Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(NC[C@@H]1OC(=O)[N:8]([C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:16]([F:18])[CH:17]=2)C1)=O.FC1C=C([N+]([O-])=O)C=CC=1N1CCOCC1.C([O-])=O.[NH4+].CC(C)=O>[Pd].C(OCC)(=O)C>[F:18][C:16]1[CH:17]=[C:12]([CH:13]=[CH:14][C:15]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[NH2:8]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
It was prepared according to the literature method (ZHAO Xiao-yu, et al., Improved synthesis of Linezolid, WEST CHINA JOURNAL OF PHARMACEUTICAL SCIENCES, 2007, 22(2), 179-181). 36.2 g (0.16 mol) 3-fluoro-4-morpholinylnitrobenzene, 3.2 g 10% Pd/C, 30.4 g (0.49 mol) ammonium formate and 500 ml acetone were added into a 1000 ml four-necked bottle equipped with reflux condenser and dropping funnel, and stirred for 4 hours at 45˜50° C. After the completion of the reaction traced by TLC (developing solvent: ethyl acetate:petroleum ether=1:1), it was cooled to room temperature. After filtering by suction, solvents were evaporated from the filtrate under reduced pressure to obtain crude solid, which was recrystallized from toluene to obtain 28.1 g solid (89.5% yield). Structural confirmation:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:63][C:64]([O:67][C:68]([NH:70][C@H:71]([C:77](OC1C=CC([N+]([O-])=O)=CC=1)=[O:78])[CH2:72][CH2:73][C:74]([NH2:76])=[O:75])=[O:69])([CH3:66])[CH3:65].C(Cl)(Cl)Cl.CO>O1CCCC1>[NH:70]([C:68]([O:67][C:64]([CH3:66])([CH3:65])[CH3:63])=[O:69])[C@H:71]([C:77]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:78])[CH2:72][CH2:73][C:74](=[O:75])[NH2:76]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
At 0° C. the solution of 467 mg (0.51 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 20 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which he pre-cold solution of 195 mg, (0.53 mmol) of Boc-Gln-Onp in 10 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 96 h and TLC (chloroform/methanol, 9:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The reaction mixture was evaporated to dryness and the residue was purified on sinica gel chromatography (CHCl3/CH3OH, 10:1) to provide 450 mg (80%) of the title compound as a glassy mass. Mp 80–82° C., FAB-MS (m/e) 1111.3[M+H]+, 1132.5[M+Na]+,1010.0[M-Boc]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[C:6]=1[C:7]#[N:8].[CH3:12][N:13]=[C:14]=[O:15].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(COC)OC>[C:7]([C:6]1[C:5]([CH:9]2[CH2:10][CH2:11]2)=[CH:4][S:3][C:2]=1[NH:1][C:14]([NH:13][CH3:12])=[O:15])#[N:8]
Reactant: CN=C=O
Reactant: N#Cc1c(C2CC2)csc1N
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: COCCOC
Product: CNC(=O)Nc1scc(C2CC2)c1C#N
Reaction time: 8 h

Procedure:
A solution of 10 g 2-amino-3-cyano-4-cyclopropylthiophene, 6.94 g methyl isocyanate and 0.1 g dibutyl tin dilaurate in 20 ml dimethoxyethane was refluxed for 7 hours and then allowed to stand at about 25°C. overnight. The reaction mixture was evaporated and the resulting residue was chromatographed on silica gel. The product, a pale-green solid melting at 169°-172°C., was eluted with 1:1 ether-hexane. Sulfur analysis for the product is tabulated in Table I.
Reaction SMILES: C(N)CCC.Br[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu](I)I>[CH:7](=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C#CCCCC
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: CCCCC#CC=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.7 %

Procedure:
A mixture of palladium tetrakis(triphenylphosphine) (21 mg, 0.018 mmol), butylamine (2.5 mL) and Compound 49a (200 mg, 0.724 mmol) were stirred at room temperature for 45 minutes. Copper iodide (10.3 mg, 0.05 mmol) was then added, followed by hex-1-yne (41.6 μL, 0.362 mmol). The solution was heated for 3-5 hours at 70° C. till change in colour to depth blue. The reaction was quenched with ammonium chloride, extracted with diethyl ether, washed with brine, dried over magnesium sulphate, filtered, concentrated to dryness and purified by preparative HPLC-MS e affording the title product (78 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].Br[CH:19]([CH3:29])[C:20]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21]>O1CCCC1>[C:10]([CH:12]([CH:19]([CH3:29])[C:20]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CC(Br)C(=O)c1cccnc1F
Reactant: CCOC(=O)CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C(C)C(=O)c1cccnc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
To a solution of diisopropylethylamine (45 mL) and ethyl cyanoacetate (11.5 g) in tetrahydrofuran (50 mL) was added dropwise a solution of 2-bromo-1-(2-fluoropyridin-3-yl)propan-1-one (29.6 g) in tetrahydrofuran (50 mL), and the mixture was stirred at room temperature for 14 hr. Insoluble materials were filtered off, and filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a brown oil (yield 18.8 g, 85%).
