Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4](Cl)=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>>[NH2:11][C:10]1[C:2]([F:1])=[C:3]([C:4]([C:24]2[C:18]3[C:19](=[N:20][CH:21]=[C:16]([CH3:15])[CH:17]=3)[NH:22][CH:23]=2)=[O:5])[C:7]([F:14])=[CH:8][CH:9]=1
Reactant: Cc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1c(F)ccc([N+](=O)[O-])c1F
Product: Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1

Procedure:
(3-Amino-2,6-difluoro-phenyl)-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 17 was prepared in two steps from 2,6-difluoro-3-nitro-benzoyl chloride 14 and 5-methyl-1H-pyrrolo[2,3-b]pyridine 15 as shown in Scheme 1a.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]([CH3:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:13][N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:15][CH:14]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CN(C)Cc1ccc(N)cc1
Solvent: c1ccncc1
Product: COC(=O)CN(C)Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of methyl 2-((4-aminobenzyl)(methyl)amino)acetate (0.680 g, 3.27 mmol) in pyridine (15 ml) was cooled to 0° C., and methane sulfonylchloride (0.280 ml, 3.59 mmol) was added. The mixture was warmed to RT and stirred for 1 hour. The solvent was removed, and the crude was portioned between DCM and water. The aqueous phase was basified with solid K2CO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and the solvent was evaporated. The crude was filtered on SCX cartridge (DCM/MeOH 1/1; MeOH/conc.aq.NH4OH 90/10). The basic fraction was evaporated to dryness to give methyl 2-(methyl(4-(methylsulfonamido)-benzyl)amino)acetate (0.750 g, 2.62 mmol, 80% yield, MS/ESI+ 287.2 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].Cl.CN(C)CCCN=C=NCC.[CH3:34][O:35][CH2:36][C:37](O)=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:10]=1[CH2:11][CH3:12]
Reactant: CCc1nn(CCN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCc1nn(CCNC(=O)COC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 12 h
Yield: 83.8 %

Procedure:
A solution of the pyrazole of Example 13 (53 mg, 0.161 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.178 mmol) and 4-(dimethylamino)pyridine (22 mg, 0.178 mmol) in dichloromethane (1 ml) was added to a stirred solution of methoxyacetic acid (14.2 μL, 0.178 mmol) in dichloromethane (1 ml) at room temperature. The reaction was stirred for 12 hours and then concentrated under a stream of nitrogen to leave a yellow solid. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (54 mg) as a brown solid, m.p. 75–76° C.
Reaction SMILES: FC1C=CC(C([N:8]2[CH2:12][CH2:11][C:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])=O)=CC=1.C(N)CCCCCCC>O1CCCC1>[CH:15]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][NH:8][C:9]1=[O:18])([CH3:17])[CH3:16]
Reactant: CC(C)C1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O
Solvent: CCCCCCCCN
Solvent: C1CCOC1
Product: CC(C)C1(C#N)CCNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of 1-(4-fluorobenzoyl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (280 mg) obtained in Step A in tetrahydrofuran (3 mL) was added n-octylamine (180 μL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added n-octylamine (168 μL) at room temperature, and the mixture was stirred at 50° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8](Br)=[CH:7][C:4]=1[CH:5]=[O:6].[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[F-].[K+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([C:8]2[CH:7]=[C:4]([CH:5]=[O:6])[C:3]([O:2][CH3:1])=[CH:10][C:9]=2[O:11][CH3:12])[CH:23]=[N:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(OC)c(C=O)cc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Product: COc1cc(OC)c(-c2cnn(C(=O)OC(C)(C)C)c2)cc1C=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
Ex-74B: To a mixture of 2,4-dimethoxy-5-bromo-benzaldehye (0.28 g, 1.13 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (Ex-76A, 0.61 g, 1.70 mmol), bis(tri-tert-butylphosphine)palladium (43 mg, 0.085 mmol) and potassium fluoride (0.24 g, 4.08 mmol) was added degassed tetrahydrofuran (15 mL). The reaction mixture was heated at 60° C. for one day. Additional potassium fluoride (0.24 g, 4.08 mmol) and water (20 μL) were added. The reaction mixture continued to stir at 60° C. for another 8 hours. The reaction was then quenched by water. The aqueous solution was extracted with ethyl acetate. The solution of ethyl acetate was washed with saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (50%, v/v, in hexane) afforded 4-(5-formyl-2,4-dimethoxy-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (0.15 g, 40%) as white solid. 1H NMR (CDCl3) δ 10.35 (s, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 6.52 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 1.68 (s, 9H). MS m/z=333 ([M+H]+, 100%).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([C:16]2[C:17]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:8]([F:30])[CH:7]=1)C.[OH-].[Li+]>O1CCCC1.O>[F:30][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[CH:11]=[CH:10][C:9]=1[CH2:12][NH:13][C:14]([C:16]1[C:17]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15]
Reactant: CCOC(=O)Cc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Temperature: 55 °C
Yield: 51.7 %

