Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[Cl:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][C:15]2[N:16]=[C:17]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:18][C:19]=2[C:20](=[O:22])[CH3:21])=[CH:12][CH:11]=1.[CH2:31]1COCC1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2[N:16]=[C:17]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:18][C:19]=2[C:20](=[O:22])[CH2:21][C:3]([O:6][CH2:7][CH3:31])=[O:8])=[CH:29][CH:30]=1
Reactant: C1CCOC1
Reactant: COC(=O)OC
Reactant: CC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Yield: 25 %

Procedure:
To a flask containing 60% NaH in mineral oil (213 mg, 5.32 mmol) under nitrogen was added THF (31.7 mL) and carbonic acid, dimethyl ester (0.448 mL, 5.32 mmol). The mixture was heated to 60 degrees and a solution of 1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)ethanone (875 mg, 2.66 mmol) in THF (12.7 mL) was then added. The mixture was heated at 60 degrees for 1 hour. The reaction was cooled and quenched with methanol (5 mL), then saturated NH4Cl (10 mL). The organic solvents were concentrated in vacuo, and the aqueous residue was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/DCM=0/100→40/60) to give 253 mg (25% yield) of the title compound as an oil. LC/MS (FA) ES+ 387, 389. 1H NMR (300 MHz, CDCl3) δ: 8.76-8.74 (m, 2H), 7.83-7.81 (m, 2H), 7.35-7.32 (m, 2H), 7.26-7.23 (m, 2H), 4.53 (s, 2H), 3.89 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)C(C)C)(C)C.[C:19](Cl)([Cl:21])=[O:20].C1(C)C=CC=CC=1>C(OCC)C>[Cl:21][C:19]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:20]
Reactant: OCc1ccccc1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(Cl)OCc1ccccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-chlorobenzyl alcohol (1.0 g, 7.0 mmol) in diethyl ether (15 ml) at 0° C. was added N,N-diisopropylethyl amine (2.4 ml, 14.0 mmol), and phosgene solution in toluene (7.5 ml, 14.0 mmol). The mixture was allowed to warm up to room temperature in 2 h while stirring, then it was filtered. The diethyl ether was removed by rotary evaporator, and the solution of 2-chlorobenzyl chloroformate in toluene was carried on for the next step reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]([SH:7])[CH3:6])C.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:33]=[CH:34][CH:35]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:20]2[C:25]3[O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[CH3:1][O:3][C:4](=[O:8])[CH:5]([S:7][CH2:10][C:11]1[CH:12]=[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH:33]=[CH:34][CH:35]=1)[CH3:6]
Reactant: BrCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1
Reactant: CCOC(=O)C(C)S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C(C)SCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1

Procedure:
Ethyl-2-mercaptopropionate (31 mg, 0.29 mmol) was added to a stirred suspension of 4-(3′-bromomethyl-biphen-3-yl)-dibenzofuran (100 mg, 0.24 mmol) and cesium carbonate (198 mg, 0.6 mmol) in 5 ml DMF. diluted with diethyl ether (30 mL) and washed with water (2×) and brine (3×). The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 30% ethyl acetate in hexane as eluent, afforded the title compound; methyl-2-(3′-dibenzofuran-4-yl-biphen-3-ylmethylsulfanyl)-propionate, as a colorless oil (105 mg, 94).
Reaction SMILES: [O:1]1[C:3]2([CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]2)[CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([CH2:2][C:3]2([OH:1])[CH2:4][NH:5][CH2:6]2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CC2(CO2)C1
Solvent: C1CCOC1
Product: OC1(CN2CCOCC2)CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
1,1-Dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (51 mg, 0.28 mmol) was taken into THF (1 mL) followed by addition of morpholine (123 μL, 1.4 mmol) and the mixture was stirred for one hour at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed once with water then brine and the organic layer dried over anhydrous sodium sulfate. Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents. The combined pure fractions were concentrated and the residue treated with neat TFA (1 mL) for 5 minutes then concentrated. The residue was taken into methanol (2 mL) and basified to pH >10 by addition of Biorad AG-1X hydroxide form resin. Filtration and concentration afforded 3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H), 3.49 (d, 2H), 2.66 (s, 2H), 2.57-2.55 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH2:21][O:22]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:11][CH2:12][P:13]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.Cl>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][OH:22])[O:11][CH2:12][P:13]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:19])[CH3:20])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)P(=O)(CO[C@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)P(=O)(CO[C@H](CO)COCc1ccccc1)C(C)C

