Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([NH2:13])[CH:7]=[CH:6][N:5]=1.[Cl:14][C:15]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[C:16]=1[C:17](Cl)=[O:18]>CN(C=O)C>[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([NH:13][C:17](=[O:18])[C:16]2[C:20]([Cl:26])=[CH:21][C:22]([C:24]#[N:25])=[CH:23][C:15]=2[Cl:14])[CH:7]=[CH:6][N:5]=1
Reactant: Nc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(Cl)c2[N+](=O)[O-])c(Cl)c1
Reaction time: 0.33 h
Yield: 46.4 %

Procedure:
NaH (0.46 g, 11.6 mmol, 60% dispersion in mineral oil) was added in one portion to a cooled (0° C.) solution of 2-chloro-3-nitropyridin-4-amine (1.00 g, 5.8 mmol) in DMF (15 mL). The mixture was stirred for 20 mins and then a solution of 2,6-dichloro-4-cyanobenzoyl chloride (0.68 g, 2.9 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 4 hours and then poured onto ice-water (20 mL). The resulting precipitate was collected by filtration and then the filtrate was extracted by EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was combined with previously collected precipirate and the material was purified by silica gel column chromatography (MeOH:CH2Cl2 1:10) to afford N-(2-chloro-3-nitropyridin-4-yl)-2,6-dichloro-4-cyanobenzamide (0.5 g, yield: 23%). LCMS (ESI) m/z: 372.6 [M+H+]
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C:8](=[O:28])[C@@H:9]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)(=[O:3])[CH3:2]>C(OC(C)C)(C)C>[C:1]([NH:4][CH2:5][CH2:6][O:7][C:8](=[O:28])[CH:9]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCOC(=O)[C@H](Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Solvent: CC(C)OC(C)C
Product: CC(=O)NCCOC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 44 °C
Reaction time: 1 h

Procedure:
(−)-(4-Chloro-phenyl)-(R)-(3-trifluoromethyl-phenoxy)-acetic acid 2-acetylamino-ethyl ester (90.0 g) was dissolved in diisopropylether (900 mL) at 55° C. The resulting mixture was polish filtered, the solution cooled to 44° C. over about 20 minutes and seeded. The resulting mixture was stirred for 1 hour at 44° C., cooled to 35° C. over 4 hours, then stirred at 35° C. for 2 hours to yield a thick suspension. The suspension was cooled to −5° C. over about 5 hours and then stirred at −5° C. The resulting crystals were filtered off with a centrifuge and washed with precooled (−5° C.) diisopropylether (100 mL). The wet product was dried at 30° C. to yield the title compound as a white crystalline solid, more specifically as white crystals, needles.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-[4-(2-Amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.040 g, 0.10 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.019 g, 0.13 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1), 1.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1) and finally 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained after trituration with diethyl ether as a pale yellow solid (0.005 g, 10%); 1H-NMR (250 Mz, DMSO-d6) 2.78 (m, 4H, piperazine N(CH2)2), 3.01 (s, 6H, N(CH3)2), 3.40 (s, 2H, NCH2CO), 3.72 (m, 4H, piperazine N(CH2)2), 6.83 (d, J=8.79 Hz, 2H, 3,5-ArH or 2,6-ArH), 7.25 (d, J=3.42 Hz, 1H) and 7.51 (d, J=3.53 Hz, 1H) (thiazole 4-H, 5-H), 8.03 (d, 3H, J=9.88 Hz, 3,5-ArH or 2,6-ArH, and imidazo[4,5-b]pyridine 5-H); 11.95 (s, 1H, CONH), 13.12 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z) 6.17 min—497, 499 [(M+H)+, Cl isotopic pattern]; ESI-HRMS Found: 497.1652, calculated for C23H26N8ClOS (M+H)+: 497.1633.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].Cl.[C:18]([NH2:26])(=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>CN(C)C(=O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:26]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:25]=1
Reactant: N#Cc1c(F)cccc1Oc1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1nc(-c2ccccc2)nc2cccc(Oc3ccccc3)c12
Temperature: 150 °C
Yield: 12.3 %