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH:9]S(C)(=O)=O)[CH:6]=[CH:7][CH:8]=1.F[C:19]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:33])[CH:20]=1>CN1C(=O)CCC1.CC(=O)OCC>[CH3:32][S:29]([C:28]1[C:19]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2]([F:1])([F:14])([F:15])([F:16])[F:17])[CH:4]=2)=[CH:20][C:21]([CH3:33])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:30])=[O:31]
Reactant: CS(=O)(=O)Nc1cccc(S(F)(F)(F)(F)F)c1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Nc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 150 °C
Reaction time: 7 h
Yield: 25.6 %

Procedure:
1.0 g of N-(3-pentafluorosulfanylphenyl)methanesulfonamide, 0.8 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate and 1.4 ml of TBTMG were dissolved in 10 ml of NMP (anhydrous) and stirred at 150° C. for 7 h. The mixture was then diluted with 100 ml of EA and washed firstly 3 times with 30 ml of a saturated aqueous Na2CO3 solution each time and then 3 times with 30 ml of a saturated aqueous NaHSO4 solution each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with DIP. 370 mg of a resinous solid were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[N:34]1[CH:35]=[N:36][N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=12>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:34]4[CH:35]=[N:36][N:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=45)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: c1ccn2ncnc2c1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1csc(N)n1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cnn4ccccc43)CS[C@H]12)c1csc(N)n1

Procedure:
7β(2-(2-Aminothiazole-4-yl)-2(Z)-methoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and [1,2,4]triazolo[1,5-a]pyridine are treated in a way analogous to that in Example 1 to yield the desired compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH2:14][NH:15][CH2:16][CH2:17][O:18][CH3:19])[CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][O:18][CH2:17][CH2:16][NH:15][CH2:14][C:12]1[CH:13]=[C:8]([NH2:7])[CH:9]=[N:10][CH:11]=1
Reactant: COCCNCc1cncc(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1cncc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To a stirred solution of 56 (0.4 g, 1.42 mmol) in DCM (3 mL) was added TFA (3 mL) at 0° C. and stirred at rt for 3 h. The reaction mixture was concentrated, the residue was dissolved in MeOH, basified with Ambersep 900-OH resin, filtered to separate the resin and the filtrate concentrated to obtain the desired amine (90 mg, 88%) as a brown color viscous liquid. Rf: 0.1 (10% MeOH/CHCl3); (m/z):182 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.77 (1H, d, J=2.4 Hz), 7.66 (1H, d, J=1.6 Hz), 6.86 (1H, d, J=2 Hz), 5.19 (2H, m), 3.66 (2H, s), 3.39-3.36 (3H, m), 3.22 (3H, s), 2.62-2.59 (2H, m), 1.93-1.92 (1H, br s).