Procedure:
[3-Fluoro-4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-acetic acid ethyl ester (1.45 g) was combined with lithium hydroxide (0.59 g) in a 30 mL solution of tetrahydrofuran:water (2:1). The reaction mixture was heated to 55° C. in an oil bath for 1 h. The reaction mixture was allowed to cool to ambient temperature, and the organic solvent was removed in vacuo. The remaining portion of the reaction mixture was brought to pH=3 with 3N hydrochloric acid. The mixture was extracted with ethyl acetate (5×40 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by recrystallization (ethyl acetate) to yield the pure product (0.700 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:53])([CH3:52])[CH2:7][CH2:8][CH:9]([O:44][Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:43])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:42])[CH2:24][CH:25]2[O:41][CH:26]2[CH:27]([CH3:40])[CH:28]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:71]([O:74][CH2:75][CH3:76])(=O)[CH3:72]>C(Cl)Cl.C(OCC)=C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:1]([O:4][CH:5]1[C:6]([O:53][CH:71]([O:74][CH2:75][CH3:76])[CH3:72])([CH3:52])[CH2:7][CH2:8][CH:9]([O:44][Si:45]([CH2:48][CH3:49])([CH2:46][CH3:47])[CH2:50][CH3:51])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:43])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:42])[CH2:24][CH:25]2[O:41][CH:26]2[CH:27]([CH3:40])[CH:28]([O:31][C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCC(OC(=O)c1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Reactant: CCOC(C)=O
Agent: C=COCC
Agent: CCC(OC(=O)c1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)/C=C/C1OC(C)=O
Solvent: ClCCl
Product: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)C=CC1OC(C)=O
Reaction time: 14.5 h

Procedure:
(8E,12E,14E)-7-acetoxy-21-benzoyloxy-6-hydroxy-6,10,12,16,20-pentamethyl-3-triethylsiloxy-18,19-epoxytricosa-8,12,14-trien-11-olide (95.6 mg, 127 μmol) was dissolved in methylene chloride (2 mL). Ethyl vinyl ether (200 μL, 2.09 μmol) and pyridinium p-toluenesulfonate (3.2 mg, 12.7 μmol) were added to the solution at room temperature, and the reaction solution was stirred at the same temperature for 14.5 hours. Ethyl vinyl ether (200 μl, 2.09 μmol) and pyridinium p-toluenesulfonate (2.5 mg, 9.9 μmol) were further added to the reaction solution at room temperature, and the reaction solution was stirred at the same temperature for 7.5 hours. The reaction solution was diluted with ethyl acetate (30 mL), and the dilution was washed with purified water (6 mL) twice and brine (6 mL). The resulting organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (MERCK Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=5:1) to obtain the title compound (89.1 mg, 108 μmol, 85.1%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][C:12]2[C:13]([F:23])=[C:14]3[C:19](=[CH:20][C:21]=2[F:22])[N:18]=[CH:17][CH:16]=[CH:15]3)=[CH:4][CH:3]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:8]=2)[N:7]=1
Reactant: O=C(Cc1c(F)cc2ncccc2c1F)NNc1ccc(Cl)nn1
Solvent: CC(=O)O
Product: Fc1cc2ncccc2c(F)c1Cc1nnc2ccc(Cl)nn12
Temperature: 60 °C