Procedure:
A mixture of 2-fluoro-6-phenoxybenzonitrile (2.7 g, 13 mmol, Maybridge), benzamidine hydrochloride (3.0 g, 19 mmol, Aldrich) and sodium acetate (1.6 g, 19 mmol) in 60 mL of N,N-dimethylacetamide was heated at 150° C. under nitrogen for 6.5 hours. After cooling to room temperature the reaction mixture was evaporated under reduced pressure. The product was suspended in a mixture of 20 mL of ethanol and 100 mL of water, and 10 mL of concentrated ammonium hydroxide was added. The solid was collected by vacuum filtration, washed with water, dried, recrystallized twice from 60 mL of 2-propanol at 4° C., and dried at 50° C. under vacuum to give 0.5 g (12% yield) of 4-amino-2-phenyl-5-phenoxyquinazoline, m.p. 190-191° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=O)[NH:2]1.[O-:14][C:15]#[N:16].[K+].Cl>C(O)(=O)C.O>[C:11]1(=[O:13])[CH:3]2[N:2]([CH2:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4]2)[C:15](=[O:14])[NH:16]1
Reactant: N#C[O-]
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)N2Cc3ccccc3CC12
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a suspension of 53.1 g (0.30 mole) of 1,2,3.4-tetrahydroisoquinoline-3-carboxylic acid in 1000 ml glacial acetic acid was added quickly a solution of 48.6 g (0.60 mole) of potassium cyanate in 150 ml water. The mixture was stirred and heated on a steam bath at 90°-95° for 90 min and all solids dissolved. 3N hydrochloric acid (2400 ml) was added and the resulting solution was stirred and refluxed for 20 hr. The solution was filtered while hot through a coarse sintered glass funnel to remove mechanical impurities and the filtrate was stored in the refrigerator for 18 hrs to deposit 44 g of the crude product. Recrystallization from 1400 ml alcohol gave 29.9 g (49%) of the cyclized material, m.p. 225°-231°. Further recrystallization from alcohol gave the analytical sample, m.p. 227°-230°.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].S(O[CH:43]1[CH2:46][O:45][CH2:44]1)(C1C=CC(C)=CC=1)(=O)=O>CC(N(C)C)=O>[O:45]1[CH2:46][CH:43]([S:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:9]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)=[O:10])=[CH:4][CH:3]=2)[CH2:44]1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(SC2COC2)cc1
Temperature: 130 °C

Procedure:
A mixture of 2-(4-mercaptophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (see EXAMPLE 146, 349 mg, 1.0 mmol), K2CO3 (152 mg, 1.1 mmol), NaI (150 mg, 1.0 mmol), and 3-(tosyloxy)oxetane (274 mg, 1.2 mmol) in anhydrous DMAc (20 mL) was heated for 2 h at 130° C. The solvent was evaporated off under reduced pressure, then the residue was partitioned between CH2Cl2 (75 mL) and 2% aqueous citric acid (20 mL). The organic layer was washed with H2O (20 mL), saturated aqueous Na2CO3 (20 mL), and brine (20 mL), before being dried (MgSO4). Filtration and solvent evaporation afforded 2-[4-(oxetan-3-ylsulfanyl)phenyl]-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=405.2 [M+H]+. This thioether was oxidised employing the protocol outlined in EXAMPLE 148 to give the title compound: RTA=3.04 min; m/z (ES+)=437.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][C:15]2([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][C:15]3([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)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: Cc1ccccc1
Solvent: O
Product: CC1(C)CC(=O)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
Prepared by coupling 3-fluorophenylboronic acid with an equivalent amount of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one using a catalytic amount of tetrakis(triphenylphosphine)palladium(0) with overnight refluxing in toluene containing an equivalent amount of potassium carbonate dissolved in water. Work up in the usual manner followed by recrystallization from ethanol gave a grey solid: mp 190-192° C. 1H-NMR (DMSO-d6) δ 10.27 (s, 1H), 7.57 (s, 1H), 7.50 (m, 4H), 7.15 (m, 1H), 6.95 (d, 1H J=8.2 Hz), 2.39 (s, 2H), 1.29 (s, 6H); MS (APCI (−)) m/z 268 [M−H]− Anal. Calc. For C17H16FNO 0.25 H2O: C, 74.57, H, 6.07, N, 5.12. Found: C, 74.86, H, 5.97, N 5.06.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[CH:33][N:32]=1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccnc(Cl)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 5, the title compound was synthesized from (1,1-dioxo-thiomorpholin-4-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Example 2) and 2-chloropyridine-4-boronic acid. The desired product was obtained in a yield of 8% as an off-white solid. MS (m/e): 531.5 (M+, 100%).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([O:9][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: BrCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)SCC(CC(C)C)C(=O)OCc1ccccc1
Yield: 83.2 %

