Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:7][NH:6][CH2:5]1)[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22](F)[C:23]=3[Br:25])[C:18](=[O:28])[C:17]([C:29]([OH:31])=[O:30])=[CH:16]2)[C:12]([F:32])=[CH:11][C:10]=1[F:33].CN1CCCC1.C(OC(C)C)(C)C>CS(C)=O>[NH2:8][C:9]1[N:14]=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([N:6]4[CH2:7][CH:4]([NH:3][CH2:1][CH3:2])[CH2:5]4)[C:23]=3[Br:25])[C:18](=[O:28])[C:17]([C:29]([OH:31])=[O:30])=[CH:16]2)[C:12]([F:32])=[CH:11][C:10]=1[F:33]
Reactant: CCNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Product: CCNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Br)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
3-Ethylaminoazetidine (700 mg), 1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1.5 g), N-methyl-pyrrolidine (2.0 g)and dimethylsulfoxide (4.5 g) were combined, and the mixture was heated under stirring at 40° C. for 24 hours. After the mixture was allowed to cool down, isopropyl ether (10 mL) was added, the mixture was stirred, and a clear layer at the top of the mixture was removed. The same procedure was repeated once more, and the residue was concentrated under reduced pressure. Ethanol (5 mL) was added, and the mixture was heated under stirring at 70° C. for 30 minutes. The precipitated solid was collected by filtration. The title compound (1.38 g) was obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[CH3:21][C:20]1[C:16]([C:13]2[S:12][C:11]([C:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][C:33](=[O:35])[CH3:34])[CH2:4]3)=[O:10])=[CH:15][CH:14]=2)=[N:17][O:18][C:19]=1[C:22]([F:25])([F:24])[F:23]
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](N)C3)s2)noc1C(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Reaction time: 48 h
Yield: 82.2 %

Procedure:
A suspension of ((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 mL) was treated with triethylamine (70 μL, 0.5 mmol) followed by acetyl chloride (22 μL, 0.3 mmol). The reaction mixture was allowed to stir 48 hr, evaporated and chromatographed on silica gel with EtOAc then MeOH/EtOAc (10%) as eluant to afford product as a colorless solid (66 mg, 83%). 1H NMR (CDCl3) 1.65 (m, 2 H), 1.81 (m, 1 H), 1.95 (s, 3 H), 2.00 (obs m, 1 H), 2.33 (d, J=1.3, 3 H), 3.30 (m, 2 H), 3.98 (m, 2 H), 4.10 (br d, J=11.0, 1 H), 6.10 (br d, J=6.6, 1 H), 7.43 (d, J=4.0, 1 H), 7.49 (br s, 1 H). 13C NMR 7.9, 23.5, 30.1, 46.5, 51.0 (br), 114.8, 118.7 (q, J=271), 128.3, 129.7, 131.7, 140.1, 155.2 (J=40), 157.9, 163.3, 170.3 19F NMR −63.1. LC/MS 5.72 min, [M+1]+ 402.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([O:25][CH2:24][CH2:23][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][CH:11]=2)[CH:17]=1)(=[O:29])=[O:28]
Reactant: OCCCc1cccc(OCc2coc(/C=C/c3ccccc3)n2)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCc1cccc(OCc2coc(/C=C/c3ccccc3)n2)c1
Yield: 78 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with methanesulfonyl chloride to give 3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 75-76° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18]>C(O)(=O)C>[Br:1][C:21]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([NH:14][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:4]=2[CH3:3])=[CH:23][CH:22]=1
Reactant: BrBr
Reactant: Cc1c(Nc2ccccc2C(=O)O)cccc1C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(Nc2ccc(Br)cc2C(=O)O)cccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
Over a 30 minute period and with constant stirring, add 16 g. of bromine dissolved in 50 ml. of glacial acetic acid to a mixture of 37 g. of N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid in 350 ml. of glacial acetic acid. Pour the resulting mixture into 1500 ml. of water, filter and dry the precipitate. Recrystallize the product from acetonitrile to obtain 5-bromo-N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid, m.p. 223°-225° C.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([C:20]2[N:21]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[C:26]([F:29])[C:25]([F:30])=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([F:39])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:40])=[O:3])=[CH:6][C:7]=3[F:39])=[O:38])=[C:28]3[C:23]([CH:24]=[C:25]([F:30])[C:26]([F:29])=[CH:27]3)=[N:22]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless oil. MS: m/e=542.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][N+:23]([O-])=O)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(C)cc1)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(C)cc1)OCC

Procedure:
A solution of 6.5 g of ethyl 2-(4-methylphenyl)-3-nitropropyl(diethoxymethyl)phosphinate in 60 ml of ethanol is added to 52 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-methylphenyl)propyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.6 ppm (CDCl3).