Procedure:
(6-Chloro-pyridazin-3-yl)-hydrazine (531 mg, 3.67 mmol) was added to an oven-dried round-bottom flask and dissolved in dimethylformamide (7 mL) and triethylamine (1.54 ml, 11.01 mmol). The solution was cooled to 0° C. (5,7-Difluoro-quinolin-6-yl)-acetyl chloride (887 mg, 3.67 mmol) was dissolved in dimethylformamide (8 mL) and added to the reaction mixture dropwise. The reaction was complete upon addition of the acid chloride. The solution was concentrated down under vacuo to dryness to afford (5,7-difluoro-quinolin-6-yl)-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide. LCMS [M+H+]=350.0. (5,7-Difluoro-quinolin-6-yl)-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide (1.28 g, 3.67 mmol) was suspended in acetic acid (30 mL) and the solution heated to 60° C. for 16 hours. The mixture was then concentrated in vacuo and the residue dissolved in dichloromethane (125 ml) and washed with saturated NaHCO3 (100 ml) and brine (100 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting solid was triturated with methanol and the title compound was collected in quantitative via filtration and dried. Analytical data presented in Table 1.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:9]C=O)[CH3:8].[CH3:12][CH:13]([CH3:19])[CH2:14][CH2:15][C:16](=[O:18])C>C1COCC1.CC(=O)OCC>[OH:18][CH:16]=[C:15]([CH2:14][CH:13]([CH3:19])[CH3:12])[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)CCC(C)C
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)C(=CO)CC(C)C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a solution of KOtBu (50 g, 446 mmol) in THF (400 mL) is added during 30 min ethylformate (92 g, 1.25 mol). Strong gas evolution occurs. The mixture is cooled during the addition with a water bath at 10° C. After complete addition, the mixture is stirred until the gas evolution ceases (15 min). The mixture is cooled with ice at 0° C. and a mixture of 5-methyl-2-hexanone (34.25 g, 300 mmol) and ethylformate (41 g, 0.55 mol) is added slowly during 30 min. The mixture is stirred for 15 h, diluted with EA (500 mL) and washed with 1 N aq. HCl (100 mL), 1 M aq. NaH2PO4 solution (100 mL) and brine (100 mL). The organic extract is dried (MgSO4), filtered and evaporated to give crude 4-hydroxy-3-isobutyl-but-3-en-2-one (28 g) which is used without further purification; LC-MS: tR=0.80 min, [M+1]=143.39.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][C:24]=1[N+:37]([O-:39])=[O:38]>CN(C=O)C.CCOCC>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][O:12][C:3]2[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])=[C:24]([N+:37]([O-:39])=[O:38])[CH:25]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1OCCOc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 70 °C
Yield: 69.4 %