Procedure:
A solution of 3-acetylthio-2-isobutylpropionic acid [obtained by Michael addition of thiolacetic acid onto 2-isobutylacrylic acid] (7 g, 34.3 mmol), benzyl bromide (4.29 ml, 36 mmol) and DBU (5.2 ml, 35 mmol) in toluene (55 ml) was stirred for 18 hours at room temperature. The solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic layer was washed with brine and dried over MgSO4. Purification of the residue by chromatography on silica gel (eluant: dichloromethane-ether (9:1)) gave benzyl 3-acetylthio-2-isobutylpropionate (8.4 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Br:1][CH2:2][C:3]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([O:7][CH3:6])=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])=[O:4]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromoacetylbromide (17.9 ml; 0.20 moles) in CH2Cl2 (30 ml) was slowly added to a mixture of 4-methoxy-2-nitroaniline (30 g; 0.18 moles) and triethylamine (28 ml; 0.2 moles) in CH2Cl2 (300 ml). The reaction mixture was stirred at room temperature overnight, then poured into water. The aqueous layer was extracted with additional CH2Cl2, dried over MgSO4 and evaporated under vacuum. The crude product was crystallized from a 7/3 Et2O/EtOH mixture to give the title compound as a white solid. 31.5 g; m.p. 94-98° C.
Reaction SMILES: [H-].[Na+].Cl[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1.[SH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CN(C)C=O>[N:23]1[CH:24]=[CH:25][C:20]([S:19][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[CH2:6][CH2:5]2)=[CH:21][CH:22]=1
Reactant: Sc1ccncc1
Reactant: O=C(Oc1ccccc1)N1CCC(Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)N1CCC(Sc2ccncc2)CC1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 81.8 %

Procedure:
60% Sodium hydride dispersion in a mineral oil (2.40 g) was slowly added to an ice-cooled solution of phenyl 4-chloro-1-piperidine-carboxylate (15.2 g) and 4-mercaptopyridine (6.66 g) in dry N,N-dimethylformamide (150 ml) with stirring under nitrogen gas. The mixture was stirred at the same temperature for 30 minutes and then at 80° C. for 4.5 hours. The resultant reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, and concentrated to dryness in vacuo. The crystalline residue was recrystallized from a mixture of n-hexane and isopropanol to give phenyl 4-[(4-pyridyl)thio]-1-piperidine-carboxylate (15.4 g) as colourless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][OH:20])[C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][O:20][C:26]([C:22]1[O:21][CH:25]=[CH:24][CH:23]=1)=[O:27])[C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:27]
Reactant: CCCCCCCCCCCC(=O)N(CCO)CCO
Reactant: O=C(Cl)c1ccco1
Product: CCCCCCCCCCCC(=O)N(CCOC(=O)c1ccco1)CCOC(=O)c1ccco1