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([OH:26])[C:22]([F:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].O>CN(C)C=O>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([C:22]([F:25])=[CH:23][CH:24]=2)[O:26][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COC(=O)CBr
Reactant: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
To a suspension 3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11-yl)-2,6 difluoro-phenol (0.200 g, 0.453 mmol) and potassium carbonate (0.085, 0.612 mmol) in N,N-dimethylformamide (2 mL) was added methyl bromoacetate (0.086 mL, 0.906 mmol) dropwise at room temperature under a dry nitrogen atmosphere. After stirring 2.5 hours the reaction mixture was combined with water (50 mL) and the organics were extracted with ether. The extract was combined with silica gel, the solvent was removed and the adsorbate was flash chromatographed (90/10 petroleum ether/ethyl acetate). The solvents were chased with benzene (2×) and petroleum ether to give [3-(6-bromo-benzo[b]naphtho[2, 3-d]thiophen-11-yl)-2, 6-difluoro-phenoxy]-acetic acid, methyl ester as a white solid (0.198 g, 85%). To a solution of this methyl ester (0.190 g, 0.370 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was added a 1 N aqueous solution of potassium hydroxide (0.55 mL, 0.55 mmol) dropwise at room temperature. After stirring 1 hour the solvents were removed and water was added to the solid residue. The aqueous mixture was acidified with 10% HCl and the organics were extracted with ether. After several minutes of vigorous shaking the layers were separated and the organic layer was washed with water and concentrated. The residue was chased with benzene and dried in vacuo to give the title compound as a white solid (0.177g, 95%): mp 195-197° C.: NMR (400 MHz, DMSO-d6): 8 13.11 (broad s, 1 H), 8.31 (d, J=8 Hz, 1 H), 8.09 (d, J=8 Hz, 1 H), 7.83-7.79 (m, 1 H), 7.64-7.46 (m, 4 H), 7.31-7.27 (m, 1 H), 7.23-7.17 (m, 1 H), 6.81 (d, J=8 Hz, 1 H), 4.89 (s, 2 H); MS(-FAB): (M-H): one bromine pattern observed: 497/499 (35%138%); HRMS: Calc. for C24H13BrF2O3S M+: 497.97368, measured mass: 497.97787, mass deviation 4.19 mmu; Anal. HPLC 97% pure; Anal. Calc. for C24H13BrF203S: C, 57.72, H, 2.62% N, 0.00. Found: C, 56.77, H, 2.79% N, 0.00.
Reaction SMILES: C[N:2](C)/[C:3](/[CH3:14])=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.[NH:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][N:25]=1)[C:21]#[N:22])N.CC(O)=O>CCO>[CH3:14][C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[N:16]([C:18]2[CH:19]=[C:20]([C:21]#[N:22])[CH:23]=[CH:24][N:25]=2)[N:2]=1
Reactant: C/C(=C\C(=O)c1ccc(C)cc1)N(C)C
Reactant: N#Cc1ccnc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(-c2cc(C)nn2-c2cc(C#N)ccn2)cc1
Yield: 56.3 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-(4-methylphenyl)but-2-en-1-one (227 mg, 1.1 mmol) and 2-hydrazinylisonicotinonitrile (150 mg, 1.1 mmol, PREPARATION 2) in 10 mL EtOH was added 2 mL AcOH. The reaction mixture was heated under reflux conditions overnight before being cooled and concentrated to dryness. The residue was adjusted to pH>8 with saturated aq. K2CO3 and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 20 mL brine, dried, and concentrated to dryness to give the title compound (170 mg, 55.6%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.38 (6H, s), 6.30 (1H, s), 7.15 (4H, s), 7.33 (1H, d, J=4.0 Hz), 7.78 (1H, s), 8.44 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H14N4, 275; Found, 275.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
A mixture of 1-ethyl-4-fluorobenzene (0.248 g, 2 mmol), NBS (0.35 g, 2 mmol) and benzoyl peroxide (0.14 g, 0.6 mmol) were dissolved in 20 mL CCl4. The mixture was stirred at 80° C. for 5 hours and then the reaction was conc. in vacuo and resulting oil was purified via silica gel chromatography (PE-EtOAC 5:1) to give the title compound (330 mg, 80%) as a yellow oil. LCMS 202 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:4][C:3]=1[CH3:19].[H-].C([Al+]CC(C)C)C(C)C.O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][C:3]=1[CH3:19]
Reactant: COC(=O)CCc1cnoc1-c1ccc(Cl)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2oncc2CCCO)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
