196 [MH+].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[I:12]I>CN(C)C=O.S([O-])([O-])(=O)=O.[Ag+2]>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([I:12])[C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: II
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ncc(C(F)(F)F)cc1I
Reaction time: 14 h

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (3-a with R4═CF3, 1.6 g, 9.87 mmol) (Maybridge Chemical company, Cornwall, England) in N,N-dimethylformamide (30 mL) was treated at room temperature with silver sulfate (3.1 g, 9.87 mmol) and iodine (2.5 g, 9.87 mol). The reaction mixture was stirred for 14 h and filtered. The filtrated solution was concentrated in vacuo. The residue was chromatographed (SiO2, 25% ethyl acetate in hexanes) to give 5-(trifluoromethyl)-3-iodopyridin-2-amine (3-b, with R4═CF3). The iodide (3-b, with R4═CF3, 1.0 g, 3.47 mmol) and cuprous cyanide (CuCN, 78 g, 8.68 mmol) was dissolved in N,N-dimethylformamide (6 mL) and heated under the microwave at 100 C for 30 min, cooled to ambient temperature, and diluted with ethyl acetate. The precipitates were removed by filtration. The filtrated solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with hexanes afforded the desired product, 2amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4═CF3). 2amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4═CF3, 545 mg, 29.2 mmol) was stirred in methanol (10 mL, saturated with ammonia) under hydrogen atmosphere in the presence of Pd/C (200 mg) overnight. The reaction mixture was filtered and the filtrate solution was concentrated in vacuo to afford the crude amine (3-d, with R4═CF3). A solution of (S)-2-phenylbutanoic acid (300 mg, 18.3 mmol) and diisopropylethylamine (888 uL, 52.4 mmol) in N,N-dimethylformamide (5 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 953 mg, 18.3 mmol). After 15 min, 3-(aminomethyl)-5-(trifluoromethyl)pyridin-2-amine (500 mg, 26.2 mmol) was added. The reaction mixture was stirred for 2 h, partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give the desired product (3-g); HRMS (M+1)=338.1405.
Reaction SMILES: [N+:1](C1C=C(C=CC=1C)C(O)=O)([O-:3])=[O:2].FC1C=C(C=CC=1C)C(O)=O.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=[CH:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][C:42]=1F)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=[CH:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][C:42]=1[N+:1]([O-:3])=[O:2])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C=Cc2ccccc2OCc2ccccc2)c(F)c1
Agent: Cc1ccc(C(=O)O)cc1F
Product: COC(=O)c1ccc(C=Cc2ccccc2OCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
Methyl 4-[2-(2-benzyloxyphenyl)ethenyl]-3-nitrobenzoate was prepared from 3-nitro-4-methylbenzoic acid using the methods described in Example 8 for the conversion of 3-fluoro-4-methylbenzoic acid to methyl 4-[2-(2-benzyloxyphenyl)ethenyl]-3-fluorobenzoate.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:8]1([C:18](O)=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>>[C:8]1([C:18]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: C1CNCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: O=C(c1cccc2ccccc12)N1CCCNCC1
Reaction time: 8 h

Procedure:
Homopiperazine (0.60 g, 6.0 mmol), naphthalene carboxylic acid (0.51 g, 3.0 mmol), 1-hydroxybenzotriazole (0.45 g, 3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (0.63 g, 3.3 mmol) were added to dry, degassed dimethylformamide (7 mL). The pH of the reaction was adjusted to 7 with triethylamine, and the reaction stirred overnight. The dimethylformamide was distilled in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was chromatographed on silica gel using chloroform/methanol as eluant and the title compound was isolated (0.100 g). NMR (CDCl3, 300 MHz) d 7.88 (2H, m), 7.50 (3H, m), 7.27 (1H, m), 4.08 (1H, m), 3.81 (1H, m), 3.28 (2H, m), 3.18 (1H, m), 3.00 (1H, m), 2.92 (1H, t, J=7 Hz), 2.72 (1H, t, J=7 Hz), 2.20 (1H, m), 1.58 (1H, m).