Procedure:
2,3-Difluoro-6-nitrophenol (0.7 g, 3.7 mmol) was stirred with K2CO3 (0.5 g, 3.7 mmol) in DMF (10 mL) for 10 min. Bromoethane 6 (1.1 g, 3.1 mmol) was added to the reaction mixture and heated at 70° C. for 24 hrs. The reaction mixture was diluted with ether (30 mL) and washed with water (20 mL) and then brine (20 mL). The ether layer was dried (MgSO4) and concentrated under reduced pressure. Fractionation of the crude product by flash chromatography with 4:1 hexane/ethyl acetate provided 7 as a yellow oil (960 mg, 63%). 1H NMR: 4.45 (t, J=5 Hz, 2H), 4.71 (t, J=5 Hz, 2H), 5.05 (s, 2H), 7.0-7.7 (m, 10H)
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:4]=1.Cl.Cl.[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][CH:33]=[C:32]([NH:38][CH2:39][CH2:40][NH2:41])[N:31]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][CH:33]=[C:32]([NH:38][CH2:39][CH2:40][NH:41][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:4]=2)[N:31]=1
Reactant: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NCCN)nc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-methylpiperidin-4-yl)[1,2,4]triazolo-[1,5-c]-pyrimidine hydrochloride (Example 49A), 32 mg (0.15 mmol) of 2-amino-6-[(2-aminoethyl)-amino]pyridine-3-carbonitrile dihydrochloride (Example 9A) and 0.13 ml (0.75 mmol) of N,N-diisopropylethylamine were initially charged in 1.5 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 43 mg (64% of theory) of the product as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:8]=[CH:9][S:10][C:11]=1[S:12][CH2:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]>CN(C)C=O>[Cl:3][CH2:6][C:7]1[N:8]=[CH:9][S:10][C:11]=1[S:12][CH2:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(CCSc1scnc1CO)c1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(CCSc1scnc1CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.5 mL) was mixed with N,N-dimethylformamide (15 mL) and stirred at room temperature for 30 min. The resulting solution was then transferred via syringe to a solution of 4-hydroxymethyl-5-(2-phenylsulfonylethyl)thio-1,3-thiazole (1.69 g, 5.36 mmol) in N,N-dimethylformamide (5 mL). After 2 h, the mixture was partitioned between ethyl acetate and water. The organic solution was washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated to dryness, affording 1.78 g of the title compound. 1H NMR (CDCl3) δ 3.05 (2H), 3.35 (2H), 4.70 (2H), 7.50-7.85 (5H), 8.82 (s, 1H).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C(O[C:31](=[O:51])[CH:32]=[C:33]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1)CCC>>[F:40][C:36]1[CH:35]=[C:34]([C:33]2[CH:32]=[C:31]([OH:51])[C:43]3[C:42](=[CH:47][CH:46]=[C:45]([N+:48]([O-:50])=[O:49])[CH:44]=3)[N:41]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: CCCCOC(=O)C=C(Nc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=[N+]([O-])c1ccc2nc(-c3cccc(F)c3)cc(O)c2c1
Temperature: 250 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Dowtherm A, 0.75 L, was placed in a 3 L three-neck flask, equipped with mechanical stirrer, Claisen adapter holding a thermocouple probe and reflux condenser with nitrogen inlet and heated to 250° C. To this was cautiously added in small portions 77.0 grams (0.215 moles) of 3-(4-nitrophenylamino)-3-(3-fluorophenyl) acrylic acid butyl ester over the course of 0.25 hours. The mixture was maintained at 250° C. for 1.5 hours and then allowed to cool to 90° C. over the course of 2 hours. The mixture was treated with 1.0 L of hexanes, and allowed to cool to room temperature while stirring overnight. The tan solids were collected by suction filtration and washed with three 0.15 L portions of hexanes. The solids were dried under vacuum at 50° C. overnight to yield 58.63 g (96.0%) of the title compound.
Reaction SMILES: O1CCCC1.[C:6]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]#[N:21])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22](I)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:6]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20]#[N:21])(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ICCc1ccccc1
Reactant: N#CC1CCCCN1C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(CCc2ccccc2)CCCCN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 200 ml of tetrahydrofuran containing 140 mmol lithium diisopropylamide was added 15 g of solid 1-benzoyl-2-piperidinecarbonitrile at -78° C. The mixture was stirred for 30 minutes, after which 100 ml of tetrahydrofuran containing 33.2 g of phenethyl iodide was added dropwise at -78° C. After completion of dropwise addition, the temperature of the reaction mixture was gradually increased to 0° C. Then, water was added and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The pooled organic layer was dried over anhydrous magnesium sulfate and filtered and the solvent was then distilled off. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:2) as the eluent. The solution containing the desired compound was distilled under reduced pressure and the resulting solid was recrystallized from ethyl acetate-hexane to provide 17.3 g of colorless crystals.
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2([C:16]([OH:18])=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[OH:33][C@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]1[NH:40][C:41](=[O:50])[C@@H:42]([OH:49])[C@@H:43]([NH2:48])[CH2:44][CH2:45][CH2:46][CH3:47]>C(Cl)(Cl)Cl.O1CCCC1>[OH:49][C@@H:42]([C@@H:43]([NH:48][C:16]([C:10]1([NH:9][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:18])[CH2:44][CH2:45][CH2:46][CH3:47])[C:41]([NH:40][C@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@@H:34]1[OH:33])=[O:50]
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Reactant: CCCC[C@H](N)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Under ice-cooling, to 10 ml of an anhydrous tetrahydro-furan solution containing 256 mg (1 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid and 202 mg (2 mmol) of triethylamine was added 1 ml of an anhydrous tetrahydrofuran solution containing 121 mg (1 mmol) of pivaloyl chloride, and the resulting mixture was stirred at the same temperature for 2 hours. Moreover, the temperature of the reaction mixture was returned to room temperature and the mixture was stirred for 18 hours. Insoluble material in the reaction mixture was filtered off, and the filtrate was added to 80 ml of a chloroform solution containing 258 mg (1 mmol) of (2S,3S)-N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-amino-2-hydroxyheptanamide, and the resulting mixture was stirred for 3 hours. Chloroform was additionally added to the reaction mixture, and the resulting mixture was washed successively with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated NaCl solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 468 mg (Yield: 94%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=O)[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C([N+:27]([O-])=O)=CC=C(O)C=1.C1(N=C=NC2CCCCC2)CCCCC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([NH2:27])=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(N)=O

Procedure:
Na -t-butyloxycarbonyl-Ne -benzyloxycarbonyl-L-lysine was dissolved in ethyl acetate and esterified with p-nitrophenol using dicyclohexylcarbodiimide as a coupling agent. Sodium bicarbonate (10%) was added and the product extracted into the organic layer and crystallized from solution, then added to aqueous ammonium hydroxide to form Na -t-butyloxycarbonyl-Ne -benzyloxycarbonyl-L-lysine amide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].[CH3:6][C:7]1[O:13]C(C)(C)O[C:9](=[O:10])[CH:8]=1>C(N(CC)CC)C>[C:9]([O:1][CH2:2][CH2:3][C:4]#[N:5])(=[O:10])[CH2:8][C:7]([CH3:6])=[O:13]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: N#CCCO
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCC#N

Procedure:
A mixture of 16.33 g (0.23 mole) of 3-hydroxy-propionitrile and 28.4 g (0.20 mole) of 2,2,6-trimethyl-1,3-dioxen-4-one in the presence of 0.1 ml of triethylamine is heated to 90°-100° C. for 4 hrs 30 mins.