Procedure:
Compound 5 (31 g) was stirred 4 h with a mixture of dioxane (250 mL) and 1 M HCl (250 mL) till the starting material disappeared (approx. 3 h). Ethyl acetate (500 mL) was added, and the aqueous phase after extraction washed twice more with ethyl acetate (250 mL each). The combined extracts were washed with saturated NaHCO3 solution (2×300 mL) dried with MgSO4 and evaporated in vacuo to give the chromatographically pure material 6 which was directly used for further steps.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C([O-])([O-])=[O:27].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:27][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: ClCCN1CCOCC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccccc2OCCN2CCOCC2)cc1
Temperature: 105 °C
Reaction time: 17 h

Procedure:
4-Benzyloxyphenol (4.0 g, 20 mmol), chloroethylmorpholine hydrochloride (3.72 g, 20 mmol) and K2CO3 (5.53 g, 40 mmol) were suspended in DMF (50 mL) under an atmosphere of argon and stirred at 105° C. for 17 h. The solvent was removed under reduced pressure and the residue was partitioned between water (80 mL) and Et2O (150 mL). The aqueous layer was extracted with Et2O (1×30 mL), the combined org. layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0-10% MeOH in EtOAc) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>O.O1CCCC1>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([O:12][C:19]([N:18]([CH3:22])[CH3:17])=[S:20])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1
Reactant: CN(C)C(=S)Cl
Reactant: CC1(C)CCC(=O)c2cc(O)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=S)Oc1ccc2c(c1)C(=O)CCC2(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 4,4-dimethyl-7-hydroxy-1-tetralone (XIV) (3.07 g, 16.16 mmol) in water (10.77 mL) containing potassium hydroxide (904 mg) cooled below 10° C. was added N,N-dimethylthiocarbamoyl chloride (2.67 g, 21.6 mmol) in tetrahydrofuran (4.30 mL); the reaction temperature kept below 12° C. After 10 minutes, reaction mixture is made basic by the addition of a 10% aqueous KOH solution (5.39 mL). Product is extracted with ethyl acetate (2×50 mL), organic phases concentrated in vacuo and the residue chromatographed on silica gel (eluted with 10% ethyl acetate in hexane) to give 3.74 g (Y: 84%) of title product; 1H-NMR (CDCl3): δ7.68 (d, J=2.6 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.5, 2.6 Hz, 1H), 3.46 (s, 3H), 3.34 (s, 3H), 2.73 (t, J=6.8 Hz, 2H), 2.04 (t, J=6.8 Hz, 2H), 1.41 (s, 6H); MS (DCI) m/e: 278 (MH+).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)#[N:4]
Reactant: CN
Reactant: COc1ccnc(CSCCN=C(NC#N)SC)c1
Solvent: CCO
Product: CNC(=NCCSCc1cc(OC)ccn1)NC#N
Reaction time: 8 h

Procedure:
Methylamine in ethanol (33%, 20 cc) was added to a stirred solution of N-cyano-N'-[2-((4-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (3.56 g) in ethanol (25 cc) at 35°, and the mixture was left to stand overnight. Nitrogen was bubbled through the solution and the crystals were filtered off to give the title product, (2.74 g) m.p. 121°-122°.
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[CH2:4][C@H:2]1[OH:3].C[O:21][P:22](OC)([O:24]C)=[O:23].P(Cl)(Cl)(Cl)=O>>[P:22]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[C@H:2]([OH:3])[CH2:4]1)([OH:24])([OH:23])=[O:21]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)C[C@H]2O)c(=O)[nH]1
Reactant: COP(=O)(OC)OC
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)O)C[C@H]2O)c(=O)[nH]1

Procedure:
3′-Deoxyguanosine (Compound 1, commercial product from Sigma, 50 mg, 0.19 mmol) was stirred overnight with trimethylphosphate (2 mL) and phosphorus oxychloride (53 μL, 0.57 mmol) at 6° C. The reaction was quenched by adding 20 mL of water and neutralizing with 1 M NaHCO3. DEAE-Sephadex chromatography using a linear gradient of 0–0.9 M TEAB afforded Compound 3 (yield: 45 mg, 43%).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:9]([C:12]1[C:13]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[N+:9]([C:12]1[C:13]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:25][CH:24]=2)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc2ccccc2nc1Nc1ccc(O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Nc2nc3ccccc3cc2[N+](=O)[O-])cc1