Reaction SMILES: [ClH:1].[N+](=[CH:4][C:5](=[O:16])[C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])=[N-]>C(OCC)C>[Cl:1][CH2:4][C:5](=[O:16])[C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]
Reactant: Cl
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)CCl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Hydrochloric acid (2.0 M in water, 21.4 mL, 42.8 mmol) was added to a mixture of (R)-tert-butyl (4-diazo-3-oxobutan-2-yl)carbamate (1.89 g, 8.86 mmol) in diethyl ether (19.27 mL) at 0° C.0. The mixture was stirred vigorously for 20 minutes and then allowed to warm to room temperature and stirred vigorously until the mixture went from yellow to colorless. The mixture was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl (4-chloro-3-oxobutan-2-yl)carbamate. 1H NMR (500 MHz, DMSO-d6) δ 7.34 (d, J=7.0 Hz, 1H), 4.64-4.51 (m, 2H), 4.23-4.02 (m, 1H), 1.36 (s, 9H), 1.16 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH2:41][CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.[ClH:49]>>[ClH:49].[ClH:49].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][NH:21][CH2:20]1)[CH2:40][CH2:41][CH3:42])=[O:17]
Reactant: CCCN(C(=O)c1nc2ccccc2n1CCCCOC)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCN(C(=O)c1nc2ccccc2n1CCCCOC)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(propyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (2.19 g) was dissolved in 4M hydrogen chloride-ethyl acetate (20 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated to give the object product (2.09 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH3:33])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:31][CH:30]5[CH:26]([CH2:27][NH:28][CH2:29]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C=O.[CH3:36]C(O)=O>C(Cl)Cl.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH3:33])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:31][CH:30]5[CH:26]([CH2:27][N:28]([CH3:36])[CH2:29]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CNCC2C1
Reactant: CC(=O)O
Agent: C=O
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CN(C)CC2C1
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)-6-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl) propoxy)-7-methoxyquinazolin-4-amine (0.20 g) in a mixture of CH2Cl2 and MeOH was added 37% HCHO (0.10 mL), AcOH (0.15 mL) and NaB(O2CCH3)3H (0.26 g) in turn. The mixture was stirred for 1.5 h, then diluted with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated and redissolved in EA, to this, a solution of HCl in EtOAc (10 mL) was added under stifling. The mixture was filtered to give the title compound as a solid (0.13 g, 68.00%), HPLC: 98.69%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.81-1.92 (m, 4H), 2.10-2.15 (m, 4H), 2.30 (s, 3H), 2.35-2.41 (m, 4H), 2.44 (t, J=8.2 Hz, 2H), 4.03 (s, 3H), 4.10 (t, J=7.8 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57-7.62 (m, 1H), 7.91-7.93 (m, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[C:17]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:23]=4)=[O:21])[CH:16]=[CH:15][C:14]=3[CH3:34])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:35][CH3:36].C1(C)C=CC(S(O[CH2:47][CH2:48][N:49]2[CH:53]=[CH:52][N:51]=[N:50]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:36][O:35][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:47][CH2:48][N:49]1[CH:53]=[CH:52][N:51]=[N:50]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:34]
Reactant: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCn1ccnn1
Temperature: 100 °C
Yield: 21.4 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (184 mg), 2-(1,2,3-triazol-1-yl)ethyl 4-toluenesulphonate (101 mg), cesium carbonate (370 mg) and N,N-dimethylacetamide (4 ml) was stirred and heated to 100° C. for 1 hour. After cooling the reaction mixture to ambient temperature, the reaction mixture was partitioned between water and methylene chloride. The organic phase was dried with brine and sodium sulphate and evaporated. The material so obtained was purified by column chromatography on silica using a 10:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (47 mg); NMR: 2.14 (s, 3H), 3.51 (t, 4H), 3.72 (t, 4H), 3.91 (s, 3H), 4.59 (t, 2H), 4.87 (t, 2H), 7.09 (d, 1H), 7.2 (s, 1H), 7.22 (d, 1H), 7.27 (d, 1H), 7.58 (m, 1H), 7.74 (s, 2H), 7.83 (s, 1H), 8.18 (s, 1H), 8.24 (d, 1H), 8.26 (s, 1H), 9.39 (s, 1H), 10.28 (s, 1H); m/s: M+H+ 582.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](Cl)=[O:19]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C(#N)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:18](=[O:19])[CH2:17][O:9][C:3]=2[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc2c(c1)OCC(=O)N2
