Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:27])([F:26])[C:7]1[CH:25]=[CH:24][C:10]([O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18](O)=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>>[F:5][C:6]([F:27])([F:26])[C:7]1[CH:25]=[CH:24][C:10]([O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18]([Cl:3])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl

Procedure:
Thionyl chloride (4.4 parts by volume) was added to 3.26 parts of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid, and the mixture was refluxed for 3 hours. After the reaction, the excess of thionyl chloride was removed under reduced pressure to give 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride. A solution of the resulting propionyl chloride in 10 parts by volume of ether was added dropwise under ice cooling to a solution of 3.34 parts of diethyl aminophosphonate in 20 parts by volume of ether. Ten minutes later, 1 part by volume of triethylamine was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, a saturated aqueous solution of sodium bicarbonate and water in this order. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.6 parts of a crude product. The crude product was recrystallized from ethyl acetate/ether to give 1.1 parts of the captioned compound. This compound had a melting point of 134.5° to 135° C., and its IR and NMR spectral data are shown in Table 1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][Si:6]([CH3:11])([O:9][CH3:10])[O:7][CH3:8].[CH:12]([N:15]=[C:16]=[N:17][CH:18]([CH3:20])[CH3:19])([CH3:14])[CH3:13].N=C=N>>[CH:12]([N:15]=[C:16]([NH:17][CH:18]([CH3:20])[CH3:19])[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][Si:6]([CH3:11])([O:9][CH3:10])[O:7][CH3:8])([CH3:14])[CH3:13]
Reactant: CNCCC[Si](C)(OC)OC
Reactant: CC(C)N=C=NC(C)C
Agent: N=C=N
Product: CO[Si](C)(CCCN(C)C(=NC(C)C)NC(C)C)OC
Reaction time: 2 h

Procedure:
A mixture of 27 g of N-methyl-(3-(methyldimethoxysilyl)propyl)amine (0.152 mol, 20% excess) and of 16 g of diisopropylcarbodiimide (0.127 mol) was heated for 8 h at 100° C. (carbodiimide conversion of 98%). The final colorless mixture was devolatilized at 100° C. under 2 mbar for 2 h to give 39.3 g of a colorless, low-viscosity liquid corresponding to the expected guanidine, containing 2 wt % of the initial amine.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1C)C.C([Li])(C)(C)C.CCCCC.[CH3:27][N:28](C)[C:29]#N>C1COCC1>[CH3:27][N:28]([CH3:29])[C:15]1[N:3]=[C:4]([OH:14])[C:5]2[C:6]([CH:16]=1)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2
Reactant: CN(C)C#N
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(N(C)C)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1000 mg, 4.52 mmol) in THF (10 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (5316 μl, 9.04 mmol) and the solution was stirred for 0.5 h before addition of N,N-dimethylcyanamide (317 mg, 4.52 mmol) in THF (10 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl, and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate, filtered, followed by removal of solvent under vacuum to give 3-(dimethylamino)-6-methoxyisoquinolin-1-ol (700 mg, 71% yield) which was carried to the next step without further purification. MS: MS m/z 219.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[BH4-].[Na+].O>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([OH:14])[CH:11]([CH3:12])[CH3:13])=[C:7]([CH3:15])[C:6]=2[CH:16]=1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(O)C(C)C)oc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
1-(5-Fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (11.66 g) synthesized above was dissolved in methanol (4 mL)-tetrahydrofuran (20 mL), and sodium tetrahydroborate (90%) (446 mg) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (1.193 g, 100%) as a colorless oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[C:12]#[N:13].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[C:12]#[N:13]
Reactant: N#Cc1cnc2cccnc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2cccnc2c1Cl
Yield: 28.5 %