Procedure:
A mixture of ethyl 2-bromopropionate (0.5 g), 4-[N-(3-nitro-2-quinolinyl)amino]phenol (0.5 g), anhydrous potassium carbonate (0.3 g) and ethyl methyl ketone (20 ml) was refluxed for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and water. The organic layer was dried and evaporated to give ethyl 2-{4-[N-(3-nitro-2-quinolinyl)amino]phenoxy}propionate as an orange oil which was purified by chromatography over silica gel. Proton magnetic resonance spectrum: (CDCl3, δ in ppm): 9.6 (1H, s, NH); 8.9 (1H, s, C4 quinoline proton); 7.8-7.6 (4H, m, quinoline protons); 6.8 (4H, s, phenyl protons); 4.6 (1H, q, CHCH3); 4.2 (2H, q, OCH2CH3); 1.6 (3H, d, CHCH3); 1.2 (3H, t, OCH2CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.CN1CCOCC1.[CH2:37]([O:41][C:42](Cl)=[O:43])[CH:38]([CH3:40])[CH3:39]>C1COCC1>[F:29][C:7]1[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:42]([O:41][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:43])[N:6]=1
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)COC(=O)NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
4-(3-Aminopropyl)-2-fluoro-1-triphenylmethylimidazole was dissolved in THF and treated with N-methylmorpholine and isobutylchloroformate. Extractive work-up followed by chromatography gave 2-fluoro-4-(3-isobutoxycarbonylaminopropyl)-1-triphenylmethylimidazole.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([O:22][CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[N:16]=1.O>CN(C)C(=O)C>[Cl:21][C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:22][CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[CH:18]=1
Reactant: Clc1cc(Cl)nc(OCc2ccsc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: FC(F)(F)c1cccc(Oc2cc(Cl)cc(OCc3ccsc3)n2)c1

Procedure:
To a solution of meta-trifluoromethylphenol (0.28 g, 0.0018×1.0 mol) in 10 ml of dry N,N-dimethylacetamide, sodium hydride (0.077 g, (ca.60% in mineral oil), 0.0018×1.1 mol) was added. After the bubbling ceased, a solution of 2,4-dichloro-6-(3-thienylmethyloxy)pyridine (0.46 g, 0.0018 mol) in 10 ml of dry N,N-dimethylacetamide was added dropwise and the resultant solution was stirred for about 7 hours at the temperature of 160° to 170° C. After allowed to cool, water was added to the reaction solution, then the mixture was partitioned by using ethyl acetate. The obtained organic layer was washed with aqueous saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, then the residue was purified successively on silica gel column chromatography and on reversed phase column chromatography (Lobar column, Lichroprep RP-18, 40-63 μm, elution solvent: CH3CN/H2O=7/3(v/v)), whereby the end product was obtained.
Reaction SMILES: [H-].[Na+].C(=N/[OH:11])\C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:32]([O:34]CC)=O)[CH2:24][CH2:23][C:22]3([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]3)[CH2:21][CH2:20]2)=[C:15]([C:37]#[C:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:14]=1>O1CCOCC1.CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[C:19]1([CH2:20][CH2:21][C:22]3([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]3)[CH2:23][CH2:24]1)[C:32](=[O:34])[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]2[OH:11]
Reactant: CCOC(=O)C#Cc1cc(Cl)ccc1C1(C(=O)OCC)CCC2(CC1)OCC(C)(C)CO2
Reactant: O/N=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC3(CC2)OCC(C)(C)CO3)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A stirred mixture of NaH (60% dispersion in mineral oil (0.39 mL, 9.3 mmol)) in 40 mL dioxane at room temperature, was treated with a mixture of (E)-benzaldehyde oxime (1.0 g, 8.6 mmol) in 40 mL DMF. The resulting mixture was stirred for 30 minutes. The mixture was then cooled to 0° C. and treated with a mixture of ethyl 4′-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)-5,5-dimethyl-spiro[1,3-dioxane-2,1′-cyclohexane]-4′-carboxylate (3.6 g, 7.8 mmol) in 30 mL DMF. The resulting mixture was stirred for 1 hour. The mixture was then carefully quenched with 10 mL H2O and brought to a pH of 5 by addition of 10% HCl. The mixture was extracted with ethyl ether (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 20-30% EtOAc to give 2.2 g of the product as a pale yellow solid. MS (m/z)=435 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:22]3[CH:27]=[C:26]([C:28](=[O:33])[NH:29][CH:30]4[CH2:32][CH2:31]4)[CH:25]=[CH:24][C:23]=3[CH3:34])[CH:14]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C.O>CO>[CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:22]3[CH:27]=[C:26]([C:28](=[O:33])[NH:29][CH:30]4[CH2:31][CH2:32]4)[CH:25]=[CH:24][C:23]=3[CH3:34])[CH:14]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)O)c2c1
Temperature: 50 °C

Procedure:
A mixture of the product of step ii) (0.88 g) and 5N sodium hydroxide (2.3 mL) in methanol (20 mL) was heated at 50° C. for 2 hours and then allowed to cool to room temperature. The reaction mixture was treated with glacial acetic acid (1 mL) and then water (20 mL). The precipitate was collected by filtration, washed with water and dried under vacuum to afford the sub-title compound (0.77 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18]([O-])(O)=O.[Na+]>ClCCCl>[CH2:11]([N:12]1[CH2:17][CH2:16][N:15]([CH2:6][CH2:7][CH2:8][C:9]#[CH:10])[CH2:14][CH2:13]1)[CH3:18]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: O=C([O-])O
Reactant: CN1CCNCC1
Agent: [Na+]
Solvent: ClCCCl
Product: C#CCCCN1CCN(CC)CC1
Temperature: 80 °C