To a solution of methyl 3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propionate (1.20 g) in tetrahydrofuran (40 ml) was gently added diisobutylaluminum hydride (1.0 M toluene solution, 9.5 ml) at 0° C., and the mixture was stirred at room temperature for 3 hr. Water was carefully added to the reaction mixture, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the crystals obtained from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio) were recrystallized from ethyl acetate-hexane to give a colorless needle of 3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propan-1-ol (780 mg, yield 72%). melting point: 50–51° C.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.C(O)(=[O:12])C.O>>[F:8][C:7]1[C:2](=[O:12])[NH:3][CH:4]=[CH:5][C:6]=1[I:9]
Reactant: Fc1nccc(I)c1F
Reactant: CC(=O)O
Solvent: O
Product: O=c1[nH]ccc(I)c1F
Reaction time: 8 h
Yield: 71.4 %

Procedure:
2,3-Difluoro-4-iodopyridine (300 mg, 1.24 mmol) was suspended in acetic acid:water (2:1, 15 mL). The mixture was heated to reflux and stirred at this temperature overnight. Reaction was concentrated to dryness, and triturated in water (10 mL) for 30 min. The solid was collected via filtration, washed with water (2×10 mL), and pentane (2×20 mL) and dried under vacuum to afford the title compound as a white solid (354 mg, 71.4%). LC-MS m/z 342.0 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 6.56-6.82 (m, 1H) 6.83-7.18 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][C:9]=3[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH:9]3[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCC1CCc2c(c(=O)oc3cc(OCC)ccc23)C1
Solvent: C1CCOC1
Product: CCCC1CCC2c3ccc(OCC)cc3OC(=O)C2C1

Procedure:
8.60 g (30 mmol) of 3-ethoxy-8-propyl-7,8,9,10-tetrahydrobenzo[c]-chromen-6-one are dissolved in THF and hydrogenated to cessation on palladium/active carbon. The solution is filtered and evaporated, giving 3-ethoxy-8-propyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-6-one as colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)=[CH:17][CH:18]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Cc1ccc(I)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (90 mg, 0.48 mmol) and iodo-4-methylbenzene (0.07 mL, 0.55 mmol) according to the general procedure IB to give 18 mg (15%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:30→1:10). Rf: 0.42 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.45-7.39 (m, 4H), 7.18-7.13 (m, 4H), 3.67 (s, 3H), 2.98-2.93 (t, 2H, J=7.8 Hz), 2.66-2.60 (t, 2H, J=7.8 Hz), 2.36 (s, 3H); 13CNMR (CDCl3) δ 173.1, 140.6, 138.3, 131.7, 131.4, 129.1, 128.3, 121.4, 120.2, 89.3, 88.6, 51.6, 35.4, 30.8, 21.5; EI-MS m/z 278 (M+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([O:55][C:56]([NH:58][C@H:59]([C:61](O)=[O:62])[CH3:60])=[O:57])([CH3:54])([CH3:53])[CH3:52]>O1CCCC1>[C:51]([O:55][C:56]([NH:58][C@H:59]([C:61]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:62])[CH3:60])=[O:57])([CH3:53])([CH3:54])[CH3:52]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 59 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-alanine. Yield 59%. [α]D =+0.2° (c=0.86, tetrahydrofuran).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH:12]([F:14])[F:13].[CH3:15][CH:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17].C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[F:13][CH:12]([F:14])[O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:21]1[CH2:22][CH2:23][N:18]([CH:16]([CH3:17])[CH3:15])[CH2:19][CH2:20]1
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)c(OC(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2OC(F)F)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