Procedure:
N,N-bis(2-furoyloxyethyl)lauramide was prepared by the procedure of example 1 from 28 gms. (0.1 mole) of N,N-bis(2-hydroxyethyl)lauramide and 26 gms. (0.2 mole) of furoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:3]1([C:1]#[N:2])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccccn2)CCNCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
tert-Butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate (I-2) (5.45 g, 19 mmole) was dissolved in TFA-DCM (1:1, 50 mL) at 0° C. The resultant reaction mixture was stirred for 40 min at 0° C. After this time, LCMS indicated that the reaction was completion. The reaction mixture solution was concentrated. The residue was treated with 2N NaOH-brine (1: 1, 80 mL) and extracted with EtOAc (5×200 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, concentrated to afford the desired product 4-pyridin-2-ylpiperidine4-carbonitrile (I-3) as a yellow solid. Analytical LCMS: single peak (214 nm), 0.962 min. This product was used in next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][C@H:38]([CH2:41][CH3:42])[CH2:39][OH:40]>>[OH:40][CH2:39][C@H:38]([NH:37][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH2:41][CH3:42]
Reactant: CC[C@@H](N)CO
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: CC[C@H](CO)NC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 89.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 51 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:20][CH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:5][CH2:6][CH2:7][S:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCSc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a solution of 2.84 g (10.0 mmol) of 4-(2-phthalimidoethylthio)pyridine in 150 ml of ethanol, 3.78 g (100 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to give 2.24 g of the desired compound (77.8% yield, colorless crystals), mp. 132°-133° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:19](O)=[O:20])[CH2:14][CH:13]1[CH2:33][CH3:34])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[N:46]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:45]C1.F[P-](F)(F)(F)(F)F.CN.C1COCC1.C(N(CC)CC)C>ClCCl.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:19](=[O:20])[NH:46][CH3:45])[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:14][CH:13]1[CH2:33][CH3:34])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Yield: 73 %

Procedure:
To a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid, 36, (1.7 g, 3.0 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (PyBOP) (2.0 g, 3.8 mmol) in anhydrous dichloromethane (10 mL) are added 2 M methyl amine solution in THF (1.5 mL, 3.0 mmol) and triethyl amine (1.0 mL, 7.4 mmol). The reaction mixture is placed in a refrigerator overnight. EtOAc (50 mL) and water (200 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product is purified over silica (EtOAc/hexane, 1:1) to afford 1.3 g (73% yield) of the desired product. 1H NMR (CDCl3, 300 MHz, δ): 7.75–7.65 (m, 3H), 7.55 (s, 1H), 7.39–7.29 (m, 2H), 7.29–7.2 (m, 1H), 7.10–7.02 (m, 2H), 6.90–6.82 (m, 2H), 6.51–6.30 (m, 1H), 5.31 (d, J=10.4 Hz, 1H), 4.85–4.15 (m, 2.5H), 3.55–3.12 (m, 3H), 3.00–2.05 (m, 10H), 1.85–1.45 (m, 10H), 0.7 (m, 3H); 13C NMR, (CDCl3, 300 MHz) δ 174.0, 172.0, 171.0, 170.0, 163.9, 160.6, 155.2, 137.4, 133.8, 132.4, 131.5, 131.4, 131.3, 131.2, 128.4, 128.0, 127.8, 126.4, 125.8, 116.0, 115.7, 115.4, 80.0, 70.9, 70.7, 60.7, 55.4, 52.1, 51.2, 51.0, 50.5, 49.8, 41.9, 40.2, 39.4, 38.0, 32.4, 28.6, 26.3, 23.3, 22.3, 21.4, 14.5, 10.8, 10.3.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28].O>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:17][C:15]1[CH:14]=[CH:13][C:5]2[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]([N+:27]([O-:32])=[O:28])[O:3][C:4]=2[CH:16]=1
Reactant: Cc1ccc2c(-c3ccccc3)c(Br)oc2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1
Reaction time: 16 h

Procedure:
To a stirred solution of 4 g (0.014 mole) of 2-bromo-6-methyl-3-phenylbenzofuran in 50 ml of acetic acid and 50 ml of chloroform is added 1.8 g (0.015 mole) of cyclohexene-4-carboxylic acid and a solution of 1.4 g (0.015 mole) of dinitrogen tetroxide in 10 ml of acetic acid. After sitting for about 16 hours the mixture is poured into water. This mixture is extracted with chloroform and the extracts are washed with water and 10% sodium bicarbonate solution and dried. Evaporation of the solvent and recrystallization of the residue from cyclohexane provides yellow crystals of 6-methyl-2-nitro-3-phenylbenzofuran, m.p. 142°-144° C.