Procedure:
A mixture of pent-4-ynyl methanesulfonate (849 mg) and N-methyl piperazine (665 μL) was heated to 80° C. for 3 h, diluted with 1,2-dichloroethane (5 mL) and heated to 70° C. for 18 h. Saturated aq. NaHCO3 was added (10 mL) and the mixture was extracted with DCM (1×40 mL), dried over Na2SO4, and concentrated to afford 0.56 g of 1-ethyl-4-(pent-4-ynyl)piperazine.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].S(Cl)([Cl:14])(=O)=O>C(O)(=O)C>[Cl:14][C:7]1[CH:6]=[C:5]([F:10])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[CH3:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(F)c(N)c1F
Solvent: CC(=O)O
Product: Cc1c(Cl)cc(F)c(N)c1F
Yield: 65.7 %

Procedure:
A solution of 2,6-difluoro-3-methylaniline (15 g, 105 mmol) in acetic acid (80 mL) was heated to 70° C. and a solution of sulfuryl chloride (16.0 g, 115 mmol) in acetic acid (40 mL) was added dropwise over 20 minutes. The temperature was maintained for 3 hours, then cooled and concentrated. The residue taken into water (100 mL) and the pH was adjusted to 9 with 2N sodium hydroxide and then extracted with methylene chloride (2×75 mL) and the combined extracts washed with brine, dried (sodium sulfate) and concentrated. The residue was distilled to give 4-chloro-2,6-difluoro-3-methylaniline (12.2 g, 69 mmol): bp 55°-65° C./55 mm.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH:54]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C@H:55]([C:75]([OH:77])=[O:76])[CH2:56][NH:57][C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59].CCCCCC.C(OC(=O)C)C>ClCCl>[NH:54]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C@H:55]([C:75]([OH:77])=[O:76])[CH2:56][NH:57][C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59].[CH2:20]([N-:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCC/C=C\CCCCCCCCNCCCCCCCCCCCCCCCC
Agent: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCC/C=C\CCCCCCCC[N-]CCCCCCCCCCCCCCCC
Reaction time: 20 h

Procedure:
521 mg (1.06 mmol)N-oleyl-palmitylamine in 10 ml anhydrous dichloromethane are dissolved in a 50 ml round-bottom flask and 289 mg (1.17 mmol) EEDQ are added. Subsequently, 500 mg (1.17 mmol) Boc-Dap(Fmoc)-OH are added under steering and the mixture is steered at room temperature for 20 hours. The solution is transferred with 80 ml dichloromethane into a separating funnel and washed three times with 20 ml 0.1 N HCl each and once with 20 ml saturated NaHCO3 solution. After drying over Na2SO4 the solvent is removed using a rotary evaporator (FIG. 4). A yellowish viscous oil is obtained which is not further purified. In thin layer chromatography using hexane/ethylacetate of 1:1 a Rf of 0.70 was observed.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[C:9]([CH3:31])[C:8]=1[F:32].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[C:9]([CH3:31])[C:8]([F:32])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: Cc1c(F)c(N)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1c(F)c(N)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 50 mg of 1-(6-amino-3,5-difluoro-4-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.4 ml of ethanol, the mixture was allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 45 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH2:12][C:13](=S)[C:14]([OH:16])=[O:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20]>[O-]CC.[Na+]>[OH:20][N:19]=[C:13]([CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: NO
Reactant: O=C(O)C(=S)Cc1cc(-c2ccccc2)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C(Cc1cc(-c2ccccc2)cs1)=NO
Yield: 90 %

Procedure:
3-(4-Phenylthiophen-2-yl)-2-thioxopropanoic acid (0.9 g, 3.4 mmol), hydroxylamine hydrochloride (740 mg, 10.6 mmol), and an ethanolic solution sodium ethoxide [prepared from 0.4 g of sodium and 30 mL of absolute ethanol] was refluxed for 1.5 h. Solvent was removed under reduced pressure and the residue was diluted with water and acidified with 1.5N HCl to adjust the pH of the solution ˜3. The solid product was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, then removal of the solvent under reduced pressure yielded 2-(hydroxyimino)-3-(4-phenylthiophen-2-yl)propanoic acid (0.8 g, yield 89%) as an off-white solid. 1H NMR (400 MHz, MeOD) δ 7.59-7.57 (m, 2H), 7.37-7.33 (m, 3H), 7.24-7.23 (m, 2H), 3.31 (s, 2H). MS (ESI) m/z: Calculated for C13H11NO3S: 262.05. found: 262.0 (M+H)+.