1-Bromo-2-difluoromethoxy-4-nitro-benzene (Step A, 2.0 g, 7.5 mmol, 1.0 eq.) and N-(2-propyl)piperazine (0.85 mL, 9.7 mmol, 1.3 eq.) were dissolved in 20 mL of DMSO. K2CO3 (1.5 g, 11.2 mmol, 1.5 eq.) and Bu4N+Br− (240 mg, 0.75 mmol, 0.1 eq.) were added and the mixture was heated to 120° C. The mixture was stirred for 3 h and cooled to RT, poured into H2O (200 mL) and 6 N HCl (20 mL). The aqueous solution was washed with EtOAc, and alkalinized with 6 N NaOH then extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated. The crude material was further purified by column chromatography (0-100% EtOAc in hexanes) providing pure 1-(2-difluoromethoxy-4-nitro-phenyl)-4-isopropyl-piperazine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[N:12]=[C:11]([NH2:13])[N:10]=[C:9]([NH2:14])[C:8]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[N:12]=[C:11]([NH2:13])[N:10]=[C:9]([NH2:14])[C:8]=2[NH2:15])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(N)nc(N)c2[N+](=O)[O-])o1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2nc(N)nc(N)c2N)o1
Temperature: 40 °C
Yield: 95.5 %

Procedure:
A suspension of 6-(5-methyl-2-furyl)-5-nitropyrimidine-2,4-diamine (6.6 g, 29.6 mmol) and 10% Pd/C (0.66 g) in MeOH (100 mL) was heated at 40° C. under an atmosphere of H2 for 3 h, cooled to room temperature, filtered through Celite, and concentrated in vacuo to give the title compound (5.8 g, 99%) as an off-whited solid; IR νmax (DR)/cm−1 3333, 2237, 1634, 1458, 1237, 1025, 963 and 828; NMR δH (400 MHz, DMSO) 6.77 (1H, dd, J 0.5, 3.2 Hz), 6.21-6.17 (3H, m), 5.14 (2H, s), 4.21 (2H, s), and 2.35 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[CH2:7][C@H:8]([NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)[CH2:31]1)=[O:29])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][F:26])[CH:18]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6](=[O:53])[CH2:7][C@H:8]([NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]2[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]2)[CH2:31]1)=[O:29])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][F:26])[CH:18]=2)[CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2cccc(OCCF)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2cccc(OCCF)c2)c1
Yield: 74.1 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[3-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (30 mg, 40 μmol) in ethyl acetate (1.2 mL) and methanol (0.2 mL) was stirred for 2.5 hours at room temperature under a hydrogen atmosphere in the presence of palladium on charcoal (10%, 3 mg). The suspension was filtrated through celite, which were washed thoroughly with methanol. The solution was concentrated under reduced pressure and purified by preparative HPLC to yield 21.9 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{2-[3-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9](O)[C:8]1=[O:18])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:28])=O>CN(C)C=O>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([Cl:28])[C:8]1=[O:18])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOCCCn1c(=O)c(O)nc2ccccc21
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOCCCn1c(=O)c(Cl)nc2ccccc21

Procedure:
To 22.5 g of (1), 330 ml of toluene, 10 ml of dimethylformamide and 10 ml of thionyl chloride are added and the resulting mixture is heated to reflux for 2 hours. The mixture is then subjected to filtration during hot and the filtrate is concentrated. The resultant is purified by silica gel column chromatography (ethyl acetate:hexane=1:3-1:2) to obtain 23.5 g of (2) in the form of yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>O>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:5](=[O:8])[N:6]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:44])[F:45])=[CH:43][CH:42]=2)[N:7]=1
Reactant: Oc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c(Cl)nn1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added 6-chloro-4,5-bis(4-chlorophenyl)pyridazin-3-ol (1.5 gm, 4.26 mmol), DMF (15 ml) and K2CO3 (1.17 gm, 8.52 mmol). The reaction was stirred at rt for 30 min. After this time, 4-trifluoromethylbenzyl bromide (1.2 gm, 5.19 mmol) was added to the reaction and the reaction was stirred at rt for an additional 8 hrs. The reaction mixture was then diluted with water (40 ml). The reaction mixture was poured into a separatory funnel and extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (4×30 ml) and saturated aqueous NaCl (30 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give product 6-chloro-4,5-bis(4-chlorophenyl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one as off white solid (1.5 gm, 65.1% yield).