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a mixture of 2-amino-5-methyl-phenol (Alfa, 15.0 g, 122 mmol), K2CO3 (50.5 g, 365 mmol) and Bu4NBr (3.94 g, 12.18 mmol) in acetonitrile (400 mL) at 0° C. was added 2-chloroacetyl chloride (15.1 g, 10.0 mL, 134 mmol) drop-wise. After addition, the mixture was heated at reflux for 2.5 h. The reaction mixture was cooled to ambient temperature and evaporated in vacuo. Water was added (500 mL) and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 25% EtOAc in petroleum ether) to give 7-methyl-4H-benzo[1,4]oxazin-3-one as a brown solid (14.1 g, 71%). 1H NMR (DMSO-d6, 400 MHz): δ 10.58 (s, 1H), 6.76 (m, 3H), 4.52 (s, 2H), 2.21 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][CH2:23][CH3:24].[C:25](O)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CO>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][CH2:23][CH3:24])[N:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1OCCCCN
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCCOn1c(CCCC)nc2c(N)nc3ccccc3c21

Procedure:
The 1-(4-aminobutoxy)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine was dissolved in dichloromethane (20 mL) and methanol (5 mL). Stearic acid (0.71 g) was added and the reaction was stirred to dissolve the stearic acid. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl (EDC, 0.45 g) was added and the reaction was stirred at ambient temperature for 16 hours. An additional portion of EDC was added (0.23 g) and the reaction was stirred for an additional 24 hours. Final portions of stearic acid (0.22 g) and EDC (0.37 g) were added to drive the reaction to completion and the reaction was stirred at ambient temperature for another 24 hours. The reaction was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography using a Biotage chromatography system (Si40+M2358-1 SiGel column, 85:15 dichloromethane/methanol isocratic elution). The semi-pure product was purified by flash column chromatography two more times using a 90:10 dichloromethane/methanol isocratic elution, followed by a 95:5 dichloromethane/methanol isocratic elution The fractions containing product were concentrated to yield 1.12 g of N-(4-{[4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl]oxy}butyl)octadecanamide as an off white waxy solid. 1H-NMR (CDCl3): δ 0.89 (t, 3H), 1.01 (t, 3H), 1.14-1.42 (m, 28H), 1.50 (m, 2H), 1.65 (m, 2H), 1.74-1.94 (m, 4H), 2.02 (m, 2H), 2.20 (t, 2H), 2.95 (t, 2H), 3.40 (q, 2H), 4.33 (t, 2H), 5.59 (t, 1H), 6.10 (broad s, 2H), 7.39 (m, 1H), δ 7.57 (m, 1H), 7.83 (d, 1H), 8.07 (m, 1H).
Reaction SMILES: C(C1C=C(SCOC[C@@H]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39](C)[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C#N)C=CC=1)(O)=O.S([O-])(O[O-])(=O)=O.[K+].[K+].OS([O-])(=O)=O.[Na+]>CC(C)=O.O>[C:29]1([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]([NH:20][C@H:19]([C:18]([NH2:17])=[O:44])[CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:35])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)N[C@@H](C#N)COCSc2cccc(C(=O)O)c2)c1
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)[C@H](Cc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of N-[2-[(3-carboxyphenyl)thiomethoxy]-1(S)-cyanoethyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide (89 mg, 0.15 mmol) in acetone (5 mL) is added a solution of potassium peroxymonosulfate (Oxone®, 0.11 g, 0.18 mmol) in water (5 mL) at 0° C., and the solution is stirred at 0° C. for 40 minutes. 5% NaHSO4 (10 mL) is added, and the cloudy suspension is filtered. The solid is washed with water (50 mL), dried in vacuo, and then recrystalized (CH2Cl2, Et2O) to yield N-[2-[(3-carboxyphenyl)methanesulfinyl]-1(S)-cyanoethyl]-3-methyl-Nα-(2,2-diphenylacetyl-L-phenylalaninamide product, as a white solid, m.p. 170-171° C.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)([O:13][CH2:14][CH3:15])=[O:12].I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Cl.CN1CCCN(C)C1=O>O1CCCC1>[C:11]([C:16]1([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CSCc1ccc(OC)cc1
Reactant: ClCCCCCI
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(SCc2ccc(OC)cc2)CCCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 56.6 %

Procedure:
Cool lithium hexamethyldisilazane (8.4 mL of a 1.0M solution in tetrahydrofuran, 8.4 mmol) to -78° C. Add, by cannula transfer, a solution of 1-(carboethoxy)-1-(4-methoxybenzylthio)methane (2.0 g, 8.3 mmol) in tetrahydrofuran (8 mL). Stir for 45 minutes then add a solution of 1-iodo-5-chloropentane (1.94 g, 8.32 mmol) in tetrahydrofuran (8 mL). Stir for 1 hour and add 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (1.21 mL, 10.0 mmol). Stir at 0° C. for 4 hours and at room temperature for 6 hours. Cool to -78° C., add lithium hexamethyldisilazane (8.4 mL, 8.4 mmol) and stir at room temperature overnight. Quench with saturated ammonium chloride (5 mL) and partition between ethyl acetate (50 mL) and water (50 mL). Separate the organic phase, dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (6:1 hexane/ethyl acetate) to give 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclohexane as an colorless oil (1.45 g, 56%).