Procedure:
A solution of 4-hydroxyl-[1.5]naphthyridine-3-carbonitrile (1.0 g, mmol) in 20 ml POCl3 was refluxed for 3 hrs. After cooling, the solvent was removed by rotary evaporation. The residue was treated with ice-water mixture, made basic by NH4OH, and extracted with CH2Cl2. Removal of the solvent gave 4-chloro-[1.5]naphthyridine-3-carbonitrile (285 mg, 28.5%). This was heated at reflux with 3-bromoaniline (3 eq) in the presence of pyridine HCl salt (350 mg) in ethoxyethanol for 3 hrs under argon. After cooling, the solvent was removed by rotary evaporation. The residue was partitioned between ice-water and ethyl acetate, made basic with (NH4OH), extracted with ethyl acetate. The combined extracts were washed (brine) and dried (Na2SO4), and concentrated. The residue was triturated with ether. The title compound was collected and washed with ether, and dried. mass spectrum (electrospray, m/e): 326.9 (M+H); IR cm-1: 3372, 2209; H-NMR δ(DMSO-d6): 7.36-7.90 (3H, m, C4′ C5′-H and C6′ Hs in bromoaniline), 7.64 (1H, s, C2′-H), 7.94 (1H, dd, C7-H), 8.36 (1H, dd, C8-H), 8.66 (1H, s, C2-H), 8.98 (1H, dd, C6-H), 10.47 (1H, bs, NH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4](F)[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C1CNCCN1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cc(Br)cc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-bromo-3-fluoro-5-(trifluoromethyl)-benzene (100 g, 0.41 moles), piperazine (194.9 g, 2.26 moles) in DMSO (800 ml) was heated at 100° C. for 5 hours, cooled at room temperature and stirred overnight. The mixture was poured into water and the yellow solid which separeted was filtered. The solid was suspended in a 5% THF solution in water (300 ml) water/THF, stirred for 1 hour and filtered again.
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[O:18]=[C:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:29][C:30]([O:32][CH3:33])=[O:31].O1C2C=CC(O)=CC=2OC1.[Cl:44][C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1>>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([C:27]2([OH:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:19]2=[O:18])=[C:47]([OH:51])[CH:46]=1
Reactant: COC(=O)CN1C(=O)C(=O)c2ccccc21
Reactant: Oc1cccc(Cl)c1
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: COC(=O)CN1C(=O)C(O)(c2ccc(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with methyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 3-chlorophenol, the title compound was obtained (29%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.48 (d, 1H), 7.38 (t, 1H), 7.19 (t, 1H), 7.01 (br, 1H), 6.80-6.64 (m, 3H), 5.28 (br s, 1H), 4.51 (d, 1H), 4.44 (d, 1H), 3.75 (s, 3H); MS (ES+) m/z 370.5 (M+23), 372.4 (M+23).
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[O:4][C:5](=[O:7])[CH:6]=1.[CH3:9][NH2:10].C(OC(=O)C)(=O)C>O.C(O)(=O)C>[Br:1][C:2]1[C:3](=[O:4])[N:10]([CH3:9])[C:5](=[O:7])[CH:6]=1
Reactant: CN
Reactant: O=C1C=C(Br)C(=O)O1
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)C=C(Br)C1=O
Reaction time: 4 h

Procedure:
A 15 mmol solution of 3-bromo-2,5-furanedione and 15 mmol of methylamine at 40% in water, in 300 ml of glacial acetic acid is carried under reflux for 16 hours. After having allowed the reaction mixture to return to ambient temperature, 20 ml of acetic anhydride are added. The reaction medium is again brought to reflux under stirring for 4 hours before evaporating the solvents under reduced pressure. The expected product is obtained after purification by silica gel chromatography (heptane/ethyl acetate: 1/1) and recrystallization in ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CC(C)=O.S([O:27][CH3:28])(OC)(=O)=O>O>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([O:27][CH3:28])=[O:9]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C)ccc1OC
Yield: 91.1 %

Procedure:
5.07 g (33.32×10-3 mol) of 5-methylsalicylic acid and 22.33 g (161.6×10-3 mol) of anhydrous potassium carbonate are introduced into a 250-cm3 two-necked flask. 175 cm3 of anhydrous acetone are added under an inert atmosphere. The reaction mixture is stirred, 7.25 cm3 (76.62×10-3 mol) of dimethyl sulfate are added with a syringe and the mixture is brought to reflux for 6 h. Hydrolysis of the dimethyl sulfate is performed by adding 5 cm3 of water. After filtration and evaporation of the solvent, the residue is taken up with dichloromethane, dried over MgSO4 and then evaporated to dryness. The crude product is purified by chromatography on a silica column (eluent: CH2Cl2) to give 5.47 g (30.36×10-3 mol) of the expected ester, equivalent to a 91% yield.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1)#[N:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:16]3[CH:20]=[CH:21][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: N
Product: N#Cc1ccc(-c2nc(-c3cccnc3)no2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 4-cyanobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 8.02 (d, J=8.8 Hz, 2H), 8.42 (d, J=8.8 Hz, 2H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.31 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1B(O)O.Cl[C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.[IH:21]>>[I:21][C:14]1[CH:19]=[C:18]([C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:17]=[CH:16][N:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1cc(F)c(F)cc1F
Reactant: I
Product: Fc1cc(F)c(-c2cc(I)ncn2)cc1F

Procedure:
The compound was prepared according to Example 1 using 2,4,5-trifluorophenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:14].CCO>CO>[ClH:14].[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2ccccn2)cc1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: c1ccc(CC2CCCCN2)cc1
Reaction time: 5 h
Yield: 94 %

Procedure:
A solution of 2-benzylpyridine (2.0 g, 12 mmol) in MeOH (50 mL) containing conc. HCl (1 mL) was hydrogenated in a Parr apparatus over Pt (PtO2, 30 mg) at 25° C. The reaction was allowed to proceed at 22 psi for 5 h, 45 psi for 4 h, then overnight at 22 to 12 psi. The catalyst was removed by filtration and the solvent was removed in vacuo to give a syrup. Absolute EtOH (50 mL) was added and then evaporated in vacuo. This was repeated to give a near colorless solid. The solid was triturated with ether (2×20 mL) and dried in vacuo to give a colorless powder (2.36 g, 94% yield); mp 128-131° C., lit. 125-130° C. (vide supra); 1H NMR (D2O) 1.45-2.05 (m, 6H), 2.80-3.05 (m, 3H), 3.27-3.45 (m, 2H) 7.26-7.46 (m, 5H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N-:18]C(C)C)(C)C.[Li+].[C:23]([O:28][CH2:29][CH2:30]Br)(=[O:27])[C:24]([CH3:26])=O>C1COCC1>[NH:18]1[C:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C:10]=2[CH:26]=[C:24]1[C:23]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(=O)C(=O)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c([nH]1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.5 h

Procedure:
A solution of N-boc-4-piperidone (1 eq.) and lithium di-isopropyl amide (1 eq.) in THF was stirred at −78° C. and for 2 hrs. A bromoethyl pyruvate (1.2 eq.) was added to above reaction mixture and stirred for 30 min. Reaction mixture was then quenched with ammonia solution and then extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. The residue was then dissolved in dichoromethane and was added silica (100-200 mesh), stirred for overnight at room temperature. Crude was then purified by silica gel column chromatography to yield 5-tert-butyl 2-ethyl 1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a solution of 1.2 g of 3-hydroxybenzaldehyde in 50 ml of N,N-dimethylformamide were added 2.4 g of 4-chlorobenzyl chloride and 2.1 g of potassium carbonate. The mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was treated with ethyl acetate-water. The resulting ethyl acetate layer was separated, washed with water, dried with anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent. The resulting residue was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=102) to obtain 1.9 g of 3-(4-chlorobenzyloxy)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[N:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([N:24]3[CH2:25][CH2:26][N:21]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:36])[F:37])[CH2:22][CH2:23]3)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCCOc1ccc(Cl)cc1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCOc1ccc(Cl)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(4-chlorophenoxy)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (13% yield). 1H NMR (400 MHz, CDCl3) δ 8.27, 8.05, 7.74, 7.64, 7.57, 7.37, 7.25-7.20, 7.00, 6.85-6.82, 4.02-3.32.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:45][CH2:46][CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:65])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH3:64])[CH:58]=2)=[CH:51][C:50]=1[C:66]1[N:70]([CH3:71])[N:69]=[CH:68][CH:67]=1>ClCCl>[C:1]([NH:4][C@@H:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([NH:45][CH2:46][CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:65])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH3:64])[CH:58]=2)=[CH:51][C:50]=1[C:66]1[N:70]([CH3:71])[N:69]=[CH:68][CH:67]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CSCC[C@H](NC(C)=O)C(=O)O
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)[C@H](CCSC)NC(C)=O)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
(S)-2-acetamido-4-(methylthio)butanoic acid (17.8 mg, 1.25 eq), triethylamine (20.8 mL, 2.0 eq) and HATU (35.4 mg, 1.25 eq) were dissolved in 3 mL of dichloromethane and stirred at room temperature for 10 minutes. At this time N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30 mg, 74.5 μmol) dissolved in 2.0 mL of dichloromethane was added and the reaction was stirred at room temperature for 3 hr. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 57.3% yield. LCMS m/z (%)=540 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 2.01 (s, 4 H), 2.07 (s, 3 H), 2.38-2.44 (m, 2 H), 3.46-3.65 (m, 2 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 4.03-4.12 (m, 2 H), 4.45-4.53 (m, 1 H), 6.39 (d, J=2.02 Hz, 1 H), 7.02 (d, J=9.60 Hz, 1 H), 7.11 (dt, J=4.80, 2.53 Hz, 1 H), 7.38-7.42 (m, 2 H), 7.43-7.46 (m, 1 H), 7.63-7.71 (m, 2 H), 7.86 (s, 1 H)
Reaction SMILES: [C:1]([N:5]1[C:13]2[N:12]3[N:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9](Cl)[C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.CO.[Pd](Cl)Cl>[C:1]([N:5]1[C:13]2[N:12]3[N:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCc2c(Cl)nc3ccnn3c21
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)N1CCc2cnc3ccnn3c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
In a mixed solvent of 300 ml of tetrahydrofuran and 150 ml of methanol were dissolved 11.30 g of 8-tert-butyl-5-chloro-6,7-dihydro-8H-pyrrolo[3,2-e]pyrazolo-[1,5-a]pyrimidine, and the reaction system was cooled to 0° C. To the solution were gradually added 3.75 g of palladium chloride and 7.83 g of sodium borohydride, and the mixture was stirred for 30 minutes at 0° C. Furthermore, 7.50 g of palladium chloride and 5.66 g of sodium borohydride were gradually added, and the resultant mixture was stirred for 30 minutes at 0° C. and for 2 hours at room temperature. The reaction solvent was distilled off under reduced pressure, and the resultant crude product was subjected to column chromatography on silica gel (ethyl acetate→ethyl acetate:methanol=10:1) to obtain 3.94 g (yield: 40.4%) of the intended product. White crystals.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.33 min; [M+H]+=473.1.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>>[Cl:19][CH2:20][S:21]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:23])=[O:22]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)CCl
Product: O=S(=O)(CCl)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with chloromethanesulfonyl chloride to obtain the desired product, m/z=475 [M−1]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH:18]=[O:19])[C:13]([CH2:20][CH2:21][CH3:22])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[CH3:23][Mg]I.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH:18]([OH:19])[CH3:23])[C:13]([CH2:20][CH2:21][CH3:22])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: C[Mg]I
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC=O
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
4-(7-Bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (2.77 g, 7.68 mmol) was dissolved in THF (75 mL), stirred at ambient temperature for 30 minutes, and cooled to 0° C. Methylmagnesium iodide (3.33 mL, 9.99 mmol, 3 M in diethyl ether) was added over 5 minutes. The reaction mixture was allowed to warm to ambient temperature. After 2 hours, 10% hydrochloric acid was added and the reaction mixture was concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate, extracted in 10% methanol in dichloromethane, dried over magnesium sulfate and concentrated under reduced pressure to provide 2.6 g of 5-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol as an orange-brown solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([OH:11])=O)[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH3:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[NH2:43]>C(Cl)Cl.CN(C=O)C>[F:12][C:5]1[C:4]([F:13])=[C:3]([CH3:14])[C:2]([F:1])=[C:7]([F:8])[C:6]=1[C:9]([NH:43][CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH:37]1[CH3:36])=[O:11]
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: CC1CCCCC1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(F)c(F)c(C(=O)NC2CCCCC2C)c(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
2,3,5,6-tetrafluoro-p-toluic acid (4.00 g, 19.22 mmol), HOBt (5.19 g, 38.44 mmol) and EDCI (4.42 g 23.06 mmol) were mixed in 200 ml of anhydrous DCM and 30 ml of anhydrous DMF. The mixture was cooled to 0° C. and allowed to stir under Ar for 15 minutes. To the mixture was added 2-methylcyclohexanamine (3.05 mL, 23.06 mmol) and the reaction mixture was allowed to slowly warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with 1N HCl, water, aqueous NaHCO3, water and brine, drying over MgSO4, filtration and removal of solvent in vacuo, afforded the crude product as a pale yellow solid Recrystallization (EtOH/H2O) and drying in vacuo gave 5.23 g of the title compound as a white solid (mixture of 2 diasteromers, 90%). 1H NMR (CDCl3) δ 0.95, 1.01 (d, J=7.0, 6.6 Hz, 3H) 1.1-2.1 (m, 9H), 2.29 (m, 3H), 3.70, 4.29 (m, 1H), 5.65, 5.92 (m, 1H). MS (304.1, M+H). m.p. 202-204° C.